Attention Deficit Hyperactivity Disorder (ADHD): Epidemiology, Treatment and Prevention 9781634831284, 9781634831550

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NEURODEVELOPMENTAL DISEASES - LABORATORY AND CLINICAL RESEARCH

ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) EPIDEMIOLOGY, TREATMENT AND PREVENTION

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NEURODEVELOPMENTAL DISEASES - LABORATORY AND CLINICAL RESEARCH

ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) EPIDEMIOLOGY, TREATMENT AND PREVENTION

FRANCISCO LÓPEZ-MUÑOZ AND

CECILIO ÁLAMO EDITORS

New York

Copyright © 2015 by Nova Science Publishers, Inc.

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Published by Nova Science Publishers, Inc. † New York

Contents Preface Chapter 1

vii Evolution of International Scientific Production on AttentionDeficit Hyperactivity Disorder: A Bibliometric Analysis of the Last 34 Years Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García, Javier Quintero and Cecilio Álamo

1

Chapter 2

Prevalence of Attention-Deficit/Hyperactivity Disorder José Carlos Peláez Álvarez, Laura Rodríguez Moya and Francisco Montañés Rada

21

Chapter 3

Limitations to a Diagnosis of ADHD Klaus Martin Beckmann

29

Chapter 4

Psychological Assessment in ADHD Children M. Poveda Fernández-Martín, Miguel Ángel Pérez-Nieto and M. José De Dios-Pérez

39

Chapter 5

Genomics, Therapeutics and Pharmacogenomics of Attention-Deficit/Hyperactivity Disorder Ramón Cacabelos, Clara Torrellas, Iván Tellado, Pablo Cacabelos and Francisco López-Muñoz

Chapter 6

Brain Development in ADHD: A Neuroimaging Perspective Victor Pereira, Pilar de Castro-Manglano and Cesar Soutullo

Chapter 7

Adult Attention-Deficit and Hyperactivity Disorder and Mild Cognitive Impairment: A Case-Control Study Ángel B. Golimstok, María J. García-Basalo, María C. Fernández, Nuria E. Campora, Waleska L. Berrios, Juan I. Rojas and Edgardo Cristiano

65

257

273

vi Chapter 8

Contents Attention Deficit Hyperactivity Disorder and Traumatic Brain Injury: Connections, Predictors, and Outcomes Christopher M. Bonfield and Joseph B. Stoklosa

283

Chapter 9

Galenic Formulations of Psychostimulant Drugs Pilar García-García, Francisco López-Muñoz and Cecilio Álamo

293

Chapter 10

Antidepressant Drugs in Attention Deficit Hyperactivity Disorder Silvia E. García-Ramos, Francisco López-Muñoz, Cecilio Álamo and Pilar García-García

315

Chapter 11

Psychological Treatment in ADHD: Clinical and Educational Perspectives M. José De Dios-Pérez, Miguel Ángel Pérez-Nieto and M. Poveda Fernández-Martín

Chapter 12

Index

Is It Possible to Prevent ADHD? Javier Quintero, Josefa Pérez-Templado and Patricia Alcindor

331

357

381

Preface Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with underlying brain anatomical and functional measures, as well as familial/genetic factors that are major foci of neuropsychiatric research. Also, ADHD is a chronic neuropsychiatric disorder characterized by inattention, motor restlessness, and impulsivity, which affects between 3% and 7% of school-age children. ADHD can affect learning, behavior social and emotional functioning. People with ADHD usually have difficulty following instructions and staying on task, completing work, controlling impulses, listening, keeping their hands to themselves, keeping work materials organized and turning in assignments. Problems with social skills such as getting along with others and making friends are also common. Moreover, prospective follow-up studies found that approximately 50% of children with ADHD show symptoms that continue into adulthood, and when left untreated are associated with substance abuse, depression, unemployment, and criminal acts. Therefore, patients suffering from ADHD are at high risk to be confronted with stigma, prejudices, and discrimination. In this context, to explore this important health and clinical problem, we have an excellent team of mental health professionals worldwide, who contribute their experience and scientific knowledge about this disorder.. To deal with some of the most relevant aspects of ADHD, this book has been structured into 12 chapters. In the minds of the editors is not performing an encyclopedia work, but the treatment of specific aspects of ADHD of interest to the researcher and clinician that relate to this subject. ADHD is one of the neuropsychiatric diseases receiving more attention in recent years in scientific literature. The awakening of ADHD as a specific pathologic entity in the field of psychiatry took place in 1980, with the creation of the ADD syndrome by the American Psychiatric Association. During this decade, numerous studies were published on implementation of diagnostic criteria and assessment tools for clinical research, the social impact of the disease, about the neurobiological disorder of nature and its approach cognitivebehavioral, which continued in the following, about genetic and neurobiological aspects. Since then, bibliographic production has grown continuously, having been published in impact journals almost 2500 articles in the last year. López-Muñoz and contributors performed a bibliometric study on ADHD in the first chapter of this book.

viii

Francisco López-Muñoz and Cecilio Álamo

Interpretation of prevalence studies is complicated by significant changes to the diagnostic criteria for ADHD for the past 30 years, culminating in the current definition specified in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSMV). Peláez and colleagues describe the prevalence of ADHD as a universal disorder. In general, there was no significant prevalence in differences between countries or regions of the world after studying for differences in the diagnostic algorithms used to define ADHD. On the other hand, today the existence of ADHD is an unquestionable fact. However, despite the very homogeneous prevalence of the disorder in different regions, there are some studies that cast doubt on the possibility of an over-diagnosis. Therefore, to know the limitations of the diagnosis of ADHD are necessary. Reading the chapter of Beckmann is very relevant since it clarifies that diagnostic instruments must be used properly. The DSM and ADHD scales (Conners and EDAH) are only based on pre-established categorical criteria which are complementary tests that should not replace clinical observation. This is intended to avoid diagnosis and inadequate drug treatments that can create an unjustified alarmism both among relatives and at the social level. The diagnosis of a possible case ADHD is broad and heterogeneous, with multiple causes neurological, pediatric and psycho-social, and must always be done rigorously by a multidisciplinary team. In this sense, the psychological evaluation of ADHD in children is an essential element. A psychological evaluation to have a clear idea of the emotional condition of the child, including tests of intellectual ability and cognitive development is highly relevant. The use of conjoint psychosocial treatments with ADHD medications may enable lower doses of each form of treatment. The development of these aspects by FernándezMartín and collaborators facilitate the diagnosis and follow-up of children with ADHD. Currently, studying ADHD, we must take into account the high genetic burden of this disorder. ADHD is a disorder that has the highest rate of heritability between the somatic and mental diseases. In fact, only the size inherited from our parents more than the ADHD. Although the number of genetic studies carried out about ADHD has increased in recent years, the results obtained are disparate among them. Therefore, the contribution of Cacabelos and collaborators is essential for the updating of genetic knowledge related to ADHD, and the future role of genomics and pharmacogenomics in this disorder. Since the 1970s, ADHD was termed Minimal Brain Dysfunction, owing to its strong association with neurologic disorders. Advances in imaging technology have shown structural and functional brain differences between individuals with and without ADHD. Longitudinal studies have enabled the elucidation of differences in developmental course. Therapeutic doses of psychostimulants normalize many measures of brain anatomy and function. Some of these aspects are described in the work of Pereira and his coworkers. The direct association between mild cognitive impairment (MCI) and ADHD has very little been explored to date. Persistent ADHD in the adult population could well be misconstrued as MCI, leading to the incorrect assumption that such persons are succumbing to a neurodegenerative disease process. The study presented by Golimstok and collaborators can be considered, in addition to highly interesting, one of the pioneers in this field. Many children after a traumatic brain injury will experience difficulties with attention and concentration; a condition termed secondary Attention Deficit-Hyperactivity Disorder. Symptoms of secondary ADHD include clinically significant difficulties with attention, concentration, impulse control and hyperactivity, although traumatic brain injury (TBI) associated hyperactivity may be less severe than with primary ADHD. Despite a good body

Preface

ix

of evidence delineating the sequelae of TBI, there are few validated interventions to remediate cognitive deficits in children following TBI. These and other aspects related to the therapeutic approach and its results are treated by Bonfield and Stoklosa in the eighth chapter. Psychostimulants are highly effective medications for the treatment of ADHD, and the development of long-acting stimulant formulations has greatly expanded the treatment options for individuals with ADHD. Strategies for the formulation of long-acting stimulants include the combination of immediate-release and delayed-release beads, and an osmoticrelease oral system. A recent development is the availability of the first prodrug stimulant, lisdexamfetamine dimesylate. The existence of different galenic presentations, as described by García-García and colleagues, facilitates the individualization of treatment, as well as therapeutic adherence. Despite the established efficacy of the stimulants in ADHD, between 10-30% of children with ADHD does not respond to stimulants or may not tolerate them for side effects. The potential for abuse and the stigma of a controlled medication, are reasons to consider alternatives to stimulants in children and adolescents with ADHD. There are some studies on the use of tricyclic antidepressants, bupropion, α2-adrenergic agonists, venlafaxine, or MAOI which, by its noradrenergic or dopaminergic effect, can be effective in ADHD. Currently, the only antidepressant approved for use in the treatment of ADHD is atomoxetine. GarcíaRamos and collaborators described the importance of these alternatives to methylphenidate in the treatment of ADHD. Multimodal treatment is ideal for the integral management of ADHD. Pharmacotherapy remains the first choice treatment for ADHD throughout life and all guidelines agree that psychological therapy increases the effectiveness of treatment as co-adjuncts to pharmacotherapy. Thus, structured psychotherapy can be useful to encourage trust, develop leadership skills, manage anxiety and depression and improve performance. Group therapy also helps to tackle the issue of social isolation. The various aspects related to the psychotherapy of ADHD are addressed by De Dios and collaborators. Personalized medicine aims to provide the right treatment for the right person at the right time, as opposed to the currently employed ‗one-size-fits-all‘ approach. This development relies on identification of ADHD subgroups using biomarkers. One important ADHD subgroup is characterized by impaired vigilance regulation, as quantified by the EEG and this subgroup responds well to stimulant medication and neurofeedback. These and other factors that may act to preventive basis in ADHD are treated in this last chapter by Quintero and collaborators. In childhood, ADHD is a psychiatric condition characterized by age inappropriate levels of inattention, hyperactivity-impulsiveness or a combination of these problems. Traditionally, ADHD is regarded as a childhood disorder, but it is now clear that ADHD affects both children and adults. Many adults with ADHD are undiagnosed and untreated. Thus, the negative outcomes reported by most follow-up studies may be a consequence of untreated symptoms. Current treatments may reduce the negative impact that untreated ADHD has on life functioning, but does not usually ‗normalize‘ the recipients. Stimulant medication has been the mainstay of symptomatic treatment for over 30 years. It is hoped that novel therapies and more individualized management will evolve over the coming decades.

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Francisco López-Muñoz and Cecilio Álamo

With this book, we have attempted to do an update of some aspects of prevalence, pathophysiology, diagnosis and treatment of ADHD. It is clear that each and every one of these issues separately would involve the development of a scientific book, but we have preferred to integrate and provide a more comprehensive overview to readers.

Dr. Francisco López-Muñoz, MD, PhD Professor of Pharmacology, Faculty of Health Sciences, Director of International Doctorate School, Camilo Jose Cela University, Madrid, Spain Email: [email protected] / [email protected] Dr. Cecilio Álamo, MD, PhD Professor of Pharmacology Department of Biomedical Sciences Faculty of Medicine and Health Sciences University of Alcala Madrid, Spain Email: [email protected]

February 2015

In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 1

Evolution of International Scientific Production on Attention-Deficit Hyperactivity Disorder: A Bibliometric Analysis of the Last 34 Years Francisco López-Muñoz1,2,3,4,, Francisco J. Povedano2, Pilar García-García3, Javier Quintero5,6,7 and Cecilio Álamo3 1

Chair of Genomic Medicine Camilo José Cela University, Madrid, Spain Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain 3 Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, Madrid, Spain 4 Neuropsychopharmacology Unit, Hospital 12 de Octubre Research Institute (i+12), Madrid, Spain 5 ADHD Across Life Spam Program, Psychiatry Department, Universitary Hospital Infanta Leonor, Madrid, Spain 6 Psychiatry Department, Faculty of Medicine, Complutense University, Madrid, Spain. 7 Psiformacion Fundation, Madrid, Spain 2

Abstract We have carried out a bibliometric analysis of scientific publications related to attention-deficit hyperactivity disorder (ADHD) and its pharmacological treatment over the period 1980-2013. We selected (EMBASE and MEDLINE databases) documents that contained in their title the descriptors attention deficit hyperactivity disorder, attention 

Correspondence to: Dr. Francisco López-Muñoz, Faculty of Health Sciences, Camilo José Cela University, C/ Castillo de Alarcón, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain. E-mail: [email protected], [email protected]

2

Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al. deficit disorder, ADHD and ADD. As bibliometric indicators of production, we applied Price‘s Law, and others as doubling time and annual growth rate of scientific literature. We also calculated the national Participation Index (PI) for ADHD and correlated it with overall PI in 12 most productive countries in biomedical and health sciences and with its social-health indicators (per capita gross domestic product, total per capita expenditure on health, and proportional gross domestic expenditure on research and development). We obtained 21,761 original documents (14,728 corresponded to pharmacological therapy). Our results indicate fulfilment of Price‘s Law, since scientific production on ADHD undergoes exponential growth (correlation coefficient r = 0.9859, vs. r = 0.9418 after linear adjustment). The most widely studied drugs are methylphenidate (3,759 documents). The most used journal in the dissemination of documents is Journal of the American Academy of Child and Adolescent Psychiatry (633 articles). Thirteen of the first 15 used journals have an Impact Factor > 2. The principal producer country is the United States (PI = 38.1). Seven of the world‘s 12 most productive countries in biomedicine and health sciences devote most attention to the study of ADHD (Netherlands, Canada, Australia, United States, Spain, Germany, and United Kingdom). The correlation between PI and gross domestic expenditure on R&D situates United States, United Kingdom, Canada, Germany and Spain in the top positions. Productivity on ADHD has undergone exponential growth in the period 1980-2013, without evidence a saturation point.

Keywords: attention-deficit hyperactivity disorder, bibliometry, treatment, psychostimulants, methylphenidate

Introduction Attention-deficit hyperactivity disorder (ADHD) is one of the neuropsychiatric conditions that has received most attention in the scientific literature in the last decades. The majority of authors acknowledge that ADHD is the most widespread problem in developmental neurology and one of the commonest reasons for neuropaediatric consultations. The prevalence of this disorder is generally accepted to be around 5-8% in children of school age (range 4-12%) [1-3], and an estimated between 2.5% and 4.7% among adults [4-7]. ADHD is, moreover, a pathology whose aetiology and biochemical substrates continue to be largely unknown [8-10]. The consequences of this disorder are very broad; delay of academic progress, difficulties understanding, instability in relationships with friends and classmates, low self-esteem and disorganization [9]. Children suffering from this disorder are more likely, as juveniles, to be involved in traffic violations and car accidents and to have early and uncontrolled sexual relations, which can lead to sexually-transmitted diseases and unwanted paternity or maternity [10-11]; furthermore, they generate a total medical cost, use of medical resources, and global burden in terms of disability far in excess of that of their peers without ADHD [12]. Such factors may have contributed to the increase in the quantity of scientific work aimed at better understanding this disorder and addressing these dramatic consequences. In spite of all these obscure aspects, considerable progress has been made in recent decades in relation to ADHD [10, 13]. In fact, it was in the 1980s that ADHD emerged as a specific pathological entity, with the creation of ADD (Attention Deficit Disorder) syndrome by the American Psychiatric Association (APA), although previous diagnostic criteria already catalogued this disorder with other nomenclatures (e.g., hyperkinetic reaction of childhood).

Evolution of International Scientific Production on Attention…

3

During that decade, numerous studies were published on the implementation of diagnostic criteria and assessment tools for clinical research, on the social impact of the disorder, on its neurobiological character and on cognitive-behavioural approaches to it. Work continued into the 1990s, with the focus on neurobiological and genetic aspects [13]. Similarly, this increase in knowledge of clinical and diagnostic aspects of ADHD seems to have extended to therapeutic aspects. Psychostimulants are the drugs that have undergone most research in children with ADHD, with more than 200 published clinical trials in the mid-2000s supporting their effectiveness, especially that of methylphenidate [14]. In recent years, pharmacological research in this field, rather than focusing on the search for new therapeutic drugs, has launched itself into the development of new formulations of stimulants [15-18], aimed at achieving better control of children with ADHD through a single daily dose. However, also one has investigated with non-stimulant drugs, as atomoxetine, clonidine, guanfacine, bupropion, modafinil and others [18-22]. Thus, since 2000 there have been substantial developments in the treatment of ADHD, which have led in turn to a considerable increase in scientific literature on the disorder [23]. But despite the large quantity of reviews published in recent years on clinical, diagnostic, epidemiological and other aspects of ADHD, and on treatment approaches to it [1, 9-10, 14-21, 24-32], to date there have been no studies assessing the growth of scientific production in relation to this disorder. Bibliometric studies, in spite of their methodological limitations, are useful tools for assessment of the social and scientific relevance of a particular discipline or subject [33], since they permit analysis of the growth, size and distribution of scientific literature on the topic in question during a given time period. Our group has studied, using a bibliometric approach, the evolution of scientific literature in psychiatry by specific research groups, on different psychiatric disorders, on aspects related to the discipline, and on specific therapeutic tools in the field of psychopharmacology [34-38], including the evolution of publications related to ADHD and its pharmacological treatment during the period 1980 to 2005 [23]. The present bibliometric study extends this analysis until 2013.

Method Data Sources In the present bibliometric study we have used the databases MEDLINE (Index Medicus, U.S. National Library of Medicine, Bethesda, MD, USA) and Excerpta Medica (EMBASE) (Elsevier Science Publishers, Amsterdam, Netherlands), considered to be the most exhaustive within the biomedical field. These databases are integrated in a single platform called OVID (Ovid Technologies Inc., New York, USA). For some specific sub-analysis has also been used SCOPUS database (Elsevier BV, The Netherlands), which includes 55 million records, 21.915 titles, and 5,000 publishers (scientific journals, books and conference proceedings). Using remote-download techniques, we selected documents that contained, in the TI (title) section, the descriptors ―attention deficit hyperactivity disorder,” “attention deficit disorder,” “ADHD” or “ADD,” always confining the year of publication to the period 19802005. We have excluded the descriptor “hyperkinetic*” (as defined by the International Classification of Diseases), since it can induce to important bias, because this symptom, in the

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Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al.

title of papers, can go associate to other many disorders (epilepsy, Parkinson disease, etc.). Within this repertoire, we created a subgroup of documents referring to pharmacological treatment specifically approved for the treatment of this disorder. In this case the descriptors employed (“drug,*” “therap,*” “treatment,*” “methylphenidate,” “dexmethylphenidate,” “dextromethylphenidate,” “amphetamine,*” amfetamine, “dexamphetamine,*” “dextroamphetamine,*” “atomoxetine,” “clonidine,” “guanfacine,” “lisdexanfetamine” or “SLI-381”) were not restricted to any field of the database. This study took into account all original articles, brief reports, reviews, editorials, letters to the editor, and so on; it was also made sure that the duplicated documents were eliminated. In this regard, the OVID platform used in the search has the useful feature of permitting the elimination of those documents that may be duplicated in the two databases (MEDLINE and EMBASE).

Bibliometric Indicators Among the bibliometric indicators of production we applied Price‘s Law [39]. This law, undoubtedly the most widely used indicator for the analysis of productivity in a specific discipline or a particular country, takes into account an essential feature of scientific production, which is its exponential growth. In order to assess whether the growth of scientific production in ADHD follows Price‘s Law of Exponential Growth, we carried out a linear adjustment of the data obtained, according to the equation y = 58.02x – 317.3, and another adjustment to an exponential curve, according to the equation y = 45.37e0,123x. Other quantities related to growth are doubling time and annual growth rate. The first is the amount of time required for the subject matter to double its production; the annual growth rate represents how the magnitude has grown over the previous year, expressed as a percentage. The equation that calculates the doubling time (D) is represented by the following expression: D = Ln2 / b. Here, b represents the constant that relates the rate of growth to the size of the science already acquired. To calculate the annual growth rate, we used the following equation: R = 100 (eb - 1). As an indicator of the publications‘ repercussion we used the Impact Factor (IF). This indicator, developed by the Institute for Scientific Information (Philadelphia, PA, USA), is published annually in the Journal Citation Reports (JCR) section of the Science Citation Index (SCI). The IF of a journal is calculated on the basis of the number of times the journal is cited in the source journals of the SCI during the two previous years and the total number of articles published by that journal in those two years. The JCR lists scientific journals by specific areas, ascribing to each of them their corresponding IF and establishing a ranking of ―prestige‖ [40] In this study, we used the IF data of 2013 published in the JCR of 2014. Another indicator included in the present analysis was the national Participation Index (PI) in overall scientific production on ADHD and on the pharmacological treatment of this disorder. The PI reflects the quotient between the number of documents generated by a given country and the total number of documents obtained in the repertoire. This PI has been correlated with some social and health data from the main countries that generate literature in this field, such as per capita gross domestic product, total per capita expenditure on health and proportional gross domestic expenditure on research and development (R&D). The PI health data were obtained from the Organisation of Economic Co-operation and Development (OECD) Health Division [41] and WHO Department of Health Statistics and Informatics

Evolution of International Scientific Production on Attention…

5

[42]. PI for ADHD has also been correlated with overall PI in biomedical and health sciences for the world‘s 12 most productive countries in biomedicine and health sciences during the period 1980-2013. Finally, we considered evolution of scientific production in relation to pharmacological treatment of ADHD, with consumption and prescription data for the principal drugs indicated for this disorder, according to the United Nations Report of the International Narcotics Control Board for 2005 (www.incb.org/pdf/e/tr/psy/2005/psychotropic_substances_2005.pdf) [43], and 2013 (www.incb.org/documents/Psychotropics/technical-publications/2013/en/5_ Part_II_comments.pdf) [44].

Results As a result of studying the journals analyzed, for the period 1980-2013, we obtained 21,761 original documents (articles, reviews, editorials, letter to the editor, etc.) covering different aspects of ADHD. Of these, 14,728 correspond to pharmacological therapy, of which 62.31% (n = 9,178) refer to drugs with approved indication for this disorder: methylphenidate (3,756), atomoxetine (1,327), mixed amphetamine salts (1,203), dexamphetamine (1,025), clonidine (603), guanfacine (401) and dexmethylphenidate (268). The 66.61% of documents corresponds to original articles, and 12.04% to reviews.

Figure 1. Growth of scientific production on ADHD. A linear adjustment of the data and an adjustment to an exponential curve were made, in order to assess whether the production fulfilled Price‘s Law of Exponential Growth. Linear adjustment: y = 58.02x – 317.3 (r² = 0.887). Exponential adjustment: y = 45.37e0,123x (r² = 0.972).

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Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al.

As Figure 1 shows, the last 34 years have seen a notable increase in the number of publications generated worldwide in relation to ADHD. Mathematical adjustment to an exponential curve, shown in Figure 1, allows us to obtain a correlation coefficient r of 0.9859, which indicates 2.8% of variability unexplained by this adjustment. On the other hand, linear adjustment to the measured values provides an r of 0.9418, and therefore a percentage of unexplained variability of 11.3%. With these data we can conclude that the repertoire analyzed is more suited to an exponential adjustment than a linear adjustment, thus fulfilling Price‘s Law. Figure 2 shows the overall increase of scientific publications during each decade of the reporting period. In percentage terms, the decade of the 2000s represents an increase of 265.29% over the decade of the 90s, and this a 250.58% over the previous decade of 80s. The annual growth rate for the entire study period was 14.06%, and the doubling time was 5.63 years.

Figure 2. Distribution by decades of international scientific literature on ADHD.

The clinical introduction of drugs specifically indicated for the treatment of ADHD in different countries of the world appears to have contributed to the increase in overall scientific production in the field of ADHD, as shown in Figure 3. This increase begins to emerge from 1994, with the clinical introduction of mixed amphetamine salts, and reaches another significant increase since the clinical introduction of atomoxetine in 2003. Figure 4 shows the evolution undergone over the last 34 years, through the documents on ADHD, of all the drugs authorized for this disorder. From 1999 onwards the growth is considerable, due largely to methylphenidate and, to a lesser extent, atomoxetine; this growth does appear to have reached a peak by the end of the decade of 2000s. Figure 5 shows the relationship between the evolution of publications on methylphenidate and world consumption data for the drug, indicating a close correlation between the two parameters.

Evolution of International Scientific Production on Attention…

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Figure 3. Number of documents on ADHD (1990-2013) and international authorization of drugs indicated for this disorder.

Figure 4. Evolution of documents on drugs authorized for ADHD in publications related to their use for this disorder (MEDLINE and EMBASE: 1980-2013).

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Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al.

Figure 5. Relationship between number of publications on methylphenidate and evolution of worldwide consumption of this drug, for the period 1987-2012. Data on consumption of methylphenidate were obtained from the UN Report of the International Narcotics Control Board, 2005 (www.incb.org/pdf/e/tr/psy/2005/psychotropic_substances_2005.pdf), and UN Report of the International Narcotics Control Board, 2013 (www.incb.org/documents/Psychotropics/technicalpublications/2013/en/5_Part_II_comments.pdf). Consumption data are expressed in defined daily doses (DDD).

Table 1 shows the most used journals in the dissemination of documents in our repertoire, as well as their corresponding IFs, according to the JCR of 2013, and the Participation Index (PI) of the documents on ADHD in the total of documents published by each journal in the analyzed period. The ranking is led by Journal of the American Academy of Child and Adolescent Psychiatry, with 633 articles, and Journal of Attention Disorders (n = 570), followed at a greater distance by Journal of Abnormal Child Psychology (n = 282), Journal of Child and Adolescent Psychopharmacology (n = 270), and Biological Psychiatry (n = 239). It was notable that the 15 most used journals accounted for 16.08% of all the documents in the repertoire under study. Noteworthy is the only journal devoted exclusively to the study of attention disorders, the Journal of Attention Disorders, with a PI = 80.96. Leaving aside this exception, the journals of this ranking that proportionally devote most scientific production to ADHD are the Journal of Child and Adolescent Psychopharmacology (PI = 20.70), Journal of Abnormal Child Psychology (PI = 14.36), Journal of the American Academy of Child and Adolescent Psychiatry (PI = 11.24), and European Child and Adolescent Psychiatry (PI = 10.95). It is also worth pointing out that journals well positioned in our ranking, such as Pediatrics, proportionally devote very few documents to this disorder (PI = 0.75).

Table 1. The 15 journals with highest number of publications on ADHD Rank

Journals

Nº Documents1

%

IF2

Eigenfactor score Article influence score

1

J Am Acad Child Adolesc Psychiatry

633

11.24

6.354

0.02287

2.528

2

J Attent Disord

570

80.96

2.397

0.00416

0.798

3

J Abnorm Child Psychol

282

14.36

3.167

0.001

1.55

4

J Child Adolesc Psychopharmacol

270

20.70

3.073

0.00472

0.922

5

Biol Psychiatry

239

2.36

9.472

0.08145

3.332

6

J Child Psychol Psychiatr Allied Discipl

201

6.26

3.076

0.00472

0.922

7

Am J Psychiatry

193

1.25

13.559

0.04917

5.204

8

J Clin Psychiatry

189

2.02

5.139

0.02791

1.745

9

Pediatrics

164

0.75

5.297

0.11997

2.022

10

Rev Neurol

161

2.16

0.926

0.00192

0.121

11

Eur Child Adolesc Psychiatry

151

10.98

3.554

0.00617

1.015

12

Am J Med Gen Part B Neuropsychiatr Gen

130

3.62

3.271

0.01320

1.058

13

J Develop Behav Pediatr

120

4.91

2.353

0.00544

0.837

14

J Learn Disabil

102

4.56

1.448

0.000

0.93

15 Psychiatry Res 94 1.55 2.682 0.02570 0.885 PI (Participation Index); IF (Impact factor). 1 Number of documents containing in the title the descriptors ADHD, attention deficit hyperactivity disorder, ADD, attention deficit disorder. 2Journal Citation Report, 2013.

10

Evolution of International Scientific Production on Attention…

As can also be observed in Table 1, the journals most extensively used for the diffusion of works on ADHD have high IFs (13 of them have an IF > 2). Within this most used group of journals, half of them are from the fields of Psychiatry and/or Psychopharmacology (8). The other half is accounted by journals from the fields of Psychology (2), Neurology (2), Paediatrics (2) and Genetics (1). The language used in 89.75% of the documents was English. The 2.81% was published in German and 1.86% in Spanish. Of the countries generating research on ADHD, the most prominent, as can be seen in Table 2, is the United States, whose production accounts for more than one third of the repertoire analyzed, with a PI of 38.10. At a considerable distance are the United Kingdom (PI = 6.96) and Germany (PI = 6.74), followed by Canada (PI = 5.38), Australia (PI = 3.51) and Netherlands (PI = 3.32).

Figure 6. Relationship between production of scientific literature on ADHD and total production in biomedicine and health science in the world‘s 12 most productive countries in biomedicine and health sciences. PI (Participation Index), ADHD (attention-deficit hyperactivity disorder).

If we consider the productivity of the world‘s 12 most productive countries in biomedicine and health sciences on this topic in relation to their overall scientific production, 7 (The Netherlands, Canada, Australia, United States, Spain, Germany, and United Kingdom) of these countries (in the period 1980-2013) devote, percentage-wise, most attention to the study of ADHD (Figure 6). Table 2 shows, likewise, the number of documents contributed and the PI of the 15 most productive countries in biomedicine in relation to the pharmacological treatment of ADHD; this ranking follows a pattern very similar to that of the general distribution of this disorder.

Evolution of International Scientific Production on Attention…

11

Table 2. Distribution of documents on ADHD and pharmacotherapy in the 12 world’s most productive countries in biomedicine and health sciences, for the period 1980-2013

1 2 3 4 5 6 7 8 9 10 11 12

Country1 USA China UK Japan Germany France Canada Italy India Spain Australia Netherlands

% 26.02 7.95 6.93 6.23 6.06 4.54 3.55 3.46 2.54 2.49 2.35 1.98

ADHD2 n (%) 8291 (38.10) 517 (2.38) 1515 (6.96) 513 (2.36) 1467 (6.74) 377 (1.73) 1170 (5.38) 569 (2.61) 233 (1.07) 604 (2.78) 763 (3.51) 723 (3.32)

Pharmacotherapy3 n (%) 6384 (43.34) 228 (1.55) 1147 (7.79) 231 (1.66) 1215 (8.25) 277 (1.88) 952 (6.46) 448 (3.04) 141 (0.95) 471 (3.19) 584 (3.96) 574 (3.89)

ADHD (attention-deficit hyperactivity disorder). 1 The world‘s 12 most productive countries in biomedicine and health sciences for the period 19802013. Data from SCOPUS. 2 n = 21,761. 3 n = 14,728 (67.68% of the documents in the repertoire).

Figure 7. Relationship between production of scientific literature on ADHD and per capita gross domestic product in the world‘s 12 most productive countries in biomedicine and health sciences, for the period 1980-2013. We have excluded the United States from the graph in order to give a clearer reflection of the rest of the countries. GDP (Gross Domestic Product), PI (Participation Index), ADHD (attention-deficit hyperactivity disorder). The economic data were obtained from the website of the World Health Organization (http://www.who.int/country/es/) (WHO, 2015). Economic data are expressed in international dollars (data 2013).

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Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al.

As far as social-health parameters are concerned, if we correlate the scientific documents contributed by the principal producers of ADHD literature with their per capita gross domestic product, we observe a homogeneous distribution for a large group of them (Italy, Spain, Canada, Germany and United Kingdom). However, there is less interest in this disorder, in relation to their economic potential, in countries such as France, Japan, or Netherlands, whilst in the United States the opposite occurs (Figure 7). In the specific analysis of correlation between PI and per capita health expenditure for each of these countries, the distribution obtained is very similar to the productivity ranking, with the exceptions of China and India (Figure 8), although in these cases it is an artefact due to the small Indian and Chinese per capita health expenditure (157, and 480 PPP Int $, respectively). In contrast, when we carried out the same type of analysis versus gross domestic expenditure on R&D, we find that the ranking is led by United States, followed by United Kingdom, Canada, Germany, Spain and Italy (Figure 8).

Figure 8. Per capita Health Expenditure and relationship between production of scientific literature on ADHD and per capita health expenditure and gross domestic expenditure on research and development, in the world‘s 12 most productive countries in biomedicine and health sciences. PI, participation index. Total Health Expenditure per capita PPP Int $ (data 2012) (http://www.who.int/country/es/) (WHO, 2015). Gross Domestic Expenditure on research and development (%). Data OECD 2013, except Australia and Japan (data 2010) and China (data 2009) (http://www.oecd-ilibrary.org/science-andtechnology/gross-domestic-expenditure-on-r-d_2075843x-table1).

Table 3 shows the most productive institutions in relation to the material under study. We defined the corresponding institution solely based on the information provided in the AD field in the EMBASE Biomedical Answer web database. The top three rankings are Massachusetts

Evolution of International Scientific Production on Attention…

13

General Hospital (Boston), King's College London, and State University of New York Upstate Medical University. The three institutions have generated 6.57% of the papers that make up the sample. Table 3. Contribution of different institutions on ADHD research Centre

n

PI (%)

Massachusetts General Hospital

704

3.24

King's College London

373

1.71

State University of New York Upstate Medical University

352

1.62

Harvard Medical School

307

1.41

UC Irvine

224

1.03

New York University

207

0.95

Hospital for Sick Children University of Toronto

201

0.92

University of Toronto

192

0.88

Radboud University Nijmegen Medical Centre

187

0.86

Duke University School of Medicine

175

0.80

University of California, Los Angeles

175

0.80

Vrije Universiteit Amsterdam

171

0.79

University at Buffalo State University of New York

171

0.79

Eli Lilly and Company

170

0.78

Discussion Bibliometric studies constitute interesting tools for assessing the social and scientific importance of a given discipline or topic during a specific time period. Despite their methodological limitations, these analyses provide a picture of the growth, size and distribution of scientific literature related to the discipline or topic and of the evolution of both the biomedical speciality, area of specialization or subject in question and the scientific production of an institution, country, author or research group [33]. Bearing in mind these premises, the design of the present analysis permits us to make an overall assessment of the growth of scientific literature in relation to ADHD and its pharmacological treatment. From the historical perspective, a renewed interest in ADHD began in the mid-1970s, after the publication of the work by Virginia Douglas [45], proposing that hyperactivity was not the principal phenomenon of this disorder, but rather attention deficits, and the first neurobiological publications, at the end of the same decade, correlating the symptoms of this disorder with alterations of the prefrontal cortex [46]. Finally, the publication of the DSM-III, in 1980, gave definitive blessing to the name Attention Deficit Disorder (ADD), precursor of the term ADHD, and established the current form of approaching this disorder. Since then, the volume of scientific publications on this topic has not ceased to grow. It is important to highlight in this regard (see Figure 1) that the number of publications on ADHD has seen exponential growth over the last 34 years, especially after

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Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al.

1995, without showing, up to the end of the period studied, the saturation process described by Price in his theory of the expansion of scientific literature [39]. The strongest growth in overall production on ADHD takes place since the mid-1990s. Several factors contributed to this pace of development. By way of example, we might mention the increase in research on neurobiological (neuroimaging studies, both structural and functional) and genetic aspects (molecular genetics) of this disorder, as well as its extension to the area of adult patients and the publication of the new DSM-IV diagnostic criteria in 1994. The recognition of adult ADHD as a specific pathology in the first half of the 1990s represented a new stimulus for the development of research in this field. It is precisely from 1994 that we can observe in our analysis an important turning point in the exponential growth of scientific literature on ADHD. Furthermore, a second upsurge in the growth of scientific production on this topic can be appreciated towards the end of the period under study here, from 2004. Possible contributing factors to this second turning point were the growth of neuropsychological and neuroimaging studies, the attempt to establish ADHD subtypes, and the massive investment of the pharmaceutical industry (e.g., new formulations of psychostimulants and other nonstimulant drugs) [15-22]. Another aspect of interest in relation to scientific production that we have analyzed is its quality. To this end we used the indicators of impact and excellence of the publications on the topic in question. The fact that such prestigious journals as American Journal of Psychiatry (IF = 13.559), Biological Psychiatry (IF = 9.472), or Journal of Child and Adolescent Psychopharmacology (IF = 6.354) publish articles on ADHD is an important factor in this regard, which indicates the significance (both clinical and social) this pathology has acquired in recent years. Moreover, it is noteworthy, as we have said, how 13 journals with an IF > 2 are among the 15 most widely used journals in our repertoire. The tremendous increase in the literature on this topic and its diffusion in some of the most prestigious scientific journals suggest that ADHD is a pathology whose development is in full swing from the clinical and basic research perspectives. Previous studies by our group have revealed a similar situation with other psychiatric disorders, such as bipolar disorder [36], as well as the specific one of psychopharmacology [35,38]. Although the symptomatology that we can today assimilate to ADHD was already identified from the early 20th century, it was not until relatively recently that ADHD began to receive the scientific and social recognition it enjoys today [13]. The appearance in 1996 of a specific scientific journal for this field, the Journal of Attention Disorders, confirms how this clinical entity has attained an important rank as specific research material within the neuropsychiatric disorders. Since the 1970s, psychostimulants have been considered the basic treatment for ADHD [13], and methylphenidate the first-choice drug [47], though in January 2003 the Food and Drug Administration (FDA) authorized the first non-stimulant drug for the treatment of adults with ADHD, and subsequently for children and adolescents – the noradrenaline reuptake inhibitor atomoxetine. The Texas Children‘s Medication Algorithm for ADHD pharmacotherapy, published in 2006, suggest that atomoxetine should be considered if patients do not respond to or cannot tolerate two different stimulants [48]. Following, the FDA approval of guanfacine and clonidine extended-release use as ADHD monotherapy and adjunctive therapy in 2009 and 2010, respectively, a new algorithm suggest that alpha agonists should be added in patients with partial response to the second stimulant, or switched if patients have no response [21]. In this regard, the scientific literature on the pharmacological tools used on ADHD has also, like the general literature on ADHD,

Evolution of International Scientific Production on Attention…

15

undergone exponential growth during the period studied. We can see in Figs. 3 and 4, a substantial increase in publications on psychostimulants from 1994, especially after the confirmation of their effectiveness in the treatment of symptoms in adults [49]. From the late 1990s, we can observe a second and definitive upturn in publications on pharmacotherapy in ADHD, especially after 1999, the year which saw the publication of several key works in this field (as the multicentric and randomized study by the US National Institute of Mental Health on treatment combinations in the long-term treatment of ADHD, known as MTA, Multimodal Treatment Study of ADHD [50]) and the start of the gradual clinical introduction of new drugs in different countries across the world [18-20,22]. Likewise, there is a close correlation between the increases observed in the number of documents on ADHD and on its pharmacological treatment. In the individual analysis of drugs authorized for ADHD, methylphenidate is that which has been most widely studied, from both the clinical and safety points of view, as revealed by the present bibliometric study, though since 2002 atomoxetine has undergone a highly relevant increase. Furthermore, the appearance of sustained-release methylphenidate formulations (the OROS system, or gelatine capsules that include immediate release and delayed release pellets) and new non-stimulant drugs (atomoxetine and alpha-2 agonists), had a decisive influence on this upturn in scientific publications in the field of ADHD. Obviously, such extensive bibliography and its growth must be correlated with the clinical use of these drugs. From the pharmaco-epidemiological perspective, consumption of psychostimulants has increased significantly, at least in the United States, over recent decades. Prevalence of use among adolescents up to age 18 increased between 3 and 7 times in the period between 1987 and 1996 [51], and prescriptions to children aged 2-4 increased threefold during the 1990s [52], methylphenidate accounting for 77-87% of all prescriptions since 1991. These increases in consumption have also remained during the 2000s: US children with ADHD treated with ADHD drugs increased from 60% to 63% between 1996 and 2005 (by 2005, long-acting ADHD drugs accounted for over 90% of stimulant spending) [53]; between 2000 and 2005, treatment prevalence increased rapidly (11.8% per year) for the ADHD population [54]; in Canada, number of medications used for children with ADHD spent 43% in 2000 to 59% in 2007 [55]. A contributing factor to this may have been the recognition of the persistence of ADHD into adulthood and the need for lifelong treatment. The UN Report of the International Narcotics Control Board, from 2005, indicate the greatest growth took place in relation to methylphenidate, whose worldwide production rose from 2.8 tonnes in 1990 to 34.2 tonnes in 2004 [43], reaching a record level of 63.2 tons in 2012 [44]. In the period 2000-2004, the increase in consumption of methylphenidate in DDD in the United States was over 100%, rising from 360 million DDDs in 2000 to 742 million DDDs in 2004 [43], reaching 1.2 billion DDD in 2011 [44]. Figure 4 represents graphically this correlation between the number of publications reported by ourselves and worldwide methylphenidate consumption data published by the United Nations (2012). The ranking of countries that produce scientific literature on ADHD is heavily dominated by the United States, which generates more than a third of total scientific production in this field (38.10%). The facts that the United States has the strongest research tradition in this field, since the mid-20th century, that it is the greatest consumer of methylphenidate (64% of world consumption in 2012) [44], and that it is home to most of the pharmaceuticals companies responsible for the development of drugs for ADHD (Smith, Kline & French,

16

Francisco López-Muñoz, Francisco J. Povedano, Pilar García-García et al.

ALZA Corp., Celgene Corp., Noven Pharmaceuticals, Rexar Pharmaceuticals, Eli Lilly) may help to explain this high PI. Curiously, Canada is third in the ranking of scientific productivity in ADHD in our analysis, and according to the latest United Nations Report of the International Narcotics Control Board it occupies second place in consumption of methylphenidate for the treatment of ADHD between 2003 and 2012 [44]. The same document reports that the main users of methylphenidate in 2012 apart from the United States and Canada were, Germany, Spain, Switzerland, the Netherlands, Brazil, Sweden, Israel, South Africa and Australia [44], which also correlates with the high relative level of scientific interest in the subject of ADHD of some of these countries, as can be seen in Table 2. Table 2 shows data for the 12 most productive countries in biomedicine and health sciences, and allows comparison of the data for general productivity with productivity in the specific field of ADHD. Notable in this regard, and as can be seen in Figure 6, is the fact that few countries (Netherlands, Canada, Australia, United States, Spain and Germany) maintain relative productivity rates in ADHD higher than the overall index in biomedicine and health sciences, which serves to underline the special interest of these countries in research on ADHD. In contrast, we can observe a lower relative interest in this disorder, within the framework of their general biomedical production, of other countries, such as China, Japan, France, India or Italy. The correlation between scientific production in ADHD and the per capita health expenditure of each country, shown in Figure 7, provides us with another parallel view on this phenomenon: in general it is confirmed that the higher the total health expenditure, the greater the productivity in research on ADHD, with a few exceptions, such as France, Japan or United Kingdom. In this regard it should be stressed that the scientific production of a country in a particular field tends to reflect a policy of scientific research and development that begins some years before the period analyzed, rather than being the product of the temporary circumstances prevailing at the time of publication. When the analysis is made in relation to the gross domestic expenditure on R&D in the country (Figure 8), as an indicator of investment in research, the leading countries are found to be United States, United Kingdom, Canada, Germany, Spain and Italy. Worthy of note, on the other hand, is the low ratio in this regard for countries such as Japan and France.

Limitations Previous bibliometric studies have revealed a series of limitations characteristic of these sociometric approaches [56], since international scientific production on a given topic, such as ADHD in this case, is clearly more extensive. However, there are many journals that are not indexed in the usual databases, as occurs with contributions to conferences and scientific meetings. Nevertheless, the recognized quality of the publications included in the databases used in the present study and their coverage make the selected documents a more than representative sample of international research on the subject under study.

Evolution of International Scientific Production on Attention…

17

Conclusion We can assert that, despite the limitations of bibliometric studies, we have been able to describe, thanks to the design used, the representativeness and evolution of international research on ADHD, taking into account the parameters of quality and diffusion most widely employed at international level. Given the documentary corpus analyzed in this study, we can conclude that ADHD is an entirely consolidated scientific field, and although this is the most widely studied child neuropsychiatric disorder [13], there are still challenges to deepen in many ways. Research in this area is likely to continue growing in the coming years, especially if we bear in mind that the ideal drug for treating ADHD patients has yet to be discovered. Thus, these therapeutic aspects, together with the great unknowns that still remain in relation to the aetiopathogeny (including neurobiological and genetic aspects) of the disorder, guarantee a promising future for research on ADHD.

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In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 2

Prevalence of AttentionDeficit/Hyperactivity Disorder José Carlos Peláez Álvarez1,*, Laura Rodríguez Moya2 and Francisco Montañés Rada3 1

Servicio de Psiquiatría, Hospital Universitario Fundación Alcorcón, Madrid, Spain 2 Centro de Salud Mental de Alcorcón, Facultad de Psicología, Universidad Complutense de Madrid, Spain 3 Servicio de Psiquiatría, Hospital Universitario Fundación Alcorcón, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos I, Alcorcón, Madrid, Spain

Abstract The ADHD worldwide pooled prevalence is around 5%. The studies about this concern show variations on this number. The main reason may be the methodology and it seems more likely that the detection of symptomatology of hyperactivity, impulsivity and inattention rather than the detection of prevalent cases is what is behind this variability. Other facts (that seem increasingly likely) are the difference in symptomatology of ADHD according to gender and the existence of a cultural factor that also influences the disorder presentation. ADHD is a disorder that continues throughout life and so far has not been considered sufficiently. Due to ADHD, adults in particular suffer interferences with life as well as a higher comorbidity; around 15% have substance abuse, 12% have an anxiety disorder and up to 8.7% a personality disorder. The growing interest on ADHD (due to the consequences experienced by patients) does that the diagnostic criteria have changed in order to have a greater diagnostic sensitivity. This topic is in vogue given that increased sensitivity can lead to a higher prevalence and consequently a lower specificity.

Keywords: ADHD prevalence, comorbidity, gender factors

*

Correspondence to: Dr. José Carlos Peláez Álvarez, Servicio de Psiquiatría, Hospital Universitario Fundación Alcorcón. C/ Budapest, 1. 28922, Alcorcón, Spain. Email: [email protected].

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Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is a public health problem. It is a common disorder that also generates significant morbidity and dysfunction throughout life. The symptomatology is more important in child and adolescent ages, but also continues into adulthood [1]. ADHD can be detrimental to many areas of life including school, work, daily activities, social and family relationships as well as psychological and physical well-being. Moreover, people with ADHD are at risk for a wide range of psychiatric disorder. If we are able to establish a more exact prevalence of ADHD, we can determine the magnitude of the problem involved for public health and allocate resources for comprehensive treatment and for decreasing the morbidity associated.

Prevalence of ADHD The prevalence in school-age population fluctuates according to different countries but is about 5% of children and 2.5% of adults [2]. According to Polanczyk et al. [3] the ADHD worldwide-pooled prevalence is 5.29%. In the same paper this author justifies that the variability of the prevalence rates between different continents is because of methodological differences. These differences were not found between studies from North America and Europe [3]. However, some cultural factors could involve lower rates of prevalence [4]. If we rely on parent-reported surveys and the percentage of children who meet criteria for ADHD, a difference in the prevalence of ADHD could be found. Wolraich et al. found a prevalence of 7.8%-9.5% in parent-reported surveys and a percentage of 8.7-10.6 of children who met ADHD criteria, in a sample of 10,427 children in two different States of USA [5]. Here lies one of the hot spots of the papers. Many of them are based on questionnaires administered to parents and/or teachers. Even many studies also combine it with selfadministered questionnaires. But if then the existence of the disorder is not verified, only would obtain prevalence rates of the symptomatology of ADHD but not of prevalence rates of ADHD. In Spain, Cardo et al. [6] develops a prevalence study where found a prevalence of ADHD of 4.6% in children aged between 6 and 11 years. Other study found a prevalence of 3.6% in ten years old children [7]. Recently was published a magnificent study on the prevalence of risk of this disorder in school children [8]. The total sample was of 4858 participants. They were divided according to gender and age ranged from 6 years to 16 years. They used the EADH [9] (Evaluation of Attention Deficit and Hyperactivity), a revised Spanish version of Conners‘ behavior scale for professors in the child population (6 to 12 years). They found that boys obtained higher mean scores than the girls in both primary and secondary school. Sánchez et al. obtained that the risk prevalence was of 11.52%. The results obtained by differentiating the symptoms were that the prevalence of presenting only symptoms of hyperactivity was 3.29%, for problems of attention was of 3.12% and presenting both, problems of hyperactivity and attention was 5.11%. Similar results were already observed in 2005 by Blázquez et al. They obtained a prevalence of 12% risk of a total of 2401 participants aged between 6 and 13 years [10]. We cannot forget that both studies conducted a screening of symptomatology of ADHD. Then it was not determined the presence or absence

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of the disorder. That is the reason for the existence of differences between prevalence rates and the prevalence of risk rates. In other countries as France, the prevalence of ADHD was between 3.5% and 5.6% [11]. It is more difficult to find studies that can calculate the prevalence in one year, in a study conducted in Sweden in 2011 it was estimated that each year 1.3 new cases per 1000 persons are diagnosed [12]. In Turkey, Erol et al. found that the prevalence of attention problems could be between 1% and 2.4%. They exposed that one of the limitations that explained a lower prevalence rates was that the information was obtained through self-administered test that could not be performed clinical interviews with participants [13]. Studies suggest that the ADHD prevalence is higher in boys than in girls. The pooled ADHD prevalence for boys is 2.45 times higher than the one detected for girls [3]. As is the case with other prevalence studies the male to female ratio varies from 3:1 to 9:1 [14]. It is possible that gender differences can be duty also to the existence of different subtypes of ADHD in terms of gender. So the girls have higher attention problems facing children, where the hyperactive-impulsive subtype is more relevant [15]. Lecendreux et al. found a greater prevalence among boys than among girls, 4.7% vs. 2.2% [11]. If we focus on the incidence an estimate of the annual rate per 1,000 persons of new diagnoses calculated in Sweden in 2011was 1.0 for women and 1.6 for men [12]. ADHD is associated with the risk of presenting a wide range of psychiatric disorders. In a study based on a population-based birth cohort, found that patients who were diagnosed with ADHD at the age of 19 years had the following diagnoses: adjustment disorder (34.5%), mood disorder (22.9%), conduct disorder or oppositional defiant disorder (22.5%), substancerelated disorders (21.2%), anxiety disorders (9.6%), tic disorders (1.8%), personality disorder (1,5%) and globally, detected the presence of any psychiatric disorder in 63.9% of ADHD patients [16]. The psychiatric comorbidities in patients with ADHD grow throughout life, serve as an example anxiety, presumably passes comorbidity in 4.5% of adolescents aged 12 to 17 years to be 13.7% of adults aged 22 or older [12]. In the same study, 43,183 ADHD adults ages 18 or older had substance abuse (15.1%), the aforementioned anxiety (12.1%), personality disorder (8.7%) and depression (7.8%) as the most prevalent psychiatric comorbidities. Classically, antisocial personality disorder, criminality and substance abuse are externalizing outcomes that are more frequent among people with ADHD compared to those without psychopatology in childhood [17-18]. Although there is a risk of generating a causal relationship between ADHD and externalizing problems, the truth is that it is a codevelopment relationship where exist a mutual interaction between both of them and timevarying etiologic factors need to be consider [19]. World Health Organization developed a study about the prevalence and effects of ADHD on workers [20]. 7,057 workers in 10 countries completed a survey with a screening questionnaire of ADHD. The mean prevalence estimated was of 3.5%. Adult with ADHD were associated with significant decrements in role performances and with an increase of sickness absence days. For a long time it was considered that ADHD was limited to child and adolescent age. Today we know that there are adults with the disorder but somehow it is considered that the clinical presentation does not vary with time, leaving aside the adaptive processes and coping strategies presented by patients with here constraints [21]. In recent years studies of prevalence of ADHD in adults have proliferated. One of the best studies to date of adult ADHD have been conducted in the United States, from a sample of 9,282 individuals the presence of ADHD criteria were evaluated in 3,199 subjects. These subjects were divided into

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four groups: those who had never had symptoms of ADHD, those who had symptoms during childhood but did not meet enough criteria to be diagnosed, those who had ADHD in children but not adults and those who had ADHD in childhood and had symptoms during adulthood. 154 people were evaluated by a personal interview and a prevalence of 4.4% in adults was determined with an age between 18 and 44 years. Adult ADHD was associated with unemployment and with being previously married [22]. In adults ADHD could remain underdiagnosed. The disorder has a major effect on patients‘ lifestyles, well-being and quality of life. Also has a negative impact on their social, work and family life. It is for this reason that more emphasis is being done today in this age. The new edition of the SM has adapted the criteria to better fit the need to diagnoses ADHD in adults [23]. An issue we would like to mention is the estimated heritability, both in adults and in children and adolescents. A large-scale genetic epidemiology study to report on the heritability of self-rated ADHD symptoms in adults were conducted in The Netherlands. They found a prevalence of adult ADHD of 6.8% in women and 7.4% in men. Heritability for attention problems in children aged 3-12 year were estimated at 75% and heritability of the ADHD index in adults at 30%. Heritability of ADHD features in adults is substantially lower than in children despite the limitations of the study, which did not justify such a difference [24]. Finally an important matter is the subthreshold symptoms. Having inattentive symptoms and hyperactive-impulsive symptoms but not met ADHD criteria can predict school difficulties and functioning academically below grade level [11]. The difficulties to assess the prevalence of subthreshold ADHD are the disparity of criteria used to define them and how to get the information. In a systematic review conducted by Balázs and Keresztény, subthreshold ADHD prevalence ranged from 0.8% to 23.1% [25]. This topic brings us to one of the conflicts around the ADHD. Given the increasing prevalence studies we may think that it is over-diagnosing ADHD. Considering the differences expose along the chapter between prevalence and prevalence of risk and if we think about the existence of subthreshold symptomatology, there is insufficient evidence for the overdiagnosis of ADHD. In any case, the existence of a single information source, the only use of screening questionnaires and the use of nonrandom samples, may increase the prevalence. However, the perception that ADHD is systematically overdiagnosed is not justified but has to be considered [26]. Another important factor that can alter the studies is the existence of diagnostic criteria that have been modified in various DSM, such as age at onset [27]. Changing this criterion in the DSM-5 has generated an increase in all subtypes of ADHD, but the greatest increase occurred in the inattentive subtype. As a result of delaying the age of onset of symptoms of 7 to 12 years, Vande Voort et al. found that the 12-month prevalence rate increased from 7.38% to 10.84% [28]. In other study, older age at onset of symptoms represented an increase of prevalence of 18% and the reduction in symptom count from 6 to 5 increased of inattentive subtype in adolescents and adults but the increase was much smaller. Changes in diagnostic criteria introduced by the DSM-5 could result in changes in the trend of prevalence already documented [29].

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Conclusion The worldwide prevalence of ADHD is around 5% and this prevalence is approximate. Cultural and gender factors have determined variations in the prevalence determinations. However, it has been the methodological differences that may have caused more confusion. Taking into account the difference between prevalence and prevalence of risk, we can understand the variability of the numbers. The acceptance that ADHD persists throughout adulthood has medical implications for the treatment. With this, one begins to consider that ADHD patients have difficulties for living a plentiful and healthy life because due to consequences of the disorder and the associated comorbidities. With this intention, diagnostic criteria have been changed in the recently published DSM-5. These changes are not without controversy, but involve the acceptance of the importance of ADHD and the consequences thereof.

References [1]

Ramos-Quiroga JA, Bosch R, Nogueira M, Castells X, Escuder G, Casas M. Trastorno por déficit de atención con hiperactividad en adultos. Curr Psychiatry Rep Spanish Ed 2005; 2: 27-33. [2] American Psychiatric Association, Force DSMT. Diagnostic and statistical manual of mental disorders, DSM-5. Washington, DC: APA, 2013. [3] Polanczyk G, de Lima M, Horta B, Biederman J, Rohde L. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007; 164: 942-948. [4] Timimi S, Taylor E. ADHD is best understood as a cultural construct. Br J Psychiatry 2004; 184: 8-9. [5] Wolraich ML, McKeown RE, Visser SN, Bard D, Cuffe S, Neas B, Danielson M. The prevalence of ADHD: its diagnosis and treatment in four school districts across two states. J Attent Disord 2014; 18: 563-575. [6] Cardo E, Servera M, Llobera J. Estimation of the prevalence of attention deficit hyperactivity disorder among the standard population on the island of Majorca. Rev Neurol 2007; 44: 10-14. [7] Andrés M, Catala M, Gómez-Beneyto M. Prevalence, comorbidity, risk factors and service utilisation of disruptive behaviour disorders in a community sample of children in Valencia (Spain). Soc Psychiatry Psychiatr Epidemiol 1999; 34: 175-179. [8] Sánchez CR, Ramos C, Díaz F, López D. Attention-deficit/hyperactivity disorder: prevalence of risk in the scholastic scope of the Canary Islands. Actas Esp Psiquiatr 2014; 42: 169-175. [9] Farré A, Narbona J. EDAH. Escalas para la evaluación del trastorno por déficit de atención con hiperactividad. Madrid: TEA Ediciones, 2001. [10] Blázquez Almería G, Joseph Munné D, Burón Masó E, Carrillo González C, Joseph Munné M, Cuyás Reguera M, Freile Sánchez R. Resultados del cribado de la sintomatología del trastorno por déficit de atención con o sin hiperactividad en el ámbito escolar mediante la escala EDAH. Rev Neurol 2005; 41: 586-590.

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[11] Lecendreux M, Konofal E, Faraone SV. Prevalence of attention deficit hyperactivity disorder and associated features among children in France. J Attent Disord 2011; 15: 516-524. [12] Giacobini M, Medin E, Ahnemark E, Russo LJ, Carlqvist P. Prevalence, Patient Characteristics, and Pharmacological Treatment of Children, Adolescents, and Adults Diagnosed With ADHD in Sweden. J Attent Disord 2014, doi: 10.1177/10870 54714554617 [13] Erol N, Simsek Z, Öner Ö, Munir K. Epidemiology of Attention Problems Among Turkish Children and Adolescents A National Study. J Attent Disord 2008; 11: 538545. [14] Polanczyk G, Rohde LA. Epidemiology of attention-deficit/hyperactivity disorder across the lifespan. Curr Opin Psychiatry 2007; 20: 386-392. [15] Pondé MP, Freire ACC. Prevalence of attention deficit hyperactivity disorder in schoolchildren in the city of Salvador, Bahia, Brazil. Arq Neuro-Psiquiatr 2007; 65: 240-244. [16] Yoshimasu K, Barbaresi WJ, Colligan RC, Voigt RG, Killian JM, Weaver AL, Katusic SK. Childhood ADHD is strongly associated with a broad range of psychiatric disorders during adolescence: a population-based birth cohort study. J Child Psychol Psychiatry 2012; 53: 1036-1043. [17] Barkley RA, Fischer M, Smallish L, Fletcher K. Young adult follow‐up of hyperactive children: antisocial activities and drug use. J Child Psychol Psychiatry 2004, 45: 195211. [18] Klein RG, Mannuzza S, Olazagasti MAR, Roizen E, Hutchison JA, Lashua EC, Castellanos FX. Clinical and functional outcome of childhood attentiondeficit/hyperactivity disorder 33 years later. Arch Gen Psychiatry 2012; 69: 1295-1303. [19] Kuja‐Halkola R, Lichtenstein P, D'Onofrio BM, Larsson H. Codevelopment of ADHD and externalizing behavior from childhood to adulthood. J Child Psychol Psychiatry 2014, doi: 10.1111/jcpp.12340. [20] de Graaf R, Kessler RC, Fayyad J, ten Have M, Alonso J, Angermeyer M, Posada-Villa J. The prevalence and effects of adult attention-deficit/hyperactivity disorder (ADHD) on the performance of workers: results from the WHO World Mental Health Survey Initiative. Occup Environ Med 2008; 65: 835-842. [21] Willoughby MT. Developmental course of ADHD symptomatology during the transition from childhood to adolescence: a review with recommendations. J Child Psychol Psychiatry 2003; 44: 88-106. [22] Kessler R, Adler L, Barkley R, Biederman J, Conners C, Demler O, Secnik K. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006; 163: 716-723. [23] Ginsberg Y, Quintero J, Anand E, Casillas M, Upadhyaya HP. Underdiagnosis of Attention-Deficit/Hyperactivity Disorder in Adult Patients: A Review of the Literature. Prim Care Comp CNS Disord 2014; 16 (3). Epub 2014 Jun 12. [24] Boomsma DI, Saviouk V, Hottenga JJ, Distel MA, De Moor MH, Vink JM, de Geus EJ. Genetic epidemiology of attention deficit hyperactivity disorder (ADHD index) in adults. PloS One 2010; 5: e10621. [25] Balázs J, Keresztény Á. Subthreshold attention deficit hyperactivity in children and adolescents: a systematic review. Eur Child Adolesc Pychiatry 2014; 23: 393-408.

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[26] Sciutto MJ, Eisenberg M. Evaluating the evidence for and against the overdiagnosis of ADHD. J Attent Disord 2007; 11: 106-113. [27] Polanczyk GV, Moffitt TE. How Evidence on the Developmental Nature of AttentionDeficit/Hyperactivity Disorder Can Increase the Validity and Utility of Diagnostic Criteria. J Am Acad Child Adolesc Psychiatry 2014; 53: 723-725. [28] Vande Voort JL, He JP, Jameson ND, Merikangas KR. Impact of the DSM-5 attentiondeficit/hyperactivity disorder age-of-onset criterion in the US adolescent population. J Am Acad Child Adolesc Psychiatry 2014; 53: 736-744. [29] McKeown RE, Holbrook JR, Danielson ML, Cuffe SP, Wolraich ML, Visser SN. The impact of case definition on attention-deficit/hyperactivity disorder prevalence estimates in community-based samples of school-aged children. J Am Acad Child Adolesc Psychiatry 2015; 54: 53-61.

In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 3

Limitations to a Diagnosis of ADHD Klaus Martin Beckmann School of Medicine, Griffith University, Queensland, Australia

Abstract Attention-deficit hyperactivity disorder (ADHD) presents with over-activity, impulsivity and distractibility. However, there are numerous other conditions that can give rise to such symptoms. These conditions may be co-morbid or occur exclusively. This chapter gives an overview on these disorders and comments on diagnostic clarification and management.

Keywords: ADHD, diagnosis

Introduction Attention-deficit hyperactivity disorder (ADHD) is a relatively common disorder starting in infancy and affecting individuals throughout their lifespan. It is a developmental disorder [1] with a reported prevalence in children and adolescents between less than 1% to over 18% and a pooled prevalence of 5.29% [2], depending on the source and criteria used. Whilst the diagnosis rests on 3 main axes (attention, activity levels and impulsivity) [3-4], these criteria are not unambiguous [5] and controversies about the validity of diagnosis continue [6-7]. Particularly controversial is the debate on adult ADHD [8]. A contributing factor is the doubtful role of medication for some clients [9], although medications clearly help some individuals. Adverse pharmacological effects vanish when patients grow out of ADHD and no longer require medication. ADHD persists into adulthood, albeit in a modified form, in 

Correspondence to: Dr. Klaus Martin Beckmann, Assoc. Professor, School of Medicine, Griffith University, Logan Campus, Queensland, QLD 4133, Australia

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around two thirds of patients. The commonly used diagnostic criteria on ADHD in ICD 10 [4] and DSM 5 [3] do not differentiate whether or not there is a response to medication nor whether there is a life trajectory of symptoms. It is therefore difficult to agree that ADHD diagnosis as it stands is a useful concept if looking at validity and reliability. This chapter looks at not only the neuropsychiatric disorder ADHD [10], but also the wider ADHD syndrome [11]. Within the differential diagnosis of clinical ADHD syndrome, which embraces the neuropsychiatric disorder commonly diagnosed as ADHD, hard evidence for a neuropsychiatric disorder can be found. However there are several other causes for clinical ADHD syndrome, many of which cannot be substantiated with diagnostic tests. The gold standard remains clinical diagnosis, which is discussed further below. This chapter acknowledges the broader clinical ADHD syndrome and the application of descriptive means to attempt to diagnose neuropsychiatric ADHD. Hard evidence tests are mentioned but not expanded upon; these lack specificity and sensitivity and information pertaining these may be found elsewhere. Response to medication as a diagnostic criterion is typically not the subject of research papers, yet the differentiation of why some patients respond.to medication and others not is likely to have an important role in ascertaining a specific clinical diagnosis. For diagnostic criteria reference is made to ICD 10 only, which is used worldwide. DSM is mandatory in the realm of the American Psychiatry Association only [12]) and DSM 5 is regarded by many as unsatisfactory [13]. This chapter does not comment on ADD.

ADHD Syndrome – The Neuropsychiatric ADHD According to Typically Used Diagnostic Criteria There is no doubt that the neuropsychiatric disorder ADHD exists [14] which is responsive to medication [15]. Functioning and academic progress is greatly enhanced with the use of ADHD medication, which may be both stimulant and non-stimulant [17]. Some research suggests that benefits are certainly maintained for the first 2 years [16] and that the prognosis can be good. Psychosocial treatments of diverse modalities have an important role [18].

ADHD Syndromes – Hard Tests to Substantiate Disorder Hyperthyroidism An overactive thyroid gland produces excess thyroid hormones which have a stimulating effect. Patients present with mood disturbance, psychomotor activation, tachycardia, diarrhea and weight loss. The diagnostic test is to check the thyroid function with a blood sample [19].

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Phaeochromocytoma This disorder has as its cause an intermittent significant extra release of adrenaline, with concomitant intermittent clinical symptoms masquerading as an ADHD. Diagnosis is through urine collection and testing for the metabolites of adrenaline that are excreted through the kidneys [20].

Cushing’s Syndrome Overproduction of cortisol and other steroids can present as an ADHD. Longer exposure to cortisol can lead to changes in bodily appearance with stigmata such as ―buffalo hump‖ and the typical adipose tissue distribution. A diagnostic test is available to check for raised cortisol levels in blood or urine [21].

Cerebral Frontal Lobe Lesions The different parts of the anterior part of the brain are increasingly defined. Depending where the lesion occurs this may also present with ADHD syndrome. The diagnostic test is a brain scan, such as CT or MRI [22].

Infectious Diseases Affecting the Brain Lesions in the frontal lobe can occur by means of an infectious disease process and present as ADHD. A historically well-known disorder is syphilis [23], with frontal lobe sequelea that may mimic ADHD. Tuberculosis may also involve front lobe impairment. Viral infections such as CMV [25] or herpes [26] in predisposed individuals can lead to encephalitis, however rarely may affect the frontal lobe and present with ADHD-type symptoms at least in the short term. Cystercercosis is another rare cause of frontal lobe impairment [27]

Other Disorders that May Theoretically Present with ADHD Syndrome Excess growth hormone [29], excess of testosterone [30], paraneoplastic syndrome [31] and autoimmune disorders such as SLE [28] may also lead to symptoms suggestive of ADHD. Diagnostic tests include growth hormone, testosterone levels and physical examination for any cancers to exclude para-neoplastic syndrome. Substances, Legal and Illegal 1) Numerous prescribed medications can have a stimulating effect [32]. In some individuals drugs may have paradoxical effects [33], while others experience placebo

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2)

3)

4) 5) 6)

effects [34]. Some prescription substances can be tested for but generally the clinical history or information from a pharmacist, or drug information database can assist. Herbal and complementary over-the-counter medications can have effects that can ameliorate ADHD [35] but also present as ADHD [36]. These effects are likely short-lasting and are related in time to the drug‘s administration and elimination. Numerous activating substances are available on the illicit drugs market, both prescribed [37] and illicit [38]. As above these effects are likely short-lasting. In some cases urinary drug screens can yield results in terms of substance detection. Legal substances (eg.caffeine) can have a stimulating effect [39]. All medications whether legal or illegal have placebo effects [33]. The placebo effect is likely to depend on client expectations and body–mind interactions. In drug dependence or harmful use ADHD symptoms can occur during drug intoxication or withdrawal [4]. In neuropsychiatric ADHD use of non-prescribed drugs may alleviate symptoms subjectively in the short term, however it is clear that sequelae of drugs dependence are likely to leave an individual more impaired than if the individual suffered from ADHD alone [40]. Research shows that individuals with ADHD are less likely to follow on an ADHD illicit drugs forensic outcome trajectory if medicated with stimulant or non-stimulant medication [41].

ADHD Syndromes Not due to Physical Ill Health and Not due to Neuropsychiatric ADHD A substantial number of individuals diagnosed with ADHD do not respond to ADHD medication [42] These individuals are unlikely to have neuropsychiatric ADHD. Several disorders can have sequelae of ADHD symptoms and need to be differentiated from neuropsychiatric ADHD [43] 1) Anxiety disorder in the wider sense may present as ADHD. A common underlying physiology to anxiety is excess of the adrenaline system with psychological and physiological effects [44]. 1.1. Generalized Anxiety Disorder [4] may present as agitation, poor concentration and distractibility. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 1.2. Panic Disorder may present with agoraphobia or without. Symptoms may include agitation, poor concentration and distractibility. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available 1.3. Post Traumatic Stress Disorder [4] in addition to the core symptoms may present with agitation, poor concentration and distractibility [45]. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 2) Personality traits [46] of a particular combination such as extrovert and neuroticism can also present with ADHD symptoms. The diagnosis is made clinically. Psychology tests but no but no diagnostic blood or radiological test is available.

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3) All individuals have their own defenses, be they helpful or otherwise, in the face of stressors or when an exit for psychological conflict is needed. One of the helpful defenses can be the manic defense [47] which can present as ADHD. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 4) A hypomanic episode [4] can present as ADHD, albeit it is time limited. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 5) A manic [4] episode can present as ADHD but psychotic symptoms are hallmark features and the time limited nature of such an episode assists with excluding a diagnosis of ADHD. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 6) Learned behaviors [45] can present as ADHD. The flight response stemming from the fight-flight-freeze response is such a learned behavior. This is not associated with ADHD but is a mammalian response that goes back to the phylogenetic history of humankind. 7) Chronic flight response [48] especially can present with ADHD symptoms as can be seen in individuals who have been exposed to chronic trauma.. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available 8) Speech and language difficulties [49] may leave the individual impaired and revert to alarming behaviors including impulsivity, overactivity and inattention to communication. This can present as ADHD until the issue that needs communicated and associated emotions have abated. Speech and language assessment can confirm a diagnosis, however it may be that the clinical interview clarifies that ADHD is not present. Speech and language tests but but no diagnostic blood or radiological test is available. 9) Impaired intelligence (II) is associated with reduced coping skills and conflict resolution as well as reduction of many other skills [50]. Children with global learning difficulties can present with overactivity, impulsivity and distractibility. Children with II may respond to the antecedent, behavior and consequences (ABC) model, which once applied may refute a diagnosis of ADHD.. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 10) If one of the identities of a dissociative identity disorder is an identity with ADHD then this will be a clinically intermittent presentation [51]. Clinical diagnosis is dependent on which part of the dissociated individual presents during the interview; collateral information is likely to provide the information required for diagnosis. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 11) Acute Stress Disorder [4] may present as ADHD syndrome but a formal diagnosis can be excluded in light of the history of clearly identifiable stressor and that no ADHD symptoms were present prior to the stressful life event. The diagnosis is made clinically. Psychology tests but no diagnostic blood or radiological test is available. 12) There are also other diagnoses which may present with ADHD symptoms such as agitated depression or agitation associated with the delusional or hallucinatory system (eg. schizophrenia) [4], however good clinical assessment can usually clarify

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Klaus Martin Beckmann the conundrum. The diagnosis is made clinically. Psychology and psychiatry tests, but no diagnostic blood or radiological test is available.

Note that the above list, while attempting to cover most of the causes of ADHD syndromes, is not exhaustive.

Conclusion Similar to the diagnosis of ―fever― in historic models of thinking about medicine [52] ADHD, as per the commonly used diagnostic guidelines [3-4], is an ill-defined, non-specific diagnosis. However, there clearly exists a neuropsychiatric ADHD that responds to medication. No better alternatives to the existing guidelines exist so far. ICD 10 [4] and DSM 5 [3] and good clinical assessment, psychological tests, experience and judgment can help with diagnostic clarification of neuropsychiatric ADHD. In some cases where physical presentation suggests underlying physical illness diagnostic medical tests can guide diagnostic work up. In case of psychological sequelae and psychiatric disorders the gold standard remains the clinical interview, psychological tests and psychiatric standardized assessments that lead to diagnostic formulation. In contemporary medicine diagnosis of ADHD can be endorsed with a psychological test–battery such as Robert N Goodman‘s Strengths and Difficulties Questionnaire and Keith Connor‘s questionnaire providing greater evidence towards the syndrome. It is unlikely in clinical practice that a single diagnosis appears in isolation. On the contrary, it is more likely that the ADHD syndrome appears in combination with other diagnoses in addition to neuropsychiatric ADHD. However, if the diagnosis includes neuropsychiatric ADHD, then ADHD medication is likely assist in alleviating ADHD symptoms. ADHD medication helps where it has the greatest clinical efficacy: to enhance concentration, enhance ability to sit still and reduce distractibility. In this context effective medication reduces impairment and enhances productivity, alleviating costs to individual and society and improving quality of life for the individual and family and friends. A focus for future research could be diagnostic tests utilizing biomarkers or genetic multi-arrays with high sensitivity and specificity for neuropsychiatric ADHD. Once reliable indicators for ADHD have been found, a simple diagnostic test, involving mouth swab or peripheral blood sample, for neuropsychiatric ADHD will be very desirable. So far, there are no commercially applicable radiological examinations that can identify gross and/or subtle brain changes that are specific to neuropsychiatric ADHD. The future may well yield an inexpensive high sensitivity and specificity test to identify those individuals with neuropsychiatric ADHD Until such time clinical diagnosis remains at the forefront and alternative conditions to neuropsychiatric ADHD, such as those listed in the differential diagnosis, must be considered in patients presenting with ADHD symptoms.

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[3] [4]

[5]

[6]

[7] [8] [9]

[10]

[11] [12] [13]

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[15]

Rubia K. ADHD under the ―micro-scope‖ of the rat model. Behav. Brain Sci. 2005; 28: 439-440. Polanczyk G, Silva de Lima M, Lessa Horta B, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am. J. Psychiatry 2007; 164: 942-948. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Diseases (DSM-IV), 4th ed. Washington, DC: American Psychiatric Publishing, 1994. World Health Organization. The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization, 1993. Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJ, Jensen PS, Cantwell DP. Review Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 1998; 351(9100): 429-433. Partridge B, Lucke J, Hall W. Over-diagnosed and over-treated: a survey of Australian public attitudes towards the acceptability of drug treatment for depression and ADHD. BMC Psychiatry 2014; 14: 74, doi:10.1186/1471-244X-14-74. Smith M. Hyperactive: The Controversial History of ADHD. London: Reaktion Books, 2012. Barkley RA, Murphy KR, Fischer M. ADHD in Adults: What the Science Says. New York: Guilford Press, 2010. Sunohara GA, Voros JG, Malone MA, Taylor MJ. Effects of methylphenidate in children with attention deficit hyperactivity disorder: a comparison of event-related potentials between medication responders and non-responders. Int. J. Psychophysiol 1997; 27: 9-14. Zuddas A, Ancilletta B, Muglia P, Cianchetti C. Attention-deficit/hyperactivity disorder: a neuropsychiatric disorder with childhood onset. Eur. J. Paediatr. Neurol. 2000; 4: 53-62. Kadesjö B, Gillberg C. The Comorbidity of ADHD in the General Population of Swedish School-age Children. J. Child Psychol. Psychiatry 2001; 42: 487-492. American Psychiatry Association. Available at: http://www.psychiatry.org/. Lane C. The NIMH Withdraws Support for DSM-5 Psychology Today. The latest development is a humiliating blow to the APA. Psychology Today, 2013. Available at: https://www.psychologytoday.com/blog/side-effects/201305/the-nimh-withdrawssupport-dsm-5. Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS, Blumenthal JD, James RS, Ebens CL, Walter JM, Zijdenbos A, Evans AC, Giedd JN, Rapoport JL. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA 2002; 288: 1740-1748. Banaschewski T, Roessner V, Dittmann RW, Janardhanan Santos, P, Rothenberger A. Non–stimulant medications in the treatment of ADHD. Eur. Child. Adolesc. Psychiatry 2004; 13:i102-i116.

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[16] Swenson CC, Schaeffer CM, Henggeler SW, Faldowski R, Mayhew AM. Multisystemic therapy for child abuse and neglect: A randomized effectiveness trial. J. Fam. Psychol. 2010; 24: 497-507. [17] Bates G. Drug treatments for attention-deficit hyperactivity disorder in young people. Adv Psychiatr Treat 2009; 15: 162-171. [18] Daly BP, Creed T, Xanthopoulos M, Brown RT. Psychosocial treatments for children with attention deficit/hyperactivity disorder. Neuropsychol. Rev. 2007; 17: 73-89. [19] Wilens TE. Impact of ADHD and Its Treatment on Substance Abuse in Adults. J. Clin. Psychiatry 2004; 65 (suppl 3): 38-45. [20] Haws R, Mark J, Adelman R. Two cases of pheochromocytoma presenting with ADHD (attention deficit hyperactivity disorder)-like symptoms. Pediatr. Nephrol. 2008; 23: 473-475. [21] Reid TC, Davtian M, Lenartowicz A, Torrevillas RM, Fong TW. Perspectives on the assessment and treatment of adult ADHD in hypersexual men. Neuropsychiatry 2013; 3: 295-308. [22] Boucugnani LL. Behaviors analogous to frontal lobe dysfunction in children with attention deficit hyperactivity disorder. Arch. Clin. Neuropsychol. 1989; 4: 161–173. [23] Nogueira de Melo A, Niedermeyer E. The EEG in infantile brain damage, cerebral palsy and minor cerebral dysfunctions of childhood. In: Niedermeyer E, Lopes da Silva F, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields, 5 th edition. Philadelphia & London: Lippincott Williams & Wilkins, 2005, pp. 403-414. [24] Bishbug E, Sunderam G, Reichman LB, Kapila R. Central Nervous System Tuberculosis with the Acquired Immunodeficiency Syndrome and Its Related Complex. Ann. Intern. Med. 1986; 105: 210-213. [25] Price RW. Neurological complications of HIV infection. Lancet 1996; 348 (9025): 445–452. [26] Norris FH, Leonards R, Calanchini PR, Calder CD. Herpes-zoster meningoencephalitis. J. Infect. Dis. 1970; 122: 335-338. [27] García HH, Evans CAW, Nash TE, Takayanagui OM, White AC, Botero D, Rajshekhar V, Tsang VCW, Schantz PM, Allan JC, Flisser A, Correa D, Sarti E, Friedland JS, Martínez SM, González AE, Gilman RH, Del Brutto OH. Current Consensus Guidelines for Treatment of Neurocysticercosis. Clin. Microbiol. Rev. 2002; 15: 747756. [28] McCune WJ, Macguire A, Aisen A. Identification of brain lesions in neuropsychiatric systemic lupus erythematosus by magnetic resonance scanning. Arthr. Rheum. 1988; 31: 159–166. [29] Jadresic A, Banks LM, Child DF, Diamant L, Doyle FH, Fraser TR, Joplin GF. The Acromegaly Syndrome, relation between clinical features, growth hormone values and radiological characteristics of the pituitary tumours. QJM Int. J. Med. 1982; 51: 189204. [30] Scarpa A, Scerbo A, Kolko DJ. Salivary Testosterone and Cortisol in Disruptive Children: Relationship to Aggressive, Hyperactive, and Internalizing Behaviors. J. Am. Acad. Child. Adolesc. Psychiatry 1994; 33: 1174–1184. [31] Vedeler CA, Antoine JC, Giometto B, Graus F, Grisold W, Hart IK, Honnorat J, Sillevis PAE, Smitt JJ, Verschuuren GM, Voltz R. Management of paraneoplastic

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neurological syndromes: report of an EFNS Task Force., Paraneoplastic Neurological Syndrome Euronetwork. Eur. J. Neurol. 2006; 13: 682–690. Bond AJ. Drug- Induced Behavioural Disinhibition. CNS Drugs 1998; 9: 41-57. Müller Y. Drug therapies for neuropsychiatric and autonomic disturbances in patients with PD. Adv. Parkinson. Dis. Manag. 2012; 76-87. Richardson AJ, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog. Neuro-Psychopharmacol Biol. Psychiatry 2002; 26: 233–239. Sarris J, Kean J, Schweitzer I, Lake J. Complementary medicines (herbal and nutritional products) in the treatment of Attention Deficit Hyperactivity Disorder (ADHD): A systematic review of the evidence. Compl. Ther. Med. 2011; 19: 216–227. Sakurai M. Perspective: Herbal dangers. Nature 2011; 480: S97. Franke AG, Bonertz C, Christmann M, Engeser S, Lieb K. Attitudes Toward Cognitive Enhancement in Users and Nonusers of Stimulants for Cognitive Enhancement: A Pilot Study. AJOB Prim. Res. 2012; 3: 48-57. Coppola M, Mondola R. 3,4-Methylenedioxypyrovalerone (MDPV): Chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicol. Lett. 2012; 208: 12–15. Franke AG, Lieb K, Hildt E. What users think about the differences between caffeine and illicit/prescription stimulants for cognitive enhancement. PloS One 2012; 7(6): e40047. doi: 10.1371/journal.pone.0040047. Hawkins JD, Catalano RF, Miller JY. Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: Implications for substance abuse prevention. Psychol. Bull 1992; 112: 64-105. Disney ER, Elkins IJ, McGue M, Iacono WG. Effects of ADHD, Conduct Disorder, and Gender on Substance Use and Abuse in Adolescence. Am. J. Psychiatry 1999; 156: 1515-1521. William G. Kronenberger, Ann L. Giauque, Deborah E. Lafata, Bradley N. Bohnstedt, Laura E. Maxey, and David W. Dunn. Journal of Child and Adolescent Psychopharmacology. June 2007, 17(3): 334-347. doi:10.1089/cap.2006.0012. Beckmann, Klaus Martin. "Neuropsychiatric Attention Deficit and Hyperactivity Disorder that Responds to ADHD Medication (NADHDM) in the International Classification of Diseases ICD-11: An Opportunity to Increase Sensitivity and Specificity of Diagnosis." International Journal of Humanities Social Sciences and Education (IJHSSE) Volume 1, Issue 6, June 2014, PP 16-28. Mintzer JE. Agitation as a possible expression of generalized anxiety disorder in demented elderly patients: toward a treatment approach. J Clin Psychiatry 1996; 57 (Suppl 7): 55-63. Perry BD, Murburg MM (Eds). Neurobiological sequelae of childhood trauma: PTSD in children. Catecholamine function in posttraumatic stress disorder: Emerging concepts. Prog. Psychiatry 1994; 42: 233-255. Cloninger CR. Temperament and personality. Curr. Opin. Neurobiol. 1994; 4: 266– 273. Baruch G. The manic defence in analysis: the creation of a false narrative. Int. J. Psycho-analysis, 1997; 78: 549-559.

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[48] Van der Kolk BA. Developmental trauma disorder. Psychiatric Annals, 2005: 35: 401408. [49] Mares S, Newman L, Warren B. Emotional and behavioural problems in toddlers. In: Mares S, Newman LK, Warren B, eds. Clinical Skills in Infant Mental Health: The First Three Years, 2nd ed. Camberwell: ACER Press, 2011, pp. 161-181. [50] Bowers TG, Risser MG, Suchanec JF, Tinker DE, Ramer JC, Domoto M. A Developmental Index Using the Wechsler Intelligence Scale for Children Implications for the Diagnosis and Nature of ADHD. J. Learn Disabil. 1992; 25: 179-185. [51] Haugaard JJ. Recognizing and Treating Uncommon Behavioral and Emotional Disorders in Children and Adolescents Who Have Been Severely Maltreated: Dissociative Disorders. Child Maltreat. 2004; 9: 146-153. [52] Medieval Medicine: The Art of Healing, from Head to Toe By Luke DeMaitre.

In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 4

Psychological Assessment in ADHD Children M. Poveda Fernández-Martín, Miguel Ángel Pérez-Nieto and M. José De Dios-Pérez Department of Psychology, Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain

Abstract Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common complaints among children. According to the APA (2000), it appears at a rate of between 3% and 10%. Subsequent updates report a prevalence of around 6% [1-2]. There seems to be some consensus across the various studies when considering ADHD to be a developmental disorder whose symptoms of inattention, hyperactivity and impulsivity last throughout a person‘s entire life. Children, adolescents and adults with ADHD constitute a heterogeneous group. They differ in terms of symptomology and the type of environment that triggers the disorder. In addition, they present comorbidity with other behavioural, learning or personality disorders [1-3]. This chapter will provide a review of the diagnostic criteria applied to ADHD, covering the pertinent requirements needed for an assessment, and describing the psychological tests most widely used in research and diagnosis involving children and adolescents.

Keywords: ADHD, assessment, attention, impulsivity, hyperactivity, executive functions



Correspondence to: Dra. Mª Poveda Fernández-Martín, Department of Psychology, Faculty of Health Sciences, Camilo José Cela University, C/ Castillo de Alarcón, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain. E-mail: [email protected]

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Introduction One of the first known definitions of ADHD was provided by Hoffman in around 1844, when he described one of his patients as a restless child who constantly fidgeted and could not sit still. He identified the symptomology of hyperactivity but not that of inattention, although he did note a performance deficit, possibly due to a lack of attention and an inability to control impulses [4-5]. Nevertheless, it was Still (1902) who first described impulsive and aggressive behaviours. However, this latter aspect, as described by DSM IV-TR [6] or DSM V [7], is not necessarily a discriminative feature of ADHD. Furthermore, he defined lack of attention and behavioural issues, which at the time he referred to as ―a defect of moral consciousness.‖ In due course, during the 1920s and 1930s Professors Hohman and Cohen reported that brain damage was followed by the same symptoms that Still had described, referring to that symptomology as human brain damage syndrome. The discovery was subsequently made in the 1960s that hyperkinetic symptomology was not only caused by brain damage, so it became known as minimal brain damage or minimal brain dysfunction. This occurred in the early 1960s by the hand of Clements and Peters. They described the following symptoms: motor behaviour disorder, hyperactivity, impaired coordination, attention disorders, sensory perception disorders, learning difficulties, lack of impulse control, altered interpersonal relations, affective disorders and emotional lability [5]. It appears for the first time in DSM II [8], being referred to ―Hyperkinetic Reaction of Childhood.‖ Until its inclusion in DSM III, in the 1970s Douglas argued that the basic deficiency in hyperkinetic children was not simply their hyperactivity, but instead their inability to pay attention and their impulsivity (deficit in behaviour self-regulation processes). These modifications were included in DSM III [9] where it became referred to as ―Attention Deficit with Hyperactivity Disorder,‖ shortened to ADHD. When the latter was reviewed [10], it was placed on the same level as attention defect. DSM-IV [11] introduced the three subtypes we know, and which are upheld in both DMS-IV-TR [6] and DSM-V [7]. DSM-IV [11] describes ADHD as a developmental disorder that involves two dimensions of symptoms: attention deficit and hyperactive-impulsive behaviour. A diagnosis of the disorder therefore requires six symptoms from any of the lists of nine symptoms, with their classification into three types: combined, attention deficit or hyperactivity-impulsivity. This means these dimensions are independent of one another, whereby a critical threshold of symptoms in any dimension suffices for a diagnosis at all ages, with account being taken of eighteen symptoms in order to accurately detect the disorder, and these dimensions may be used to form significant subtypes (clinically and scientifically useful) of the disorder, and these are the best symptoms for accurately diagnosing the disorder at each major stage of development (childhood, adolescence and adulthood). Research is currently being conducted that questions these assumptions and suggests that not all eighteen symptoms are required for a diagnosis, and these symptoms change depending on the stage of the individual‘s development [5, 12]. The latest classification proposed by the APA appeared in DSM V in 2013. It classifies childhood hyperactivity disorders as attention deficit with hyperactivity consisting of three different subtypes (the third edition attributes the same importance to attention deficit and hyperactivity when defining the disorder), with the key symptoms being inattention, impulsivity and hyperactivity, besides other associated symptoms such as low self-esteem, emotional lability and low frustration tolerance. In the prior classification, it was

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located in disorders in infancy, childhood, and adolescence, while it is now located in neurodevelopmental disorders. These subtypes are as follows: 1. Combined type of Attention Deficit Hyperactivity Disorder. This will be used whenever symptoms of inattention, hyperactivity or impulsivity (six or more symptoms) have prevailed over a period of six months. 2. Inattentive type of Attention Deficit Hyperactivity Disorder. This will apply when there have been symptoms of inattention (six or more) for at least six months, but there have not been enough symptoms of hyperactivity–impulsivity (fewer than six). 3. Hyperactive–Impulsive type of Attention Deficit Hyperactivity Disorder. This diagnosis will be made when there have been symptoms of hyperactivity–impulsivity (six or more) for six months, with those of inattention not be so obvious (fewer than six). In the case of adolescents and adults, as of the age of 17, all that is required is the presence of five of the symptoms described in any one of the subtypes [7]. This disorder involves alterations, over a significant period of time (at least six months) and in different contexts, in any one of the following three areas (or in all three) (Tables 1-3): 





Inattention: not paying sufficient attention to details or making mistakes through carelessness; finding it difficult to pay attention even during leisure activities; not appearing to listen when spoken to directly; not following instructions and not completing tasks, when this is not due to oppositional behaviour or to an inability to understand instructions; having difficulties organising tasks or activities; avoiding, disliking or being reluctant to perform tasks that require a sustained mental effort; losing things; being easily distracted by extraneous stimuli; being careless in everyday activities. Hyperactivity: excessive fidgeting with hands and feet, or squirming in the seat or getting up in class or in other situations when expected to remain seated; running about or climbing excessively in situations where it is inappropriate to do so (in adolescents or adults it may be limited to subjective feelings of restlessness); finding it difficult to play or quietly go about leisure activities; appearing to be constantly ―on the go‖; talking too much. Impulsivity: blurting out answers before questions have been completed; difficulty waiting one‘s turn; interrupting or intruding on what other people are doing.

As regards the latest classification made by the World health organization (WHO) in 1992 corresponding to ICD–10 [13] it identifies child hyperactivity disorders within hyperkinetic disorders (hyperactivity, distractibility, impulsivity and excitability), being categorised as follows:    

Activity and attention disorder Dissocial hyperkinetic disorder Other hyperkinetic disorders Unspecified hyperkinetic disorders

Table 1. Signs and symptoms of inattention in the different versions of the DSM DSM III [9] 1. Often fails to finish things he or she starts 2. Often doesn't seem to listen 3. Easily distracted 4. Has difficulty concentrating on schoolwork or other tasks requiring sustained attention 5. Has difficulty sticking to a play activity

DSM-III-R [10] 1. Is easily distracted by extraneous stimuli 2. Has difficulty following through on instructions from others (not due to oppositional behaviour or failure of comprehension) 3. Has difficulty sustaining attention in tasks or play activities 4. Often does not seem to listen to what is being said to him or her 5. Often loses things necessary for tasks or activities at school or at home

DSM-IV [11], DSM-IV-TR [6] and DSM-V [7] 1. Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities 2. Often has difficulty sustaining attention in tasks or play activities 3. Often does not seem to listen when spoken to directly 4. Often does not follow through on instructions and fails to finish school·work, chores, or duties in the workplace (not due to oppositional behaviour or failure to understand instructions) 5. Often has difficulty organizing tasks and activities 6. Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort 7. Often loses things necessary for tasks or activities 8. Is often easily distracted by extraneous stimuli 9. is often forgetful in daily activities

Table 2. Signs and symptoms of hyperactivity in the different versions of the DSM DSM III [9] 1. Runs about or climbs on things excessively 2. Has difficulty sitting still or fidgets excessively 3. Has difficulty staying seated 4. Moves about excessively during sleep 5. Is always "on the go" or acts as if "driven by a motor"

DSM-III-R [10] 1. Often fidgets with hands or feet or squirms in seat 2. Has difficulty remaining seated when required to do so 3. Has difficulty playing quietly 4. Often talks excessively 5. Often interrupts or intrudes on others, e.g., butts into other children's games

DSM-IV [11], DSM-IV-TR [6] and DSM-V [7] 1. Often fidgets with hands or feet or squirms in seat 2. Often leaves seat in classroom or in other situations in which remaining seated is expected 3. Often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) 4. Often has difficulty playing or engaging in leisure activities quietly 5. Is often "on the go‖ or often acts as if ―driven by a motor" 6. Often talks excessively

Table 3. Signs and symptoms of impulsivity in the different versions of the DSM DSM III [9] 1. Often acts before thinking 2. Shifts excessively from one activity to another 3. Has difficulty organizing work (this not being due to cognitive impairment) 4. Needs a lot of supervision 5. Frequently calls out in class 6. Has difficulty awaiting turn in games or group situations

DSM-III-R [10] 1. Has difficulty awaiting turn in games or group situations 2. Often blurts out answers to questions before they have been completed 3. Often shifts from one uncompleted activity to another

DSM-IV [11], DSM-IV-TR [6] and DSM-V [7] 1. Often blurts out answers before questions have been completed 2. Often has difficulty awaiting turn 3. Often interrupts or intrudes on others

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The ICD-10 [13] criteria for attention deficit are as follows: often fails to give close attention to details, or makes careless errors in school work, or in other activities; often fails to sustain attention in tasks or play activities; often appears not to listen to what is being said to him or her; persistent impossibility to follow through on school work assigned or other missions; reduction in capacity to organise tasks and activities; often avoids or strongly dislikes tasks, such as homework, that require sustained mental effort; often loses things necessary for tasks and activities; is often easily distracted by external stimuli, and is often forgetful in the course of daily activities. With regard to hyperactivity, the criteria are as follows: often fidgets with hands or feet or squirms in seat; leaves seat in classroom or in other situations in which remaining seated is expected; often runs about or climbs excessively in situations in which it is inappropriate; is often unduly noisy in playing or has difficulty in engaging quietly in leisure activities, and exhibits a persistent pattern of excessive motor activity that is not substantially modified by social context or demands. Finally, the ICD-10[13] criteria for Impulsivity are as follows: often blurts out answers before questions have been completed; often fails to wait in lines or await turns in games or group situations; often interrupts or butts into others‘ matters, and often talks excessively without appropriate response to social constraints. The age of onset is probably around 3-4, although it does not raise concern until the age of 7, when the child has to interact with a larger amount of information, or the age of 12, according to DSM V [7]. Depending on the study, its rate of diagnosis ranges between 3% and 10% [6] although subsequent reviews have placed its prevalence at around 6% [14]. Its main features are a lack of persistence in activities that require the involvement of cognitive processes, and a tendency to change from one activity to another without finishing any one of them, together with behaviour that is disorganised, poorly regulated and excessive. This disorder entails serious difficulties both within an academic context [15-16] and within a family environment [17-18]. It therefore seems expedient to have a series of tools that permit the most accurate assessment possible of this complaint. The following chapter will describe some of the assessment instruments that are most commonly used in the diagnosis of ADHD, as designed for children, parents and educators alike. It is important to have an explanatory model that will enable us as specialists to detect or rule out this problem, with the aim being to design effective care strategies.

Diagnosis and Assessment The purpose of the psychological assessment of children and adolescents is to understand the problems and factors that hinder the development process at this important time in life. Accordingly, such an assessment needs to gather data on the children‘s background environments, their family and school, as well as on the individuals themselves, considering their age and level of development, as well their different functional areas [19-20]. Experts report that although the average age for the onset of ADHD is four-five years, most children are not diagnosed until problems arise with their academic and social performance during primary education, when their environment begins to make demands of them [5, 21]. ADHD creates problems in many areas of a child‘s life, with difficulties in behaviour, adapting to

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home and family, and social and school relationships, where its impact often becomes problematic as it involves executive functions. The nature of ADHD highlights the importance of adopting a multidisciplinary approach to the assessment. It is important for specialists to consider different sources of information and the contexts within which the child or adolescent interacts. [22] reports at least four categories in assessment methods: control lists, structured interviews, IQ tests on cognitive function, and instruments that measure the specific correlates of ADHD, with inclusion also of neuroimaging tests (which are described in a later chapter in this handbook). The following steps will need to be considered in this process [21] (Figure 1). This section on the diagnosis of ADHD has been structured as follows:    

Clinical interviews with parents and teachers Scales and questionnaires on the child administered to parents and teachers Impulsivity scales Tasks that assess the executive functions that may be involved or be affected in ADHD: attention, memory, cognitive flexibility and planning.

Figure 1. Chart for diagnosing ADHD.

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A) Clinical Interviews with Parents and Teachers Different methods and instruments are available for the proper assessment of ADHD. A clinical interview is the initial procedure most commonly used with parents and teachers. As with all clinical interviews, they are used to gather information, in this case on the child, on any difficulties they may have and on how these may affect their everyday lives [23]. An array of both structured and semi-structured psychological interviews has been developed in recent years that allow identifying behavioural disorders and determining both the frequency and the intensity of the subject‘s conduct. The questions we encounter in these interviews usually apply DSM diagnostic criteria, and more specifically, at least to date, those of DSM-IV-TR [6] (it should be noted that the criteria for diagnosing ADHD remain unchanged in DSM-V [7]). These clinical interviews include the following: 1. Clinical Interview form for Child and Adolescent ADHD Patients [24] This is a semi-structured interview designed for the parents of children with ADHD. It consists of five blocks of information that cover the following aspects:  Background to the child‘s development: mother‘s state of health during pregnancy, the child‘s state of health, milestone‘s in the child‘s development or their adaptation to the environment.  Medical record: any illnesses, surgery or hospital stays involving the child, history of prior medical or psychological treatments  School report: assessment of academic performance, level of curricular competence, whether there have been or are any specific curricular adjustments or measures in response to diversity, adaptation to the school context, motivation, learning style, relationships with peers and figures of authority, etc.  Family background: parents educational background, presence of behaviour issues, as well as their frequency and duration.  Child‘s social background: presence of behaviour issues, as well as their frequency, intensity and persistence, social interaction with peers and adults, and the demands and expectations of different environments, and the child‘s adaptation to them. 2. Diagnostic Interview for Children and Adolescents DICA-P [25] This is one of the more widely known and used for assessment and diagnosis in childhood, with a version for children aged between 6 and 12, and another for adolescents between the ages of 13 and 17. It is a standard interview whose purpose is to gather detailed and reliable information on the child‘s behaviour. Specifically, it consists of 247 items that gather information according to the diagnostic criteria provided by DSM-IV [11], on the following: ADHD, oppositional defiant disorder, dyssocial personality disorder, separation anxiety disorder, bipolar disorders, phobias and enuresis and encopresis. They are all applied criterion A of DSM-IV and criterion B for specifying the clinically significant impairment of those problems in the child‘s social, academic or school life. When interviewing parents, the specialist should analyse the presence of other symptoms not directly linked to ADHD, but indicative of other typical disorders in childhood and adolescence. These disorders may appear alongside ADHD, or may lead to a differential

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diagnosis [6]. Table 4 lists the main symptoms that may lead to the differential diagnosis of ADHD with regard to other disorders with similar characteristics [5-6].

B) Scales and Questionnaires on the Child Administered to Parents and Teachers Besides the clinical interview, there are sundry scales and questionnaires for parents and teachers, which constitute an instrument that is very widely used. Its rapid application, low cost and ability provide information on behaviours that are difficult to observe. Furthermore, many of the scales and questionnaires used have been standardised, which means a child‘s direct scores can be easily compared with the reference group [26]. There follows a description of some of these scales and questionnaires: 1. Child Behavior Checklist/4-18: CBCL [27] and Teacher’s Report Form/518: TRF [28] These scales are widely used in the assessment of ADHD, as they allow differentiating between children with or without ADHD, besides identifying the presence of other comorbid disorders [29]. CBCL is a peer evaluation questionnaire focusing on the parents of children and adolescents between the ages of 4 and 18. The scale provides separate profiles for both sexes and age ranges (from 4 to 11, and from 12 to 18). The TRF is the version for teachers, and covers children and adolescents between the ages of 5 and 18. It also provides separate profiles for both sexes and different age ranges (from 5 to 11, and from 12 to 18). Table 4. Differential diagnosis of ADHD ADHD, with prevalence of symptoms of inattention Apparent state of lethargy, staring, or daydreaming Slow processing of information Absence of the impulsive, uninhibited or aggressive behaviour that is often noted in other subtypes of ADHD Greater likelihood in the family of anxiety and/or learning disorders A significantly weak academic performance is recorded due the mistakes made in school tasks Lower risk of the development of oppositional defiant disorder and dyssocial disorder Oppositional defiant disorder and dyssocial disorder Absence of impulsive and uninhibited behaviour Defiant behaviour tends to be focused above all on the mother or on both parents Under certain circumstances, the child is capable of cooperating and readily fulfilling their allotted tasks Absence of problems related to the low ability to pay sustained attention, as well as of behaviour that suggests a state of major restlessness Tendency to refuse to do as they are told from the start The presence of the disorder is often related to the parents‘ difficulties when controlling their child‘s behaviour, as well as with the existence of a dysfunctional family No delay is noted at neurological level in the maturing process involving motor skills

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Bipolar disorder Characterised by the presence of a severe and persistent irritable mood There is a noticeable prevalence of days of depression Generally, during periods of irritable/depressive moods, there are occasional episodes of destructive or violent behaviour in response to the slightest provocation Mood swings tend to be difficult to predict or related to the slightest changes in the environment Onset tends to be at an older age Possible presence of symptoms such as excessive talking Maniac periods may give rise to psychotic symptoms or similar The family often has past cases of bipolar disorder The expansive mood, euphoria, feelings and delusions of grandeur and hyperactivity observed in adults do not tend to be present in children, who usually manifest largely dysphoric symptoms Suicidal ideation occurs more frequently in children Thought disorders Unusual or atypical thought patterns that do not tend to be a feature of ADHD Strange or peculiar sensory reactions Fascinated by strange objects or activities No apparent interest in social relationships, behaving in a distant manner Often shows no concern for personal hygiene or appearance (adolescence) Strange mannerisms, stereotypies and postures Labile mood that is difficult to predict, whose changes do not seem to correspond to real events in the environment Low ability for empathy Difficulty in properly evaluating the importance of certain events Learning difficulties The child has a general intelligence quotient that is significantly below average (more than 1 standard deviation) Academic performance lower than the 10th percentile No observed presence of symptoms of hyperactivity during early childhood Problems for paying attention appear in middle childhood and are not generalisable (they manifest themselves in connection with specific people or tasks) Does not usually behave in an aggressive or disruptive manner Does not usually behave in an impulsive or uninhibited manner Anxiety disorder Tends to find it difficult to pay constant attention, not sustained Tends not to be aggressive or impulsive, sometimes appears overly inhibited Possible family history of anxiety disorder The restlessness noted in these children is associated with irritable behaviour, excessive worrying, fear and phobic behaviours, rather than with behaviours linked to impulsivity and motor hyperactivity No apparent symptoms of hyperactivity and impulsivity during early childhood Does not usually behave in a disruptive manner in social relations, tends to be inhibited

[19] found two main factors: inattention and hyperactivity-impulsivity. Both instruments score on a Likert-type assessment scale from 0 to 3, where 0 means there is no problem, and 3 means the problem is always present: social competences, behavioural problems that are internalised (anxiety/depression disorder, somatic complaints and isolation) and externalised (aggressive behaviour and criminal behaviour), and the mixed factor (social problems, and problems with mental processes and attention).

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2. Behavior Assessment System for Children (BASC) by Reynolds and Kamphaus [30] This is a multi-method and multi-causal approach to the assessment of behaviour and self-perception among children and adolescents aged between 3 and 18, with three levels, from 3 to 6, from 6 to 12, and from 12 to 18. It involves a questionnaire for parents and teachers that takes 10-20 minutes to complete, using a Likert-type scoring system from 1 to 4 to analyse behaviour related to the following dimensions: exteriorising problems (aggressiveness, hyperactivity and behavioural problems), interiorising problems (anxiety, depression and somatisation), school problems (attention and learning), other problems (atypicality, withdrawal), adaptive skills (adaptability, leadership and social skills), and other adaptive skills (learning abilities). It also includes a catalogue of behavioural symptoms. In addition, it provides a personality self-report designed for children aged 8 to 18 with two answer options, true or false. Statements are used to assess the following dimensions: clinical maladjustment (anxiety, atypicality, locus of control, and somatisation), school maladjustment (negative attitude towards the school, towards teachers and search for sensations), other problems (depression, feeling of inadequacy and social stress), and personal adjustment (relationship with parents, interpersonal relationships, self-esteem and selfconfidence). It also includes a catalogue of emotional symptoms. The test provides a parent interview protocol that covers aspects of the child or adolescent‘s family, social and medical background, as well as a scale for observing both positive and negative classroom behaviour. 3. Conners’ Parent Rating Scale-Revised (CPRS-R) [31] and Conners’ Teacher Rating Scale-Revised (CTRS-R9 [32] The Conners scale is one of the instruments more commonly used for assessing and diagnosing children with ADHD. This scale has been revised on numerous occasions over time [33-37]. It is a peer evaluation questionnaire to be answered by parents (CPRS-R) or teachers (CTRS-R) of children aged between 3 and 17. It is available in either a full or an abridged version. The full parents‘ scale consists of 93 items distributed into eight factors: alterations in behaviour, fear, anxiety, restlessness-impulsivity, immaturity-learning problems, psychosomatic problems, obsession and antisocial behaviour and hyperactivity. The abridged version contains 48 items covering five factors: behavioural problems, learning problems, psychosomatic complaints, impulsivity-hyperactivity, and anxiety. The full teachers‘ scale consists of 39 items grouped into six factors: hyperactivity, behavioural problems, emotional lability, anxiety-passivity, antisocial behaviour, and problems with sleeping. In its abridged version, the 28 items are arranged into four factors: oppositional behaviour, inattention, hyperactivity-impulsivity, and an overall ADHD index. The items follow the criteria of DSM-IV-TR [6]. The items are scored on a Likert-type scale from 0 to 3. On the parents‘ scale, boys who record a score of 15 or over require a more thorough study, as they may be hyperactive. In the case of girls, the score is 13 or over. On the teachers‘ scale, scores of 17 for boys and 13 for girls may point to the existence of possible hyperactivity.

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4. Strengths and Difficulties Questionnaires for Parents and Teachers [38-39] The SDQ is a brief behavioural screening questionnaire with 25 items grouped into five scales: emotional symptoms, behavioural problems, hyperactivity, peer relationship problems, and pro-social behaviour. Each one of the items is rated on a three-point scale according to its frequency of appearance over the preceding six months (0 = not true; 1 = somewhat true; 2 = certainly true). 5. ADHD Rating Scale-IV [40] There are two versions of the questionnaire, one for parents and one for teachers. It contains 18 items and two subscales, inattention and hyperactivity/impulsivity, as per the diagnostic criteria of DSM-IV [11] with nine items in each one of them. Its application to parents and teachers helps to identify the subtypes of ADHD, and the criteria for the presence of the symptoms in at least two environments. Furthermore, each answer has to consider the child‘s response over the preceding six months. An overall score is also provided. Each one of the items is rated on a four-point Likert-type scale, and the higher the score, the greater the presence of the problem. 6. Vanderbilt ADHD Parent Rating Scale (VADPRS) [41-42] This scale is designed for parents and teachers (the first version to appear was the one designed for teachers, around 1998) for the diagnosis of children and adolescents with ADHD. It includes the eighteen criteria of DSM-IV [11] for ADHD, both for inattention and for hyperactivity/impulsivity, eight items for the oppositional defiant disorder, twelve for the conduct disorder, and seven criteria from the Pediatric Behavior Scale [43] for anxiety and depression. It also includes four items referring to academic performance (average academic performance in reading, writing and arithmetic) and a further four related to relationships with peers, authority, and parents, and involvement in organised activities. The behaviours are assessed on a five-point Likert-type scale. 7. NICHQ Vanderbilt (National Initiative for Children's Healthcare Quality [41-42] The NICHQ scale is used in clinical diagnosis because of its psychometric properties for detecting ADHD, as well as in the research into this complaint. It is available in English and Spanish, and in two versions, one for parents with 55 questions and another for teachers with 43 questions; 18 items are specifically for diagnosing ADHD (nine for inattention and the other nine for hyperactivity/impulsivity). It also includes items referring to the oppositional defiant disorder, conduct disorder, anxiety and depression, which permit an assessment to be made of possible comorbidities. It involves a Likert-type assessment scale from 0 to 3, where 0 is never, and 3 is very often. 8. Brown ADD Rating Scales for Children, Adolescents, and Adults [44] This scale has four age brackets: from 3 to 8, from 8 to 12, from 12 to 18 and over 18. The first three levels are designed for parents and teachers. The second and third levels may also be answered by the child in question.

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The test consists of 40 items following the criteria of DSM-IV [11] distributed into five factors: organisation and activation for work (as a result of chronic problems with a high excitation threshold or a great deal of anxiety); attention and concentration (whether receptively, when listening, or actively, when taking part in an activity such as reading); maintaining energy or effort (inconsistent energy or sustained effort due to laziness or lack of supervision); management of affective interference (mood states that impact upon social interactions, related to irritability, frustration and anger); and the use of working memory and access to recall (forgetting to bring an item that is required or to do a necessary task, incorrect placement of things). It features a Likert-type assessment scale from 0 to 3, where 0 is the absence of such behaviour, 1 means the behaviour appears once a week, 2 means twice a week, and 3 means the behaviour appears almost daily. The timeframe for the assessment is the preceding six months. Scores of over 50 indicate a possible diagnosis of ADHD.

C) Impulsivity On the other hand, the measures for assessing impulsivity include the following: 1. Test for Matching Familiar Figures (MFF-20) [45] This test involves finding the identical figure to a model, choosing between different options that are very similar, thereby assessing cognitive impulsivity. Low and erroneous latencies are interpreted as a sign of impulsivity and indicate a lack of cognitive control. It is assumed that the subject is incapable of delaying the answer and of analysing stimuli carefully in order to choose the right option. Children with ADHD would record a higher number of errors and fewer latencies in this test than those subjects without this disorder. The authors provide regulatory data, and reach the conclusion that whereas errors tend to decrease with age, latencies steadily increase until the ages of 9 or 10, whereupon they subsequently appear to stabilise and even diminish. Some authors consider that this test omits social impulsivity, which is highly prevalent among children with ADHD [46] as an alternative, they propose the tasks of delay, included in the Gordon Diagnostic System. It is a differential reinforcement of low rates task, as the child, sitting in front of a computer, has to press a key to score points. In order to earn points, the child has to wait before pressing the key again. If the child is impatient and presses the key too soon, no points are scored. 2. Self-Control Rating Scale: SCRS [46] This is a scale that assesses the dimension of impulsivity/self-control of ADHD. It consists of 33 items, of which ten rate impulsivity, thirteen rate self-regulation, and the other ten rate behaviours in which both variables are involved. It is based on the diagnostic criteria of DSM-IV [11] and the scale features six criteria of inattention, three of hyperactivity, and the three of impulsivity. Behavioural problems are covered by four items that allude to respect for rules, resistance to frustration, dominance and throwing/breaking things. They are rated using a Likert-type assessment scale from 1 to 7, where the higher the score, the greater

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the child‘s impulsivity. The scale is answered by the teachers of children aged between 8 and 12, and refers to certain specific classroom situations. 3. Kansas Reflection-Impulsivity Scale for Preschoolers [48] KRISP is designed for children aged between 3 and 6, and consists of 10 items. In each one, the subject is simultaneously shown the drawing of a model figure that is familiar to them (a ball, a jacket, a bucket, a spade, etc.) and four variations (items one, two, three and six), five variations (items four, five, seven and ten) or up to six variations (items eight and nine); of these, one is an exact replica of the model, while the others are different. The test is administered on an individual basis. The subject is told to find the alternative that is the exact replica of the model, with no limit on the time they have to do so. The test contains five practice items to ensure the task is clearly understood The assessor has to record the number of mistakes the subject makes (the most number of mistakes permitted per item is three) and the time, in seconds, taken to provide the first answer, regardless of whether or not it is correct, thereby providing two scores: the total number of mistakes made and the average latency of the first answer.

D) Executive Functions Although attention has been the target of analysis in the study of ADHD for a long time, the interest of experts has now broadened to include other possible deficits in cognitive abilities that have been grouped under the concept of executive functions [49]. Since the pioneering study by Barkley [46] through to the present day, numerous works have corroborated the involvement of neuropsychological deficits in developmental ADHD, especially in executive functions [50]. Thus, under this heading we find evidence to assess attention, working memory, cognitive patterns, cognitive flexibility, and planning ability. The following are some of the tests used for the assessment of attention in the diagnosis of ADHD: The Continuous Performance Test, CPT [51] for assessing sustained attention and impulsivity. It is a test designed for children aged between 3 and 16, in which the subject has to wait until the XA pairing appears before answering, committing an error of commission when answering impulsively in response to any stimulus. The test contains the following indicators: number of correct answers, number of errors of omission, number of errors of commission, reaction time, variability in the subject‘s answers throughout the entire task, number of anticipatory answers and number of multiple answers. The display time for each letter or reactive is 250 ms. The time lapse between the presentation of the stimuli varies, and no distracting stimuli are used. The task lasts approximately 14 minutes. Children with ADHD record fewer correct answers, commit more errors of omission and commission, and show less awareness [52-56]. There are, nonetheless, authors who suggest that the errors in the CPT reflect an individual‘s ability to self-regulate and remain motivated while undertaking the test, rather than problems of attention per se [45]. The Test of Variables of Attention [57] is one of the most widely used continuous performance computer tests for this diagnosis and in the assessment of the response to medication, if any. It has been standardised, and it is extremely accurate for assessing

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attention and impulsivity in more specific or more complex tasks, compared to other continuous performance tests. There are two versions, a visual one and an auditory one, with the visual test being the one most commonly used. Geometric shapes are displayed on the screen, and the child answers by pressing a key when identifying the sequence specified in the instructions. Use is made of two tones, one for prompting an answer and the other for inhibiting it. The task lasts approximately 23 minutes. The fact that the stimuli are not letters or numbers (they are squares) minimises the effects of possible learning difficulties associated with ADHD. The task provides results on the following: errors of omission, errors of commission, reaction time and variability in reaction time. Gordon Diagnostic System is an offshoot of CPTs. It generates eleven different tasks grouped as follows: delayed response task, distractibility task, and vigilance task. The vigilance task uses numbers (9 preceded by 1) instead of letters. The stimuli are displayed for 200 ms with a time lapse of 1000 ms between stimuli. This task, designed for children aged between 6 and 16 lasts nine minutes. There is also a version for adults. A variation in the distractibility task is the inclusion of additional digits to have a distracting effect. The delayed response time was included for measuring impulsivity. The greater the number of inhibited answers, the lower the score in impulsivity. The Stroop Colour-Word Interference test, or simply Stroop [58] is another scale that measures attention. As its name suggests, it focuses on the colour-interference subscale, in which the subject is shown a series of words for colours that are printed in different colours. The subject is required to say the colour in which the word is written without reading out the actual word. The Go-no go Test [59] involves the display of four shapes: two squares (red and blue) and two triangles (red and blue), with the subject being required to press the buttons go or nogo depending on the instructions that appear. The Wisconsin Card Sorting Test (WCST) [60]. Designed initially by Grant and Berg [61] it is one of the tests that have been most widely used in the assessment of attention, specifically analysing abstract reasoning and the ability to alter cognitive strategies in response to changing environmental contingencies. This test consists of 64 cards with figures that vary in shape (triangle, square, circle and cross), colour (red, blue, green and yellow) and number (one, two, three and four). The subjects taking the test are required to learn the rules of the game at each moment, whereby they will be able to match the present card with one of the four options that appear on the upper part of the screen. The rules depend successively on colour, shape and number, with a total of six series. The rule change occurs when ten consecutive answers are given in a row. The test ends when the subject has completed the six series or categories, or when the subject has made 128 attempts. This test provides a range of significant variables, such as the number of correct answers, the number of categories passed, the number of perseverative errors (errors that involve perseveration on the previously acquired set) and the number of non-perseverative errors. As regards the assessment of working memory, special note should be taken of the Working Memory Sentences (WMS) task [62], where the subject is shown sentences in which a word is missing, and they have to guess the word. Subsequently, once all the sentences have been seen, they have to remember all the words they have said. Then there is the Spatio-Temporal Memory task [63]. This is a computer task that assesses visuospatial memory. It consists of 30 tests, with each one showing 12 blue squares. The child has to pay attention as their colour switches sequentially from blue to red. The

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screen then goes dark, and the blue squares reappear, with the child then being required to reproduce the sequence in which the squares changed from blue to red. The most common method for assessing cognitive patterns has involved the Wechsler Intelligence Scale for Children, WISC [64-65], for the diagnosis of both ADHD and autism or acquired brain damage [66-69]. Amongst these, WISC-IV has proven to be the most sensitive to the symptoms ADHD, outperforming WISC-III [70-71]. As regards the matter in hand here, use has been made of the Memory for Digit Span Assessment of the Wechsler Intelligence Scale for Children, WISC-III [64] or WISC-IV [65]. It is a task for children and adolescents aged between 6 and 16, who are required to repeat a series of digits that the experimenter reads aloud at a rate of one digit per second. It has two parts: digits in direct order, containing series that run from three to nine digits in length, and digits in reverse order, which contain series of two to eight digits. There are two series of digits for each sequence, and the level of difficulty increases in each one of the sequences. The task ends once two mistakes have been made in the two attempts at a sequence. It is similar to the Dot Matrix test within the Automated Working Memory Assessment battery test [72] for the visual component. Children with ADHD record lower scores than expected for their age group and level of development, specifically in the sub-task of reverse order digits [73]. Regarding cognitive flexibility, application may be made of the Wisconsin Card Sorting Test, WCST [74-75]. The subject in this task is asked to sort a series of cards, classifying them according to colour, shape or number. The examiner changes the sorting criteria throughout the task, and this measures the number of attempts made, perseverative errors and nonperseverative errors [76]. Finally, the assessment of executive functions is completed with a series of tasks that assess the following: the subject‘s ability to plan, reflect and resolve problems. The highlights among these tasks are the Tower of London [77] which involves placing colour balls mounted on three sticks in certain specific positions, using a stipulated number of moves accordingly. The task‘s level of complexity is adjusted according to a minimum increase in moves. This takes into account the number of attempts the subject makes before achieving the goal. In response to the questioned ecological validity of the aforementioned tasks, recent decades have witnessed the emergence of a new type of measures based on instrumental activities in everyday life. These tasks, also performancebased, involve carrying out mundane tasks; with the aim being to reproduce conditions that are similar to those occurring in real contexts. Although measures of this type are less numerous, the best known, applicable to children and adolescents, are the following: Assessment of Motor and Process Skills-AMPS [78] and Children´s Kitchen Task Assessment-CKTA [79]. The latter is the one more widely used, and assesses the level of assistance and supervision that children aged between 8 and 12 require during a kitchen task through the number of cues they need to complete the task. This allows assessing the cognitive and executive aspects present in the effective undertaking of this task, which includes the components of initiation, planning/sequencing, safety judgement, organisation and completion. It involves asking the child to cook a dish following a recipe with pictures and text. The child also receives cues from the examiner, but only those necessary for successfully completing the task. The cues are provided in a structured sequence, and vary according to the level of assistance the child is given. These cues increase following a continuum, from no help at all through to direct and even physical assistance to complete the task.

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A more recent development is the Barkley Deficits in Executive Functioning Scale Children and Adolescents (BDEFS-CA) [12] consisting of 70 items in which parents have to use a Likert-type scale from 1 to 4 to rate the frequency with which their child encounters difficulties in five domains of executive functions: self-management of time, self-organisation and problem-solving, inhibitory control, self-motivation, and self-regulation of internal emotion. Within this context, the BRIEF scale [80] is one of the ones most commonly used, featuring in numerous studies that provide data on its validity and reliability [81-82]. This scale is applicable from the ages of 5 to 18, and is available in several formats, including selfreport. Nevertheless, the best known are the ones to be completed by families and teachers, respectively. Consisting of 86 items, it explores eight basic areas of executive functions: inhibition, change, emotional control, initiative, working memory, organisation and planning, order and monitoring. These components are in turn grouped into basic indices: the Behaviour Regulation Index, or BRI, and the Metacognition Index, or MI. Both indices are grouped into the so-called Global Executive Composite (GEC). High scores in these components and indices would be indicative of problems in executive functioning. Table 5. Overview of some of the instruments used in the diagnosis of ADHD Instrument Child Behaviour Checklist/4-18: CBCL [27] and Teacher’s Report Form/5-18: TRF [28] Behaviour Assessment System for Children (BASC) [30]

Conners’ Parent Rating Scale-Revised (CPRS-R [31] and Conners’ Teacher Rating Scale-Revised (CTRS-R) [32]

Strengths and Difficulties Questionnaires for Parents and Teachers [38-39] ADHD Rating Scale-IV [40] Vanderbilt Attention Deficit/Hyperactivity Disorder Parent Rating Scale (VADPRS) [41-42]

Age of application (years) 4-11 12 -18 Teachers‘ version: 5-11 12-18 Level 1: 3-6 Level II: 6-12 Level III: 12-18

3-17

6-18

6-18 6-18

Factors Inattention and hyperactivity-impulsivity. In addition: social competences, internalised behavioural problems and the mixed factor

Exteriorising problems, interiorising problems, problems at school, other problems, adaptive skills, other adaptive skills Personality self-report: clinical maladjustment, maladjustment at school, other personal adjustment problems Interview protocol: child or adolescent‘s family, social and medical background CPRS-R: changes in behaviour, fear, anxiety, restlessnessimpulsivity, immaturity-learning problems, psychosomatic problems, obsession and antisocial behaviour and hyperactivity. Abridged version: behavioural and learning problems, psychosomatic complaints, impulsivity-hyperactivity and anxiety CTRS-R: hyperactivity, behavioural problems, emotional lability, anxiety-passivity, antisocial behaviour and difficulties sleeping. Abridge version: oppositional behaviour, inattention, hyperactivity-impulsivity and an overall index of ADHD Emotional symptoms, behavioural problems, hyperactivity, problems with peers and pro-social behaviour. Inattention and hyperactivity/Impulsivity Inattention, hyperactivity/impulsivity, oppositional defiant disorder, behavioural disorder, anxiety and depression. In addition, items referring to academic performance in reading, writing and arithmetic and to relationships with peers, authority and parents, and involvement in organised activities

Psychological Assessment in ADHD Children Instrument NICHQ Vanderbilt (National Initiative for Children's Healthcare Quality), AAP9 [41-42] Brown ADD Rating Scales for Children, Adolescents, and Adults [43] Test for Matching Familiar Figures (MFF-209) [44] Self-Control Rating Scale: SCRS( [46] Kansas ReflectionImpulsivity Scale for Preschoolers by Wright [47] (KRISP) Continuous Performance Test, CPT [50]

Age of application (years) 6-18

Factors

Level I: 3-8 Level II: 8-12 Level III: 12-18 Level IV: over 18

Organisation and activation for work, attention and concentration, maintaining energy and effort, management of affective interference, use of working memory and access to recall Cognitive impulsivity

8-12

Impulsivity, self-regulation, inattention, hyperactivity, impulsivity, behaviour Total number of errors committed, average latency of first answer

3-6

3-16

The Tests of Variables of Attention [56]

3-16

Barkley Deficits in Executive Functioning Scale - Children and Adolescents (BDEFSCA) [12] BRIEF [78]

6-18

5-18

57

Attention deficit , hyperactivity, oppositional defiant disorder, behavioural disorder, anxiety and depression

Number of correct answers, number of errors of omission, number of errors of commission, reaction time, variability in the subject‘s answers throughout the entire task, number of anticipatory answers, and number of multiple answers Errors of omission, number of errors of commission, reaction time, variability in reaction time Two versions: visual and auditory Self-management of time, self-organisation and problemsolving, inhibitory control, self-motivation and self-regulation of internal emotion Inhibition, change, emotional control, initiative, working memory, organisation and planning, order and monitoring. Indices: Behaviour regulation and Metacognition

Table 5 provides an overview of some of the tasks described in this chapter.

Conclusion The detail of the assessment instruments provided in this chapter should not let specialists overlook the fact that ADHD is a neurodevelopmental disorder and should involve child, family and school. The assessment process does not end with the diagnosis, but instead continues throughout the entire treatment as an indicator of improvement [44]. ADHD appears at a rate of approximately 5% in children and 2.5% in adults, and it is one of the most common disorders in childhood and adolescence [84]. DSM-V [7] indicates that ADHD is characterised by a persistent pattern of inattention and/or hyperactivity/impulsivity that has a negative impact on an individual‘s development and normal conduct, with symptoms appearing before the age of 12. This disorder entails serious difficulties both within an academic context [16,85] and within the family environment [17-18]. It is therefore essential to find the most suitable strategies and tools for reducing the possibility of errors in the diagnostic process [86]. The understanding and definition of ADHD has gradually varied over time [87]. The main aim of assessment is to diagnose the presence of ADHD, as well as the differential

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diagnosis of ADHD with regard to other disorders; which implies establishing lines of treatment that are more suited to each particular case and deciding how the child‘s personal circumstances, which coexist with ADHD, will have a bearing on the disorder itself and on the success of the treatment; for example, research suggests that the presence of high levels of anxiety and the internalisation of the symptoms of ADHD in a child are predictors of the poor performance of psycho-stimulant medication [5, 88]. Research suggests that the best way of assessing ADHD involves a combination of approaches and information sources: medical check-ups, family and school backgrounds, interviews with parents and teachers, behaviour assessment scales, results from other kinds of assessment (e.g., assessment of cognitive functioning), and direct observation in diverse contexts [89] Assessment scales are important because they complement clinical information and help to confirm the diagnosis of ADHD and evaluate the response to treatment. They are easy to apply and readily accessible; nevertheless, they are subjective, indirect and non-specific tests, with answers possibly differing depending on the informant. For their part, performance tests are objective and direct, although they need longer to apply. In most cases tests require premises provided with computer equipment, which means they are not as accessible as questionnaires. Over the course of this chapter we have considered the assessment instruments that have been most effective in the diagnosis of children and adolescents with ADHD. Nevertheless, there is a need for further research to make these assessment instruments even more accurate.

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[30] Reynolds CR, Kamphaus RW. Behavior assessment system for children. Madrid: TEA, 2004. [31] Conners CK. Conners’ Parent Rating Scale‐ Revised Manual. New York: Multi‐ Health Systems, 1997. [32] Conners CK. Conners’ Teacher Rating Scale‐ Revised Manual. New York: Multi‐ Health Systems, 1997. [33] Conners CK. A teacher rating scale for use in drug studies with children. Am. J. Psychiatry 1969; 126: 884‐888. [34] Conners CK. Symptom patterns in hyperkinetic, neurotic, and normal children. Child. Develop. 1970; 41: 667‐682. [35] Conners CK. Conners’ Rating Scale Manual. Nueva York: Multi‐Health Systems, 1989. [36] Conners CK. Conners Rating Scales. In Maruish ME (Ed.), The use of psychological testing for treatment planning and outcomes assessment. Hillsdale, Nueva York: Erlbaum, 1994, pp. 550‐578. [37] Conners CK. Rating scales in attention deficit/hyperactivity disorder. J. Clin. Psychiatry 1998; 59 (Suppl): 24–30. [38] Goodman R. The Strengths and Difficulties Questionnaire: A Research Note. J. Child. Psychol Psychiatry 1997; 38: 581-586. [39] Goodman R. Psychometric properties of the Strengths and Difficulties Questionnaire (SDQ). J. Am. Acad. Child. Adolesc. Psychiatry 2001; 40: 1337-1345. [40] DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. Manual for the AD/HD Rating ScaleIV. New York: Guilford Press, 1998. [41] Wolraich ML, Bard DE, Neas B, Doffing M, Beck L. The psychometric properties of the Vanderbilt attention deficit hyperactivity disorder diagnostic teacher rating scale in a community population. J. Dev. Behav. Pediatr. 2013; 34: 83-93. [42] Wolraich ML, Lambert W, Doffing MA, Bickman L, Simmons T, Worley K. Psychometric properties of the Vanderbilt ADHD diagnostic parent rating scale in a referred population. J. Pediatr. Psychol. 2003; 28: 559-567. [43] Lindgren SD, Koeppl GK. Assessing child behavior problems in a medical setting: Development of the Pediatric Behavior Scale. In Prinz R (Ed.), Adv. Behav. Assessm. Children Fam. 1987; 3: 57-90. [44] Brown TE. ADD Rating Scales for Children, Adolescents, and Adults. PsychCorp/Pearson: San Antonio, 2011. [45] Cairns E, Cammock T. The development of a more reliable version of the Matching Familiar Figures Test. Dev. Psychol 1978; 5: 555-560. [46] Barkley RA. ADHD and the nature of self-control. New York: The Guilford, 1997. [47] Kendal P, Wilcox L. Self-control in children: Development of a rating scale. J. Consult. Clin. Psychol. 1979; 47: 1020-1029. [48] Wright JC. The Kansas Reflection-Impulsivity scale for Preschoolers. (KRISP). St. Louis: CEMREL. Inc., 1971. [49] Gropper RJ, Tannock, R. A pilot study of working memory and academic achievement in college students with ADHD. J. Attent. Dis. 2009; 12: 574-581.

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[50] Shimoni M, Engel-Yeger B, Tirosh E. Executive dysfunctions among boys with Attention Deficit Hyperactivity Disorder (ADHD): performance-based test and parents report. Res. Dev. Disabil. 2012; 33: 858-865. [51] Conners CK. Conners Continuous Performance Test (CPT). Toronto: Multi‐Health Systems, 1995. [52] Cynthia L, Huang-Pollock SL, Karalunas H, Moore, A. Evaluating Vigilance Deficits in ADHD: A Meta-Analysis of CPT Performance. J Abnorm. Psychol. 2012; 12: 360– 371. [53] Huang-Pollock CL, Karalunas SL, Tam H, Moore AN. Evaluating vigilance deficits in ADHD: A meta-analysis of CPT performance. J Abnorm. Psychol. 2012; 121: 360-371. [54] Mullins C, Bellgrove MA, Gill M, Robertson IH. Variability in Time Reproduction: Difference in ADHD Combined and Inattentive Subtypes. J. Am. Acad. Child. Adolesc. Psychiatry 2005; 44: 169-176. [55] Shallice T, Marzocchi GM, Coser S, Del Savio M, Meurter RF, Rumiati RI. Executive function profile of children with Attention Deficit Hypersensitivity Disorder (ADHD). Dev. Neuropsychol. 2002; 21: 75-86. [56] Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol. Psychiatr 2005; 57: 1336-1346. [57] Greenberg ML. Test of Variables of Attention (TOVA). Los Alamitos, CA: Universal Attention Disorders, 1996. [58] Golden C. Stroop test de colores y palabras. Madrid: Ediciones TEA, 1994. [59] Trommer BL, Hoeppner JB, Zecker SG. The go-no go test in attention deficit disorder (ADD) is sensitive to methylphenidate. J. Child. Neurol. 1991; 6 (Suppl.): 128- 131. [60] Nelson HE. A modified card sorting test sensitive to frontal lobe defects. Cortex 1976; 12: 13-24. [61] Grant DA, Berg EA. A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card sorting problem. J. Exp. Psychol. 1948; 34: 404-411. [62] Siegel, LS, Ryan EB. The development of working memory in normally achieving and subtypes of learning disabled children. Child. Develop. 1989; 60: 973-980. [63] Dubois B, Levy R, Verin M, Teixeira C, Agid Y, Yillon B. Experimental approach to prefrontal functions in humans. In Grafman J, Holyoak KJ, Boller F (Eds.), Structure and function of the human prefrontal cortex. New York: Annals of the New York Academy of Science, 1995, pp. 41-60. [64] Wechsler D. Wechsler Intelligence Scale for Children-third edition. San Antonio, TS: Psychological Corporation, 1997. [65] Wechsler D. Wechsler Intelligence Scale for Children-four edition. San Antonio, TS: Psychological Corporation, 2003. [66] Scheirs J, Timmers E. Differentiating among children with PDD-NOS, ADHD, and those with a combined diagnosis on the basis of WISC-III profiles. J. Autism. Develop. Disord. 2009; 39: 549-556. [67] Schwean VL, McCrimmon A. Attention-Deficit/Hyperactivity Disorder: Using the WISC-IV to inform intervention planning. In Prifitera A, Saklofske D, Weiss L (Eds.),

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In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 5

Genomics, Therapeutics and Pharmacogenomics of AttentionDeficit/Hyperactivity Disorder Ramón Cacabelos1,2,*, Clara Torrellas1,2, Iván Tellado1,2, Pablo Cacabelos1,2 and Francisco López-Muñoz1,3,4 1

Chair of Genomic Medicine, Camilo José Cela University, Madrid, Spain 2 EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Corunna, Spain 3 Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, Madrid, Spain 4 Neuropsychopharmacology Unit, ―Hospital 12 de Octubre‖ Research Institute, Madrid, Spain

Abstract Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder in which genomic, epigenetic, and environmental factors might be involved. Over 50 different genes and multiple copy number variants are distributed across the human genome, reflecting multilocative genomic defects in conjunction with diverse exogenous risk factors, appear to be responsible for the expression of a complex phenotype. The clinical phenotype is characterized by 3 different subtypes (inattentive, hyperactiveimpulsive, and combined type) which share abundant comorbidity with many neuropsychiatric and developmental childhood disorders. Conventionally, the pathogenic mechanisms underlying ADHD are associated with neurotransmitter dysfunction, compromising dopaminergic, noradrenergic, serotonergic, gluatamatergic and cholinergic transmission, and potentially being responsible for hypofunctional medial prefrontal and *

Correspondence to: Ramón Cacabelos, M.D., Ph.D., D.M.Sci., Professor & Chairman. Chair of Genomic Medicine, Camilo José Cela University, C/Castillo de Alarcón, 49, Villafranca del Castillo, Villanueva de la Cañada. 28692-Madrid, Spain; [email protected].

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Ramón Cacabelos, Clara Torrellas, Iván Tellado et al. orbitofrontal cortical networks; however, this oversimplification of ADHD pathogenesis needs a profound revision, since microstructural white and gray matter abnormalities are common in ADHD, and many other neurochemical anomalies contribute to ADHD. The pharmacological treatment of ADHD relies on 3 major categories of drugs: stimulant, non-stimulant and psychotropic medication, not devoid of adverse drug events, addressing behavioral symptomatology but not pathogenic tenets and/or neuromaturation. Considering the interplay of genomic-epigenomic-environmental factors in ADHD, preventive strategies should be implemented. Novel pharmacological strategies are also necessary, and the introduction of pharmacogenomics in clinical practice is essential for the optimization of limited therapeutic resources.

Keywords: atomoxetine, attention-deficit/hyperactivity disorder, epigenomics, genomics, methylphenydate, pathogenic mechanisms, phenotype, pharmacogenomics, therapeutics

Introduction ADHD is a neurodevelopmental disorder in which genomic, epigenomic and environmental factors are involved [1-8]. ADHD is one of the most prevalent psychiatric disorders in children [9]. ADHD is estimated to affect 8-12% of school-age children worldwide. In an epidemiological analysis, including 41 studies conducted in 27 countries from every world region, the worldwide-pooled prevalence of mental disorders was 13.4% (anxiety disorder, 6.5%; depressive disorder, 2.6%; ADHD, 3.4%; any disruptive disorder, 5.7%) [10]. The overall prevalence of DSM-IV disorders in Chinese children is 9.49%; anxiety disorders are the most common (6.06%), followed by depression (1.32%), oppositional defiant disorder (1.21%) and ADHD (0.84%). Of the 805 children with a psychiatric disorder, 15.2% had two or more comorbid disorders. Approximately one in ten Chinese school children has psychiatric disorders involving a level of distress or social impairment [11]. Similar frequencies have been found in the UK. Among 10,438 children assessed using the Development and Well-Being Assessment (DAWBA), the overall prevalence of DSM-IV disorders was 9.5%, but 2.1% of children were assigned "not otherwise specified" rather than operationalized diagnoses. Roughly 1 in 10 children have at least one DSM-IV disorder, involving a level of distress or social impairment likely to warrant treatment. Comorbidity reported between some childhood diagnoses may be due to the association of both disorders with a third [12]. In Iran, the overall prevalence of DSM-IV TR disorders in this population was 24.4%; the most common disorder was ADHD (11.9%) and then generalized anxiety disorder (11.3%), social phobia (6.2%), and separation anxiety disorder (6.2%) [13]. In Italy, of the 1887 assessed children, 4.45% met the ADHD cut-off on teacher ratings, 1.43% had ADHD symptoms endorsed by both teacher and parent, and 1.32% were further confirmed by the psychiatric evaluation. The male to female ratio was 7:1. The inattentive type accounted for about half of the ADHD cases. When applying stringent criteria for both severity and pervasiveness of symptoms, it is estimated that about 1.3% of the Italian elementary and middle-school children suffer from severe ADHD [14]. In Korea, the estimated prevalence of any full-syndrome and subthreshold DSM-IV disorders were 16.2% and 28.1%, respectively. The most prevalent disorders were specific phobia (9.6%), ADHD (5.9%), and oppositional defiant disorder (ODD; 4.9%). The estimated prevalence of depressive disorder was 0.1-1.9%. ADHD, ODD, and anxiety disorders were highly comorbid

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[15]. Compared with published general population prevalence, there is a fivefold increase in prevalence of ADHD in youth prison populations (30.1%) and a 10-fold increase in adult prison populations (26.2%) [16]. ADHD is the most frequently diagnosed neurodevelopmental disorder, with 6.4 million children and adolescents diagnosed with ADHD as of 2011 in the USA and a current economic burden estimated in the region of $77 billion in the USA alone [17]. Only 3.5 million children and adolescents are taking medication for ADHD [18]. Increasing numbers of adult ADHD patients are reported. Incidence increases exponentially; 40.4% of all patients have another psychiatric diagnosis before being diagnosed with ADHD. Afterwards, 17.4% received other diagnoses. Diagnoses contraindicating stimulants were found in 25.8% of the patients with other diagnoses before (10.5% of total) and in 40.0% (6.9% of total) after a diagnosis of ADHD. There is an increasing incidence and instability in the diagnosis of ADHD [19]. The prevalence of adult ADHD is estimated to be 3.8% in some regions. Men, when compared with women, are more likely to have ADHD (5.5% men vs 2% women) [20]. Attentional deficits are frequently seen in isolation as the presenting sign and symptom of neurodegenerative disease, manifest as mild cognitive impairment (MCI). Persistent ADHD in the geriatric population could well be misconstrued as MCI, leading to the incorrect assumption that such persons are succumbing to a neurodegenerative disease process. Alternatively, the molecular, neuroanatomic or neurochemical abnormalities seen in ADHD may contribute to the development of de novo late life neurodegenerative disease [21]. During the last few years several clinical guidelines on ADHD have been published by national and international medical societies. The methodological quality of ADHD guidelines is moderate to good, reflecting similarities and differences of healthcare systems. Diagnosis throughout the lifespan is based on a detailed clinical history. There is greater agreement on evidence-based pharmacological treatment than on psychosocial interventions [22]. Most guidelines do not include specific recommendations on genetic screening and pharmacogenetic intervention [23]. A note of caution should be mentioned regarding overdiagnosis. As pointed out by Coon et al. [24], overdiagnosis occurs when a true abnormality is discovered, but detection of that abnormality does not benefit the patient. It should be distinguished from misdiagnosis, in which the diagnosis is inaccurate and is not synonymous with overtreatment or overuse; excess medication or procedures are provided to patients for both correct and incorrect diagnoses. Overdiagnosis in pediatrics, affecting commonly diagnosed conditions such as ADHD, bacteremia, food allergy, hyperbilirubinemia, obstructive sleep apnea, and urinary tract infection may be harmful for children.

Phenotype Biomarkers to characterize the ADHD phenotype include clinical data, psychometric assessment, laboratory analysis, brain neuroimaging, brain electrophysiology, and genomic, proteomic and metabolomic profiles [25]. These biomarkers are essential for defining the phenotypic features of the disease and for monitoring therapeutics (efficacy and safety issues) [26, 27].

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The onset of ADHD in childhood is characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention. Three subtypes of the disorder have been proposed in the current clinical view of ADHD: (i) inattentive, (ii) hyperactive-impulsive, and (iii) combined type. Numerous problems are associated with ADHD: poor academic performance, learning disorders, subtle cognitive deficits, conduct disorders, antisocial personality disorder, poor social relationships, and a higher incidence of anxiety and depression symptoms into adulthood [28, 29]. Other clinical features include emotional instability, mental retardation, circadian rhythm disorders, epilepsy, stereotyped movements, autistic behavior, polydipsia, and an extensive plethora of potential comorbidities including oppositional defiant disorder (>60%), conduct disorder (>20%), anxiety disorder (>30%), major depression disorder (20-30%), mania/mood liability (>15%), and learning disorders (25-30%)[18]. Males show higher rates of ADHD) than do females. Cognitive endophenotypes mediate 14% of the sex difference effect [30].

Neuroimaging ADHD is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex, the caudate nucleus and putamen. Abnormalities affecting other cortical regions and the cerebellum are also currently seen. Anatomical studies suggest widespread reductions in volume throughout the cerebrum and cerebellum, while functional imaging studies suggest that affected individuals activate more diffuse areas than controls during the performance of cognitive tasks. Reductions in volume have been observed in the total cerebral volume, the prefrontal cortex, the basal ganglia (striatum), the dorsal anterior cingulate cortex, the corpus callosum and the cerebellum. Hypoactivation of the dorsal anterior cingulate cortex, the frontal cortex and the basal ganglia (striatum) have also been reported [28]. Caudate volume is reduced in association with externalizing disorders of childhood/adolescence. Working Memory deficits appear in familial high-risk offspring and those with externalizing disorders of childhood [31]. There are specific white matter abnormalities in patients with ADHD. Different ADHD subtypes may have some overlapping microstructural damage, but they may also have unique microstructural abnormalities. ADHD-I is related to abnormalities in the temporo-occipital areas, while the combined subtype (ADHD-C) is related to abnormalities in the frontalsubcortical circuit, the fronto-limbic pathway, and the temporo-occipital areas. An abnormality in the motor circuit may represent the main difference between the ADHD-I and ADHD-C subtypes [32]. Voxel-based morphometry (VBM) was used to test differences in structural grey matter (GM) and white matter (WM) volumes. There was a significant group difference in the GM of the right posterior cerebellum and left middle/superior temporal gyrus (MTG/STG). Posthoc analyses revealed that this was due to ADHD boys having a significantly smaller right posterior cerebellar GM volume compared to healthy controls and ASD boys, who did not differ from each other. ASD boys had a larger left MTG/STG GM volume relative to healthy controls and at a more lenient threshold relative to ADHD boys. The GM reduction in the cerebellum in ADHD is disorder specific relative to ASD whereas GM enlargement in the MTG/STG in ASD may be disorder specific relative to ADHD [33]. Despite some shared

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biological features and frequent comorbity, ADHD and ASD exhibit distinct large-scale connectivity patterns in middle childhood [34]. Adult ADHD is associated with neuroanatomical abnormalities mainly affecting the WM microstructure in fronto-parieto-temporal circuits that have been implicated in cognitive, emotional and visuomotor processes. MRI studies revealed higher fractional anisotropy in ADHD encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus. Reductions in trace (diffusivity) in ADHD were also found in fronto-striatal-parieto-occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced GM in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus [35]. Tract-based analyses showed that greater adult inattention, but not hyperactivity-impulsivity, was associated with significantly lower fractional anisotropy in the left uncinate and inferior fronto-occipital fasciculi. ADHD cases with symptoms persisting into adulthood have significantly lower fractional anisotropy than the never-affected controls in these tracts, differences associated with medium to large effect sizes. By contrast, ADHD cases that remit by adulthood do not differ significantly from controls. The anomalies are found in tracts that connect components of neural systems pertinent to ADHD, such as attention control (inferior fronto-occipital fasciculus) and emotion regulation and the processing of reward (the uncinate fasciculus). Change in radial rather than axial diffusivity is the primary driver of this effect, suggesting pathophysiological processes including altered myelination as future targets for pharmacological and behavioral interventions [36]. Youth with ADHD showed greater activation in the left dorsolateral prefrontal cortex (DLPFC) and left posterior cingulate cortex (PCC), greater functional connectivity between the left DLPFC and left intraparietal sulcus, and reduced left DLPFC connectivity with left midcingulate cortex and PCC for the high load contrast compared to controls. Youth with ADHD show decreased efficiency of DLPFC for high-load visuospatial working memory and greater reliance on posterior spatial attention circuits to store and update spatial position than healthy control youth [37]. By using structural T1-weighted MRI, Dang et al. [38] found that larger right relative to left caudate volumes correlated with both higher attentional impulsiveness and worse ADHD scores. Higher attentional impulsiveness also correlated with worse ADHD scores, establishing coherence between the objective measure and the self-report measure of attentional problems. A differential passage of information through frontal-striatal networks may produce instability leading to attentional problems. Sripada et al. [39] investigated whether individuals with ADHD (ages 7.2-21.8) exhibit a lag in maturation of the brain's developing functional architecture. Using connectomic methods applied to a large, multisite dataset of resting state scans, they quantified the effect of maturation and the effect of ADHD at more than 400,000 connections throughout the cortex. They found significant and specific maturational lag in connections within default mode network (DMN) and in DMN interconnections with two task positive networks (TPNs): frontoparietal network and ventral attention network. In particular, lag was observed within

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the midline core of the DMN, as well as in DMN connections with right lateralized prefrontal regions (in frontoparietal network) and anterior insula (in ventral attention network). Current models of the pathophysiology of attention dysfunction in ADHD emphasize altered DMNTPN interactions. Posner et al. [40] used MRI to examine the volumes and resting-state functional connectivity of the hippocampus in a sample of 32 medication naive children with ADHD (ages 6 - 13) and 33 age- and sex-matched healthy control (HC) participants. Compared with the HC participants, the participants with ADHD had (i) reduced volumes of the left hippocampus and (ii) reduced functional connectivity between the left hippocampus and the left orbitofrontal cortex (OFC); these hippocampal effects were associated with more severe depressive symptoms, even after controlling for the severity of inattentive and hyperactive/impulsive symptoms. Altered hippocampal structure and connectivity were not associated with anxiety or more general internalizing symptoms. A developmental improvement of symptoms in ADHD is frequently reported, but the underlying neurobiological substrate has not been identified. Francx et al. [41] studied whether white matter microstructure is related to developmental improvement of ADHD symptoms. A cross-sectional MRI analysis was embedded in a prospective follow-up of an adolescent cohort of ADHD and control subjects (NeuroIMAGE). Fractional anisotropy (FA) and mean diffusivity (MD) indices of white matter microstructure were measured using whole brain diffusion tensor imaging at follow-up only. In a dimensional analysis FA and MD were related to change in ADHD symptoms. Over time, participants with ADHD showed improvement mainly in hyperactive/impulsive symptoms. This improvement was associated with lower FA and higher MD values in the left corticospinal tract at follow-up. Findings of the dimensional and the categorical analysis strongly converged. Changes in inattentive symptoms over time were minimal and not related to white matter microstructure. The corticospinal tract is important in the control of voluntary movements, suggesting the importance of the motor system in the persistence of hyperactive/impulsive symptoms. Deficits in executive function (EF), impaired school functioning and altered white matter integrity in frontostriatal networks have been associated with ADHD [42]. Mous et al. [43] investigated the relationship between cortical thickness and inattention and hyperactivity symptoms in a large population of young children. They found that greater attention problems and hyperactivity were associated with a thinner right and left postcentral gyrus. The postcentral gyrus, being the primary somatosensory cortex, reaches its peak growth early in development. Therefore, the thinner cortex in this region may reflect either a deviation in cortical maturation or a failure to reach the same peak cortical thickness compared with children without attention or hyperactivity problems. Differences in cerebellar structure have been identified in autism spectrum disorder (ASD), ADHD, and developmental dyslexia. Data from ASD studies revealed reduced grey matter (GM) in the inferior cerebellar vermis (lobule IX), left lobule VIIIB, and right Crus I. In ADHD, significantly decreased GM was found bilaterally in lobule IX, whereas participants with developmental dyslexia showed GM decreases in left lobule VI. The cerebellar regions identified in ASD showed functional connectivity with frontoparietal, default mode, somatomotor, and limbic networks; in ADHD, the clusters were part of dorsal and ventral attention networks; and in dyslexia, the clusters involved ventral attention, frontoparietal, and default mode networks. Different cerebellar regions are affected in ASD, ADHD, and dyslexia, and these cerebellar regions participate in functional networks that are

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consistent with the characteristic symptoms of each disorder [44]. Children with developmental coordination disorder (DCD) and/or ADHD exhibit disruptions in motor circuitry, which may contribute to problems with motor functioning and attention [45], and hypoactivation in right inferior frontal cortex is specifically associated with motor response inhibition in adult ADHD [46]. Relative to healthy control subjects, patients with ADHD show impaired executive function, along with the following: lower amplitude of lowfrequency fluctuations (ALFF) in the left orbitofrontal cortex and the left ventral superior frontal gyrus; higher ALFF in the left globus pallidus, the right globus pallidus, and the right dorsal superior frontal gyrus; lower long-range functional connectivity (FC) in the frontoparietal and frontocerebellar networks; and higher FC in the frontostriatal circuit that correlated across subjects with ADHD with the degree of executive dysfunction. These findings of focal spontaneous hyper- and hypofunction, together with altered brain connectivity in the large-scale resting-state networks, which correlates with executive dysfunction, point to a connectivity-based pathophysiologic process in ADHD [47].

Figure 1. MRI of a patient with ADHD at EuroEspes Biomedical Research Center.

Advances in imaging technology have shown structural and functional brain differences between individuals with and without ADHD (Figure 1). Longitudinal studies have enabled the elucidation of differences in developmental course. Studies comparing persisting and remitting cases of ADHD are particularly promising [48-50]. The NeuroIMAGE dataset

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allows examining the course of ADHD over adolescence into young adulthood, identifying phenotypic, cognitive, and neural mechanisms associated with the persistence versus remission of ADHD, and studying their genetic and environmental underpinnings [51]. Functional MRI has provided evidence that methylphenidate administration has acute effects on brain functioning, and even suggests that methylphenidate may normalize brain activation patterns as well as functional connectivity in children with ADHD during cognitive control, attention, and during rest. The effects of methylphenidate on the developing brain appear highly specific and dependent on numerous factors, including biological factors such as genetic predispositions, subject-related factors such as age and symptom severity, and taskrelated factors such as task difficulty [52, 53].

Optical Topography Mapping Cortical activity in children with ADHD or other neuropsychiatric disorders differs from that of healthy subjects. Optical topography mapping reveals that cortical oxygenation in schizophrenics and in patients with ADHD (Figure 2) exhibit differential patterns in both basal conditions and after stimulation. Different forms of therapeutic intervention can modified these patterns in a time- and dose-dependent manner. Furthermore, these cortical profiles are disease- and genotype-specific [27, 54-57].

Figure 2. Brain optical topography mapping of a child with ADHD and a healthy child at baseline, during auditory stimulation, and 20 seconds after stimulation.

Electroencephalography For over 40 years, electroencephalography (EEG) research has attempted to characterize and quantify the neurophysiology of ADHD, most consistently associating it with increased frontocentral theta band activity and increased theta to beta (θ/β) power ratio during rest

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compared to non-ADHD controls [58] (Figure 3). While these EEG measures demonstrate strong discriminant validity for ADHD, significant EEG heterogeneity also exists across ADHD-diagnosed individuals [59]. EEG has been used to examine the possibility of dysfunctional brain activity in externalizing behavior. Studies of ADHD versus other externalizing behaviors, such as disruptive behavior disorders or antisocial behavior, have developed parallel literatures. Results of a meta-analysis of 62 EEG studies showed significantly higher delta and theta power and lower beta power in externalizing participants compared to controls. Alpha and gamma power were marginally lower in externalizing samples. These results are consistent with the hypoarousal theory of externalizing behavior [60].

Figure 3. Brain mapping activity and EEG of a patient with ADHD.

Adolescents with ADHD displayed more absolute theta activity than adolescents with ASD + ADHD during the eyes open and task conditions, independent of stimulant medication use. Only the adolescents with ADHD showed an association between diminished attention test performance and increased theta in the eyes open condition. Although there is behavioral overlap between ADHD characteristics in adolescents with ADHD and adolescents with

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combined ASD + ADHD, the underlying psychophysiological mechanisms may be different. Adolescents with ASD + ADHD exhibited fewer of the EEG physiological signs usually associated with ADHD, although there was an overlap in attentional problems between the groups. This may indicate that treatments developed for ADHD work differently in some adolescents with ASD + ADHD and adolescents with ADHD only [61]. ADHD shows an increased prevalence in delinquents compared to the normal population. A subgroup of subjects with ADHD as well as a subgroup of delinquents displayed excessive EEG beta activity, which has been associated with antisocial behavior in ADHD children. Delinquents with ADHD symptomatology showed more beta power at frontal, central and parietal brain regions than nondelinquents with ADHD symptoms. Excessive beta power may thus represent a risk factor for delinquent behavior in adults with ADHD symptomatology [62]. About half of the children with ADHD have abnormal EEG findings and over 20% of them show epileptiform discharges. Patients without comorbidity of autism spectrum disorder are especially likely to show abnormal EEG findings (51.0%) including epileptiform discharges (24.5%) [63]. In children with ADHD, an increased theta/beta ratio in the resting EEG typically serves as a rationale to conduct theta/beta neurofeedback (NF) training. In children with ADHD of the DSM-IV combined type (ADHD-C) and of the predominantly inattentive type (ADHD-I) and in typically developing children, EEG spectral analysis was conducted for segments during the attention network test (ANT) without processing of stimuli and overt behavior. Particularly in the ADHD-C group, higher theta and alpha activity was found with the most prominent effect in the upper-theta/lower-alpha (5.5-10.5 Hz) range. In the ADHD-I group, a significantly higher theta/beta ratio was observed at single electrodes (F3, Fz) and a tendency for a higher theta/beta ratio when considering all electrodes (large effect size). Higher 5.510.5 Hz activity was associated with higher reaction time variability with the effect most prominent in the ADHD-C group. A higher theta/beta ratio was associated with higher reaction times, particularly in the ADHD-I group. In an attention demanding period, children with ADHD are characterized by an underactivated state in the EEG with subtype-specific differences. The functional relevance of related EEG parameters is indicated by associations with performance (reaction time) measures [64]. Across resting conditions, children with ADHD exhibited divergent topographic distribution for theta, alpha and beta power compared to typically developing children. In addition, less alpha and theta suppression to eye opening was found in children with ADHD, but only in those without comorbid ODD/CD [65]. Frontal brain asymmetry in the alpha band (8-13Hz) in resting-state EEG represents a neural correlate of global motivational tendencies, and abnormal asymmetry, indicating elevated approach motivation, was observed in pediatric and adult patients. ADHD symptoms are associated with approach-related asymmetry (stronger relative right-frontal alpha power). Approach-related asymmetry is pronounced in females, and also associated with depression. The association between reliably assessable alpha asymmetry and ADHD symptoms supports the motivational dysfunction hypothesis. ADHD symptoms mediating an atypical association between asymmetry and depression may be attributed to depression arising secondary to ADHD [66]. The Food and Drug Administration has approved a medical device using the EEG theta/beta ratio (tbr) to help assess pediatric ADHD. Tbr is reported to be higher in ADHD, with increased theta and decreased beta. Sangal et al. [67] examined theta and beta-1 power

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differences between ADHD and normal children, during tasks of selective attention, and elucidated topographical differences. Tbr was higher in ADHD than in normal children, with lower beta-1, but no difference in theta power. There was lower beta-1 and higher tbr over Broca's area (electrode locations F7 and FC5). Beta-1 power over Broca's area was the best diagnostic test, with sensitivity 0.86 and specificity 0.57. Tbr is higher and beta-1 power lower in ADHD than in normal children, especially over Broca's area. Schreiber et al. [68] examined the prevalence of EEG abnormalities in Smith-LemliOpitz syndrome (SLOS) as well as the relationship between interictal epileptiform discharges (IEDs) and within-subject variations in attentional symptom severity. Of 85 EEGs, 43 (51%) were abnormal, predominantly because of IEDs. Only one subject had documented clinical seizures. IEDs clustered in 13 subjects (57%), whereas 9 subjects (39%) had EEGs consistently free of IEDs. While there were no significant group differences in sex, age, intellectual disability, language level, or baseline ADHD symptoms, autistic symptoms tended to be more prevalent in the "IED" group. Within individuals, the presence of IEDs on a particular EEG predicted, on average, a 27% increase in ADHD symptom severity. Epileptiform discharges are common in SLOS, despite a relatively low prevalence of epilepsy. Fluctuations in the presence of epileptiform discharges within individual children with a developmental disability syndrome may be associated with fluctuations in ADHD symptomatology, even in the absence of clinical seizures. Helgadóttir et al. [69] developed a multivariate diagnostic classifier of ADHD based on EEG coherence measures and chronological age.

Comorbid Phenogenotypes Comorbidity of ADHD with other neuropsychiatric disorders is a common phenotype worldwide. As an example, in a study of 14,825 Danish patients reported by Jensen and Steinhausen [70], 52.0% of the patients had at least one psychiatric disorder comorbid to ADHD and 26.2% had two or more comorbid disorders. The most frequent comorbid disorders were disorders of conduct (16.5%), specific developmental disorders of language, learning and motor development (15.4%), autism spectrum disorders (12.4%), and intellectual disability (7.9%). Male sex was generally associated with an increased risk for neuropsychiatric disorders while female sex was associated more frequently with internalizing disorders. The analysis of associations between the various comorbid disorders identified several clusters highlighting the differential developmental trajectories seen in patients with ADHD. Comorbidity with mental disorders is developmentally sensitive. Lee and colleagues of the Cross-Disorder Group of the Psychiatric Genomics Consortium [71] used genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and ADHD. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder, moderate between schizophrenia and major depressive disorder, bipolar disorder and major depressive disorder, and ADHD and major depressive disorder, low between schizophrenia and ASD and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease.

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Circadian Abnormalities and Sleep Disorders ADHD patients often display circadian abnormalities [72-74]. Irregular sleep-wake patterns and delayed sleep in individuals with ADHD and delayed sleep phase syndrome are associated with delays and dysregulations of the core and skin temperatures, with no apparent changes in melatonin [75]. Patients with ADHD had more sleep problems, including significantly increased sleep latency, wake after sleep onset (WASO), and fragmentation index, and poorer cognitive function, compared with controls. Some of these sleep problems, including WASO and the fragmentation index, were positively correlated with impulsivity, illustrated by the cognitive function tests in patients with ADHD [76]. ADHD may cause sleep problems as an intrinsic feature of the disorder; sleep problems may cause or mimic ADHD; ADHD and sleep problems may interact, with reciprocal causation and possible involvement of comorbidity; and ADHD and sleep problems may share a common underlying neurological etiology [77]. Restless Legs Syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder that can result in considerable sleep disruption. RLS and mood disorders are frequently comorbid. Recognition and appropriate treatment of comorbid RLS are particularly important in patients with psychiatric disorders, as RLS is a common medical reason for insomnia, and antidepressant use may exacerbate sensory symptoms [78]. Patients with RLS often present with ADHD symptoms and vice versa. In Korean children, approximately 42.9% of patients with ADHD exhibit RLS symptoms and 7.1% of these are diagnosed as RLS. Patients with ADHD also experienced various other sleep disorders [79]. Polydipsia Frequent short bursts of activity characterize hyperactivity associated with ADHD. Such pattern is also visible in schedule-induced polydipsia (SIP) in the spontaneously hypertensive rat (SHR), an animal model of ADHD [80]. Autism Spectrum Disorders (ASD) ASDs are now recognized to occur in up to 1% of the population and to be a major public health concern because of their early onset, lifelong persistence, and high levels of associated impairment. A combined phenotype between ASDs and ADHD has been reported [81]. Seventy percent of ASD have at least one comorbid disorder and 41% had two or more. The most common diagnoses are social anxiety disorder (29.2%), ADHD (28.2%), and oppositional defiant disorder (28.1%). Of those with ADHD, 84% receive a second comorbid diagnosis (anxiety disorders, depressive disorders, oppositional defiant and conduct disorders, tic disorders, trichotillomania, enuresis, and encopresis) [82]. Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997. ASD is a pervasive developmental disorder (PDD) which includes a wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: (i) social interaction, (ii) language, communication, and imaginative play, and (iii) range of interests and activities. Except for Rett syndrome (attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2

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(MeCP2) gene), the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified) are probably linked to multiple interacting genetic factors as the main causative determinants and environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections. Idiopathic autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of approximately 3 to 6/1000, with a male to female ratio of 3:1. The recurrence rate in siblings of affected children is approximately 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA-A receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (SLC6A4) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. Animal models and linkage data from genome screens implicate many other genes [83-85]. According to recent data major genetic defects in ASD include (i) copy number variants (CNVs)(DNA segments ranging in size from 50 base pairs to several megabases among individuals due to deletion, insertion, inversion, duplication, or complex recombination), accounting for 5%–8% of the cases of simplex forms of ASD; (ii) mutations in several neuroligins, SHANK, and neurexin genes encoding proteins crucial to synapse formation, maturation, and stabilization; and (iii) epigenetic phenomena. Neuroligins are encoded by the NLGN1, NLGN2, NLGN3, NLGN4X, and NLGN5 genes. Mutations in the NLGN3, NLGN4, and NLGN4Y genes may possibly cause autism. Three members of the SHANK gene family (SHANK1, SHANK2, SHANK3), which encode the scaffolding proteins are required for the proper formation and function of neuronal synapses. SHANK2 mutations have been reported in ASD and intellectual disability. Neurexins, encoded by the three highly conserved genes (NRXN1, NRXN2, NRXN3) are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in ASD patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy [86]. The MECP2 gene is important for the correct brain function and development. Loss of MECP2 has been shown to delay neuronal maturation and synaptogenesis. MECP2 de novo loss-of-function mutations cause Rett syndrome in approximately 70% of the affected females, while they are generally found to be lethal in males. Macrocephaly is seen in approximately 20% of children with autism. The Hoxgenes play a crucial role during embryonic patterning and organogenesis. The phosphatase and tensin homolog (PTEN) gene located in chromosome 10q23, harbors mutations associated with a broad spectrum of disorders, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. PTEN is a tumor suppressor gene that favors cell cycle arrest in G1 and apoptosis. Genetic syndromes linked to PTEN germline

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haploinsufficiency are often associated with autism or mental retardation. The eukaryotic translation initiation factor 4E gene (EIF4E) located on 4q21-q25 plays a pivotal role in protein translation downstream of mammalian target of rapamycin. A balanced translocation disrupting the EIF4E locus was found in a case with ASD. Some ASD cases may also result from abnormal Ca2+ homeostasis during neurodevelopment and some rare cases may be associated with mDNA mutations [85]. ASD is associated with preterm birth (PTB), although the reason underlying this relationship is still unclear. Behnia et al. [87] examined DNA methylation patterns of 4 ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth. The OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2 genes, involved in ASD, are epigenetically modified. DNA methylation in fetal leukocyte DNA in 4 of these genes (OXTR, SHANK3, BCL2, and RORA) was associated with PTB. Higher methylation of the OXTR promoter was seen in fetal membranes from PTB, compared with term labor or TNIL. No other gene showed any methylation differences among groups. Fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, which suggest that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. Similar epigenetic phenomena might be present in comorbid cases of ADHD [88-89]. Polderman et al. [90] examined the genetic and environmental etiology of the association between ASD and ADHD in a community sample of 17,770 adult Swedish twins. The ASDr dimension (reflecting restricted, repetitive and stereotyped patterns of behavior, interests and activities) showed the strongest association with dimensions of ADHD, on a phenotypic, genetic and environmental level. Gilles de la Tourette Syndrome Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with a strong genetic etiology. Over 70% of individuals with GTS meet criteria for obsessive-compulsive disorder (OCD) or ADHD, and genetic analyses suggest that some comorbidities may be more biologically related to OCD and/or ADHD rather than to GTS [91]. GTS is a disorder characterized by childhood onset of motor and phonic tics, often with improvement of tic symptoms by young adult years. The temporal course of tics and commonly comorbid behavioral symptoms is characterized by a mean age at symptom onset 7.9 ±3.6 years for tics, 7.9 ±3.5 for ADHD, and 9.2 ±5.0 for OCD. Age at peak symptom severity is 12.3 ±4.6 years for tics, 10.8 ±3.8 for ADHD, and 12.6 ±5.5 for OCD. Tics, ADHD, and OCD are reported to be no longer present in 32.0%, 22.8%, and 21.0% of subjects, respectively. Decline in symptom severity began at age 14.7 ±3.7 years for tics, 13.9 ±2.9 for ADHD, and 15.1 ±5.0 for OCD. Remission of symptoms occur at age 17.4 ±3.8 years for tics, 17.4 ±1.3 for ADHD, and 15.6 ± 2.3 for OCD [92]. One of the few genes that has been linked to GTS is the SLITRK1 (Slit and Trk-like 1) gene, where four variations have been suggested as possible disease-associated changes. One of these variations, which has been reported in six unrelated GTS patients, was a noncoding variant (var321) at the 3'-untranslated region of SLITRK1 within a conserved binding site for microRNA has-mir-189. To elucidate the potential role of var321 in disease pathogenesis, Yasmeen et al. [93] studied a cohort of 112 deeply phenotyped Danish TS patients in whom the var321 variation could not be found. The membrane protein SLITRK1 functions as a developmentally regulated stimulator of neurite outgrowth. The genomic organization of

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SLITRK1 lacks introns. RT-PCR cloning revealed two SLITRK1 transcripts: a full-length mRNA and a transcript variant that results in a truncated protein. The encoded SLITRK1 protein, consisting of 695 amino acids, displays a very high homology to human SLITRK1 (99%). The porcine SLITRK1 gene is expressed exclusively in brain tissues [94]. The involvement of DRD2, MAO-A, and DAT1 has been supported by independent findings. The study of chromosomal aberrations in GTS etiology has implicated multiple genes, with SLITRK1 being the most prominent example. Common underlying themes with other neurodevelopmental disorders are emerging and attention on neurexins, neuroligins, and genes from the histaminergic and glutamatergic pathways is increased [95]. Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. Some studies have implicated rare variants of the SLITRK1gene in disorders in the OC spectrum, specifically GTS and trichotillomania (TTM). Ozomaro et al. [96] sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. They found that the combined mutation load in OCD relative to controls was significant, and identified a missense N400I change in an individual with OCD, which was not found in more than 1,000 control samples. The N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Bertelsen et al. [97] reported a case of a male patient with GTS, obsessive compulsive disorder, ADHD, as well as other comorbidities, and a translocation t(3;9)(q25.1;q34.3) inherited from a mother with tics. Mate-pair sequencing revealed that the translocation breakpoints truncated the olfactomedin 1 (OLFM1) gene and two uncharacterized transcripts. Reverse-transcription PCR identified several fusion transcripts in the carriers, and OLFM1 expression was found to be high in GTS-related human brain regions. As OLFM1 plays a role in neuronal development it is a likely candidate gene for neuropsychiatric disorders and haploinsufficiency of OLFM1 could be a contributing risk factor to the phenotype of the carriers. One of the fusion transcripts may exert a dominant-negative or gain-of-function effect. OLFM1 is unlikely to be a major GTS susceptibility gene as no point mutations or copy number variants affecting OLFM1 were identified in 175 additional patients. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, Bertelsen et al. [98] identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5'-exons (one including the ATG start codon). Both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus.

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Tic Disorders Tic disorders have commonly occurring and well recognized comorbidities including obsessive-compulsive disorder (OCD) and ADHD [99]. Asperger’s Syndrome Asperger's syndrome (AS), a behavioral disorder that is related to autism, is associated with abnormal social functioning and repetitive behaviors but not with a decrease in intelligence or linguistic functionality. AS may be present with several comorbid disorders including: ADHD, anxiety, schizophrenia, bipolar disorder, depression, and Tourette's syndrome. About 40% of AS patients exhibit typical clinical signs of ADHD [100]. Pervasive Developmental Disorder Among Japanese patients with pervasive developmental disorder (PPD), 98% met the criteria for at least one comorbidity. The median number of the present comorbidities per child was 2, and the mode was 2. Depression (37%), ADHD (49%), and oppositional defiant disorder (45%) were frequently observed [101]. Schizophrenia Some studies have shown associations between child and adolescent psychiatric disorders and schizophrenia. Particularly, ADHD and autism have been linked with schizophrenia. In a Danish cohort, a total of 25,138 individuals with child and adolescent psychiatric disorders were identified, out of which 1,232 individuals were subsequently diagnosed with schizophrenia spectrum disorders. The risk of schizophrenia spectrum disorders was highly elevated, particularly within the first year after onset of the child and adolescent psychiatric disorder, and remained significantly elevated >5 years with an incidence rate ratio of 4.93. Among persons diagnosed with a child and adolescent psychiatric disorder between the ages 0-13 years and 14-17 years, 1.68% and 8.74%, respectively, will be diagnosed with a schizophrenia spectrum disorder 2.3 (4q13.1, 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). Of these five regions, three have been previously implicated in dyslexia (4q13.1, 16p12.1, and 17q22), three have been implicated in ADHD, which highly co-occurs with dyslexia (4q13.1, 7q36.3, 16p12.1) and four have been implicated in autism (a condition characterized by language deficits; 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). These results highlight the reproducibility of dyslexia linkage signals, even without formally significant lod scores, and suggest dyslexia predisposing genes with relatively major effects and locus heterogeneity. The largest lod score (2.80) occurred at 17q22 within the MSI2 gene, involved in neuronal stem cell lineage proliferation. The 4q13.1 linkage peak (lod 2.34) occurred immediately upstream of the LPHN3 gene, recently reported both linked and associated with ADHD. Separate analyses of larger pedigrees revealed lods >2.3 at 1-3 regions per family; one family showed strong linkage (lod 2.9) to a known dyslexia locus (18p11), demonstrating the value of analyzing single large pedigrees. Association analysis identified no SNPs with genomewide significance, although a borderline significant SNP occurred at 5q35.1 near FGF18, involved in laminar positioning of cortical neurons during development. Dyslexia genes with relatively major effects exist, are detectable by linkage analysis despite genetic heterogeneity, and show substantial overlapping predisposition with ADHD and autism. Depression There is a potential association between ADHD and depression. ADHD and depression are positively related, but substantial variability existed across the studies [109]. Suicide Individuals with ADHD (probands) have increased risks of attempted and completed suicide, even after adjusting for comorbid psychiatric disorders. The highest familial risk was

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observed among first-degree relatives, whereas the risk was considerably lower among more genetically distant relatives [110]. Rates of suicide attempts and non-suicidal self-injury (NSSI) peak in adolescence and early adulthood. Females and individuals with psychiatric symptoms and diagnoses appear to beat particular risk. Young women with histories of childhood ADHD diagnoses exhibit higher rates of suicide attempts and NSSI than nondiagnosed, comparison women [110]. ADHD in females, especially when featuring childhood impulsivity and especially with persistent symptomatology, carries high risk for self-harm [112]. Personality Disorder Some data suggest a significant association between ADHD and borderline personality disorder (BPD). Moderation analyses revealed a significant association between ADHD and BPD symptoms among only female (vs. male) outpatients. In the female subsample, mediation analyses revealed that both impulsivity and emotion dysregulation fully mediated the relationship between retrospectively assessed ADHD symptoms and current BPD features [113]. Legg-Calvé-Perthes Disease Hyperactive behavior pattern, such as ADHD, is proposed to be present in individuals with Legg-Calvé-Perthes disease (LCPD). Individuals with LCPD have a raised hazard ratio (HR) of 1.5 for ADHD. The risks is higher for female individuals than for male individuals. Individuals with LCPD have a modestly higher hazard ratio for depression than healthy subjects. Individuals with LCPD have a slightly higher mortality risk than controls. According to these data, reported by Hailer and Nilsson [114], individuals with LCPD have a higher risk of ADHD, and hyperactivity could expose the femoral head to higher mechanical stress and contribute to the etiology of LCPD. Individuals with LCPD have a higher mortality risk, with higher risk of depression, suicide and cardiovascular diseases. Generalized Anxiety Disorder Generalized anxiety disorder (GAD) and ADHD commonly co-occur in childhood. Inattention symptoms can be hallmarks of both conditions [115]. Post-Traumatic Stress Disorder There is a link between ADHD and posttraumatic stress disorder (PTSD), which is characterized by (i) chronically reexperiencing a traumatic event, (ii) hyperarousal, and (iii) avoiding stimuli associated with the trauma while exhibiting numbed responsiveness. The lifetime prevalence of PTSD is significantly higher among adults with ADHD compared with controls (10.0% vs 1.6%). ADHD patients and those with ADHD + PTSD do not differ in core symptoms of ADHD nor in age at onset, but those with ADHD + PTSD have higher rates of psychiatric comorbidity than those with ADHD only (including higher lifetime rates of major depressive disorder, oppositional defiant disorder, social phobia, agoraphobia, and generalized anxiety disorder) and worse quality of life ratings for all domains. Familial risk analysis revealed that relatives of ADHD probands without PTSD had elevated rates of both ADHD (51%) and PTSD (12%) that significantly differed from rates among relatives of controls (7% and 0%, respectively). A similar pattern of elevated risk for ADHD and PTSD

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(80% and 40%) was observed in relatives of probands with ADHD + PTSD. According to Antshel et al. [116], the comorbidity of PTSD and ADHD in adults leads to greater clinical severity in terms of psychiatric comorbidity and psychosocial functioning. The familial coaggregation of the 2 disorders suggests that these disorders share familial risk factors and that their co-occurrence is not due to diagnostic errors. Mental Retardation Individual differences in ADHD symptoms and executive function (EF) in children with Down syndrome (DS) in relation to the dopamine receptor D4 (DRD4) gene, a gene often linked to ADHD in people without DS, have been investigated. Non-trisomy genetic factors may contribute to individual differences in ADHD symptoms in persons with DS [117]. Fragile X syndrome (FXS), a disorder caused by a mutation in the FMR1 gene, is often associated with ADHD. The Fmr1 knockout (KO) mouse has been found to be a valid model for FXS both biologically and behaviorally. The Fmr1 KO mouse has been demonstrated to show increased locomotion in comparison to wild type (WT) littermates. Methylphenidate increases motor activity in both genotypes and clonidine decreases motor activity in both genotypes, but the effect is delayed in the Fmr1 KO mice [118]. Reading Difficulties Twin studies indicate that the frequent co-occurrence of ADHD symptoms and reading difficulties (RD) is largely due to shared genetic influences [119]. Eating Disorder Evidence suggests a comorbidity of childhood ADHD and subsequent eating disorders [120]. Substance Use Disorders ADHD is highly associated with substance use disorders (SUD). First-degree relatives of ADHD probands are at elevated risk for SUD compared with relatives of control subjects. The corresponding relative risk in second-degree relatives is substantially lower. The familial aggregation patterns remained similar for first-degree and second-degree relatives after excluding individuals with coexisting disorders such as schizophrenia, bipolar disorder, depression, and conduct disorder. The co-occurrence of ADHD and SUD is due to genetic factors shared between the two disorders, rather than to a general propensity for psychiatric disorders or harmful effects of ADHD medication [121]. In the Swedish population, ADHD have a substantially increased risk for future DUD with a hazard ratio (HR) of 3.34 after accounting for gender and parental education. Examining discordant cousin pairs, discordant half-siblings and discordant siblings, those with ADHD had HRs for DUD of 3.09, 2.10 and 2.38 respectively. Controlling for the number of ADHD registrations, ADHD patients with and without stimulant treatment were similarly associated with later DUD risk. ADHD diagnosed before 15 years of age was strongly related to future risk for DUD. The magnitude of this association was modestly reduced in relative pairs discordant for ADHD, suggesting that the ADHD-DUD association is partly causal and partly a result of familial confounding [122].

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Hypospadias Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. Butwicka et al. [123] reported an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability. Patients with hypospadias were more likely to be diagnosed with intellectual disability, ASD, ADHD, and behavioral/emotional disorders compared with controls. Brothers of patients with hypospadias had an increased risk of ASD and other behavioral/emotional disorders with onset in childhood in comparison to siblings of healthy individuals. Williams-Beuren Syndrome Children with Williams-Beuren syndrome (WBS) have a deletion of the long arm of chromosome 7 (7q 11.23). All have elfin facies. Neurological examination reveals hypotonia in 25% of patients and rigidity (12.50%), brisk deep tendon reflexes (25%), and abnormal plantar response (12.50%). Cerebellar and extrapyramidal signs are frequent: dysmetria (31.25%), dysdiadochokinesia (31.25%) and ataxia (18.75%). Epileptic seizures are present in 31.25% of patients and ADHD in 37.5%. Autism may also be present in some patients. EEG abnormalities appear in 31.25% of cases. Congenital cardiopathies can be found in over 60% of Egiptian cases [124]. Food Allergy Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Cross-sectionally, food allergies were associated with more symptoms of separation and generalized anxiety, disorder, ADHD, and anorexia nervosa. Longitudinally, adolescents with food allergy experienced increases in symptoms of generalized anxiety disorder and depression from one assessment to the next. Food allergies were not, however, associated with a higher likelihood of meeting diagnostic criteria for a psychiatric disorder [125]. Hong et al. [126] conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 and rs9275596, in 2,197 participants of European ancestry. Both SNPs are associated with differential DNA methylation levels at multiple CpG sites, and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. Brain Tumors Messina et al. [127] described two cases of pediatric extraventricular neurocytomas (EVN) with clinical onset characterized by behavioral changes and ADHD. EVNs are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. The Italian

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authors suggest that in childhood, the attention/hyperactivity disorders seem to be often overdiagnosed and that when these deficits are more subtle and do not fit well into a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion.

Genomics ADHD is a polygenic/complex disorders in which hundreds of genes distributed across the human genome are potentially involved [128] (Table 1). ADHD is a highly heritable disorder. Twin studies revealed that inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73%, respectively). Mathematics ability is moderately heritable (46%) [129]. Genetic factors are believed to be important in the development and course of ADHD. Many candidate genes studies and genome-wide association studies (GWAS) have been conducted in search for the genetic mechanisms underlying the phenotypic expression of ADHD in different societies [1, 3]. Despite ADHD being a highly heritable disorder, most candidate genes with replicated findings across association studies only account for a small proportion of genetic variance. The genetic architecture of ADHD comprises both common and rare variants. Table 1. Selected genes potentially associated with ADHD Symbol ADHD1

ADHD2

ADHD3

ADHD4

ADHD5

ADHD6

ADORA2A ADRA1A ADRA2A ADRA2C

Title/Gene Attention deficithyperactivity disorder, susceptibility to, 1 Attention deficithyperactivity disorder, susceptibility to, 2 Attention deficithyperactivity disorder, susceptibility to, 3 Attention deficithyperactivity disorder, susceptibility to, 4 Attention deficithyperactivity disorder, susceptibility to, 5 Attention deficithyperactivity disorder, susceptibility to, 6 Adenosine A2a receptor Adrenergic, alpha-1A-, receptor Adrenergic, alpha-2A-, receptor Adrenergic, alpha-2C-, receptor

OMIM 608903

Locus 16p13

Size (Kb)

608904

17p11

608905

6q12

608906

5p13

612311

2q21.1

612312

13q12.11

102776 104221

22q11.23 8p21.2

14.80 kb 117.26 kb

104210

10q25.2

3.65 kb

104250

4p16

1.00 kb

Other related diseases

- Susceptibility to type 2 diabetes - Susceptibility to congestive heart failure

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Symbol ADRB2

Title/Gene OMIM Adrenoceptor beta 2, surface 109690

Locus 5q31-q32

ANK3

Ankyrin 3, node of Ranvier 600465 (ankyrin G) Apolipoprotein E 107741

10q21.2

10q24.32

ASTN1 ASTN2

Arsenic (+3 oxidation state) 611806 methyltransferase Astrotactin 1 600904 Astrotactin 2 612856

1q25.2 9q33.1

Size (Kb) Other related diseases 2.04 kb - Susceptibility to asthma, nocturnal - Susceptibility to obesity 707.23 kb - Mental retardation, autosomal recessive, 37 3.61 kb - Alzheimer disease - Familial dysbetalipoproteinemia, hyperlipoproteinemia type III - Age related macular dystrophy, 2 - Sea-blue histiocyte disease 32.45 kb - Susceptibility to arsenicdependent carcinogenesis 303.00 kb 990.00 kb - Susceptibility to schizophrenia

BAIAP2

BAI1-associated protein 2

605475

17q25.3

82.29 kb

BCHE

Butyrylcholinesterase

177400

3q26.1

64.56 kb

BDNF

Brain-derived neurotrophic factor

113505

11p14.1

67.16 kb

CADM2 CAMTA1

Cell adhesion molecule 2 Calmodulin binding transcription activator 1

609938 611501

3p12.1 1p36.31

CES1

Carboxylesterase 1 (monocyte/macrophage serine esterase 1)

114835

16q12.2

CDH13

Cadherin 13, H-cadherin

601364

16q23.3

CHRNA4

Cholinergic receptor, nicotinic, alpha polypeptide 4

118504

20q13.33

CHRNA7

Cholinergic receptor, 118511 nicotinic, alpha 7 (neuronal)

15q13.3

342.00 kb 984.38 kb - Cerebellar ataxia, nonprogressive, with mental retardation 30.31 kb - Carboxylesterase 1 deficiency - Susceptibility to alteration of pharmacokinetics and drug response 1169.62 kb 18.09 kb - Epilepsy, nocturnal frontal lobe, type 1 - Susceptibility to nicotine addiction 139.70 kb - Chromosome 15q13.3 microdeletion

CLOCK

Clock circadian regulator

601851

4q12

COMT

Catechol-Omethyltransferase

116790

22q11.21

APOE

AS3MT

19q13.32

28.24 kb

- Apnea, postanesthetic, suxamethonium sensitivity - WAGR complex - Central hypoventilation syndrome (congenital) - Susceptibility to anorexia nervosa and bulimia nervosa. - Susceptibility to memory impairment.

- Susceptibility to obesity - Susceptibility to metabolic syndrome - Susceptibility to behavioral disorders - Susceptibility to schizophrenia - Susceptibility to panic disorder

Genomics, Therapeutics and Pharmacogenomics... Symbol CYFIP1

87

Title/Gene Cytoplasmic FMR1 interacting protein 1 Disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila) Dopamine beta-hydroxylase (dopamine betamonooxygenase) Dopa decarboxylase (aromatic L-amino acid decarboxylase) Disrupted in schizophrenia 1

OMIM 606322

Locus 15q11.2

Size (Kb) 110.92 kb

601236

5p13.1

53.56 kb

609312

9q34

22.98 kb

- Dopamine beta-hydroxylase deficiency

107930

7p12.1

107.02 kb

- Aromatic L-amino acid decarboxylase deficiency

605210

1q42.2

414.46 kb

- Susceptibility to schizophrenia - Susceptibility to schizoaffective disorder

DRD1 DRD2 DRD4

Dopamine receptor D1 Dopamine receptor d2 Dopamine receptor d4

126449 126450 126452

5q35.2 11q23.2 11p15.5

3.49 kb 65.68 kb 3.40 kb

DRD5

Dopamine receptor d5

126453

4p16.1

2.38 kb

ELK3

ELK3, ETS-domain protein (SRF accessory protein 2) Fatty acid desaturase 2 F-box only protein 33 Fragile X mental retardation 1

600247

12q23

72.00 kb

606149 609103 309550

11q12.2 14q21.1 Xq27.3

39.00 kb 34.00 kb 39.18 kb

FTO

Fat mass and obesity associated

610966

16q12.2

410.50 kb

GDNF

Glial cell derived neurotrophic factor

600837

5p13.2

24.03 kb

GNPDA2

Glucosamine-6-phosphate 613222 deaminase 2 G protein-coupled receptor, 605948 family C, group 5, member B G protein-coupled receptor 139 Glutamate receptor, 604102 metabotropic 5

4p12

24.45 kb

16p12.3

27.08 kb

16p13.11

41.00 kb

11q14.3

559.07 kb

Glutamate receptor, 604101 metabotropic 7 Guanylate cyclase 2C (heat 601330 stable enterotoxin receptor) 5-hydroxytryptamine 109760 (serotonin) receptor 1A

3p26.1p25.1 12p12.3

880.29 kb

DAB2

DBH

DDC

DISC1

FADS2 FBXO33 FMR1

GPRC5B

GPR139 GRM5 GRM7 GUCY2C HTR1A

83.95 kb

5q11.2-q13 1.00 kb

Other related diseases - Angelman syndrome

- Dystonia myoclonic - Autonomic nervous system dysfunction - Novelty seeking personality - Primary cervical dystonia - Blepharospasm, primary benign

- Susceptibility to osteoporosis - Fragile X syndrome - Premature ovarian failure, fragile X-associated - Fragile-X tremor ataxia syndrome - Growth retardation, psychomotor delay, early death - Severe obesity - Central hypoventilation syndrome - Susceptibility to Hirschsprung disease - Susceptibility to obesity

- Susceptibility to age-related hearing impairment - Diarrhea - Meconium ileus - Periodic fever, menstrual cycle dependent

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Symbol HTR1B

Title/Gene 5-hydroxytryptamine (serotonin) receptor 1B 5-hydroxytryptamine (serotonin) receptor 1E 5-hydroxytryptamine (serotonin) receptor 2A

OMIM 182131

Locus 6q13

Size (Kb) Other related diseases 1.00 kb

182132

6q14-q15

78.00 kb

182135

13q14.2

63.48 kb

5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled Inter-alpha (globulin) inhibitor H3 Kalirin, RhoGEF kinase

312861

Xq24

146650

3p21.1

604605

3q21.2

626.48 kb - Susceptibility to coronary heart disease

600734

11q24.3

26.65 kb

KLF13

Potassium inwardlyrectifying channel, subfamily J, member 5 Kruppel-like factor 13

605328

15q13.3

51.02 kb

LPHN3 MAOA

Latrophilin 3 Monoamine oxidase A

309850

4q13.1 Xp11.3

MAP2K5

Mitogen-activated protein kinase kinase 5 Methylenetetrahydrofolate reductase (NAD(P)H)

602520

15q23

575.00 kb 90.00 kb - Brunner síndrome - MAOA/B deletion syndrome - Susceptibility to antisocial behavior 264.43 kb -

607093

1p36.22

20.33 kb

Myotubularin related protein 10 Neural cell adhesion 116930 molecule 1

15q13.3

46.00 kb

11q23.2

317.19 kb - Susceptibility to neural tube defects - Susceptibility to alcohol dependence - Susceptibility to left ventricular wall thickness and relative wall thickness in hypertensive families

HTR1E HTR2A

HTR2C

ITIH3 KALRN KCNJ5

MTHFR

MTMR10 NCAM1

- Susceptibility to alcohol dependence - Susceptibility to anorexia nervosa - Susceptibility to obsessivecompulsive disorder - Susceptibility to schizophrenia - Susceptibility to seasonal affective disorder 358.68 kb - Susceptibility to obesity - Susceptibility to behavioral disorders 14.24 kb

- Hyperaldosteronism, familial, type III - Long QT syndrome 13

- Homocystinuria due to MTHFR deficiency - Susceptibility to vascular disease - Susceptibility to thromboembolism - Susceptibility to schizophrenia - Susceptibility to neural tube defects

Genomics, Therapeutics and Pharmacogenomics... Symbol NGF

89

Title/Gene Nerve growth factor (beta polypeptide) Nerve growth factor (beta polypeptide)

OMIM 162030

Locus 1p13.1

162030

1p13.1

608145

15q11.2

43.16 kb

- Spastic paraplegia 6

608146

15q11.2

29.74 kb

- Susceptibility to childhood absence epilepsy

NPSR1

Non-imprinted in PraderWilli/Angelman syndrome 1 Non-imprinted in PraderWilli/Angelman syndrome 2 Neuropeptide S receptor 1

608595

7p14.3

220.00 kb - Susceptibility to Asthma

NTF3

Neurotrophin 3

162660

12p13.31

63.19 kb

- Severe movement defects of the limbs

NTF4

Neurotrophin 4

162662

19q13.33

3.84 kb

- Glaucoma, primary open angle, O

NTRK1

Neurotrophic tyrosine kinase, receptor, type 1

191315

1q23.1

66.10 kb

- Hereditary sensory and autonomic neuropathy, type IV

NTRK3

Neurotrophic tyrosine kinase, receptor, type 3

191316

15q25.3

379.67 kb - Susceptibility to tumour development

NUDT3

Nudix (nucleoside diphosphate linked moiety X)-type motif 3 Parkinson protein 2, E3 ubiquitin protein ligase (parkin) Paraoxonase 1

609228

6p21.2

104.00 kb

602544

6q26

1380.25 kb

- Parkinson disease 2, juvenile

168820

7q21.3

26.21 kb

PTGER4

Prostaglandin E receptor 4 (subtype EP4)

601586

5p13.1

1380.25 kb

- Susceptibility to coronary artery disease - Susceptibility to coronary artery spasm 2 - Microvascular complications of diabetes 5 - Sensitivity to organophosphate poisoning - Susceptibility to Crohn disease

PTPRD

Protein tyrosine phosphatase, receptor type, D Solute carrier family 6 (neurotransmitter transporter), member 2 Solute carrier family 6 (neurotransmitter transporter), member 3

601598

9p23

2298.26 kb

- Restless legs syndrome 3

163970

16q12.2

50.56 kb

- Orthostatic intolerance

126455

5p15.33

52.64 kb

Solute carrier family 6 (neurotransmitter transporter), member 4

182138

17q11.2

39.58 kb

- Parkinsonism-dystonia, infantile - Idiopathic epilepsy - Dependence on alcohol and cocaine - Anxiety-related personality traits - Obsessive-compulsive disorder - Susceptibility to sudden infant death

NGF NIPA1

NIPA2

PARK2

PON1

SLC6A2

SLC6A3

SLC6A4

Size (Kb) Other related diseases 52.32 kb - Neuropathy, hereditary sensory and autonomic, type V 52.32 kb - Neuropathy, hereditary sensory and autonomic, type V

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Symbol SLC9A9

OMIM 608396

Locus 3q24

Size (Kb) 583.28 kb

600322 186590 313475

20p12p11.2 7q11.23 Xp11.23

88.60 kb

STX1A SYP

Title/Gene Solute carrier family 9, subfamily A (NHE9, cation proton antiporter 9), member 9 Synaptosomal-associated protein, 25kDa Syntaxin 1A (brain) Synaptophysin

SYT1 TACR1 TPH2

Synaptotagmin I tachykinin receptor 1 Tryptophan hydroxylase 2

185605 162323 607478

12q21.2 2p13.1 12q21.1

588.02 kb 153.06 kb 93.00 kb

TRIM32

Tripartite motifcontaining 32

602290

9q33.1

26.65 kb

TSHR

Thyroid stimulating hormone receptor

603372

14q31.1

190.80 kb

TUBGCP5

Tubulin, gamma complex 608147 associated protein 5 UPF3 regulator of nonsense 300298 transcripts homolog B (yeast) Vesicle-associated 185881 membrane protein (synaptobrevin 2) XK, Kell blood group complex subunit-related family, member 4

15q11.2

40.49 kb

Xq24-q26

18.00 kb

17p13.1

3.83 kb

SNAP25

UPF3B

VAMP2

XKR4

20.48 kb 12.40 kb

Other related diseases - Autism susceptibility 16

- Mental retardation, X-linked 96

- Susceptibility to bipolar disorder - Susceptibility to major depression - Bardet-Biedl syndrome 11 - Muscular dystrophy, limbgirdle, type 2H - Hyperthyroidism, familial gestational - Hyperthyroidism, nonautoimmune - Hypothyroidism, congenital, nongoitrous, 1 - Thyroid adenoma, hyperfunctioning, somatic - Thyroid carcinoma with thyrotoxicosis

- FG syndrome 6 - Lujan-Fryns syndrome 1 - Mental retardation, 27

8q12.1

Candidate genes for ADHD focused on genes involved in the dopaminergic neurotransmission system, such as DRD4, DRD5, DAT1/SLC6A3, DBH, and DDC. Genes associated with the noradrenergic (such as NET1/SLC6A2, ADRA2A, ADRA2C) and serotonergic systems (such as 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2) have also received considerable interest. Additional candidate genes related to neurotransmission and neuronal plasticity that have been studied less intensively include SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF [130]. A meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25) revealed that a major part of the previously postulated associations were nonconsistent in the pooled odds ratios. There is a weak

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significant association with a SNP located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences. Previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported [131]. However, the contribution of several candidate genes has been supported by other meta-analyses (DRD4, DRD5, DAT1, HTR1B and SNAP25), whereas others indicate that little evidence supports an important role for the 'classic' ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1 [1]. Several genome-wide linkage studies have been conducted and, although there are considerable differences in findings between studies, several regions have been supported across several studies (bin 16.4, 5p13, 11q22-25, 17p11) [132]. Linkage studies have been successful in identifying loci for adult ADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan [133]. Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. A study screening the degree of genetic commonality across six major neuropsychiatric disorders, including ADHD, anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), identified a total of 180 genes on the basis of low but liberal GWAS p-values. 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disordersincluded ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Two distinct genetic components were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants [134]. About 45 of the 85 top-ranked ADHD candidate genes encode proteins that fit into a neurodevelopmental network involved in directed neurite outgrowth. Data on copy number variations in patients with ADHD and data from animal studies provide further support for the involvement of this network in ADHD etiology [135]. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. Several GWAS have been performed on the diagnosis of ADHD and related phenotypes. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the 'classic' ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. Some GWAS indicate that basic processes like cell division, adhesion (cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and

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extracellular matrix regulation, and cytoskeletal remodeling processes might be involved in ADHD [1, 136]. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Meta-analyses (1,519 meta-analyses across 157 studies) examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness such as major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and ADHD, identified 134 genes (206 variants) as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported [137]. Data from the Psychiatric Genomics Consortium [71] including 896 ADHD cases and 2,455 controls, and 2,064 parent-affected offspring trios, provided sufficient statistical power to detect gene sets representing a genotype relative risk of at least 1.17. Although all synaptic genes together showed a significant association with ADHD, this association was not stronger than that of randomly generated gene sets matched for same number of genes. Further analyses showed no association of specific synaptic function categories with ADHD after correction for multiple testing. Given current sample size and gene sets based on current knowledge of genes related to synaptic function, the results reported by Hammerschlag et al. [138] do not support a major role for common genetic variants in synaptic genes in the etiology of ADHD. The adult form of ADHD has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for ADHD compared with childhood ADHD, whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. Linkage studies led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. Studies of rare genetic variants have identified probable causative mutations for ADHD [133].

Dopamine Receptors and Transporters DAT1/ SLC6A3 A significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene was reported in the late 1990s [139-141]. This association was later replicated in additional studies [142-144]. The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. Specifically, the 10-repeat allele of the 40-bp variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region (UTR) of the gene has been found to be associated with ADHD. Variability in the repeat number, and sequence variation in the 3'-UTR of the DAT1 gene may influence the level of the dopamine transporter

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protein [145,146]. Feng et al. [147] investigated whether DNA variation in the DAT1 3'UTR contributed to ADHD by genotyping DNA variants around the VNTR region including a MspI polymorphism (rs27072), a DraI DNA change (T/C) reported to influence DAT1 expression levels, and a BstUI polymorphism (rs3863145) in addition to the VNTR. DAT1 was associated with ADHD, but not with alleles of the VNTR polymorphism. Meta-analyses indicate that the gene coding for the dopamine transporter (DAT1 or SLC6A3) is associated with an increased risk for ADHD. The majority of studies did not find a relation between DAT1 and neurophysiological or neuropsychological measures. Several of the polymorphisms of DAT1 were associated with ADHD and ADHD was associated with impaired neuropsychological functioning. However, none of the DAT1 polymorphisms was convincingly associated with neuropsychological dysfunctioning. This suggests that the effect of DAT1 on ADHD was not mediated by neuropsychological performance. However, since DAT1 is mainly expressed in the striatum and not in the prefrontal cortex, it may influence striatum-related functions more heavily than prefrontal related functions. Associations of DAT1 with ADHD were only found in adolescents, which may suggest that DAT1 mainly exerts its effect in adolescence, and/or that having a more persistent form of ADHD may mark a more severe or homogeneous genetic form of the disorder [148]. The DAT1/SLC6A3 locus may be a small-effect susceptibility gene for ADHD [149]. The dopamine transporter does play a major role in ADHD. Among the several polymorphisms already described in the SLC6A3 locus, a 40 bp variable number of tandem repeats (VNTR) polymorphism has been extensively investigated in association studies with ADHD. The allele with ten copies of the 40 bp sequence (10-repeat allele) is the risk allele for ADHD. This polymorphism can be implicated in dopamine transporter gene expression in vitro and dopamine transporter density in vivo, even though it is located in a non-coding region of the SLC6A3 locus [150]. Two SNPs (rs2617605 and rs37020) were significantly associated with the double errors after adjustment for multiple testing. A haplotype rs403636 (G)/rs463379 (C)/rs393795 (C)/rs37020 (G) was significantly associated with total within-search errors, within-search errors in eight boxes, total double errors and double errors in eight boxes, indicating that the haplotype rs403636 (G)/rs463379 (C)/rs393795 (C)/rs37020 (G) is a novel genetic marker for spatial working memory in ADHD [151]. Genro et al. [152] observed a preferential transmission of the haplotype A/C/C/C/A derived from five SNPs (rs2550948, rs11564750, rs261759, rs2652511, rs2975223) in 5' region and no association with any allele/haplotype at the 3' region of the gene, including the 3' VNTR and the VNTR of intron 8, suggesting a potential role for the promoter region in ADHD susceptibility. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. Tong et al. [153] probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. They also genotyped the exon 3 VNTR of DRD4, the 7repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR.

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Emerging evidence associates dysfunction in the dopamine transporter with the pathophysiology of autism spectrum disorder (ASD). The human DAT (SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was reported in individuals with bipolar disorder or ADHD. This variant is hyper-phosphorylated at the amino (N)terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Bowton et al. [154] reported the novel identification of hDAT A559V in two unrelated ASD subjects and provided the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C β (PKCβ) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCβ activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. The inability of hDAT A559V to traffic in response to AMPH is probably due to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these Nterminal Ser to Ala restores AMPH-induced trafficking. hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCβ or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission, including ADHD, bipolar disorder, and now ASD. Abnormalities of frontostriatal circuits, which are modulated by dopamine, have been found by brain imaging studies in patients with ADHD. With special radiolabeled ligands selective imaging of the dopamine transporter, which has a key function in dopamine metabolism, can be performed by SPECT and PET. Most of the studies showed a higher DAT availability in untreated patients with ADHD compared with controls. The relationship between DAT availability and a polymorphism of DAT1 gene in patients with ADHD is not clear and the results are controversial [155]. A number of studies have investigated the association of the VNTR with striatal DAT availability in humans using single photon emission computed tomography (SPECT). Costa et al. [156] carried out a meta-analysis of the association between the SLC6A3 VNTR and striatal DAT binding measured in human SPECT studies. The meta-analysis of five samples of healthy individuals failed to find a significant difference in DAT availability between SLC6A3 9-repeat carriers and 10-repeat homozygotes although the 9R carriers had nominally higher striatal DAT levels. The results remained nonsignificant after the inclusion of patient samples, namely schizophrenia, ADHD, and Parkinson's disease. This meta-analysis provides no evidence to support the hypothesis that the SLC6A3 VNTR is significantly associated with interindividual differences in DAT availability in the human striatum. Spencer et al. [157] examined the relationship between dopamine transporter binding in the striatum in individuals with and without ADHD, attending to the 3'-untranslated region of the gene (3'-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene. The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status and 3'-UTR of SLC6A3 9 repeat carrier status were independently and additively associated with increased

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DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3'-UTR genotype, and 3'-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3'-UTRintron8 haplotype with DAT binding. The 3'-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3'-UTR polymorphism status had an additive effect on DAT binding. An ADHD risk polymorphism (3'-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding. Hansen et al. [158] analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DATAsp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxyglucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DATAsp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. These results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies. Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or ADHD. This variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Bowton et al. [154] reported the novel identification of hDAT A559V in two unrelated ASD subjects and provided the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. hDAT A559V is resistant to AMPHinduced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C β (PKCβ) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCβ activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. The authors linked the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N-terminal Ser to Ala restores AMPH-induced trafficking. hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCβ or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH

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accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission, including ADHD, bipolar disorder, and now ASD. Mergy et al. [159] identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of ADHD, with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. In a DAT Val559 knock-in mice, the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior have been demonstrated. de Azeredo et al. [160] analyzed the -839 C/T (rs2652511) promoter variant and the 3'UTR and intron 8 (Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls from Brazil. A significant association was detected in the rs2652511 C-allele with ADHD. The 6-repeat allele of Int8 VNTR was associated with higher inattention scores. The haplotype analysis including DAT1 3'-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of DAT1 as a risk factor for ADHD susceptibility. DRD2 and DRD4 Genetic studies of ADHD mainly focused on the DAT1 and the Dopamine Receptor 4 (DRD4) genes. SNPs of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. Hasler et al. [161] investigated how polymorphic variants within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, they detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD. Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls. Significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness and trait anger scores. The rs1800497 (TaqIA) SNP of the DRD2 gene has been extensively studied. However, this locus has recently been identified within the exon 8 of ankyrin repeat and kinase domain containing 1 (ANKK1), giving rise to a Glu713-to-Lys substitution in the putative ANKK1 protein. Pan et al. [162] performed a meta-analysis to determine whether ANKK1 polymorphism influences the risk of ADHD and examined the relationship between rs1800497 genetic variant and the etiology of ADHD. A total of 11 studies with 1645 cases and 1641 controls were included. In the dominant model, the rs1800497 locus was associated with ADHD. Subgroup analysis for ethnicity indicated that the polymorphism was associated with ADHD in Africans, but not in East Asians and Caucasians. Fear of strangers is a developmental milestone in childhood that encompasses behavioral inhibition and decreased novelty seeking. Children with ADHD often exhibit fearless and impulsive behaviors, similar to those observed in children with atypically low levels of stranger fear. Longer DRD4 variants were associated with increased ADHD symptoms at 6

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years, and this relationship was partially mediated by lower levels of observed stranger fear at 3 years. Variation in DRD4 may be an important contributor to this mechanism [163]. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. DRD4 may serve as a "plasticity" gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context [164]. The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of ADHD and substantially exists in Asian populations, which have a lower ADHD prevalence. Takeuchi et al. [165] investigated the effect of this allele on microstructural properties of the brain and on its functional activity during externally directed attention-demanding tasks and creative performance in the 765 Asian subjects. The 5-repeat allele was significantly associated with increased originality in the creative performance, increased mean diffusivity in the widespread gray and white matter areas of extensive areas, particularly those where DRD4 is expressed, and reduced task-induced deactivation in the areas that are deactivated during the tasks in the course of both the attention-demanding working memory task and simple sensorimotor task. The neural characteristics of 5-repeat allele carriers may lead to an increased risk of ADHD and behavioral deficits. Studies of functional brain activity in response to unpleasant images in individuals with the 7-repeat (7R) allele compared to individuals with the 4-repeat (4R) allele of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3) showed increased brain activity in response to unpleasant images compared to neutral images in the right temporal lobe in participants with the DRD4-4R/7R genotype versus participants with the DRD4-4R/4R genotype. The increase in right temporal lobe activity in individuals with DRD4-4R/7R suggests greater involvement in processing negative emotional stimuli. Individuals with the 7R allele are more responsive to negative emotional stimuli compared to individuals with the 4R allele of the DRD4 gene [166]. Children with an orofacial clefting (OFC) history are at increased risk of familial stressors, anxiety disorders, learning disabilities, and abnormal brain development. Children with OFC may be more likely to exhibit ADHD symptoms than children without OFC. The DRD4 4-repeat allele was associated with increased inattentive ADHD symptoms. Having the DRD2 Taq1A1 allele and OFC predicted fewer inattentive ADHD symptoms. Children with OFC were significantly less likely to have the DAT1 10-repeat allele [167]. Carriers of 7-repeats in the Variable Number of Tandem Repeats (VNTR) of DRD4 (7R+) would recruit prefrontal brain regions involved in successful inhibitory control to a lesser degree than non-carriers (7R-) and demonstrate less inhibitory control as confirmed by observation of locally reduced blood oxygenation level dependent (BOLD) % signal change and lower accuracy while performing "No-Go" trials of a Go/No-Go task. The DRD4 7-repeat allele may alter dopaminergic function in brain regions involved in inhibitory control. When individuals must inhibit a prepotent motor response, presence of this allele may account for 56% of the variance in BOLD signal in brain regions critically associated with inhibitory control, but its influence may be associated with a greater effect on brain than on behavior in 18-year-olds from the general population [168]. Reaction time variability (RTV) is considered a valid endophenotype of ADHD. It is also often used to examine the efficacy of drug treatment or individual patients' treatment

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responses and has been furthermore suggested to significantly reduce the potential number of false-positive diagnoses. Grant et al. [169] examined whether the effects of dopamine-related candidate polymorphisms in the genes DRD2, SLC6A3, COMT and MAOA may be differentially associated with discrete subcomponents of RTV, rather than global RTV. Functional polymorphisms in the genes encoding for dopamine-catabolizing enzymes (COMT and MAOA) are associated with motor RTV but not with sensory RTV. DRD2 influences sensory but not motor RTV. No significant associations for the gene SLC6A3 were found. Gadow et al. [170] evaluated the association of dopaminergic gene variants with emotion dysregulation (EMD) and ADHD symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. Global EMD severity (parents' ratings) was associated with DAT1 intron8 and rs2283265. Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety and depression, and for DRD2 rs2283265, depression. DRD2 rs2283265 was associated with teachers' global ratings of ADHD. DAT1 intron8 was associated with parent-rated hyperactivity and both DAT1 9/10 VNTR and DRD2 rs2283265 were associated with teacher-rated inattention. Dopaminergic gene polymorphisms might modulate EMD and ADHD symptoms in children with ASD. Maitra et al. [171] explored association of functional variants in the DRD2 (rs1799732 and rs6278), DRD4 (exon 3 VNTR and rs914655), and SLC6A3 (rs28363170 and rs3836790) with hyperactivity, cognitive deficit, and co-morbid disorders in eastern Indian probands. Case-control analysis showed statistically significant difference for rs6278 and rs28363170 while family-based analysis exhibited preferential paternal transmission of rs28363170 '9R' allele. MDR analyses revealed independent effects of rs1799732, rs6278, rs914655, and rs3836790 in ADHD. Significant independent effects of different sites on cognitive/hyperactivity traits and co-morbid disorders were also noticed. Genetic heterogeneity in the VNTR is an important factor in the pathophysiology of ADHD. All 7R rare variants as well as non-synonymous 7R rare variants were associated with high hyperactivity/inattention scores. A trend for association was observed with 4R rare variants. New coding mutations covered 10 novel motifs and many of them are previously unreported deletions leading to different stop codons. DRD4 7R rare variants contribute to high hyperactivity-inattention scores [172]. Three SNPs located on 5' and 3'UTR regions of the ADRA2A gene have been extensively explored but none of them have been definitely validated as a predisposition or a causative sequence variation. Castro et al. [173] sequenced the complete ADRA2A coding region in a panel of ADHD children of Colombian origin and identified the c.1138 C>A (p.Arg380Arg) silent substitution. ADRA2A non-synonymous sequence variants do not cause ADHD in this population. Ghosh et al. [174] have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission. rs3837091 "AGAG," rs3735273 "A," rs1799732 "C," rs740603 "G," rs165599 "G" and single repeat alleles of

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rs4646984/rs4646983 showed positive correlation with co-morbid characteristics. Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes, while family-based data showed interaction between DDC and DRD2.

Dopamine Beta-Hydroxylase (DBH) Kwon and Lim [175] investigated the association between the genetic type and alleles for the dopamine beta-hydroxylase (DBH) gene in Korean children with ADHD and found a significant correlation among the frequencies of rs1611115 of the alleles of DBH, but no final conclusion was defined.

Norepinephrine Transporter Gene (SLC6A2, NET1) ADHD and oppositional defiant disorder (ODD) often coexist and shared some genetic influences. Liu et al. [176] investigated the role of norepinephrine transporter gene (SLC6A2, NET1) for ADHD comorbid with ODD. Six SNPs of NET1 were genotyped for a total of 1,815 ADHD cases, including 587 subjects (32.3%) with ODD. The pseudo case-control study showed different allelic and genotypic distributions of SNP rs3785143 between ADHD with ODD and those without ODD. Family-based association tests indicated overtransmission of the T allele of rs3785143 in ADHD with ODD trios, but no biased transmission in those without ODD. ANCOVA showed association between genotypes of rs3785143 with ODD symptoms in ADHD probands, especially with 'Argumentative/Defiant Behavior (ADB)' dimension after controlling gender, age, clinical subtypes and intelligence. NET1 was associated with comorbidity of ODD and ODD symptoms in ADHD probands. Based on the evidence from treatment effect of atomoxetine, which interacts directly with the norepinephrine transporter, on visual memory in children with ADHD, Shang et al. [177] examined the linkage disequilibrium structure of the norepinephrine transporter gene (SLC6A2) and the association between SLC6A2 and ADHD and visual memory. In haplotype analyses, a haplotype rs36011 (T)/rs1566652 (G) was significantly associated with ADHD. In quantitative analyses, this TG haplotype also demonstrated significant associations with visual memory measures. The norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD; however, no involvement of changes in brain NET availability or distribution in the pathogenesis of ADHD has been observed in PET studies [178].

Catechol-O-methyltransferase (COMT) The Val158-allele of the catechol-O-methyltransferase (COMT) Val158Met (rs4680) functional polymorphism has been identified as a risk factor for antisocial behavior in ADHD. This SNP affects grey matter (GM) volumes in ADHD. ADHD have a significant decrease of GM volume in the inferior frontal gyrus (IFG). Volume in this region is negatively correlated with ratings of hyperactivity/impulsivity symptoms. The smaller GM volume in the IFG is

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attributed to the presence of the Met158-allele, as only children with ADHD carrying a Met158-allele exhibit such decrease in the IFG. Children with ADHD homozygotes for the Val158-allele exhibit increased GM volume in the caudate nucleus when compared with normal children [179]. Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. Hong et al. [180] studied wholebrain characterization of large-scale axonal connectivity differences in ADHD associated with COMT Val158Met polymorphism. A network of white matter connections linking 18 different brain regions was significantly weakened in youth with ADHD who were COMT Met-carriers compared to those who were Val-homozygous. A measure of white matter integrity, fractional anisotropy, was correlated with impaired pretreatment performance in continuous performance test omission errors and response time variability, as well as with improvement in continuous performance test response time variability after MPH treatment. Altered white matter connectivity was exclusively based on COMT genotypes, and was not evident in DAT1 or DRD4. White matter connectivity in youth with ADHD is associated with COMT Val158Met genotypes. Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. It has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. There is a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between the anterior medial prefrontal cortex (amPFC) and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve [181]. Preliminary data also provide support for a differential impact of COMT genotype on working memory measures in adult patients with ADHD compared to healthy controls [182]. The Continuous Performance Task (CPT) is a widely-used measure of sustained attention and impulsivity. Deficits in CPT performance have been found in several psychiatric disorders, such as ADHD and schizophrenia. Park and Waldman [183] tested the associations of the COMT Val(108/158)Met polymorphism with AX-CPT indices, as well as the variability of these indices across blocks, in a sample of clinic-referred and non-referred children. Significant associations between COMT and variability in the Signal Detection Theory (SDT) indices d‫ ׳‬and lnβ across blocks, as well as a statistical trend for association between COMT and commission errors were found. For some indices the effect of COMT is stronger at higher levels of externalizing psychopathology. Studies in Croatian children with ADHD revealed that the Met/Met genotype or the Met allele of the COMT Val108/158Met, contributing to higher dopaminergic activity, are significantly overrepresented in subjects with moderate or severe hyperactive-impulsive and inattentive symptoms, and that this polymorphism is significantly associated with hyperactive-impulsive and inattentive symptoms in young boys and adolescents [184].

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Monoamine Oxidase (MAO) There is a correlation among the frequencies of the rs5906883 and the rs3027407 alleles of MAO and ADHD [185]. ADHD is the most frequently diagnosed behavioral disorder in children with a high frequency of co-morbid conditions like conduct disorder (CD) and oppositional defiant disorder (ODD). These traits are controlled by neurotransmitters like dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of amines, has been reported to be associated with aggression, impulsivity, depression, and mood changes. MAOA can have a potential role in ADHD associated CD/ODD. Eight markers were found to be polymorphic. rs6323 "G" allele showed higher frequencies in ADHD, ADHD + CD and ADHD + ODD as compared to controls. Haplotype analysis revealed statistically significant difference for three haplotypes in ADHD cases. Statistically significant differences were also noticed for haplotypes in ADHD + CD and ADHD + ODD cases. Genotypes showed correlation with behavioral problems in ADHD and ADHD + CD. MAOA gene variants may contribute to the etiology of ADHD as well as associated co-morbid CD and ODD in an ethnic group from India [186]. MAOA and synaptophysin (SYP) are both on the X chromosome, and have been suggested to be associated with the predominantly inattentive subtype of ADHD (ADHD-I). Potential gene-gene interaction (G × G) between rs5905859 of MAOA and rs5906754 of SYP for ADHD have been reported in Chinese Han subjects [187]. Using functional magnetic resonance imaging and genetic analysis of the MAOA gene, Nymberg et al. [188] investigated how striatal and inferior frontal activation patterns contribute to ADHD symptoms depending on MAOA genotype in a sample of adolescent boys and demonstrated an association of ADHD symptoms with distinct blood oxygen leveldependent (BOLD) responses depending on MAOA genotype. In A hemizygotes of the expression single nucleotide polymorphism rs12843268, which express lower levels of MAOA, ADHD symptoms are associated with lower ventral striatal BOLD response during the monetary incentive delay task and lower inferior frontal gyrus BOLD response during the stop signal task. In G hemizygotes, ADHD symptoms are associated with increased inferior frontal gyrus BOLD response during the stop signal task in the presence of increased ventral striatal BOLD response during the monetary incentive delay task. Depending on MAOA genotype, ADHD symptoms in adolescent boys are associated with either reward deficiency or insufficient response inhibition.

Glutamate Receptors The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. Park et al. [189] investigated the association between the ionotropic and glutamate receptors, N-methyl D-asparate 2A (GRIN2A) and 2B (GRIN2B), and the metabotropic glutamate receptor mGluR7 (GRM7) gene polymorphisms and ADHD in the Korean population. There were no significant differences in the genotype or allele frequencies of the GRIN2A rs8049651, GRIN2B rs2284411, or GRM7 rs37952452 polymorphisms between the ADHD and control groups. For 148 ADHD trios, the TDT analysis also showed no preferential transmission of the GRIN2A rs8049651 or GRIN2B

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rs2284411 polymorphisms. However, the TDT analysis of the GRM7 rs3792452 polymorphism showed biased transmission of the G allele. In the ADHD probands, the subjects with GG genotype in the GRM7 rs37952452 polymorphism had higher mean Tscores for omission errors on the CPT than did those with the GA or AA genotype. ADHD subjects who were homozygous for the G allele in the GRM7 rs37952452 polymorphism had higher STAIC-T and STAIC-S scores than did those with the GA or AA genotype. These results could not be replicated in other populations [190]. Akutagawa-Martins et al. [191] investigated if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD. The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases, but not in individuals without ADHD. Elia et al. [192] performed a whole-genome CNV study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs, and found GRM5 deletions in ten cases and one control, GRM7 deletions in six cases, and GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases. Hadley et al. [193] searched for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. They found significant enrichment of structural defects in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact ADHD and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, were significantly enriched, as is the calmodulin 1 (CALM1) gene interaction network, which regulates voltage-independent calcium-activated action potentials at the neuronal synapse.

Serotonin Transporter (SLC6A4; 5-HTTLPR) The role of the serotonin transporter gene polymorphism 5-HTTLPR in ADHD is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to psychosocial stress than Lallele homozygotes. Van der Meer et al. [194] investigated whether 5-HTTLPR genotype moderates the effects of stress on ADHD in a multisite prospective ADHD cohort study. The interaction between genotype and stress significantly predicted ADHD severity, which was driven by the effect on hyperactivity-impulsivity. S-allele carriers had a significantly more positive correlation between stress and ADHD severity than L-allele homozygotes. The interaction between 5-HTTLPR and stress is a mechanism involved particularly in the hyperactivity/impulsivity dimension of ADHD, and this is independent of comorbid internalizing problems. The 44-base-pair polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been implicated in the etiology of depression. Li and Lee [195] examined individual differences in dimensions of temperament [negative emotionality (NE), prosociality (PRO), and daring (DA)] as potential mediators of 5-HTTLPR genotype and child

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depression in cases of ADHD. The long allele of 5-HTTLPR was associated with higher NE and lower PRO, but not DA. High NE mediated the association of 5-HTTLPR genotype and separate parent and teacher ratings of depression. ADHD status did not moderate the mediational role of NE for 5-HTTLPR and depression.

HTR1A Park et al. [196] investigated the association between the genetic type and alleles for the HTR1A gene in Korean children with ADHD. There was a significant correlation among the frequencies of the rs10042486, rs1423691, and rs878567 alleles of HTR1A with ADHD symptoms.

TPH2/5-HT2C Polymorphisms in the gene encoding the serotonin synthesis enzyme tryptophan hydroxylase 2 (Tph2) have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT-2C receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Identification of a role for a 5-HT2 receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms [197]. In Korean children with ADHD, a significant correlation among the frequencies of the rs11179027 and rs1843809 of alleles of TPH2 was found [198]. Tryptophan hydroxylase-2 (TPH2) is also a potential candidate gene for screening tic disorder (TD). For rs4565946, individuals with the TT genotype showed a significantly higher risk of TD than those with TC plus CC genotypes, as did male TD children with the TT genotype. The G allele of rs4570625 was significantly more frequent in TD children with higher levels of tic symptoms (Yale Global Tic Severity Scale, YGTSS) than those in controls among the male children. TD children with severe tic symptoms had significantly higher frequencies of rs4546946 TT genotype than did normal controls in boys. Genotype distributions of both SNPs were found to be different between the Asian and European populations [199].

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Nicotinic Acetylcholine Receptor Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster have been shown to be involved in tobacco smoking susceptibility. The minor alleles of two polymorphisms (rs578776 and rs3743078) in the CHRNA3 gene are associated with an increased risk of tobacco smoking only among patients with ADHD. These alleles have been shown to be protective factors for smoking in subjects without ADHD [200].

Disrupted-in-Schizophrenia 1 (DISC1) The DISC1 gene was named after its discovery in a Scottish pedigree with schizophrenia (SCZ) patients. The Disrupted-in-schizophrenia 1 (DISC1) gene is involved in vulnerability to neuropsychiatric disorders, especially in psychosis [55-57]. Behavioral and neurochemical effects of immunization against multimeric rat DISC1 protein in adult NHE (Naples highexcitability) rats, an animal model of ADHD, and their Random-Bred (NRB) controls have been reported by Ruocco et al. [201]. Different studies have shown association of DISC1 variants with a range of different neurocognitive phenotypes and psychiatric disorders, including bipolar disorder (BPD), and major depression. ADHD shares some symptoms with BPD and ADHD patients often suffer from comorbid affective disorders. Jacobsen et al. [202] examined the role of DISC1 in ADHD. Eleven SNPs previously implicated in SCZ and BPD, and a DISC1 duplication involving exon 1, were genotyped in 561 adult ADHD cases and 713 controls of Norwegian ancestry. The intronic SNP rs1538979 was associated with ADHD in the Norwegian sample and replicated in a Spanish adult ADHD sample of 694 cases and 735 controls, using the tagging SNP rs11122330. In the Norwegian ADHD sample an association between the Phe607-variant of rs6675281 and a positive score on the Mood Disorder Questionnaire was also observed. This was the first study to show an association between DISC1 variants and ADHD.

Arsenite Methyltransferase Gene (AS3MT) and the Inter-α-Trypsin Inhibitors Heavy Chain-3 Gene (ITIH3) Park et al. [203] examined the association between the selected polymorphisms in two candidate genes, the arsenite methyltransferase gene (AS3MT, rs11191454) and the inter-αtrypsin inhibitors heavy chain-3 gene (ITIH3, rs2535629), and ADHD in a Korean population, and found overtransmission of the A allele at the AS3MT rs11191454 polymorphism in children with ADHD, with no preferential transmission at the ITIH3 rs52535629 polymorphism.

Synaptosome-Related (SNARE) Genes The N-ethylmaleimide-sensitive attachment protein receptor (SNARE) complex which is involved in neurotransmission via exocytosis was implicated in ADHD. Gao et al. [204]

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genotyped 8 SNPs of Syntaxin 1A (STX1A), vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25kDa (SNAP25) and conducted case-control studies in 1404 males with ADHD in China. Genotypic distribution of rs875342 of STX1A was significantly different between ADHD and controls. The SNPs, rs363039 of SNAP25 and rs1150 of VAMP2, were significantly associated with the Rey-Osterrieth complex figure test (RCFT) scores, while rs875342 of STX1A with digit span. They also found genetic interaction models between these three genes and ADHD susceptibility as well as working memory function.

Brain-Derived Neurotrophic Factor (BDNF) Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the central nervous system that plays a critical role in the physiological brain functions via its two independent receptors: tropomyosin-related kinase B (TrkB) and p75, especially in the neurodevelopment. Disrupting of BDNF and its downstream signals has been found in many neuropsychological diseases, including ADHD. Association studies on the functional genetic variation of BDNF and ADHD by a case-control study in the Chinese mainland population revealed the potential correlation between BDNF and ADHD [205]. Park et al. [206] studied whether early parenting is associated with externalizing and internalizing symptoms in children with ADHD and whether such an association is affected by the BDNF Val66Met polymorphism. After adjusting for the child's gender, the child's age, the family's gross annual income, and the maternal education level, there was a significant interaction for the BDNF genotype and mother's positive feelings about caring in relation to the development of childhood anxiety/depression in ADHD children, indicating an interaction between the BDNF Met allele and early parenting on the development of depression/anxiety symptoms.

Neurotrophin-3 (NTF3) Neurotrophin-3 (NTF3), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, has been identified as a factor in the development of ADHD. In case-control and family-based analyses, NTF3 was not significantly associated with ADHD. However, in the ADHD probands, the subjects with AA genotype in the rs6332 SNP had significantly higher mean T-scores for commission errors on the CPT than did those with the AG genotypes. The mean IQ of the ADHD probands who had the CC genotype of the rs6489630 SNP were higher compared with those who had the CT or TT genotype. The mean T-score for response time on the CPT was higher in the subjects with TT genotype in the rs6489630 SNP compared to those with the CC or CT genotype in the Korean population [207].

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GDNF Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for dopaminergic neurons with promising therapeutic potential in Parkinson's disease. A few association analyses between GDNF gene polymorphisms and psychiatric disorders such as schizophrenia, ADHD, drug abuse, anxiety and depression have been reported. Kotyuk et al. [208] studied an association between eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF SNPs and anxiety and depression. Two SNPs (rs3812047 and rs3096140) associated witho anxiety scores but not with depression scores. A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males.

NOS Altered levels of nitric oxide (NO) and its stable metabolites (NOx-) are frequently seen in blood and cerebrospinal fluid of psychiatric patients. Kittel-Schneider et al. [209] studied the concentrations of NO2- and NO3- in peripheral blood of patients with ADHD and bipolar disorder (BPD), as well as genotypes of a three marker haplotype in the NOS3 gene (rs2070744, rs1799983 and Intron 4 VNTR) and genetic variants of the NOS1 gene (NOS1 ex 1c, NOS1 ex 1f). The German authors found significantly lower NOx- levels in BPD. rs2070744 T/T-carriers of the whole sample showed increased mRNA expression of NOS3. Only in BPD an influence of rs2070744 was seen regarding NO metabolite levels, with C/C carriers displaying lower NOx- levels. These results replicate previous findings showing altered NOx- levels in BPD and an influence of NOS3 rs2070744 on NOS3 expression and NOx- concentration, with no apparent influence of the nitrinergic pathway in adult ADHD.

FTO Several studies have reported that ADHD subjects are more likely to be overweight/obese and that this comorbidity may be due to shared genetic factors. Choudhry et al. [210] explored the association between ADHD and FTO, a gene strongly associated with obesity in genome-wide studies. One tag SNP (rs8050136, risk allele A) in the FTO gene was selected and its association with ADHD was tested. Statistically significant associations were observed between rs8050136 and several of the traits tested in the total sample.

Per1b The zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. The circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine β hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and

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organization in the ventral diencephalic posterior tuberculum. Per1 knock-out mice display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD [72].

Neurokinin-1 Receptors (NK1R/TACR1) Mice lacking functional neurokinin-1 receptors (NK1R-/-) display abnormal behaviors seen in ADHD (hyperactivity, impulsivity and inattentiveness). NK1R-/- mice are hyperactive compared with their wild-types and their diurnal rhythm is also disrupted. NK1R-/- mice express more impulsive and perseverative behavior than their wild-types. The hyperactivity, perseveration and, possibly, inattentiveness of NK1R-/- mice is a direct consequence of a lack of functional NK1R. The greater impulsivity of NK1R-/- mice probably depends on an interaction between a functional deficit of NK1R and other environmental and/or epigenetic factors [211]. Atomoxetine reduces hyperactive/impulsive behaviors in NK1R-/- mice [212].

SNAP-25 The synaptosomal-associated protein of 25 kDa (SNAP-25) gene is a presynaptic plasma membrane protein and an integral component of the vesicle docking and fusion machinery mediating secretion of neurotransmitters. SNAP25 is a member of the soluble Nethylmaleimide-sensitive factor attachment receptor (SNARE) protein complex, which plays essential roles in the modulation of different voltage-gated calcium channels and neurotransmitter release. Several studies reported association between SNAP-25 polymorphisms (MnlI T/G and DdelI T/C) and ADHD in different populations [213]. Shared genetic variants have been demonstrated in 5 major psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorders, and ADHD. Two SNPs, rs3787283 and rs3746544, were found to be associated with both schizophrenia (rs3746544) and major depressive disorder (rs3746544). The AG haplotype consisting of rs3787283 and rs3746544 was also significantly associated with both schizophrenia and major depressive disorder in the Han Chinese population [214]. SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. Braida et al. [215] analyzed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and EEG abnormalities. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice.

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Polymorphic variants of the SNAP-25 gene emerged as putative genetic components of impulsivity, as SNAP-25 protein plays an important role in the central nervous system, and its SNPs are associated with several psychiatric disorders. Genotypes and haplotypes of two polymorphisms in the promoter (rs6077690 and rs6039769) and two SNPs in the 3' UTR (rs3746544 and rs1051312) of the SNAP-25 gene were determined in a healthy Hungarian population. Significant association was found between the T-T 3' UTR haplotype and impulsivity, whereas no association could be detected with genotypes or haplotypes of the promoter loci. According to sequence alignment, the polymorphisms in the 3' UTR of the gene alter the binding site of microRNA-641. Haplotypes altering one or two nucleotides in the binding site of the seed region of microRNA-641 significantly increased the amount of generated protein in vitro [216]. Gálvez et al. [217] found a significant association of ADHD with the GT haplotype (rs3746554|rs1051312) of SNAP-25 in Colombian children. Evidence of association was also found for the G/G genotype of rs3746554 and C/C genotype of rs1051312. Polymorphisms are located in 3' untranslated region of SNAP-25, positions T1065G and T1069C. Significant associations with the A allele of SNP rs362990 and three marker haplotypes (rs6108461, rs362990 and rs362998) were observed in ADHD. DNA variation at SNAP-25 confers risk to ADHD and reduces the expression of the transcript in a region of the brain that is critical for the regulation of attention and inhibition [218].

LPHN3 Linkage studies have been successful in identifying loci for adult ADHD and led to the identification of LPHN3 as a novel gene associated with ADHD across the lifespan [219]. Fallgatter et al. [220] examined the impact of an LPHN3 haplotype that has recently been associated with ADHD on neural activity in a visual Go-NoGo task. Patients carrying two copies of the LPHN3 risk haplotype made more omission errors and had a more anterior Gocentroid of the P300 than patients carrying at least one LPHN3 non-risk haplotype. Accordingly, the NoGo-Anteriorization (NGA; topographical ERP difference of the Go- and NoGo-condition), a neurophysiological marker of prefrontal functioning, was reduced in the LPHN3 high risk group. In the NoGo-condition itself no marked differences attributable to the LPHN3 haplotype could be found. Within a sample of ADHD patients, the LPHN3 gene impacts behavioral and neurophysiological measures of cognitive response control.

FBXO33 Sánchez-Mora et al. [221] found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in ADHD. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1,300 adult subjects. This finding points for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establishes a rationale for searching for additional risk variants in ubiquitination-related genes.

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GUCY2C Transmission disequilibrium tests (TDT), case-control studies and quantitative analyses indicated association between GUCY2C with ADHD and its core symptoms. Guanylyl cyclase-C knock-out mice exhibit hyperactivity and attention deficits [222].

ZBTB20 A number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. In a patient with developmental delay, ADHD, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. In a second patient with developmental delay and autism, there was a microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, 68 genes were found to be associated with NDD. Rasmussen et al. [223] validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25). These studies links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome. BTBD9 Variants of the BTBD9 gene (rs4714156, rs9296249 and rs9357271) have been reported to be associated with GTS in French Canadian and Chinese Han populations. Janik et al. [224] tested the association between GTS and polymorphisms of the BTBD9 gene in Polish patients. No significant differences were found in minor allele frequencies (MAFs) of the SNPs tested in this population. The frequency of MAFs of the genotyped SNPs was lower in GTS patients with ADHD and higher in GTS patients without comorbidities. There was a trend toward an association between the minor allele of the SNPs and mild tics. BTBD9 variants are not associated with GTS risk, but may be associated with comorbidity and tic severity in the Polish population.

Folate-Related Genes ADHD-related cognitive deficit might be attributed to abnormalities in the folate cycle. Saha et al. [225] explored functional single nucleotide polymorphisms in methylenetetrahydrofolate dehydrogenase (rs2236225), reduced folate carrier (rs1051266), and methylene-

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tetrahydrofolate reductase (rs1801131 and rs1801133) in families with ADHD probands and ethnically matched controls. Genotypic frequencies of the Indian population were strikingly different from other ethnic groups. rs1801133 "T" allele showed biased transmission in female probands. Significant difference in genotypic frequencies for female probands was also noticed. rs1801131 and rs1801133 showed an association with low intelligence quotient (IQ). MDR analysis exhibited independent effects and contribution of these sites to IQ, thus indicating a role of these genes in ADHD related cognitive deficit. Spellicy et al. [226] examined the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to ADHD in individuals with myelomeningocele. 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. A positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the ADHD phenotype was observed in myelomeningocele participants. Behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population.

Thyroid Hormone Receptor β ADHD has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor β (TRβ) gene. TRβ is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself [227].

eNHE There has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na+/H+ exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, ADHD, intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na+, K+) content in early and recycling endosomal compartments. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain,

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including hippocampus and cortex. eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters [228].

KCNJ5 Linkage and association of Tourette Syndrome (TS) and ADHD have been reported in the 11q24 chromosomal region. To identify the risk gene within the region, Gomez et al. [229] studied the potassium inwardly-rectifying channel J5 (KCNJ5) gene in a sample of 170 nuclear families with TS. The authors genotyped eight markers across the gene and observed biased transmission of haplotypes from parents to probands in this sample. The same haplotype was significantly over transmitted to ADHD probands. Significant evidence for association with the 3' repeat and ADHD was found. A small gene (c11orf45) of unknown function lies within the first intron of KCNJ5 that is transcribed in the opposite orientation and this gene may regulate the expression of KCNJ5. The antisense transcript and the short KCNJ5 isoform are co-expressed in three brain regions. KCNJ5 is associated with TS and ADHD in a Canadian sample.

TRIM32 Tripartite motif-containing protein 32 (TRIM32) was strongly associated with autism spectrum disorder, ADHD, anxiety and obsessive compulsive disorder based on a study of copy number variation, and deletion of TRIM32 increased neural proliferation and reduced apoptosis. TRIM32 is involved in chronic stress-induced affective behaviors. Using a chronic unpredictable mild stress mouse depression model, Ruan et al. [230] studied expression of TRIM32 in brain tissue samples and observed behavioral changes in Trim32 knockout mice. TRIM32 protein but not its mRNA was significantly reduced in hippocampus in a timedependent manner within 8 weeks of chronic stress. These stress-induced affective behaviors and reduction of TRIM32 protein expression were significantly reversed by antidepressant fluoxetine treatment. Trim32 knockout mice showed reduced anxiety and depressive behaviors and hyperactivities compared with Trim32 wild-type mice under normal and mild stress conditions. TRIM32 may play some role in regulation of hyperactivities and positively regulates the development of anxiety and depression disorders induced by chronic stress.

PON1 Paraoxonase 1 (PON1) is an enzyme involved in detoxifying some organophosphate (OP) pesticides and its polymorphisms influence enzyme activity and quantity. Fortenberry et al. [231] examined whether maternal and/or child PON1 genotypes (PON1R192Q and PON1L55M) were associated with ADHD-LP in a Mexico City, Mexico birth cohort. PON1R192Q and PON1L55M genotypes in mothers and children from blood DNA were determined. Significant associations were observed with maternal genotypes but not with the child genotypes. A higher DSM IV Hyperactivity/Impulsivity score and a 2.17 higher score in

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child DSM IV Total were observed for maternal PON155MM in comparison to PON155LM+LL. The child attention problems score was 2.27 points higher for maternal PON1192QQ in comparison to PON1192QR+RR. Because maternal PON1 polymorphisms were associated with child ADHD-LP, this may be a viable biomarker of susceptibility for ADHD-LP.

TACR1 SNPs in the tachykinin receptor 1 gene (TACR1) were nominally associated with bipolar affective disorder (BPAD) in a genome-wide association study and in several case-control samples of BPAD, alcohol dependence syndrome (ADS) and ADHD. Eighteen TACR1 SNPs were associated with BPAD in a sample from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD and BPALC compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1-susceptibility haplotypes identified 19 SNPs in the promoter region, 5' UTR, exons, intron/exon junctions and 3' UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10-fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders [232].

Zinc Finger Genes ZNF804A has been identified as one of the most compelling risk genes associated with broad phenotypes related to psychosis. Sun et al. [233] conducted a systematic meta-analysis and reviewed ZNF804A variants in psychosis-related disorders, including schizophrenia, bipolar disorder, and ADHD. The meta-analysis included a total of six variants of ZNF804A and three variants of other ZNFs (ZDHHC8 and ZKSCAN4), and the effects of ZNF variants on neurocognition and neuroimaging phenotypes were reviewed. ZNF804A was significantly related to psychiatric diseases, and the association between ZNF804A rs1344706 and psychosis (schizophrenia and bipolar disorder) did not vary with disease or ethnicity. The main brain area regulated by ZNF804A rs1344706 was the dorsolateral prefrontal cortex. ZNF804A might play an important role in common pathogenesis of psychiatric diseases, and its variants are likely involved in regulating the expression of psychosis-related genes, especially the dopamine pathway genes. Evidence from large GWAS indicates that the SNP rs1344706 in the zinc-finger protein 804A gene (ZNF804A) is associated with psychotic disorders including bipolar disorder and schizophrenia. One study also found significant association between rs1344706 and the executive control network of attention. Xu et al. [234]

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examined the role of the rs1344706 polymorphism that previously showed association with BD and is known to alter expression of the gene in two clinical family-based ADHD samples from the UK and Taiwan, but results showed no significant association of rs1344706 with ADHD in UK and Taiwanese samples.

SorCS2 SorCS2 is a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. In PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2-/- mice. Two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins [235].

Ankyrin 3 (ANK3) AnkyrinG, encoded by the ANK3 gene, is involved in neuronal development and signaling. It has been implicated in bipolar disorder and schizophrenia by association studies. De novo missense mutations in this gene were identified in autistic patients. Iqbal et al. [236] reported inactivating mutations in the ANK3 gene in patients with severe cognitive deficits. In a patient with a borderline intelligence, severe ADHD, autism and sleeping problems, all isoforms of the ANK3 gene were disrupted by a balanced translocation. In a consanguineous family with moderate intellectual disability (ID), an ADHD-like phenotype and behavioral problems, they identified a homozygous truncating frameshift mutation in the longest isoform of the same gene, which represents the first reported familial mutation in the ANK3 gene. The causality of ANK3 mutations in the two families and the role of the gene in cognitive function were supported by memory defects in a Drosophila knockdown model. ANK3 plays a role in intellectual functioning.

CAMTA1 Intragenic copy number variations involving the CAMTA1 (calmodulin-binding transcription activator 1) gene have recently been reported in four unrelated families with intellectual disability (ID), ataxia, behavioral- and cerebellar-abnormalities. Shinawi et al. [237] reported a detailed phenotypic and molecular characterization of three individuals with novel intragenic CAMTA1 deletions from two unrelated families and compared the findings to those of previously reported patients. These patients had deletions of exons 6-11 and

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presented with ID, developmental delay (DD), ADHD and constipation. Two individuals from one family had also unsteady gait. Consistent phenotypes associated with CAMTA1 intragenic rearrangements include ID, speech problems and some dysmorphic features whereas neurobehavioral abnormalities are variable. Phenotypic differences between patients with in-frame and those with frameshift rearrangements were not observed. CAMTA1 has a role in brain and cerebellar function. CAMTA1 should be added to the growing list of genes associated with ID/DD, especially when behavioral problems, cerebellar signs, and/or dysmorphism are also present.

CDH13 and Adiponectin Mavroconstanti et al. [238] investigated serum levels of adiponectin in adult patients with ADHD and examined the effects of rare missense mutations in T-cadherin, an adiponectin receptor encoded by the ADHD candidate gene CDH13, on serum adiponectin levels. Decreased serum adiponectin levels were found in ADHD patients. HMW adiponectin and its ratio to total adiponectin were significantly associated with ADHD. HMW adiponectin and its ratio to total adiponectin were significantly inversely correlated with self-reported psychiatric symptomatology. A non significant trend for higher levels of total adiponectin was observed in patients carrying CDH13 missense mutations compared to patients with wild type CDH13. ADHD patients have decreased serum adiponectin levels, which are inversely correlated to psychiatric symptoms, suggesting a possible involvement of adiponectin, in particular the HMW form, in the pathophysiology of ADHD. Cadherin-13 (CDH13) is a cell adhesion molecule which was associated with liability to ADHD and related neuropsychiatric conditions. Alterations in Cadherin-13 signaling may contribute to the pathophysiology of neurodevelopmental disorders [239].

BAIAP2 Hemisphere asymmetry has been found in ADHD probands at behavioral level, electrophysiological level and brain morphology. An association between BAIAP2, which is asymmetrically expressed in the two cerebral hemispheres, with ADHD has been reported in European and Chinese populations. Transmission disequilibrium tests (TDTs) for familybased association studies showed significant association between the CA haplotype comprised by rs3934492 and rs9901648 with predominantly inattentive type (ADHD-I). There is also evidence for the contribution of SNP rs4969239, rs3934492 and rs4969385 to ADHD and its two clinical subtypes, ADHD-I and ADHD-C [240].

Oxytocin Oxytocin has repeatedly been shown to influence human behavior in social contexts; and a relationship between oxytocin and the pathophysiology of autism spectrum disorder (ASD) has been suggested. Hovey et al. [241] investigated SNPs in the oxytocin gene (OXT) and the

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genes for single-minded 1 (SIM1), aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) and cluster of differentiation 38 (CD38) in a population of 1771 children from the Child and Adolescent Twin Study in Sweden (CATSS). They found a statistically significant association between the SIM1 SNP rs3734354 (Pro352Thr) and scores for language impairment. Nominal associations were found between ASD scores and SNPs in OXT, ARNT2 and CD38.

VAMP-2 and Syntaxin 1A Kenar et al. [242] investigated the association of the synaptobrevin-2 (VAMP-2) gene Ins/Del polymorphism and STX1A gene intron 7 polymorphism, which take place in encoding presynaptic protein, with adult ADHD. A significant difference was observed between ADHD and VAMP-2 Ins/Del polymorphism and STX1A intron 7 polymorphism according to the control group. These polymorphisms were found not to be associated with subtypes of ADHD.

CES1 CES1 markers in linkage disequilibrium with two SNP markers of the noradrenaline transporter gene (SLC6A2) are significantly associated with ADHD. Genetic variation of the CES1 gene coding for carboxylesterase 1A1 (CES1A1), the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate, may play some role in the pharmacogenetics of methylphenidate [243].

ADORA2A The adenosine A2A receptor (ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with ADHD traits. Animal studies suggest that the ADORA2A may influence ADHD-like behavior. Molero et al. [244] examined the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population-based sample. This study was based on the Child and Adolescent Twin Study in Sweden (CATSS), and included 1747 twins. Results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474.

NPSR1 Neuropeptide S and its receptor NPSR1 are involved in the regulation of arousal, attention and anxiety. Laas et al. [245] examined whether the NPSR1 gene functional polymorphism Asn¹⁰⁷Ile (rs324981, A>T) influences personality, impulsivity, and ADHDrelated symptoms in a population-representative sample, and whether any eventual

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associations depend on age, sex, family relations and stressful life events (SLE). Males with the TT genotype displayed more ADHD-related symptoms. Adaptive impulsivity and extraversion increased the most from age 18 to 25. While highest increases were observed in AA men, TT women exhibited the largest decreases. For participants with the AA genotype, warmth in family was inversely associated with neuroticism, and positively associated with extraversion and adaptive impulsivity. High exposure to SLE increased impulsivity and ADHD scores in TT genotype subjects. NPSR1 A/T polymorphism is associated with impulsivity, ADHD symptoms and personality, mirroring the activity- and anxiety-mediating role of NPSR1. Heterozygous individuals were the least sensitive to environmental factors, whereas subjects with the AA genotype and TT genotype reacted to different types of environmental adversities.

FMR1 Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM-carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Compared to controls, PM-carriers are significantly elevated on self-reported social anxiety and ADHD-PI symptoms. Irrespective of mental symptoms, female PM-carries perform significantly worse than controls on a response inhibition test, and there are significant correlations between executive function performance and self-reported symptoms of anxiety, depression and ADHD-PI. Among PM-carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%) [246].

CLOCK Circadian rhythm disturbance is highly prevalent in ADHD. The association between the CLOCK gene and ADHD has been demonstrated in clinical samples, and the CLOCK gene's role was thought to be mediated by rhythm dysregulation. Jeong et al. [247] found that rs1801260 (=T3111C) was associated with Wender Utah Rating Scale (WURS) scores in both allele-wise and haplotype-wise analyses in Korean males only. The CLOCK gene's association with ADHD in clinical samples may be generalizable to traits measured in the normal population.

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BCHE A copy number variation (CNV) in ADHD revealed a de novo chromosome 3q26.1 deletion in one of the patients. Candidate genes at this locus include the acetylcholinemetabolizing butyrylcholinesterase (BCHE) expressing gene. Jacob et al. [248] investigated the hypothesis that the heterozygous deletion of the BCHE gene is associated with adult ADHD (aADHD). 96 individuals displayed entirely homozygous genotype reads in all 12 examined SNPs, making them possible candidates to harbor a heterozygous BCHE deletion. DNA from these 96 probands was further analyzed by real-time PCR using a BCHE-specific CNV assay; however, no deletion was found. Of the 12 tag SNPs that passed inclusion criteria, rs4680612 and rs829508 were significantly associated with aADHD, as their minor alleles occurred more often in cases than in controls. The risk variant rs4680612 is located in the transcriptional control region of the gene and predicted to disrupt a binding site for MYT1, which has previously been associated with mental disorders. However, when examining a second independent adult ADHD sample of 353 cases, the association did not replicate. When looking up the deletion in three genome-wide screens for CNV in ADHD and combining it with this study, it became apparent that 3 from a total of 1030 ADHD patients, but none of 5787 controls, featured a deletion of the BCHE promoter region including rs4680612. There are several lines of evidence suggesting a potential involvement of BCHE in the etiopathology of ADHD, as a rare hemizygous deletion as well as a common SNP in the same region are associated with disease, although with different penetrance. Both variations result in the disruption of the binding site of the transcription factor MYT-1 suggesting epistatic effects of BCHE and MYT-1 in the pathogenesis of ADHD.

miR-183-96-182 Cluster SNPs within miRNAs or miRNA target sites may modulate the miRNA-mediated regulation of gene expression through the alteration of the miRNA maturation, structure or expression pattern as well as the silencing mechanisms of target genes. Genetic studies and animal models support the involvement of the serotonin receptor (HTR1B) in ADHD. Sánchez-Mora et al. [249] evaluated the contribution of one SNP in the miR-96 target site at HTR1B and eight tagSNPs within the genomic region containing this miRNA in 695 adults with ADHD, 403 subjects with SUD without life-time diagnosis of ADHD and 485 sexmatched controls from Spain. Single and multiple marker analyses revealed association between two SNPs located at the 3' region of miR-96 (rs2402959 and rs6965643) and ADHD without SUD. These results provide preliminary evidence for the contribution of two sequence variants at the miR-183-96-182 cluster to ADHD without comorbid SUD, and emphasize the need to take comorbidities into account in genetic studies to minimize the effect of heterogeneity and to clarify these complex phenotypes.

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UPF3B Loss-of-function mutations in UPF3B result in variable clinical presentations including intellectual disability (ID, syndromic and non-syndromic), autism, childhood onset schizophrenia and ADHD. UPF3B is a core member of the nonsense-mediated mRNA decay (NMD) pathway that functions to rapidly degrade transcripts with premature termination codons (PTCs). Traditionally identified in thousands of human diseases, PTCs were recently also found to be part of 'normal' genetic variation in human populations. Many human transcripts have naturally occurring regulatory features compatible with 'endogenous' PTCs strongly suggesting roles of NMD beyond PTC mRNA control. Jolly et al. [250] investigated the role of Upf3b and NMD in neural cells. Upf3b-dependent NMD (Upf3b-NMD) is regulated at multiple levels during development including regulation of expression and subcellular localization of Upf3b. Complementary expression of Upf3b, Upf3a and Stau1 stratify the developing dorsal telencephalon, suggesting that alternative NMD, and the related Staufen1-mediated mRNA decay (SMD) pathways are differentially employed. A loss of Upf3b-NMD in neural progenitor cells (NPCs) resulted in the expansion of cell numbers at the expense of their differentiation. In primary hippocampal neurons, loss of Upf3b-NMD resulted in subtle neurite growth effects. The cellular consequences of loss of Upf3b-NMD can be explained in-part by changes in expression of key NMD-feature containing transcripts, which are commonly deregulated also in patients with UPF3B mutations.

Synapsin III (SYN3) Kenar et al. [251] investigated the association of the SYN3 gene -196 G> A and -631 C>G polymorphisms that takes place in an encoding presynaptic protein, with adult ADHD. A significant difference was determined between ADHD and synapsin III gene -631 C>G polymorphism compared to the control group. No significant difference was observed between ADHD and SYN3 gene -196 G>A polymorphism. These polymorphisms were found not to be associated with subtypes of ADHD.

SYP Genes encoding proteins involved in the vesicular release process of neurotransmitters are attractive candidates in ADHD genetics. One of these genes is SYP, which encodes synaptophysin, a protein known to participate in regulating neurotransmitter release and synaptic plasticity. Several studies have reported an association between SYP and ADHD. Liu et al. [252] investigated this association in Chinese Han subjects by family-based and casecontrol studies. Transmission disequilibrium tests (TDTs) in 1112 trios found significant association between SYP and the predominantly inattentive subtype (ADHD-I), especially for males with ADHD-I, both from SNP and haplotypic analyses. Chi-square tests in 1682 ADHD probands and 957 comparison subjects indicated possible association of SYP with female ADHD and female ADHD-I. However, the associated alleles and haplotypes between

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males and females were reversed. SYP may be primarily associated with ADHD-I and its genetic mechanism may be gender-specific.

Figure 4. Distrution of APOE genotypes in patients with anxiety (ANX), depression (DEP), psychosis (PSY), ADHD, epilepsy (EPI), mental retardation (MR), and controls.

APOE Apolipoprotein E (APOE) participates in brain maturation, cerebrovascular and cardiovascular function, cognition, and neurodegeneration [253]. Although APOE variants are not different in ADHD as compared with the general population (Figure 4), cortical oxygenation is APOE genotype-dependent in ADHD (Figure 5), schizophrenia, and Alzheimer‘s disease. In addition, APOE variants influence behavior, cognitive function, and the therapeutic response to conventional drugs [254].

Multilocative Defects and GWAS As a general rule, most CNS complex disorders are the result of multiple genetic defects distributed across the human genome [253], with substantial overlap of similar genomic segments in different brain disorders. The Psychiatric GWAS Consortium Coordinating Committee [255] conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. Most of the genomic DNA sequence differences between any two people are common (frequency >5%) SNPs. Because of

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localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and ADHD.

Figure 5. APOE-related brain optical topography mapping of a child with ADHD at baseline, during auditory stimulation, and 20 seconds after stimulation.

Guilmatre et al. [256] investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci was significantly increased in cases with autism, schizophrenia, and mental retardation compared with controls. Individual significance was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs are present in different CNS conditions, supporting the existence of shared biologic pathways in neurodevelopmental disorders.

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Significant linkage of ADHD to 4q, 5q, 8q, 11q and 17p has been found in an isolate population. Several analytical models converged to show significant interaction between 4q and 11q and 11q and 17p. Common variants of the LPHN3 gene were responsible for the 4q linkage signal. Latrophilins (LPHN) are part of a yet unexplored family of receptors comprising three isoforms, LPHN1-3, and belonging to a unique branch of G protein-coupled receptors (GPCR) named adhesion GPCR (aGPCR). LPHN are considered to be prototypical models for the study of aGPCR as they are one of the most evolutionary conserved members [257]. SNPs harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD [258] also to increase ADHD severity. Genetic interactions may predict the severity of ADHD, which in turn may predict long-term ADHD outcome [259]. Haplotypes co-segregating with ADHDaffected individuals were identified at chromosomes 1q25, 5q11-5q13, 9q31-9q32, and 18q11-18q21 in the German population [260]. Many GWAS have been performed for the past few years with variable results. When evaluating uncommon variants (minor allele frequency, ≤ 5%) that have reached genomewide significance (p ≤ 10⁻⁷) in GWAS, although the number of uncommon variants with genome-wide significance is still limited, it appears that there is a possible confluence of rare/uncommon and common genetic variation on the same genetic loci [1, 261]. Recent genome-wide analyses for risk genes revealed synaptic adhesion molecules (latrophilin-3, LPHN3; fibronectin leucine-rich repeat transmembrane protein-3, FLRT3), glutamate receptors (metabotropic glutamate receptor-5, GRM5) and mediators of intracellular signalling pathways (nitric oxide synthase-1, NOS1). These genes encode principal components of the molecular machinery that connects pre- and postsynaptic neurons, facilitates glutamatergic transmission, controls synaptic plasticity and empowers intersecting neural circuits to process and refine information [262]. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤ 1%) CNVs that increase the risk of ADHD, Jarick et al. [263] performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult populationbased controls and identified one significantly associated CNV region. In tests for a global burden of large (> 500 kb) rare CNVs, they observed a nonsignificant 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases and rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls. The PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. The authors validated 11 of the 12 CNVs in ADHD patients. CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control. Copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease. Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. Nudel et al. [264] reported the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. The authors found genomewide significant paternal parent-of-origin effects on chromosome 14q12 and suggestive maternal parent-of-origin effects on chromosome 5p13. A subsequent targeted association of

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six SNPs on chromosome 5 in 313 language-impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. A genome-wide significant locus for ASD/ADHD was found on chromosome 7q11, and 2 other suggestive loci were identied on chromosomes 4q35 and 7p12 [265]. Children with ADHD have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. Albayrak et al. [266] examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). They screened 32 obesity risk alleles of SNPs in a GWAS for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD metaanalysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk. In the meta-analysis data the authors found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample, rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/ impulsivity. In another GWAS of ADHD in Australia, Ebejer et al. [267] observed that neither the GWAS nor subsequent meta-analyses yielded genome-wide significant results; the strongest effect was observed at rs2110267 for symptoms of hyperactivity-impulsivity. The strongest effect in the gene-based test was for GPR139 on symptoms of inattention.

Copy Number Variants Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in ADHD. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD. This increased rate of CNVs was particularly high in those with intellectual disability, although there was also a significant excess in cases with no such disability. An excess of chromosome 16p13.11 duplications was noted in ADHD. CNVs identified in ADHD were significantly enriched for loci previously reported in both autism and schizophrenia [268].

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15q11.2 (BP1-BP2) Microdeletion Syndrome Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Clinical features include developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%); seizures/epilepsy (26%), autism spectrum disorder (27%), ADHD (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%) [269]. Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Vanlerberghe et al. [270] investigated the phenotypes associated with this microdeletion in a cohort of 52 patients. This CNV was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as ADHD, autistic spectrum disorder or obsessive-compulsive disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, `de novo` microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. 15q13.3 Microdeletions Evidence has supported a role for rare CNVs in the region 15q13, which is also a hot spot for several neuropsychiatric disorders. This region spans several genes. Valbonesis et al. [271] found 15q13 deletions in two ADHD patients and identified 129 genes as significantly dysregulated in the blood of the two ADHD patients carrying 15q13 deletions compared with ADHD patients without 15q13 deletions. Genes in the deleted region (KLF13, MTMR10) were down-regulated in the two patients with deletions. A pathway analysis identified apoptosis, oxidation reduction, and immune response as the mechanisms that were altered most significantly in the ADHD patients with 15q13 deletions. Deletions in KLF13 and CHRNA7 influenced the expression of genes belonging to the same immune/inflammatory and oxidative stress signaling pathways. A small rare paternal inherited microdeletion (∼64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset obsessive-compulsive disorder (OCD) [272]. Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined. Lowther et al. [273] identified a total of 246

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cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4-BP5) region, including seven novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin. Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and ADHD in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases. 15q13.3 Duplications Williams et al. [274] observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. 15q13.3, 15q11.2, and 16p13.11 Microdeletions Ramos-Quiroga et al. [275] performed for the first time a whole-genome CNV study on 400 adults with ADHD and 526 screened controls. In agreement with recent reports in children with ADHD or in other psychiatric disorders, they identified a significant excess of insertions in ADHD patients compared to controls. The overall rate of CNVs >100 kb was 1.33 times higher in ADHD subjects than in controls, an observation mainly driven by a higher proportion of small events (from 100 kb to 500 kb; 1.35-fold). CNVs are also common in children with epilepsy and intellectual disability (ID-GGE) with recurrent deletions at 15q13.3, 15q11.2, and 16p13.11 [276]. ID-GGE probands show a significantly higher rate of CNVs compared with probands with GGE alone, with 17 of 60 (28%) ID-GGE probands having one or more potentially causative CNVs. The patients with ID-GGE had a 3-foldhigher rate of the 3 GGE-associated recurrent microdeletions than probands with GGE alone (10% vs 3%). They also showed a high rate (13/60, 22%) of rare CNVs identified using genome-wide CGH [276]. Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for idiopathic generalized epilepsies (IGE) and other neurodevelopmental disorders. Ten microdeletions in 15q11.2, 15q13.3 and 16p13.11 were identified (1.8%). 9/10 microdeletions were identified in patients with IGE (6/101, 6.0%) or patients with generalized EEG patterns without seizures (3/122, 2.5%). 6/10 microdeletion carriers had various degrees of intellectual disability; the frequency of microdeletions in patients with epilepsy and ID was higher (4.6%) compared to patients with normal intellect (0.9%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes. Recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are mainly associated with phenotypes related to idiopathic generalized epilepsies

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or related EEG patterns. These recurrent microdeletions are virtually absent in focal epilepsies, or other forms of epilepsy. Microdeletion carriers have a five-fold risk to present with various degrees of intellectual disability compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data [277]. Jerkovich and Butler [278] reported the case of a 10-year-old Caucasian male identified with copy number variation detected by microarray analysis including a maternally inherited 15q11.2 microdeletion involving 4 genes, paternally inherited 13q12.2 microdeletion with 10 genes, and a de novo 2q14.3 duplication involving 4 genes. This child had a history of speech delay, cognitive deficits, ADHD and a posterior lenticonus cataract removed at 5 yr of age. The genes on chromosomes 2 and 13 are not known to be involved with cataract formation, which lends further support of the role of the 15q11.2 region and additional evidence for phenotypic expansion of the 15q11.2 BP1-BP2 microdeletion (termed Burnside-Butler) syndrome. 16p11.2 and 19p13 Microdeletions Other two large, rare CNVs have been identified in cases of epilepsy and intellectual disability: a deletion of chromosome 16p11.2, which has been previously associated with intellectual disability and autism, and a 0.9 Mb deletion of 19p13.2, which results in the deletion of a cluster of zinc finger genes. Bassuk et al. [279] suggest that, while the 16p11.2 deletion is likely the primary cause of the obesity and intellectual disability, the 19p13.2 deletion may act as a modifier of the epilepsy phenotype, which is not a core feature of the 16p11.2 deletion syndrome. ZNF44, a gene within the deleted region, is associated with a cohort of patients with generalized epilepsy. 16p11.2-p12.2 Duplication Syndrome Chromosome 16 contains multiple CNVs that predispose to genomic disorders. Barber et al. [280] differentiated pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An 1.11-Mb CNV of 10q11.21 is a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. Euchromatic variants are amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis. 3q29 Microdeletion Syndrome The screening of individuals with mild dysmorphic features and mental retardation using whole genome scanning technologies has resulted in the delineation of several previously

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unrecognized microdeletion syndromes. Microdeletion of 3q29 has been recently described as one such new syndrome. The clinical phenotype is variable despite an almost identical submicroscopic deletion size in most cases. Quintero-Rivera et al. [281] reported the cases of two individuals that further expand the clinical presentation of this rare disorder and compared the findings with earlier reports to refine the 3q29 microdeletion syndrome phenotype. The propositi were a 10-year-old female and a 15-year-old male, who have in common intellectual disabilities, a history of autism and psychiatric symptoms ranging from bipolar disorder presenting with increasing suicidal ideation to aggressive behavior and general anxiety. Other shared physical findings include asymmetric face, high-nasal bridge, crowded/dysplastic teeth, and tapered fingers. Oligonucleotide array-based chromosomal microarray analysis (CMA) using a genome-wide SNP array identified a de novo subtelomeric microdeletion of chromosome region 3q29 ranging from 1.6 to 2.1 Mb. The region of overlap encompasses 20 RefSeq genes, including FBX045, DLG1, and PAK2. These genes are related to neuronal postsynaptic membrane function and PTEN signaling, suggesting a role for synaptic connectivity dysfunction in the etiology of autism in these children. The novel clinical presentation of these patients expands the clinical spectrum of the 3q29 microdeletion syndrome. The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations [282]. 1q41-42 Microdeletion Syndrome Shaffer et al. [283] tested more than 10,000 patients with developmental disabilities for patients with a potential 1q41q42 microdeletion syndrome. They found cases with de novo deletions of 1q41q42. The smallest region of overlap was 1.17 Mb and encompasseed five genes, including DISP1, a gene involved in the sonic hedgehog signaling pathway, the deletion of which has been implicated in holoprosencephaly in mice. Although none of these patients showed frank holoprosencephaly, many had other midline defects (cleft palate, diaphragmatic hernia), seizures, and mental retardation or developmental delay. Dysmorphic features were present in all patients at varying degrees. Some patients showed more severe phenotypes and carry the clinical diagnosis of Fryns syndrome. Multilocative Deletion Syndromes Other microdeletion syndromes associated with neurodevelopmental disorders, which have been identified in recent times, include the 17q21.31 deletion and 17q21.31 duplication syndromes, 15q13.3 deletion syndrome, 16p11.2 deletion syndrome, 15q24 deletion syndrome, 1q41q42 deletion syndrome, 2p15p16.1 deletion syndrome and 9q22.3 deletion syndrome [284]. Elia et al. [285] identified 222 inherited CNVs within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions,

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including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. ADHD and autism spectrum disorder (ASD) often co-occur and share genetic risks. Martin et al. [286] compared CNV data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. The biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample. These results indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions. 16p11.2 Microdeletion Syndrome The 16p11.2 microdeletion syndrome is characterized by a wide range of phenotypic expressions and is frequently associated with developmental delay, symptoms from the autism spectrum, epilepsy, congenital anomalies, and obesity. These phenotypes are often related to a proximal 16p11.2 deletion of approximately 600 kb (BP4-BP5) that includes the SH2B1 gene that is reported to be causative for morbid obesity. This more centromeric deletion is most strongly related to autism spectrum susceptibility and is functionally different from the more distal 16p12.2p11.2 region, which includes the so-called atypical 16p11.2 BP2-BP3 deletion (approximately 220 kb) presenting with developmental delay, behavioral problems and mild facial dysmorphisms. Egger et al. [287] reported the case of an adult male with a long history of maladaptive behaviors who was referred for diagnostic assessment of his amotivational features. Extensive neuropsychological examination demonstrated rigid thinking, anxious beliefs, and ideas of reference in the presence of normal intelligence. Microarray analysis demonstrated a de novo 970 kb 16p11.2 BP1-BP4 microdeletion that can be regarded as explanatory for his behavioral profile. Microdeletion syndromes are not exclusively related to intellectual disabilities and genetic testing is of putative relevance for the understanding of neuropsychiatric and neuropsychological phenomena. 22q11.2 Deletion Syndrome Schneider et al. [288] performed the the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. ADHD is the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders is more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders are overrepresented in females. Psychotic disorders are present in 41% of adults over age 25. Males do not predominate in psychotic or autism spectrum disorders. Children with 22q11.2 deletion syndrome (22q11DS) have congenital heart disease (CHD) and high prevalence of psychiatric disorders and neurocognitive deficits. Yi et al. [289] investigated whether CHD contributes to the high prevalence of psychiatric disorders

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and neurocognitive impairments in 22q11DS. There were no significant differences between the prevalence of psychiatric disorders in the 22q11DS with and without CHD. In 22q11DS with CHD, the prevalence rates were 41% anxiety disorders, 37% ADHD and 71% psychosis spectrum. In 22q11DS without CHD, the rates were 33% anxiety disorders, 41% ADHD and 64% psychosis spectrum. In comparison, the non-deleted CHD group had lower rates of psychopathology (25% anxiety disorders, 6% ADHD, and 13% psychosis spectrum). Similarly, the 22q11DS groups, regardless of CHD status, had significantly greater neurocognitive deficits across multiple domains, compared to the CHD-only group. CHD in this sample of children with 22q11.2DS does not have a major impact on the prevalence of psychiatric disorders and is not associated with increased neurocognitive deficits. Psychopathology is common, with 79% of individuals meeting diagnostic criteria for a disorder at the time of assessment. Diagnoses of psychosis are made in 11% of cases, attenuated positive symptom syndrome (APS) in 21%, and 47% experienced significant subthreshold symptoms. Peak occurrence of psychosis risk is during adolescence (62% of those aged 12-17 years). Criteria for a mood disorder are met by 14%, for anxiety disorder 34% and for ADHD 31%. In an US cohort reported by Tang et al. [290], mental health care had been received by 63% of individuals in their lifetime, but only 40% continued therapy and 39% used psychotropics. Antipsychotics were used by 42% of participants with psychosis and none of the participants with APS. Half of those at risk for psychosis were receiving no mental health care. Psychopathology is common in 22q11DS but is not adequately treated or clinically followed. 22q11.2 and 8q22.1 Microduplications The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6Mb. Tarsitano et al. [291] described a case of a child with macrocephaly, overgrowth with advanced bone age, attention deficits, evidence of mild mental retardation and dysmorphic features. An array-CGH analysis detected a 252 Kb duplication at the 22q11.2 region inherited from mother and 142 Kb duplication at 8q22.1 region inherited from father. Both parents show mild dysmorphic features. The duplicated genes in chromosomes 22q and 8q are TOP3B and PGCP, respectively. ASTN2/TRIM32 Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. Lionel et al. [292] screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89,985 individuals across 10 sites, including 64,114 NDD subjects, and identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms, were significantly enriched in the NDD subjects compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), ADHD, speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls

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in males with NDDs, but not in females. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex.

Personality, Emotional, and Intellectual Profiles of Parents Personality disorders are prevalent in parents of children with ADHD, including depressive personality (25.3%), histrionic personality (20%), and compulsive personality (17.1%). These personality traits are more frequent in mothers than in fathers [293]. Maternal depression and parenting are robust predictors of developmental outcomes for children with ADHD. Mothers were less likely to respond optimally than non-optimally to child compliant and noncompliant behaviors during observed parent-child interactions; however, currently depressed mothers are least likely to reinforce child compliance and responded most coercively to child noncompliance relative to the other groups. Remitted mothers are more coercive than never clinically depressed mothers, but are more likely to follow through with commands than never clinically depressed mothers [294]. A study of potential pathways between inattentive symptom severity, positive and negative parenting practices, and functional impairment in a sample of children diagnosed with ADHD, Predominantly Inattentive Type (ADHD-I) supported both main effects of symptoms and parenting on impairment, as well as a mediational path between symptoms and impairment via parenting, as observed by parents in the home setting. Specifically, higher severity of inattention was associated with higher rates of homework, social, and home impairment. Negative parenting contributed to homework and home impairment, and positive and negative parenting contributed to social impairment, incrementally above and beyond the impact of inattention symptom severity alone. Negative parenting partially mediated the relationship between inattentive symptom severity and impairment, such that higher rates of inattention were associated with higher rates of negative parenting, which in turn was associated with higher rates of homework, social, and home impairment [295]. Young adults born to population-representative mothers with intellectual disability (ID) are at high risk of adverse experiences and negative outcomes, such as increased childhood mortality, a relatively large proportion of children taken into care, high rates of ID and ADHD in the children and of criminality in young adulthood [296]. Among a sample of Iranian children suffering from ADHD, the ADHD and ADHD-related symptoms in childhood were found to be related to the male gender and to the occurrence of ADHD in siblings [297]. Parental severe mental illness (SMI) is associated with an increased risk of offspring autism spectrum disorder (ASD) and ADHD. McCoy et al. [298] conducted a study to examine the extent to which risk of preterm birth, low birth weight, and small for gestational age mediated this association using data obtained on offspring born 1992-2001 in Sweden (N = 870,017) through the linkage of multiple population-based registers. Maternal and paternal SMI were associated with an increased risk for preterm birth, low birth weight, and gestational age, and for offspring ASD and ADHD. These pregnancy outcomes were also associated with an increased risk of ASD and ADHD. Pregnancy outcomes did not mediate the association between parental SMI and offspring ASD and ADHD. Parental SMI and

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adverse pregnancy outcomes appear to be independent risk factors for offspring ASD and ADHD. A few reports indicate the presence of neural abnormalities within the families of children with ADHD. Functional magnetic resonance imaging was used to compare cerebral activation of ADHD and control biological parent-child dyads during forethought, a prospective function of working memory. Reduced activations in ADHD dyads were found in the inferior frontal gyrus, right superior parietal lobule and left inferior parietal lobule, suggesting that fronto-parietal abnormalities are shared within ADHD families [299].

Rare Phenogenotypes Sox6 Sox6 is a transcription factor that is crucial for the differentiation and development of cortical interneurons and dopaminergic neurons of the substantia nigra pars compact. Loss-offunction mutations might thus result in complex paroxysmal diseases such as epilepsy syndromes or movement disorders. Ebrahimi-Fakhari et al. [300] reported the case of a 15year-old boy with delayed speech development and ADHD who presented with a rapid-onset generalized dopa-responsive dystonia. Treatment with levodopa/carbidopa led to a complete and sustained remission of neurological symptoms. Genetic testing revealed a mono-allelic de novo 84-kb deletion on chromosome 11p15.2 encompassing exons 14-16 of the SOX6 gene (chr11: 15944880-16029095, NCBI 37/hg19). CNKSR2 Vaags et al. [301] described the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike-waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders. ELFN1 Tomioka et al. [302] showed that a transinteraction of Elfn1 and mGluR7 controls targeted interneuron synapse development and that loss of Elfn1 results in hyperactivity and sensory-triggered epileptic seizures in mice. Elfn1 protein increases during postnatal development and localizes to postsynaptic sites of somatostatin-containing interneurons (SOM-INs) in the hippocampal CA1 stratum oriens and dentate gyrus (DG) hilus. Elfn1 knockout (KO) mice have deficits in mGluR7 recruitment to synaptic sites on SOM-INs, and presynaptic plasticity is impaired at these synapses. In patients with epilepsy and ADHD, the Japanese authors found damaging missense mutations of ELFN1 that are clustered in the carboxy-terminal region required for mGluR7 recruitment. SIRPB1 Impulsive-disinhibited personality (IDP) is a behavioral trait mainly characterized by seeking immediate gratification at the expense of more enduring or long-term gains. This trait

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has a major role in the development of several disinhibitory behaviors and syndromes, including psychopathy, ADHD, cluster-B personality disorders, criminality and alcoholism. Available data consistently support a strong heritable component, accounting for 30-60% of the observed variance in personality traits. A genome-wide analysis of copy-number variants was designed to identify novel genetic pathways associated with the IDP trait. A common CNV mapping to the immune-related gene SIRPB1 was significantly associated with IDP scores in a dose-dependent manner. Expression quantitative trait locus analysis of the critical region revealed higher SIRPB1 mRNA levels associated with the haplotype containing the deleted allele. Epigenetic marks highlighted the presence of two potential insulators within the deleted region, confirmed by functional assays in zebrafish embryos, which suggests that SIRPB1 expression rates are affected by the presence/absence of the insulator regions. Upregulation of SIRPB1 has been described in prefrontal cortex of patients with schizophrenia, providing a link between SIRPB1 and diseases involving disinhibition and failure to control impulsivity [303]. Dock GEFs The dedicator of cytokinesis (Dock) family is composed of atypical guanine exchange factorss (GEFs) that activate the Rho GTPases Rac1 and Cdc42. Rho GTPases are best documented for their roles in actin polymerization and they regulate important cellular functions, including morphogenesis, migration, neuronal development, and cell division and adhesion. 11 Dock family members have been identified. Among the Dock proteins, Dock3 is predominantly expressed in the central nervous system. Dock proteins are potential therapeutic targets for various diseases, including glaucoma, Alzheimer's disease, cancer, ADHD and combined immunodeficiency [304]. TAAR1 Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor that is expressed in brain and periphery and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA), tyramine, tryptamine, octopamine. The receptor is known to have a very rich pharmacology and could be also activated by different classes of compounds, including dopaminergic, adrenergic and serotonergic ligands. It is expected that targeting hTAAR1 could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, ADHD, Parkinson's disease and metabolic diseases. A small number of selective hTAAR1 agonists (RO5166017, T1 AM) and antagonist (EPPTB), have been reported in literature [305]. STS Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. Maladaptive response control is a feature of many neuropsychiatric conditions, including ADHD. As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Davies et al. [306] examined whether deletion of the Sts gene in the 39,X(Y*)O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in

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individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. CDH11 Crepel et al. [307] reported the case of a sporadic patient with autism spectrum disorder (ASD), mild intellectual disability and ADHD with a de novo partial deletion of CADHERIN 11 (CDH11). The deletion is associated with one of the breakpoints of a de novo complex chromosomal rearrangement 46,XY,t(3;16;5)(q29;q22;q15)inv4(p14;q21)i ns(4;5) (q21;q14.3q15). Cadherins are cell adhesion molecules involved in synaptic plasticity. A case-control association study for 14 SNP variants in 519 ASD cases and 1,192 controls showed significant overrepresentation of rs7187376C/C genotypes in the patient group. There was no association for C/T versus T/T nor was there association at the allelic level. Three novel variants were found in the coding region of CDH1, of which two variants were unlikely to be causal. Targeted CNV screening in these 247 patients did not reveal copy number variation in CDH11. Usual Sleep Duration Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality. A GWAS of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8. This finding was replicated in an African-American sample of 4,771 individuals. The strongest combined association was at rs1823125, with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of ADHD [308]. HLA Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. Nudel et al. [309] investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory and A3 with expressive language ability. Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother but are positively correlated with the same trait when paternally inherited. Case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls, as has been reported for individuals with ADHD.

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HLA DQB1*06:02 Negative Narcolepsy with Hypocretin/orexin Deficiency Han et al. [310] studied rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% of all cases with cataplexy and 1.8% of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. Smith-Magneis Syndrome The Smith-Magenis syndrome (SMS) is a rare microdeletion dysmorphic syndrome (interstitial microdeletion of chromosome 17p11.2), which occurs sporadically. Mutations in the RAI1 gene are found in part of the patients. SMS is characterized by intellectual disability and behavioural disturbances (sleep disturbances, hyperactivity, attention deficit, self-injury behaviour), craniofacial dysmorphism and defects of other organs and systems (teeth, eyes and upper respiratory and hearing disturbances, short stature, brachydactyly, scoliosis, cardiac and genitourinary defects). There are also neurological problems (muscular hypotonia, peripheral neuropathy, epilepsy and decreased sensitivity to pain). Many of the features that appear in the SMS may occur in other genetic syndromes, which may cause diagnostic difficulties [311]. Gnanavel [312] reported the case of a mentally retarded 7-year-old male child presented with inattention and hyperactivity which was initially diagnosed as ADHD. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function [313]. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. This heptameric C-tract is a preferential

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hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1 [314]. Potocki-Lupski Syndrome Potocki-Lupski syndrome (PTLS) is a microduplication syndrome characterized by infantile hypotonia, failure to thrive, cardiovascular malformations, developmental delay, intellectual disability, and behavior abnormalities, the latter of which can include autism spectrum disorder. The majority of individuals with PTLS harbor a de novo microduplication of chromosome 17p11.2 reciprocal to the common recurrent 3.6 Mb microdeletion in the Smith-Magenis syndrome critical region. Magoulas et al. [315] reported on the transmission of the PTLS duplication across two generations in two separate families. Individuals in these families presented initially with developmental delay, behavior problems, and intellectual disability. ProSAP/Shank Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan-McDermid Syndrome or Alzheimer's disease. ProSAP/Shank proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the ProSAP/Shank scaffold. Grabrucker et al. [316] examined the interplay between zinc and ProSAP/Shank in vitro and in vivo using neurobiological approaches. Low postsynaptic zinc availability affects the activity dependent increase in ProSAP1/Shank2 and ProSAP2/Shank3 levels at the synapse in vitro and a loss of synaptic ProSAP1/Shank2 and ProSAP2/Shank3 occurs in a mouse model for acute and prenatal zinc deficiency. Zinc-deficient animals displayed abnormalities in behaviour such as over-responsivity and hyperactivity-like behaviour (acute zinc deficiency) and autism spectrum disorder-related behaviour such as impairments in vocalization and social behaviour (prenatal zinc deficiency). A low zinc status seems to be associated with an increased incidence rate of seizures, hypotonia, and attention and hyperactivity issues in patients with Phelan-McDermid syndrome, which is caused by haploinsufficiency of ProSAP2/Shank3. Distal 10q Monosomy Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600 kb Smallest Region of deletion Overlap (SRO) has been proposed. Plaisancié et al. [317] described 4 patients with a distal 10q26 deletion, who displayed ADHD. One of them had a marked behavioral profile and relatively preserved cognitive functions. The SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal

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models. Haploinsufficiency of CALY might play a crucial role in the development of behavioral symptoms in these patients. NROB1/DAX1 Mutations on the NROB1 (DAX1) gene can cause different phenotypes of adrenal insufficiency in infancy. Long-term evolution of these patients shows that it is possible to have an association with hypogonadotropic hypogonadism. Calliari et al. [318] described the evolution of a patient with NROB1 gene mutation, diagnosed with a mild form of adrenal insufficiency, with hypogonadotropic hypogonadism, short stature, and ADHD. Alternating Hemiplegia of Childhood Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by early-onset recurrent distinctive hemiplegic episodes commonly accompanied by other paroxysmal features and developmental impairment. De novo mutations in ATP1A3 were identified as a genetic cause of AHC. Hoei-Hansen et al. [319] described the entire Danish cohort of paediatric AHC patients. Mean present age was 10.0 years (range 1-16). Mean age at presentation was 7.4 months (range 1-18 months). Sequencing of ATP1A3 in all ten patients revealed a pathogenic mutation in seven. Two females with moderate psychomotor impairment were heterozygous for the known p.G947R mutation, whereas one severely retarded boy was heterozygous for the common p.E815K mutation. The prevalent p.D801N mutation was identified in two moderate to severely retarded children. In a set of monochorionic male twins a novel p.D801E mutation was identified, underscoring that the asparagine at position 801 is a mutation hotspot. Three girls aged 5-13 years did not reveal any ATP1A3 mutations. They were rather mildly clinically affected and displayed a normal or near-normal psychomotor development. The patients harboured a wide range of psychomotor difficulties. Patients with no mutation detected tended to be less severely affected. Prevalence was approximately 1 per 100,000 children. Coffin-Lowry Syndrome The ribosomal protein S6 kinase, 90 kb, polypeptide 3 gene (RPS6KA3) is responsible for Coffin-Lowry syndrome (CLS), which is characterized by intellectual disability (ID) and facial and bony abnormalities. This gene also affects nonsyndromic X-linked ID and nonsyndromic X-linked ID without bony abnormalities. Two families have been reported to have genetic microduplication including RPS6KA3. Matsumoto et al. [320] detected a 584-kb microduplication spanning 19.92-20.50 Mb of Xp22.12 (including RPS6KA3) in the members of one Japanese family, including three brothers, two sisters, and their mother. The 15-yearold male proband and one of his brothers had mild ID and localization-related epilepsy, whereas his other brother presented borderline intelligence quotient (IQ) and ADHD. One sister presented pervasive development disorder (PDD). Analysis of this family suggests that RPS6KA3 duplication is responsible for mild ID, ADHD, and localization-related epilepsy, and possibly for PDD. ATP7B Arruda et al. [321] reported the case of a 44-year-old man with a history of ADHD, obsessive compulsive behaviour, vocal tics, depression, and anxiety, in whom a compound

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heterozygous ATP7B mutation was found, associated with hypoceruloplasminemia, but without clinical or pathological manifestation of Wilson's disease (WD). Genetic testing revealed a compound heterozygous ATP7B mutation already described in WD, p.Met645Arg (C1934TG/c.51+4A→T). MECP2 Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in MECP2, and there have been people identified with MECP2 mutations that do not have the clinical features of RTT. Suter et al. [322] presented four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include global developmental delay with obsessive compulsive disorder and ADHD. 15q13.3 and Xq21.31 Microduplication In a male patient with Tourette syndrome, ADHD, and OCD (obsessive compulsive disorder) Melchior et al. [323] identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. 4q13 Duplication/EPHA5 An insertional translocation (IT) can result in pure segmental aneusomy for the inserted genomic segment allowing to define a more accurate clinical phenotype. Matoso et al. [324] reported on two siblings sharing an unbalanced IT inherited from the mother with a history of learning difficulty. An 8-year-old girl with developmental delay, speech disability, and ADHD, showed by GTG banding analysis a subtle interstitial alteration in 21q21. Oligonucleotide array comparative genomic hybridization (array-CGH) analysis showed a 4q13.1-q13.3 duplication spanning 8.6 Mb. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones confirmed the rearrangement, a der(21)ins(21;4)(q21;q13.1q13.3). The duplication described involves 50 RefSeq genes including the EPHA5 gene that encodes for the EphA5 receptor involved in embryonic development of the brain and also in synaptic remodeling and plasticity thought to underlie learning and memory. The same rearrangement was observed in a younger brother with behavioral problems and also exhibiting ADHD. There are few reports of patients with duplications involving the proximal region of 4q and a mild phenotype. 16p13.11 CNVs CNVs at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors

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underlying such sex-specific features remain unclear. Tropeano et al. [325] tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH). In the clinical referral series, the authors identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls, and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases, but not in females. The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II, located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, with sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus. 47,XYY Syndrome Bardsley et al. [326] described auxologic, physical, and behavioral features in a large cohort of males with 47,XYY (XYY). In 90 males with XYY (mean age 9.6 ± 5.3 years [range 0.5-36.5]), mean height SD was above average (1.0 ± 1.2 SD). Macrocephaly (head circumference >2 SD) was noted in 33%, hypotonia in 63%, clinodactyly in 52%, and hypertelorism in 59%. There was testicular enlargement for age (> 2 SD) in 50%, but no increase in genital anomalies. No physical phenotypic differences were seen in boys diagnosed prenatally vs postnatally. Testosterone, luteinizing hormone, and follicle stimulating hormone levels were in the normal range in most boys. There was an increased incidence of asthma, seizures, tremor, and autistic spectrum disorder (ASD) compared with the general population rates. Prenatally diagnosed boys scored significantly better on cognitive testing and were less likely to be diagnosed with ASD. The XYY phenotype commonly includes tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor. 8p23.1 Duplication The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Barber et al. [327] described another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, ADHD, ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only

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GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000. Xp22.3 Interstitial Deletion X-linked ichthyosis is a genetic disorder affecting the skin and caused by a deficit in the steroid sulfatase enzyme (STS), often associated with a recurrent microdeletion at Xp22.31. Most of the STS deleted patients have X-linked ichthyosis as the only clinical feature and it is believed that patients with more complex disorders including mental retardation could be present as a result of contiguous gene deletion. The VCX3A gene, a member of the VCX (variable charge, X chromosome) gene family, was proposed as the candidate gene for Xlinked non-specific mental retardation in patients with X-linked ichthyosis. Ben Khelifa et al. [328] reported the case of a boy in Tunisia with familial ichthyosis, dysmorphic features and moderate mental retardation with approximately 2 Mb interstitial deletion on Xp22.3 involving VCX3A and STS genes. 17q22 Microdeletion Syndrome Deletions involving 17q21-q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1-q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Laurell et al. [329] described five new patients with 1.8-2.5-Mb microdeletions involving 17q22 identified by array-CGH, also presented one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to ~8.2 Mb using array-CGH. The commonly deleted region in these patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of these patients includes intellectual disability, ADHD, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. These common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome. 4p13 to 4p12 Duplication Clusters of GABAA receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. Polan et al. [330] described a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array

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comparative genomic hybridization, that contains 13 genes including a cluster of four GABAA receptor subunit genes. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). Another individual unrelated to this family, with a similar duplication, was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. The duplication might act through a dosage effect of GABAA receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders. LGI1/epitempin Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene have been reported in up to 50% of families with ADLTE. In a family with five affected members reported by Berghuis et al. [331] heterozygous c.431+1G>A substitution in LGI1 was detected in all members. Significantly more hyperactivity symptoms were found in family members carrying the LGI1 mutation. 15q26 Monosomies Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree of pre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26, Poot et al. [332] found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, ADHD, hearing loss and autism, have been found.

Epigenomics Epigenetics involves heritable alterations of gene expression and chromatin organization without changes in DNA sequence. Epigenetic mechanisms are crucial to stabilize cell typespecific gene-expression programs [333]. Both hypermethylation and hypomethylation of DNA and chomatin changes can affect AD-related gene expression leading to the multistep process of premature neurodegeneration. Epigenetic modifications are reversible and can be potentially targeted by pharmacological and dietary interventions [334]. Classical epigenetic mechanisms, including DNA methylation and histone modifications, and regulation by microRNAs (miRNAs), are among the major regulatory elements that control metabolic pathways at the molecular level, with epigenetic modifications regulating

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gene expression transcriptionally and miRNAs suppressing gene expression posttranscriptionally [335]. Vertebrate genomes undergo epigenetic reprogramming during development and disease. Stable transmission of DNA methylation, transcriptomes and phenotypes from parent to clonal offspring are demonstrated in various asexual species, and clonal genotypes from natural populations show habitat-specific DNA methylation [336]. Methylation varies spatially across the genome with a majority of the methylated sites mapping to intragenic regions [337]. Not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) may be subjected to epigenetic modifications related to disease development, environmental exposure, drug treatment and aging. mtDNA methylation is attracting increasing attention as a potential biomarker for the detection and diagnosis of diseases and the understanding of cellular behavior [338-340]. Many prospective studies have shown that if a mother is depressed, anxious or stressed while pregnant, this increases the risk for her child having a wide range of adverse outcomes including emotional problems, symptoms of ADHD or impaired cognitive development. Although genetics and postnatal care clearly affect these outcomes, evidence for a prenatal causal component also is substantial. Prenatal anxiety/depression may contribute 10-15% of the attributable load for emotional/behavioural outcomes. The role of epigenetic changes in mediating alterations in offspring outcome following prenatal stress is likely to be importan [341]. The transgenerational epigenetic programming involved in the passage of environmental exposures to stressful periods from one generation to the next has been examined in human populations, and mechanistically in animal models. Epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, ADHD, schizophrenia, and autism spectrum disorders. Both maternal and paternal life experiences with stress can be passed on to offspring directly during pregnancy or through epigenetic marks in the germ cell [341]. Stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Transgenerational epigenetic inheritance of stress exposure in humans, associated with changes in miRNA expression and DNA methylation in placenta and brain, may be linked to greater risks of schizophrenia, ADHD, autism, anxiety- or depressionrelated disorders later in life [343,344]. Early life environmental factors contribute to the occurrence of ADHD. DNA methylation has emerged as a mechanism potentially mediating genetic and environmental effects. Van Mil et al. [345] investigated whether newborn DNA methylation patterns of selected candidate genes involved in psychiatric disorders or fetal growth are associated with ADHD symptoms in childhood. DNA methylation levels were negatively associated with ADHD symptom score. This association was largely explained by associations of DRD4 and 5-HTT regions. Associations between DNA methylation levels and ADHD symptom score were attenuated by co-occurring oppositional defiant disorder and total symptoms. Lower

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DNA methylation levels of the 7 genes assessed at birth, were associated with more ADHD symptoms of the child at 6 years of age. Gene set enrichment analyses in offspring stress regulating brain regions, the paraventricular nucleus (PVN) and the bed nucleus of stria terminalis, revealed global pattern changes in transcription suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, Rodgers et al. [346] found robust changes in sperm microRNA (miR) content, where nine specific miRs were significantly increased in both paternal stress groups. Paternal experience across the lifespan can induce germ cell epigenetic reprogramming and impact offspring HPA stress axis regulation. Kandemir et al. [347] evaluated miR18a-5p, miR22-3p, miR24-3p, miR106b-5p, miR107, miR125b-5p and miR155a-5p levels in child and adolescent ADHD patients. miRNA 18a-5p, 22-3p, 24-3p, 106b-5p and 107 levels were statistically significantly decreased in ADHD patients. miRNA 155a-5p levels were increased in patients group. The positive predictive value (PPV) and negative predictive value of miR107 was estimated for the cutoff point of 0.4480. PPV was 70% and NPV was 86.5% for the taken cut off point. There might be a close relationship between levels of circulating miRNAs and ADHD. Malfunction of synaptic plasticity in different brain regions, including the amygdala plays a role in impulse control deficits that are characteristics of several psychiatric disorders, such as ADHD, schizophrenia, depression and addiction. A locus for impulsivity (Impu1) containing the neuregulin 3 (Nrg3) gene, of which the level of expression determines levels of inhibitory control, was discovered. MicroRNAs (miRNAs) are potent regulators of gene expression, and have recently emerged as important factors contributing to the development of psychiatric disorders. Pietrzykowski and Spijker [348] used the GeneNetwork database of BXD mice to search for correlated traits with impulsivity using an overrepresentation analysis to filter for biologically meaningful traits. They determined that inhibitory control was significantly correlated with expression of miR-190b, -28a, -340, -219a, and -491 in the amygdala, and that the overrepresented correlated traits showed a specific pattern of coregulation with these miRNAs. A bioinformatics analysis identified that miR-190b, by targeting an Nrg3-related network, could affect synaptic plasticity in the amygdala, targeting bot impulsive and compulsive traits. miR-28a, -340, -219a, and possibly -491 could act on synaptic function by determining the balance between neuronal outgrowth and differentiation. miRNAs are attractive candidates of regulation of amygdala synaptic plasticity, possibly during development but also in maintaining the impulsive phenotype. Although epigenetic studies are still insufficient to establish a clear association between epigenetic changes and ADHD, it is very likely that in the coming future novel data provide clear clues for this association.

Proteomics The application of different proteomic techniques is becoming an important help in diagnosis and treatment of psychiatric disorders such as major depression, suicidal behavior, schizophrenia, and ADHD. Different analytic approaches can be applied for the discovery of

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specific biomarkers for diagnosing specific disorders, as well as for monitoring the effect of their treatment [349].

Pathogenic Mechanisms An excellent description of the pathophysiology of ADHD by Arnsten in 2009 is still valid nowadays under the following terms: The higher-order association cortices in the temporal and parietal lobes and prefrontal cortex (PFC) interconnect to mediate aspects of attention. The parietal association cortices are important for orienting attentional resources in time/space, while the temporal association cortices analyze visual features critical for identifying objects/places. These posterior cortices are engaged by the salience of a stimulus. The PFC is critical for regulating attention based on relevance. The PFC is important for screening distractions, sustaining attention and shifting/dividing attention in a taskappropriate manner. The PFC is critical for regulating behaviour/emotion, especially for inhibiting inappropriate emotions, impulses and habits. The PFC is needed for allocating/planning to achieve goals and organizing behaviour/thought. These regulatory abilities are often referred to as executive functions. In humans, the right hemisphere of the PFC is important for regulating distractions, inappropriate behaviour and emotional responses. These regions are hypoactive with weakened connections to other parts of the brain. The PFC regulates attention and behaviour through networks of interconnected pyramidal cells. These networks excite each other to store goals/rules to guide actions and are highly dependent on their neurochemical environment, as small changes in the catecholamines noradrenaline (NA) or dopamine (DA) can have marked effects on PFC function. NA and DA are released in the PFC according to our arousal state. The beneficial effects of NA occur at postsynaptic alpha2A-receptors on the dendritic spines of PFC pyramidal cells. Stimulation of these receptors initiates a series of chemical events inside the cell. These chemical signals lead to the closing of special ion channels, thus strengthening the connectivity of network inputs to the cell. Conversely, the beneficial effects of moderate amounts of DA occur at D1 receptors, which act by weakening irrelevant inputs to the cells on another set of spines. Genetic linkage studies of ADHD suggest that these catecholamine pathways may be altered in some families with ADHD. Alterations in the enzyme that synthesizes NA (DA beta-hydroxylase) are associated with weakened PFC abilities. Pharmacological studies in animals indicate catecholamine actions in the PFC are highly relevant to ADHD. Blocking NA alpha2A-receptors in the PFC with yohimbine produces a profile similar to ADHD: locomotor hyperactivity, impulsivity and poor working memory. Conversely, drugs that enhance alpha2-receptor stimulation improve PFC function. Guanfacine directly stimulates postsynaptic alpha2A-receptors in the PFC and improves functioning, while methylphenidate and atomoxetine increase endogenous NA and DA levels and indirectly improve PFC function via alpha2A- and D1 receptor actions. Methylphenidate and atomoxetine have more potent actions in the PFC than in subcortical structures, which may explain why proper administration of stimulant medications does not lead to abuse [350, 351]. Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in ADHD [352]. The basal ganglia are implicated in the pathophysiology of ADHD.

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Shaw et al. [353] mapped basal ganglia development from childhood into late adolescence using methods that define surface morphology with an exquisite level of spatial resolution. In the ventral striatal surfaces, there was a diagnostic difference in developmental trajectories. The typically developing group showed surface area expansion with age (estimated rate of increase of 0.54 mm2 per year), whereas the ADHD group showed progressive contraction (decrease of 1.75 mm2 per year). The ADHD group also showed significant, fixed surface area reductions in dorsal striatal regions, which were detected in childhood at study entry and persisted into adolescence. There was no significant association between history of psychostimulant treatment and developmental trajectories. Progressive, atypical contraction of the ventral striatal surfaces characterizes ADHD, localizing to regions pivotal in reward processing. This contrasts with fixed, nonprogressive contraction of dorsal striatal surfaces in regions that support executive function and motor planning.

Catecholamines: Dopamine and Norepinephrine It is commonly believed that the symptoms of ADHD are closely associated with hypofunction of the dopaminergic system. Dopamine D2 receptor activation decreases the excitability of dopamine neurons, as well as the release of dopamine. Several genes associated with the catecholaminergic system including the dopamine receptor genes (DRD4 and DRD5), the dopamine transporter gene, and the gene for dopamine beta-hydroxylase, which catalyzes conversion of dopamine to norepinephrine are associated with ADHD. ADHD is believed to be a result of abnormalities in the frontal regions of the brain, particularly the prefrontal cortex and associated subcortical structures and circuits. Underpinning these abnormalities are disturbances of catecholamine neurotransmission. Patients with ADHD have depleted levels of dopamine and norepinephrine thought to be largely the result of dysfunction of their respective transporter systems [353].

Serotonin Gene and genome-wide association studies have suggested that serotoninergic gene variants are associated with increased risk of ADHD. A chronic deficit of serotonin (5-HT) at the synapse may trigger symptoms of ADHD. Serotonin through the orbitofrontal-striatal circuitry may regulate behavioral domains of hyperactivity and impulsivity interacting with abnormal dopaminergic neurotransmission in ADHD. Selective serotonin re-uptake inhibitors, L-tryptophan (the amino acid precursor of 5-HT), and non-stimulant drugs acting on the 5-HT system are modestly effective in some ADHD cases [355].

Serotonin-Dopamine Interactions Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate.

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DAT KO mice may model features of ADHD and these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuate locomotor hyperactivity in DAT KO mice. DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regain cocaine-stimulated locomotion, which is absent in DAT KO mice with normal levels of 5HT1B receptor expression. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and DA systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics, according to data reported by Hall et al. [356].

GABA and Glutamate It has been reported that balance between excitatory glutamate and inhibitory GABA neurotransmitter is essential and critical for proper development and functioning of brain. GABAergic (gamma aminobutyric acid) and glutamatergic interneurons maintain excitability, integrity and synaptic plasticity. Loss of inhibitory GABA and glutamate-mediated hyperexcitation may contribute to the development of autism spectrum disorder (ASD) and ADHD [357]. Increases in glutamatergic metabolites were found in the anterior cingulate cortex (ACC) and other regions in youth with ADHD. Increases in glutamatergic metabolites in youth with autism spectrum disorders, emotional dysregulation, and high risk for schizophrenia and decreases in youth with major depression, bipolar disorder, and obsessivecompulsive disorder have also been observed. There is limited but consistent evidence for normalization of glutamatergic levels with treatment, particularly in bipolar disorder and ADHD [358].

Protein Kinases Protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of neurodevelopmental disorders. ADHD is associated with dopaminergic insufficiencies, which are attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. Neurobeachin, a brain-enriched multi-domain scaffolding protein, has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder. Neurobeachin and CADM1 may contribute to vesicle transport in endosomal trafficking [359].

Iron, Ferritin, and Vitamin D Ferritin, iron, and vitamin D deficiencies may be related to the path physiology of ADHD. In a study conducted at the School Health and Primary Healthcare Clinics of Qatar,

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there were statistically significant differences between ADHD versus control children for vitamin D (16.81 ±7.84 vs. 22.18 ± 9.00 ng/ml), serum iron (82.11 ± 13.61 vs. 85.60 ± 12.47 ng/ml), ferritin (36.26 ± 5.93 vs. 38.19 ± 5.61 ng/ml), hemoglobin (12.02 ± 2.13 vs. 12.89 ± 2.02 g/dL, magnesium (0.82 ± 0.08 vs. 0.88 ± 0.06 mmol/L), serum calcium level (2.35 ± 0.12 vs. 2.39 ± 0.14 mmol/L), and phosphorous (1.47 ± 0.30 vs. 1.54 ± 0.26 mmol/L). 18.4% had severe vitamin D deficiency (4or 500 Kb) copy number variants (CNVs) identified among individuals with ADHD. Taylor et al. [375] examined the genes affected by 71 large, rare, and predominantly inherited CNVs identified among 902 individuals with ADHD, and applied both mouse-knockout functional enrichment analyses, exploiting behavioral phenotypes arising from the determined disruption of 1:1 mouse orthologues, and human brain-specific spatio-temporal expression data to uncover molecular

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pathways common among genes contributing to enriched phenotypes. Twenty-two percent of genes duplicated in individuals with ADHD that had mouse phenotypic information were associated with abnormal learning/memory/conditioning ("l/m/c") phenotypes. They identified a similar enrichment among genes duplicated by eight de novo CNVs present in eight individuals with Hyperactivity and/or Short attention span ("Hyperactivity/SAS," the ontologically-derived phenotypic components of ADHD). In the brain, genes duplicated in patients with ADHD and Hyperactivity/SAS and whose orthologues' disruption yields l/m/c phenotypes in mouse ("candidate-genes"), were co-expressed with one another and with genes whose orthologues' mouse models exhibit hyperactivity. Genes associated with hyperactivity in the mouse were significantly more co-expressed with ADHD candidate-genes than with similarly identified genes from individuals with intellectual disability. These findings support an etiology for ADHD distinct from intellectual disability, and mechanistically related to genes associated with hyperactivity phenotypes in other mammalian species. Elfn1 Mutant Mice A growing number of proteins with extracellular leucine-rich repeats (eLRRs) have been implicated in directing neuronal connectivity. Dolan and Mitchell [376] identified a novel family of eLRR proteins in mammals. Elfns are transmembrane proteins with 6 LRRs, a fibronectin type-3 domain and a long cytoplasmic tail. Elfn1 protein, expressed postsynaptically, can direct the elaboration of specific electrochemical properties of synapses between particular cell types in the hippocampus. Analyses of an Elfn1 mutant mouse line showed that Elfn1 is expressed in distinct subsets of interneurons of the hippocampus and cortex, and also in discrete subsets of cells in the habenula, septum, globus pallidus, dorsal subiculum, amygdala and several other regions. Elfn1 is expressed in diverse cell types, including local GABAergic interneurons as well as long-range projecting GABAergic and glutamatergic neurons. Elfn1 protein localises to axons of excitatory neurons in the habenula, and long-range GABAergic neurons of the globus pallidus, suggesting the possibility of additional roles for Elfn1 in axons or presynaptically. While gross anatomical analyses did not reveal any obvious neuroanatomical abnormalities, behavioural analyses clearly illustrate functional effects of Elfn1 mutation. Elfn1 mutant mice exhibit seizures, subtle motor abnormalities, reduced thigmotaxis and hyperactivity. The hyperactivity is paradoxically reversible by treatment with the stimulant amphetamine, consistent with phenotypes observed in animals with habenular lesions. These analyses reveal a requirement for Elfn1 in brain function and are suggestive of possible relevance to the etiology and pathophysiology of epilepsy and ADHD [376]. Lead Exposure-Induced Histone Acetylation Lead (Pb) exposure was commonly considered as a high environmental risk factor for the development of ADHD. Epigenetic changes may modulate some pathogenic aspects of ADHD in response to neurotoxic events. Luo et al. [377] studied the alterations of histone modifications in the hippocampus of rats exposed by various doses of lead, along with concomitant behavioral deficits. Lead exposure resulted in increased locomotor activity, similar to the hyperactivity subtype of ADHD. The levels of histone acetylation increased significantly in the hippocampus by chronic lead exposure, while no dramatic changes were detected in terms of expression yields of ADHD-related dopaminergic proteins, indicating

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that histone acetylation plays essential roles in this toxicant-involved pathogenesis. The increased level of histone acetylation might be attributed to the enzymatic activity of p300, a typical histone acetyltransferase, as the transcriptional level of p300 was significantly increased upon higher-dose Pb exposure. Cortical Glutamatergic mGluR5 Knockout Mice The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. Jew et al. [378] showed that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased noveltyinduced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions. Grin1(Rgsc174)/Grin1+ Mutan Mice The Grin1 (glutamate receptor, ionotropic, NMDA1) gene expresses a subunit of Nmethyl-D-aspartate (NMDA) receptors that is considered to play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. Grin1 is a candidate susceptibility gene for neuropsychiatric disorders, including schizophrenia, bipolar disorder, and ADHD. Umemori et al. [379] examined an N-ethyl-N-nitrosourea (ENU)-generated mutant mouse strain (Grin1(Rgsc174)/Grin1+) that has a non-synonymous mutation in Grin1. These mutant mice showed hyperactivity, increased novelty-seeking to objects, and abnormal social interactions. Grin1(Rgsc174)/Grin1+ mice may serve as a potential animal model of neuropsychiatric disorders. There is no significant difference in nociception between Grin1(Rgsc174)/Grin1+ and wild-type mice. The mutants display abnormal anxiety-like behaviors in the light/dark transition and the elevated plus maze tests. Both contextual and cued fear memory are severely deficient in the fear conditioning test. The mutant mice exhibit slightly impaired working memory in the eight-arm radial maze test. The startle amplitude is markedly decreased in Grin1(Rgsc174)/Grin1+ mice, whereas no significant differences between genotypes are detected in the prepulse inhibition (PPI) test. The mutant mice show no obvious deficits in social behaviors in three different social interaction tests. The Grin1(Rgsc174)/Grin1+ mutation causes abnormal anxiety-like behaviors, a deficiency in fear memory, and a decreased startle amplitude in mice. Although Grin1(Rgsc174)/Grin1+ mice only partially recapitulate symptoms of patients with ADHD, schizophrenia, and bipolar disorder, they may serve as a unique animal model of a certain subpopulation of patients with these disorders.

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SNAP-25 Deficient Mice The synaptosomal-associated protein of molecular weight 25 kDa (SNAP25) is a plasma membrane protein known to be involved in synaptic and neural plasticity. Animal model studies have shown that SNAP25 gene is responsible for hyperkinetic behavior in the coloboma mouse [217]. Multiple studies have indicated that the gene for the SNARE protein SNAP-25 is a candidate susceptibility gene for ADHD, as well as schizophrenia, while maternal smoking is a candidate environmental risk factor for ADHD. Baca et al. [380] used mice heterozygous for a Snap25 null allele and deficient in SNAP-25 expression to model genetic effects in combination with prenatal exposure to nicotine to explore genetic and environmental interactions in synaptic plasticity and behavior. SNAP-25 deficient mice exposed to prenatal nicotine exhibit hyperactivity and deficits in social interaction. Using a high frequency stimulus electrophysiological paradigm for long-term depression (LTD) induction, the authors examined the roles of dopaminergic D2 receptors (D2Rs) and cannabinoid CB1 receptors (CB1Rs), both critical for LTD induction in the striatum. Prenatal exposure to nicotine in Snap25 heterozygote null mice produced a deficit in the D2Rdependent induction of LTD, although CB1R regulation of plasticity was not impaired. Prenatal nicotine exposure altered the affinity and/or receptor coupling of D2Rs, but not the number of these receptors in heterozygote null Snap25 mutants. These results refine the observations made in the coloboma mouse mutant, a proposed mouse model of ADHD, and illustrate how gene×environmental influences can interact to perturb neural functions that regulate behavior. NK1R-/- Mice Genetically-altered mice, lacking functional NK1 receptors (NK1R-/-), express abnormal behaviours that are prominent in ADHD, such as inattentiveness and impulsivity and locomotor hyperactivity. Weir et al. [381] investigated how behaviour in the 5-CSRTT is affected by repeated testing and whether the abnormalities expressed by NK1R-/- mice are mimicked by treating wild type mice with a NK1R antagonist (L 733060 or RP 67580; 5 or 10 mg/kg). Repeated testing with a variable (VITI) or fixed, prolonged (LITI) intertrial interval reduced% omissions. Premature responses also declined, but only in NK1R-/- mice, in the VITI test. By contrast, perseveration increased in both genotypes. RP 67580 (10 mg/kg) increased the % omissions in both genotypes in the VITI, an action which cannot be attributed to NK1R antagonism. Neither drug affected perseveration. However, for premature responses, the response profile suggested that the low and high doses of RP 67580 (VITI) and L 733060 (LITI) had opposing effects on this behaviour. The effect of NK1R antagonists in the 5CSRTT is confounded by animals' test experience and non-specific drug effects at sites other than NK1R, possibly L-type Ca²⁺(v) channels. Gat1-/- Knockout Mice Some studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1-/-) is hyperactive and exhibited impaired memory performance in the Morris water maze. Yang et al. [382] found that the gat1-/- mice showed low levels of attentional focusing and increased impulsivity. In addition, the gat1-/- mice displayed ataxia characterized by defects in motor coordination and balance skills. The hyperactivity in the ko mice was reduced by both methylphenidate and amphetamine. GAT1

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ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD. NET Knockout Mice Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and ADHD. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, Gallagher et al. [383] detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. The mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of more robust connectivity in the frontal portion of the reward circuit of the DAT and NET knockout mice compared to the SERT knockout mice [383].

Environmental Risk Factors Many different environmental factors may contribute to increase the risk of ADHD. Yolton et al. [384] reviewed a part of the literature to determine evidence of associations between exposure to prenatal and postnatal environmental agents and the development of ADHD and related behaviors. A review of published research literature was conducted on associations between exposures to prenatal and postnatal cigarette smoke, prenatal exposure to alcohol, cocaine, and heroin, childhood exposure to lead, and prenatal exposure to organophosphate pesticides and outcomes of ADHD or behaviors related to ADHD. Review of the literature in these areas provides some evidence of associations between each of the exposures and ADHD-related behaviors, with the strongest evidence from prenatal cigarette and alcohol exposure and postnatal lead exposure. In another review Polish authors investigated the association between ADHD or ADHD-related symptoms and industrial chemicals, such as organophosphates and organochlorine pesticides, polychlorinated biphenyls (PCBs), lead, mercury and manganese. The findings indicate that children's exposure to organophosphate pesticides may cause symptoms consistent with pervasive developmental disorder, ADHD or attention problems. Exposures to organochlorine pesticides and PCBs were associated with ADHD-like behaviors such as alertness, quality of

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alert response, and cost of attention. The studies provided evidence that blood lead level below 10 μg/dl was associated with ADHD or ADHD-related symptoms [385]. Metallic Trace Elements Exposure to metallic trace elements (arsenic, manganese, lead, mercury) may exert a potential neurotoxic effect on the developing brain. A dose-response relationship was observed between the urine levels of arsenic and inattention and impulsivity scores, indicating that postnatal arsenic exposure impairs neurological function in children [386]. Existing evidence on the effects of manganese and selenium during fetal life on neurodevelopmental disorders is inadequate. An association between hair manganese level and symptoms of ADHD has been observed in Korean children, suggesting that excess exposure or deficiency of Mn are associated with ADHD [387]. In a study in Sweden reported by Ode et at [388] no association between manganese concentrations in umbilical cord serum and ADHD was found. Neurotoxic mechanisms of manganese involve striatal dopamine neurotransmission, implicated in the pathophysiology of ADHD. Hong et al. [389] investigated whether the adverse impact of manganese is particularly pronounced in children with ADHD. A significant interaction was found between ADHD status and blood manganese level in predicting CBCL total problems score as well as anxiety/depression, social problems, delinquent behavior, aggressive behavior, internalizing problems, and externalizing problems. Blood manganese level was more positively correlated with CBCL scores in ADHD children than in the healthy population. In ADHD children, only the fifth quintile of blood manganese concentration was significantly associated with the CBCL total problems score. ADHD children may be more vulnerable than the general school-age population to the neurotoxic effects of manganese exposure, which lead to an elevated risk of developing comorbid mental conditions. Exposure to lead even at low levels correlates with ADHD. However, lead-contaminated environments are often contaminated with other heavy metals that could exacerbate leadinduced ADHD. Liu et al. [390] conducted a study in China to evaluate the relationship between multiple heavy metals and child behaviors, and the involvement of S100 calciumbinding protein β (S100β) expression in ADHD children in Guiyu, an internationally-known e-waste contaminated recycling town. The prevalence of children with ADHD symptoms in Guiyu was 18.6%, with the percentage of children suspected to have behavior problems being 46.2% or 46.5%, based on the Rutter parents' or teachers' scale scores, respectively. Child blood levels of Pb, Cd, and Mn correlated with certain behavioral abnormalities, such as conduct problems and antisocial behavior. Serum S100β levels were associated with heavy metal levels in blood, and certain behavioral abnormalities. Low-level lead exposure was adversely associated with intelligence in school-age children independent of ADHD, and environmental lead exposure was selectively associated with impulsivity among the clinical features of ADHD in a South Korean sample [391]. In the US ADHD population, blood lead levels closely matched US population exposure averages, with a maximum level of 3.4 mug/dL. Blood lead levels were statistically significantly higher in ADHD-combined type than in non-ADHD control children. Blood lead was associated with symptoms of hyperactivity-impulsivity but not inattention-disorganization. Blood lead levels were linked with a lower IQ, but IQ did not account for effects on hyperactivity. Instead, hyperactivity mediated effects of lead on IQ. Effects of blood lead on hyperactivity-

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impulsivity were mediated by poor performance on the stop task. This mediation effect was independent from effects of lead on IQ. Low-level lead exposure might be an important contributor to ADHD. Its effects seem to be mediated by less effective cognitive control, consistent with a route of influence via striatal-frontal neural circuits [392, 393]. Although a measurable number of epidemiological studies have been conducted to clarify the associations between mercury exposure during embryo or early infancy and later incidences of autism spectrum disorders (ASD) or ADHD, the conclusion still remains unclear. A meta-analysis of two major exposure sources (thimerosal vaccines that contain ethylmercury (clinical exposure), and environmental sources), revealed that while thimerosal exposures did not show any material associations with an increased risk of ASD or ADHD, significant associations were observed for environmental exposures in both ASD and ADHD [394]. Drugs Some studies found opposing results regarding the association between prenatal exposure to oxytocin for labor augmentation and ADHD. Oxytocin for labor augmentation is widely used in obstetric care in Western countries. A large cohort study based on 546,146 cases from the Danish Medical Birth Registry does not support an association between medical augmentation of labor and ADHD in the child (0.9% of the children were identified as having ADHD) [395]. Some studies suggested that risk for autism spectrum disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. Clements et al. [396] studied children with ASD or ADHD delivered in a large New England health-care system, and each diagnostic group was matched 1:3 with children without ASD or ADHD. A total of 1,377 children diagnosed with ASD and 2,243 with ADHD were matched with healthy controls. Antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression. Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression. The risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but such exposure may still be associated with ADHD risk. N‘Goran et al. [397] investigated the relationships between six classes of nonmedical prescription drug use (NMPDU) and five personality traits in 5,777 Swiss men around 20 years old. NMPDU of opioid analgesics, sedatives/sleeping pills, anxiolytics, antidepressants, beta-blockers and stimulants over the previous 12 months was measured. Personality was assessed using the Brief Sensation Seeking Scale; attention deficithyperactivity (ADH) using the Adult Attention-Deficit-Hyperactivity Disorder Self-Report Scale; and aggression/hostility, anxiety/neuroticism and sociability using the ZuckermanKuhlmann Personality Questionnaire. About 10.7% of participants reported NMPDU in the last 12 months, with opioid analgesics most prevalent (6.7%), then sedatives/sleeping pills (3.0%), anxiolytics (2.7%), and stimulants (1.9%). Sensation seeking (SS), ADH, aggression/hostility, and anxiety/neuroticism (but not sociability) were significantly positively associated with at least one drug class. Aggression/hostility, anxiety/neuroticism and ADH were significantly and positively related to almost all NMPDU. Sociability was inversely related to NMPDU of sedatives/sleeping pills and anxiolytics. SS was related only to stimulant use. People with higher scores for ADH, aggression/hostility and

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anxiety/neuroticism are at higher risk of NMPDU. Sociability appeared to protect from NMPDU of sedatives/sleeping pills and anxiolytics. Acetaminophen (APAP)/paracetamol is one of the most commonly used over-the-counter drugs taken worldwide for treatment of pain and fever. Although considered as safe when taken in recommended doses not higher than 4 g/day, APAP overdose is currently the most important cause of acute liver failure (ALF). Results from large scale epidemiological studies provide increasing evidence for second generation effects of APAP, even when taken in pharmacological doses. APAP medication during pregnancy has been associated with health problems including neurodevelopmental and behavioral disorders such as ADHD and increase in the risk of wheezing and incidence of asthma among offspring [398]. Maternal Separation-Induced Stress Developmental stress induced by maternal separation (MS) increases the risk of developing psychological disturbances compatible with ADHD in animal models (spontaneously hypertensive rat (SHR) as compared with their progenitor strain, the WistarKyoto (WKY)). Proteomic analysis in striata of SHR revealed changes in proteins related to energy metabolism, neuroprotection, protein folding, protein metabolism, signalling and structure. Striatal SHR protein levels were consistent with delayed neuronal maturation and altered neurotransmission and energy metabolism [399]. Studies with iTRAQ labeling and matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) also detected that SHR had decreased levels of several proteins involved in energy metabolism, cytoskeletal structure, myelination and neurotransmitter function when compared to WKY [400]. Pesticides and Pollutants Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data. Liew et al. [401] investigated whether prenatal exposure to PFASs is associated with ADHD or childhood autism in children. Among 83,389 mother-child pairs enrolled in the Danish National Birth Cohort during 1996-2002, they identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; 4 other PFASs were quantified in ≥ 90% of the samples. The Danish authors did not find consistent evidence of associations between mother's PFAS plasma levels and ADHD or autism [401]. Prenatal exposure to polychlorinated biphenyls (PCBs) and lead are thought to be risk factors for ADHD, whereas the prenatal influence of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) on attention performance has been less studied. Increasing prenatal PCDD/F and PCB concentrations are significantly associated with a higher number of omission errors in the subtest Divided Attention. Prenatal lead concentrations had few significant associations with attention performance, whereas ADHD-related behavior is increased with increasing lead exposure. ADHD-related behavior is negatively associated with prenatal PCDD/F or PCB exposures [402]. Mice exposed to the pyrethroid pesticide deltamethrin during development exhibit several features reminiscent of ADHD, including elevated dopamine transporter (DAT) levels,

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hyperactivity, working memory and attention deficits, and impulsive-like behavior. Increased DAT and D1 dopamine receptor levels appear to be responsible for the behavioral deficits. Children aged 6-15 with detectable levels of pyrethroid metabolites in their urine were more than twice as likely to be diagnosed with ADHD [403]. Quirós-Alcalá et al. [404] examined the cross-sectional association between postnatal pyrethroid exposure and parental report of learning disability (LD) and ADHD in US children 6-15 years of age. The prevalence rates of parent-reported LD, ADHD, and both LD and ADHD were 12.7%, 10.0%, and 5.4%, respectively. Metabolite detection frequencies for 3-PBA [3-phenoxybenzoic acid], cisDCCA [cis-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid], and transDCCA [trans-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid] were 77.1%, 35.6%, and 33.9%, respectively. The geometric mean 3-PBA concentration was 0.32 μg/L. cis- and trans-DCCA 75th-percentile concentrations were 0.21 μg/L and 0.68 μg/L, respectively. Log10-transformed 3-PBA concentrations were associated with adjusted odds ratios (ORs) of 1.18 for parent-reported LD, 1.16 for ADHD, and 1.45 for both LD and ADHD. No significant associations were observed for cis- and trans-DCCA. Postnatal pyrethroid exposure was not associated with parental report of LD and/or ADHD. Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short-branched phthalates. This differential distribution is of special concern as, in particular, the hydrophobic phthalates and their metabolites are shown to have adverse effects following in utero and lactational exposures in animal studies [405]. After oral application of di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP) and di(2-propylheptyl) phthalate (DPHP), at least 74, 44 and 34%, respectively, are excreted via urine. In contrast to the short chain phthalates, their oxidized products, not the simple monoesters, were found to be the main metabolites. Based on urinary phthalate metabolite concentrations Wittassek and Angerer [406] estimated in 102 German subjects between 6 and 80 years of age median daily intakes (µg/kg/day) of 2.7 for DEHP, 2.1 for di-n-butyl phthalate, 1.5 for diisobutyl phthalate, 0.6 for DiNP, and 0.3 for butylbenzyl phthalate. Children have higher exposures compared to adults and seem to have a more effective oxidative metabolism of phthalates. Concentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, are significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite are significantly higher in the combined or hyperactive-impulsive subtypes compared to the inattentive subtype, and the metabolite is positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite are negatively correlated with cortical thickness in the right middle and superior temporal gyri. These results reported by Park et al. [407] in Korean patients suggest an association between phthalate concentrations and both the

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diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical maturation in children with ADHD. There is some evidence supporting the existence of an association between prenatal maternal or postnatal child's urine phthalate metabolite concentrations and poor attentional performances. Park et al. [408] studied whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, α-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. These results suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown to be neurotoxic. High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously. After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive and DSM-IV Total subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. These results reported by Perera et al. [409] suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood ADHD behavior problems. Some studies have reported associations between air pollution exposure and neurodevelopmental disorders in children. Gong et al. [410] explored the risk for autism spectrum disorders (ASD) and ADHD among children in relation to pre- and postnatal exposure to air pollution from road traffic in Sweden. Parents of 3,426 twins born in Stockholm during 1992-2000 were interviewed, when their children were 9 or 12 years old, for symptoms of neurodevelopmental disorders. Residence time-weighted concentrations of particulate matter with a diameter G (Asn21Asp) and 1199G>A (Ser400Asn) that have been studied in vivo and in vitro. To date, there is no clear consensus on the impact of any of these variants on drug disposition, response or toxicity. Variants of the ABCB1 gene have been associated with a diverse number of diseases and with a great variety of drugs, natural products and endogenous agents [588]. Over 1270 drugs have been reported to be associated with the Abcb1 transporter protein (P-gp), of which 490 are substrates, 618 are inhibitors, 182 are inducers, and 269 additional compounds which belong to different pharmacological categories of products with potential Abcb1 interaction [588]. Also of importance for CNS pharmacogenomics are transporters encoded by genes of the solute carrier superfamily (SLC) and solute carrier organic (SLCO) transporter family, responsible for the transport of multiple endogenous and exogenous compounds, including folate (SLC19A1), urea (SLC14A1, SLC14A2), monoamines (SLC29A4, SLC22A3), aminoacids (SLC1A5, SLC3A1, SLC7A3, SLC7A9, SLC38A1, SLC38A4, SLC38A5, SLC38A7, SLC43A2, SLC45A1), nucleotides (SLC29A2, SLC29A3), fatty acids (SLC27A1-6), neurotransmitters (SLC6A2 (noradrenaline transporter), SLC6A3 (dopamine transporter), SLC6A4 (serotonin transporter, SERT), SLC6A5, SLC6A6, SLC6A9, SLC6A11, SLC6A12,

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SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19), glutamate (SLC1A6, SLC1A7), and others [598]. Some organic anion transporters (OAT), which belong to the solute carrier (SLC) 22A family, are also expressed at the BBB, and regulate the excretion of endogenous and exogenous organic anions and cations [600]. The transport of amino acids and di- and tripeptides is mediated by a number of different transporter families, and the bulk of oligopeptide transport is attributable to the activity of members of the SLC15A superfamily (Peptide Transporters 1 and 2 [SLC15A1 (PepT1) and SLC15A2 (PepT2)], and Peptide/Histidine Transporters 1 and 2 [SLC15A4 (PHT1) and SLC15A3 (PHT2)]). ABC and SLC transporters expressed at the BBB may cooperate to regulate the passage of different molecules into the brain [600]. Polymorphic variants in ABC and SLC genes may also be associated with pathogenic events in CNS disorders and drug-related safety and efficacy complications [54, 598].

ADHD-Related Pharmacogenetics Methylphenidate Pathogenic genes involved in MPH pharmacogenetics include ADRA2A, COMT, DRD2, DRD4, DRD5, SLC6A2, and SLC6A3. Mechanistic genes regulating the mechanism of action of MPH are ADRA2A, ATXN1, CES1, COMT, DRD2, DRD3, DRD4, DRD5, GRM7, NAV2, NTF3, SLC6A2, SLC6A3, and SNAP25. MPH is a substrate of CES1, and an inhibitor or CES1 and SLC6A3, and a weak inhibitor of CYP2D6. MPH is transported by SLC6A2 and SLC6A3 proteins, and probably by ABCB1 [588] (Table 2). Dexmethylphenidate Pathogenic genes affected by (or influencing) dexmethylphenidate are ADRA2A, COMT, DRD4, SLC6A2, and SLC6A3. Mechanistic genes include ADRA2A, DRD4, SLC6A2, and SLC6A3. Dexmethylphenidate is a substrate of CES1, COMT, and CYP2D6; and is transported by SLC6A2 and SLC6A3 [588] (Table 2). Amphetamine Pathogenic genes associated with amphetamine effects include ADRA2A, ADRA2C, COMT, DRD1, DRD2, DRD4, DRD5, HTR1A, HTR1D, HTR1B, MAOA, SLC6A3, SLC6A2, and SLC6A4. Mechanistic genes of amphetamine are ADRAs, ADRBs, DRDs, HTRs, MAOs, and SLC18A2. Amphetamine is a major substrate of CYP2D6 and CYP3A4, a moderate substrate of COMT, CYP2B6, and CYP19A1, a moderate inhibitor of CYP1A2, CYP2D6, and CYP3A4, and a weak inhibitor of CYP2A6. Amphetamine is transported by ABCG2, SLC6A2, SLC6A3, SLC6A4, and SLC18A2. FOS and CSNK1E are pleiotropic genes potentially involved in amphetamine effects [588] (Table 2). Dextroamphetamine Pathogenic genes associated with dextroamphetamine include CSNK1E and SLC6A3. Mechanistic genes are ADRA1A, ADRA1B, FOS, SLC6A2, SLC6A3, and SLC18A2. Dextroamphetamine is a major substrate of CYP2D6 and a minor substrate of COMT, and an inhibitor of MAOA and MAOB enzymes. Genes involved in the transport of

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dextroamphetamine include the protein products of the SLC6A2, SLC6A3, SLC6A4, and SLC18A2 genes [588] (Table 2). Methamphetamine Several pathogenic genes may influence the effects of methamphetamine, including ADRA2A, ADRA2C, ADRB2, ADRB3, BDNF, CNR1, COMT, CRY1, DBH, MAOA, SLC6A2, SLC6A3, and SLC6A4. Abundant mechanistic genes participate in its mechanism of action at different levels (ADRAs, ADRBs, BDNF, CASP3, CNR1, COMT, CRY1, DBH, DTNBP1, MAOA, MAOB, GAD2, GABRs, GSTM1, GSTP1, SLC6A2, OPRM1, SLC6A3, SLC6A4, SLC6A9, SLC18A2, SLC22A3, TAAR1). Methamphetamine is a mjor substrate of CYP2D6, a minor substrate of CYP1A2, CYP2E1, and CYP3A4, and an inhibitor of BCL2, BAX, COX, CRY1, GSTA3, GSTM1, MAOA, and TH. Methamphetamine is transported by SLC6A2, SLC6A3, SLC6A4, SLC6A9, SLC18A2, SLC22A3, and SLC22A5 gene products. The PARK2 gene is also involved in methamphetamine efficacy and safety issues [588] (Table 2). Lisdexamfetamine Lisdexamfetamine is a mayor substrate of CYP2D6 and CYP3A4, and inhibitor of MAOA and MAOB7. Pathogenic genes involved in lisdexamfetamine effects are COMT, MAOA, SLC6A2, SLC6A3, SLC6A4. CSNK1E, SLC6A2, and SLC6A3 may act as mechanistic genes. SLC6A2, SLC6A3, and SLC6A4 are major transporters of lisdexamfetamine [588] (Table 2). Atomoxetine Atomoxetine is a major substrate of CYP2D6, a minor substrate of CYP2C19, a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CES1, CYP1A2, CYP2C9, CYP2D6, and SLC6A2. The pathogenic genes involved in the effects of atomoxetine are ADRA2C, DRD4, SLC6A2, and SLC6A3; and its most important mechanistic gene is SLC6A2. SLC6A2 and SLC6A3 participate in the transport of atomoxetine [588] (Table 2). Guanfacine Guanfacine is a substrate of ABCB1 and CYP3A4. ADRA1B and ADRA2A are pathogenic genes involved in guanfacine effects, and ADRA2A is the most important mechanistic gene. ABCB1 is a fundamental transporter for guanfacine intro the BBB [588] (Table 2).

Selected Studies There are few studies devoted to the pharmacogenetics of ADHD which might provide conclusive results with practical application in the clinical setting [588, 601-594]; however, if compared with other brain disorders [54], ADHD pharmacogenetics has been relatively well documented, especially in the case of MPH and amphetamines.

Table 2. Pharmacological profile and pharmacogenetics of agents used for ADHD CEREBRAL STIMULANTS Drug

Properties

Pharmacogenetics

Name: Methylphenidate Hydrochloride, Centedrine, Methylphenidate HCl, Centedrin, Concerta, Ritalin hydrochloride, Ritalin IUPAC Name: Methyl 2-phenyl-2-piperidin-2ylacetate;hydrochloride Molecular Formula: C14H20ClNO2 Molecular Weight: 269.7671 g/mol Category: Centrally acting sympathomimetics Mechanism: Blocks reuptake of norepinephrine and dopamine into presynaptic neurons. Appears to stimulate cerebral cortex and subcortical structures. Effect: Central Nervous System stimulant, Dopamine uptake inhibitor

Pathogenic genes: ADRA2A, COMT, DRD2, DRD4, DRD5, SLC6A2, SLC6A3 Mechanistic genes: ADRA2A, CES1, COMT, DRD2, DRD3, DRD4, DRD5, SLC6A2, SLC6A3, SNAP25 Drug metabolism-related genes: - Substrate: CES1 - Inhibitor: CES1, CYP2D6 (weak), SLC6A3 Transporter genes: SLC6A2, SLC6A3 Pleiotropic genes: CES2

Name: Dexmethylphenidate, d-threo-Methylphenidate, DTMP, UNII-M32RH9MFGP, CHEBI:51860. IUPAC Name: methyl (2R)-2-phenyl-2-[(2R)-piperidin-2yl]acetate Molecular Formula: C14H19NO2 Molecular Weight: 233.30616 g/mol Category: Centrally acting sympathomimetics Mechanism: Blocks the reuptake of norepinephrine and dopamine, and increases their release into the extraneuronal space. Effect: Central Nervous System stimulant, Dopamine uptake inhibitor

Pathogenic genes: ADRA2A, COMT, DRD4, SLC6A2, SLC6A3 Mechanistic genes: ADRA2A, DRD4, SLC6A2, SLC6A3 Drug metabolism-related genes: - Substrate:: CES1, COMT, CYP2D6 Transporter genes: SLC6A2, SLC6A3 Pleiotropic genes: DRD4

CEREBRAL STIMULANTS Drug

Properties

Pharmacogenetics

Name: Amphetamine, Desoxynorephedrine, 1-phenylpropan-2amine, Mydrial, 1-Phenyl-2-aminopropane, Adderall IUPAC Name: 1-phenylpropan-2-amine Molecular Formula: C9H13N Molecular Weight: 135.20622 g/mol Category: Centrally acting sympathomimetics Mechanism: Release of norepinephrine from stores in adrenergic nerve terminals and direct action on both α- and β- receptor sites. Effect: Adrenergic agent, Adrenergic uptake inhibitor, Appetite depressant, Central Nervous System stimulant, Dopamine Agent, Dopamine uptake inhibitors, MAO inhibitor

Pathogenic genes: ADRA2A, ADRA2C, COMT, DRD1, DRD2, DRD4, DRD5, HTR1A, HTR1D, HTR1B, MAOA, SLC6A3, SLC6A2, SLC6A4 Mechanistic genes: ADRAs, ADRBs, DRDs, HTRs, MAOs, SLC18A2 Drug metabolism-related genes: -Substrate: COMT, CYP2B6, CYP2D6 (major), CYP3A4 (major), CYP19A1 -Inhibitor: CYP1A2 (moderate), CYP2A6 (weak), CYP2D6 (moderate), CYP3A4 (moderate), MAO Transporter genes: ABCG2, SLC6A2, SLC6A3, SLC6A4, SLC18A2 Pleiotropic genes: FOS, CSNK1E Pathogenic genes: CSNK1E, SLC6A3 Mechanistic genes: ADRA1A, ADRA1B, FOS, SLC6A2, SLC6A3, SLC18A2 Drug metabolism-related genes: -Substrate: COMT, CYP2D6 (major) -Inhibitor: MAOA, MAOB Transporter genes: SLC6A2, SLC6A3, SLC6A4, SLC18A2

Name: Dextroamphetamine, Dexamphetamine, DAmphetamine, Dexamfetamine, (S)-Amphetamine, Dexedrine, (+)-Amphetamine IUPAC Name: (2S)-1-phenylpropan-2-amine Molecular Formula: C9H13N Molecular Weight: 135.104799 g/mol Category: Centrally acting sympathomimetics Mechanism: Blocks reuptake of dopamine and norepinephrine from the synapse, thus increasing the amount of circulating dopamine and norepinephrine in the cerebral cortex to reticular activating system. Inhibits action of monoamine oxidase and causes catecholamines to be released. Effect: Adrenergic agent, Adrenergic uptake inhibitor, Appetite depressant, Central Nervous System stimulant, Dopamine agent, Dopamine uptake inhibitors, MAO inhibitor

Table 2. (Continued)

Name: Methamphetamine, Metamfetamine, d-Deoxyephedrine, d-Desoxyephedrine, d-N-Methylamphetamine, Metamphetamine, d-Phenylisopropylmethylamine IUPAC Name: (2S)-N-methyl-1-phenylpropan-2-amine Molecular Formula: C10H15N Molecular Weight: 149.2328 g/mol Category: Centrally acting sympathomimetics Mechanism: Triggers a cascading release of norepinephrine, dopamine and serotonin. Acts as a dopaminergic and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase inhibitor. Effect: Adrenergic agent, Adrenergic uptake inhibitor, Appetite depressant, Central Nervous System stimulant, Dopamine agent, Dopamine uptake inhibitors, MAO inhibitor

Pathogenic genes: ADRA2A, ADRA2C, ADRB2, ADRB3, BDNF, CNR1, COMT, CRY1, DBH, MAOA, SLC6A2, SLC6A3, SLC6A4 Mechanistic genes: ADRAs, ADRBs, BDNF, CASP3, CNR1, COMT, CRY1, DBH, DTNBP1, MAOA, MAOB, GAD2, GABRs, GSTM1, GSTP1, SLC6A2, OPRM1, SLC6A3, SLC6A4, SLC6A9, SLC18A2, SLC22A3, TAAR1 Drug metabolism-related genes: -Substrate: CYP1A2, CYP2D6 (major), CYP2E1, CYP3A4 -Inhibitor: BCL2, BAX, COX, CRY1, GSTA3, GSTM1, MAOA, TH Transporter genes: SLC6A2, SLC6A3, SLC6A4, SLC6A9, SLC18A2, SLC22A3, SLC22A5 Pleiotropic genes: PARK2

Name: Lisdexamfetamine, UNII-H645GUL8KJ, NRP104, 608137-32-2, DB01255, LS-187377 IUPAC Name: (2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2yl]hexanamide Molecular Formula: C15H25N3O Molecular Weight: 263.3785 g/mol Category: Centrally acting sympathomimetics Mechanism: Blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Effect: Central Nervous System Stimulant

Pathogenic genes: COMT, MAOA, SLC6A2, SLC6A3, SLC6A4 Mechanistic genes: CSNK1E, SLC6A2, SLC6A3 Drug metabolism-related genes: -Substrate: CYP2D6 -Inhibitor: MAOA, MAOB7 Transporter genes: SLC6A2, SLC6A3, SLC6A4 Pleiotropic genes: CYP3A4

NON-STIMULANTS AGENTS Drug

Properties

Pharmacogenetics

Name: Atomoxetine Hydrochloride, Tomoxetine, Tomoxetina, Tomoxetinum, (-)-Tomoxetine, Strattera, Tomoxetinum. IUPAC Name: (3R)-N-methyl-3-(2-methylphenoxy)-3phenylpropan-1-amine Molecular Formula: C17H21NO Molecular Weight: 255.35474 g/mol Category: Norepinephrine Reuptake Inhibitor. Mechanism: Selectively inhibits the presynaptic norepinephrine transporter. Effect: Adrenergic uptake inhibitor, Antidepressive agent

Pathogenic genes: ADRA2C, DRD4, SLC6A2, SLC6A3 Mechanistic genes: SLC6A2 Drug metabolism-related genes: -Substrate: CYP2C19 (minor), CYP2D6 (major) -Inhibitor: CES1, CYP1A2 (weak), CYP2C9 (weak), CYP2D6 (moderate), CYP3A4 (moderate), SLC6A2 Transporter genes: SLC6A2, SLC6A3 Pleiotropic genes: DRD4

Name: Guanfacine, Intuniv, Estulic, Guanfacinum, Guanfacina. IUPAC Name: N-carbamimidoyl-2-(2,6dichlorophenyl)acetamide Molecular Formula: C9H9Cl2N3O Molecular Weight: 246.09326 g/mol Category: Adrenergic alpha-2 Receptor Agonists Mechanism: Selectively stimulates central alpha(2)adrenergic receptors, resulting in inhibition of sympathetic vasomotor centers. Effect: Antihypertensive effects, Adrenergic alpha-agonists, Strengthening prefrontal cortex functions

Pathogenic genes: ADRA1B , ADRA2A Mechanistic genes: ADRA2A Drug metabolism-related genes: -Substrate: ABCB1, CYP3A4 Transporter genes: ABCB1

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The dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate). The DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3' untranslated region (3'-UTR) of DAT1. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. Methylphenidate, the most prescribed stimulant, seems to act mainly by inhibiting the dopamine transporter protein and dopamine reuptake. Its effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions enriched in this protein. Dopamine transporter densities seem to be particularly elevated in the brain of ADHD patients, decreasing after treatment with methylphenidate [605]. Few studies have addressed the relationship between genetic markers (specifically the VNTR) at the SLC6A3 locus and response to methylphenidate in ADHD patients. A significant effect of the 40 bp VNTR on response to methylphenidate has been detected. However, the findings are inconsistent regarding both the allele (or genotype) involved and the direction of this influence (better or worse response) [150]. Joober et al. [606] tested the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to MPH. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3'-UTR VNTR polymorphism of SLC6A3. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3'-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH. Left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. MPH may be most efficacious in a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention, because it ameliorates a DAT1-mediated hypodopaminergic state [607]. Contini et al. [608] investigated 3 potentially relevant polymorphisms in DAT1 gene (-839 C > T; Int8 VNTR and 3'-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD, and found no effect of any DAT1 polymorphisms or haplotypes on MPH response. However, Kooij et al. [609] found that the VNTR polymorphism in the 3' untranslated region of SLC6A3 was significantly associated with an increased likelihood of a response to MPH treatment in carriers of a single 10-repeat allele compared to patients with the 10/10 genotype. The polymorphisms in DRD4 and the SLC6A2 were not associated with treatment response. Kirley et al. [610] also reported an association

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between the 10-repeat VNTR DAT1 polymorphism and retrospectively rated methylphenidate response in a sample of 119 Irish children with ADHD. Park et al. [611] investigated the associations between the MspI and DraI polymorphisms of the alpha-2A-adrenergic receptor gene (ADRA2A) and treatment response to methylphenidate according to subtype of ADHD. There was no statistically significant association between the MspI or DraI genotypes and the relative frequency of CGIimprovement (CGI-I) 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those subjects with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status posttreatment. These results do not support the association between the MspI or DraI genotypes and treatment response to methylphenidate in ADHD, but suggest that subtypes might influence pharmacogenetic results in ADHD. McGoug et al. [612] explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with ADHD. Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter and synaptosomal-associated protein 25 (SNAP25) allelesT1065G andT1069C. SNAP25 variants were also associated with tics, buccal-lingual movements, and irritability. DRD4 variants were also associated with picking. Increasing dose predicted irritability and social withdrawal with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1). Methylphenidate lowers DAT availability very effectively in normal people and in patients with ADHD. Nonresponders to methylphenidate among ADHD patients have a low primary DAT availability, whereas patients with a good response to the drug have high DAT. Nicotine seems to lower DAT availability such as stimulant medication; this may explain the high percentage of smokers among patients with ADHD. Zinc is a DAT inhibitor and seems to have a positive therapeutic effect on ADHD symptoms [155]. Stein et al. [613] determined if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (DMPH) and mixed amphetamine salts (MAS) in children with ADHD. Doses of 10-20 mg of either D-MPH or MAS had little to no effect on hyperactivity-impulsivity and total ADHD symptom scores in subjects with the 9/9 genotype; this was in contrast to the dose-response curves of subjects with either the 10/10 or 10/9 genotype. ADHD youth with the 9/9 genotype may require higher stimulant doses to achieve adequate symptom control. Kambeitz et al. [614] presented results of a meta-analysis of studies investigating the moderating effect of the SLC6A3 VNTR on response to methylphenidate treatment in subjects with ADHD. There was no significant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment and no effect on specific symptom dimensions of hyperactivity/impulsivity and inattention. However, in a subanalysis of naturalistic trials, the authors observed a significant effect of d=-0.36, indicating that 10R homozygotes show less improvement in symptoms following treatment than the non-10/10 carriers. This metaanalysis indicates that SLC6A3 VNTR is not a reliable predictor of methylphenidate treatment success in ADHD. However, Pasini et al. [615] found that the variable number of tandem repeat polymorphism in the 3'-untranslated region of the dopamine transporter gene (DAT) may influence the variability of the therapeutic response to MPH in ADHD. Patients with 9/9 genotype evidenced an improvement in response inhibition and working memory

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only at 4 weeks of treatment, in planning at 24 weeks of therapy and after 8 weeks of MPH suspension. Patients with 9/10 showed an improvement in response inhibition at 4, 8 and 24 weeks of treatment, in planning at 24 weeks and after 8 weeks of MPH suspension. Patients with 10/10 evidenced an improvement in response inhibition and working memory at 4, 8 and 24 weeks of treatment and in planning at 4, 8 and 24 weeks of treatment and after 8 weeks of suspension. The 9/9 ADHD genotype has a different response at 24 weeks treatment with MPH. 10/10 DAT allele seems to be associated with an increased expression level of the dopamine transporter and seems to mediate the MPH treatment response in ADHD patients. Song et al. [616] studied the association of norepinephrine transporter gene (SLC6A2), synaptosomal-associated protein of the 25-kDa gene (SNAP-25), and latrophilin 3 gene (LPHN3) with osmotic-controlled release oral delivery system methylphenidate (OROS MPH) treatment response. They selected rs192303, rs3785143 in SLC6A2; rs3746544 (1065 T>G) in SNAP-25; and rs6551665, rs1947274, and rs2345039 in LPHN3 to examine the association of OROS MPH treatment response with each single nucleotide polymorphism. The Korean authors first defined good response group when the Korean version of the ADHD rating scale score at 8 weeks was decreased for more than 50% of baseline scores and compared genotype frequencies in good response group with poor group; second, they defined it when the Clinical Global Impression-Improvement score at 8 weeks was 1 or 2, and then analyzed the genotype frequencies. There was a significant association between the 1065 T>G of SNAP-25 gene and OROS MPH response, with the good response group defined by the Korean version of ADHD rating scale scores; 33.3% of the subjects with GG genotype showed a good response, whereas 74.7% of those with TT genotype and 72.5% of those with TG genotype showed good responses. SLC6A2 rs192303 was related with OROS MPH treatment response. Schwarz et al. [617] investigated the impact of MPH treatment on gene expression levels of lymphoblastoid cells derived from adult ADHD patients and healthy controls by hypothesis-free, genome-wide microarray analysis. 138 genes may be marginally regulated due to MPH treatment. GUCY1B3 expression was differential due to diagnosis. Chronic MPH treatment affects the expression of ATXN1, HEY1, MAP3K8 and GLUT3 in controls and acute treatment affects the expression of NAV2 and ATXN1 specifically in ADHD patients. Park et al. [618] investigated the association between the metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7) polymorphism and treatment response to methylphenidate in Korean children with ADHD. After the 8 week course of methylphenidate, children with the GRM7 rs37952452 polymorphism G/A genotype had a more pronounced response rate to the treatment than did children with the G/G genotype according to the ADHD-RS scores (72.2% vs. 55.4%, respectively) and the more stringent standard of combined ADHD-RS and CGI-Improvement (CGI-I) scores (50.0% vs. 35.3%, respectively). The GRM7 rs37952452 polymorphism may play a role in the treatment response to methylphenidate in children with ADHD. Park et al. [619] examined the association between the MspI C/G and DraI C/T genotypes of the ADRA2A gene and white-matter connectivity and attentional performance before and after medication with MPH in 53 Korean children with ADHD. Subjects who carried the T allele at the DraI polymorphism showed fewer changes in the mean commission error scores after 8 weeks of medication and decreased fractional anisotropy (FA) values in the right middle frontal cortex than subjects without the T allele. Subjects with the C allele at

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the MspI polymorphism showed decreased FA values in the right postcentral gyrus than subjects without. The influence of genetic variation of the CES1 gene coding for carboxylesterase 1A1 (CES1A1), the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate, was investigated by Johnson et al. [243]. None of the CES1 gene variants were associated with the dose of methylphenidate provided or the clinical response recorded at the 6 week time point. An association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate was found. The two associated CES1 markers were in linkage disequilibrium and were significantly associated with ADHD in a larger sample of ADHD trios. The associated CES1 markers were also in linkage disequilibrium with two SNP markers of the noradrenaline transporter gene (SLC6A2). MPH reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. McCracken et al. [620] hypothesized that monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with ADHD. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1, ADRA2A, COMT, DRD3, DRD4, SLC6A3 and SLC6A4 genotypes were found for responders versus non-responders. Variants in DRD2 and DRD3 were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability. Kim et al. [621] demonstrated that the TT genotype at position 2677 in the ABCB1 gene is associated with adverse drug reactions (ADRs) to OROS-MPH. Osmotic-release oral system (OROS)-methylphenidate (MPH) is a safe and well-tolerated drug. Some patients cannot continue this regimen with ADRs. As drug efflux transporters of the central nervous system, ABCB1 plays an important role in the clearance of psychotropic drugs and their metabolites from brain tissues, it was hypothesized that genetic variations in the ABCB1 gene may affect ADRs to OROS-MPH. MPH is a substrate for ABCB1. c.2677G>T (p.Ala893Ser, rs2032582) showed a strong association with OROS-MPH-related ADRs. The TT genotype at the ABCB1 2677 locus is an independent determinant of ADRs attributed to OROS-MPH. In a functional study, the 893Ser variant markedly reduced MPH transport across the cell membrane. Kim et al. [622] examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment with methylphenidate (MPH)-OROS for 12 weeks. Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained and auditory selective attention tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task. After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task. This study suggests an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD.

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Neurotrophin 3 (NTF3) has been studied in relation to the pathophysiology of ADHD and mood disorders as well as psychostimulant action. The risk of an emotional side effect to methylphenidate (MPH) treatment may be associated with NTF3 genotypes. ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Emotionality' and 'Over-focus/euphoria' factor scores, followed by those with the G/A genotype and those with the G/G genotype. ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Proneness to crying' and 'Nail biting' item scores, followed by those with the G/A genotype and those with the G/G genotype. Genetic variation in the NTF3 gene is related to susceptibility to emotional side effects in response to MPH treatment in Korean children with ADHD [623]. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound affects gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B). In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in hippocampus, and NMDAR subunit 2B in both striatum and hippocampus. mRNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits. NMDAR protein levels were reduced. The levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered by atomoxetine. Atomoxetine seems to decrease glutamatergic transmission in a brain regionspecific manner [624]. Yang et al. [625] evaluated the association of the genetic variants of multiple genes of the noradrenergic neurotransmitter system with atomoxetine response. Twelve SNPs in SLC6A2, ADRA2A, and ADRA1A were genotyped to analyze their association with response or remission status. rs3785143 in SLC6A2 was associated with responder status. rs2279805 of SLC6A2 was nominally significantly associated with the remission status. The GG haplotype of rs1800544 and rs553668 in ADRA2A achieved nominal significance for association with non-remission. DNA variants of both SLC6A2 and ADRA2A in the adrenergic neurotransmitter system might alter the response to atomoxetine. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. Choi et al. [626] investigated the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). The CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0-∞ and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups. The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups. The maximum plasma concentration and AUC 0-∞ of 4hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups, whereas the corresponding values for Ndesmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups. These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine.

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Conclusion ADHD is a major problem of health in the infant-juvenile population worldwide, with pathogenic projections into adulthood and later in life when neurodegenerative processes can be exacerbated in susceptible people with CNS disorders. From a pathogenic perspective, ADHD is a polygenic/complex disorder in which multiple genomic defects distributed across the human genome, together with epigenetic changes and a vast array of environmental factors, may be involved. The phenotypic expression of ADHD, reflected by its clinical symptomatology, shares frequent comorbid features with an extensive number of neuropsychiatric disorders. An accurate diagnosis requires the convergence of multiple biomarkers including clinical data, laboratory analysis, psychometric assessment, structural and functional neuroimaging, qEEE and brain mapping, and genomic, proteomic and metabolomic studies. ADHD is a highly heritable disorder, as are many other neuropsychiatric disorders with which this neurodevelopmental disorder shares genetic and behavioral features. The genetic defects associated with ADHD are diverse and multilocative in different segments of the human genome. CNVs are frequently found in ADHD and ADHD-related disorders with microdeletions and duplications in critical regions of the genome potential involved in brain maturation, cognition, learning, attention, and psychomotor function. Neurotransmission dysfunction is probably the consequence of microstructural changes and brain disconnectivity rather than the pathogenic mechanism underlying ADHD. Many other molecular dysregulations are pending discovery for a better understanding of ADHD neuropathology. Although pharmacological and alternative treatments have been used in children with ADHD to ameliorate their behavioral symptomatology, at the present time pharmacological treatment with stimulants, nonstimulant medications and psychotropic drugs appears to be the most effective form of therapeutic intervention, not devoid of side-effects. Recent advances in drug development and pharmacogenomics predict a better future in terms of novel therapeutic options in order to avoid the still unknown long-term consequences derived from the chronic administration of conventional drugs on brain, cardiovascular, metabolic and endocrine functions. It is important to assume that by trial-and-error, without information on the pharmacogenetic profiles of ADHD patients, only 30% of the children receive the appropriate medication at the right dosage. In this regard, the introduction of pharmacogenetic procedures in clinical practice is the best option for the optimization of therapeutics while reducing costs and adverse drug reactions.

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In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 6

Brain Development in ADHD: A Neuroimaging Perspective Victor Pereira, Pilar de Castro-Manglano and Cesar Soutullo Child and Adolescent Psychiatry Unit, Department of Psychiatry and Medical Psychology, University of Navarra Clinic, Pamplona, Spain

Abstract ADHD is a complex and heterogeneous neurodevelopmental disorder with a mainly genetic etiology, that causes delays in volumetric, functional and connectivity brain development in patients, as compared with age-matched healthy controls. Neurobiological studies, from different approaches and techniques, suggest that ADHD is a frontal-striatum-cerebellum disorder, also with limbic connections involvement. These regions have delayed grey matter thickness/volume and activity maturation in patients with inattention, impulsivity and hyperactivity.

Keywords: ADHD, neuroimaging, MRI, fMRI, DTI, PET, functional connectivity

Introduction In recent decades, ADHD has been the subject of much neuroimaging research. The development of biomedical knowledge and technology has allowed the use and integration of epidemiological, clinical, psychological, neurobiological and genetic data from many 

Correspondence to: César Soutullo, MD, PhD, Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic (IdiSNA: Navarra Institute for Health Research), Ave. Pío XII, 36, 31008-Pamplona; Spain, E-mail: [email protected]

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different perspectives and novel neuroimaging techniques to describe their neurodevelopmental correlates. The result found different neurochemical, structural, functional and connectivity alterations, in patients (children, adolescents and adults) with ADHD. The three most common MRI techniques include: structural or morphological studies, that measures the size and shape of brain structures; diffusion tensor imaging (DTI), that provides insight into the integrity of white matter fiber tracts; and functional MRI that can be used to measure task-dependent brain activity or task-independent functional connectivity. These techniques, while improving in resolution, still have low sensitivity and specificity to give an explanation to abnormalities underlying ADHD. They cannot be used as diagnostic tools but can facilitate research on the disorder. The current DSM-5 diagnostic definition of ADHD, focuses on a neurodevelopmental disorder that appears early in life, and includes the presence of symptoms of inattention, hyperactivity and impulsivity in intensity and frequency much higher than what is usually expected for the developmental age of the person, and that causes functional impairment in several areas of the child´s life. Its etiology is mostly genetic (Heritability: 77%), and these alterations in neurotransmission proteins, receptors, second messengers, and cathecolamine transporters, cause different brain structure and function disruptions that include delays in the maturation of global and regional cortical and basal ganglia gray matter, and dysfunctions in anterior-posterior attentional networks and default mode network connectivity. Reviews such as Castellanos & Proal [1] and De la Fuente et al. [2], integrate functional neuroimaging findings in activity and at rest [1], and structural imaging of gray and white matter [2], from the perspective of connectivity of neural networks. This chapter´s objective is to integrate the findings and evidence of these techniques, and those of nuclear imaging, from a dynamic or developmental viewpoint. We are still far way from being able to integrate all this knowledge to achieve a clear and specific vision of the pathophysiology of ADHD, and to transfer these findings to clinical practice as biomarkers for diagnosis, therapy and prognosis. However, understanding the pathways opens a trail to clarify the anatomical and functional brain dysfunction in ADHD, to improve the validity of the diagnosis, to understand the symptoms and how to tackle them, and most importantly, to reduce stigma and self-blame of parents of children with ADHD, that tend to think that their child´s disorder is their fault.

Brain Anatomy in ADHD: MRI & DTI Structural MRI Neuroanatomical or structural magnetic resonance imaging (MRI) applies radiofrequency and a magnetic field to describe the anatomy based on the intensity of magnetism reflected by tissues depending on its water content. It is the technique with the highest resolution for anatomical studies of soft tissues such as the brain. This technique allows the use of software to enhance the detail of structures and quantify parameters such as area, thickness, and volume. Research in recent years has described, structural alterations in multiple cortical and subcortical regions, many associated with neuropsychological functions classically impaired in ADHD [3]. There is also evidence of normalizing effects of methylphenidate on the

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developing brain anatomy [4], that could be related to its pharmacological mechanism in dopaminergic transmission. Recent MRI longitudinal designs have provided valuable information about the neural development in patients from childhood to adulthood, compared with healthy controls, through the study of the cerebral cortex. The cortex is the upper cognitive integration area, with a complex architecture of neuronal and glial cells, and its volume is determined by its thickness and surface area [5]. Its macroscopic development over the years, can be summarized in a quadratic curve progressively increasing volume in the early years of development to reach a peak from which synaptic pruning and myelination, the result of the maturation of cognitive associations, leads to a slow decline in adolescence and adulthood [6-8]. In 2002, Castellanos et al., presented the results of research on cortical volumes developmental trajectories in patients compared with typically developing children, suggesting a parallel but delayed development in patients with ADHD [9]. Longitudinal measurements of cortical parameters in patients by structural imaging, developed in recent years mainly by Shaw et al, have made numerous observational evidence of brain maturation in ADHD (Figure 1). From 2006 to date, they described delays in the development of cortical thickness in both the ascendant phase, coarsening during middle childhood and then thinning down in late childhood, adolescence [10] and early adulthood, in several brain regions, mostly in prefrontal and cingulate regions in patients with ADHD.

Figure 1. Structural volumetric brain areas affected in patients with ADHD, based on different studies. Numbers show the following references where structural abnormalities were found: (1) Shaw et al. Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with Attention-Deficit/Hyperactivity Disorder. Arch Gen Psychiatry 2006; 63: 540—549. (2) Shaw et al. Polymorphisms of the Dopamine D4 Receptor, clinical outcome, and cortical structure in AttentionDeficit/Hyperactivity Disorder. Arch Gen Psychiatry 2007; 64: 921—931. (3) Shaw et al. Attentiondeficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Nat Acad Sci USA 2007; 104: 19649–19654. (4) Shaw et al. Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. Am J Psychiatry 2009; 166: 58–63. (5) Shaw et al. Development of Cortical Asymmetry in Typically Developing Children and Its Disruption in AttentionDeficit/Hyperactivity Disorder. Arch Gen Psychiatry 2009; 66: 888–896. (6) Shaw et al. Cortical Development in Typically Developing Children With Symptoms of Hyperactivity and Impulsivity: Support for a Dimensional View of Attention Deficit Hyperactivity. Am J Psychiatry 2011; 168: 143– 151. (7) Shaw et al. Trajectories of Cerebral Cortical Development in Childhood and Adolescence and Adult Attention—Deficit/Hyperactivity Disorder. Biol Psychiatry 2013; 74: 599–606.

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Delays were also found in the temporal, parietal, occipital, angular and supramarginal gyrus, supplementary motor area, precuneus and cuneus regions. Some of these delays had a gradual correlation with inattention, hyperactivity and impulsivity symptoms in patients and in healthy controls [11, 12], they were associated with genetic polymorphisms in the dopamine D4 receptor synapses [13] affecting the development of brain asymmetry [14] and the formation process of brain gyrus and surface area [15]. In addition, better clinical outcomes and maintained stimulant treatment were seen in some patients to converge pathways making them end up similar in thickness to those observed in normal controls´ brain development. However, the strength of the findings on the effect of medication was limited and it was not associated to clinical differences [16]. Mackie and colleagues studied the temporal evolution of cerebellar volumes and demonstrated delayed trajectories in ADHD patients more impaired in those with worse progression of symptoms [17]. From an experimental approach, a group of researchers in South Korea studied the effect of methylphenidate on cortical thickness, and a preliminary analysis found that after eight weeks of treatment in patients without prior drug treatment, cortical thickness in frontal, parietal regions, occipital and cingulate, which was initially decreased, with treatment reached values close to normal cortices [18]. A recent meta-analysis that included studies with a total of 378 patients and 344 healthy controls showed reductions in the volumes of gray matter in patients, more consistent in right caudate and lenticular nuclei, which tended to normalize with age and taking stimulant medication [19]. Ducharme and colleagues, in a longitudinal study in healthy children, found a correlation between reduced cortical thickness and slowed progressive thinning and an increased number of symptoms of inattention [20], which contributes to the dimensional perspective of ADHD symptoms as a continuum spectrum of alterations in brain development that generates a proportional and variable symptoms.

Diffusion Tensor Imaging (DTI) The Diffusion Tensor Imaging (DTI) is an anatomical imaging technique that has recently been used to study white matter in patients with ADHD. Based on MRI, DTI analyzes fractional anisotropy (FA), a structural cerebral unit expressing decreased regional axonal branching or increased packet density or axonal myelination. It provides an assessment of axonal brain organization measuring the translational motion of water molecules, thus allowing structural inferences regarding connectivity of brain anatomy and potential axonal injury [21]. The results of these DTI studies are limited and difficult to understand with regard to ADHD. However, it is important to keep in mind when it comes to understanding neuroimaging findings in a more comprehensive way. A study of patients with ADHD with 33 years of follw-up found a significantly decreased FA in several white matter fibers relative to control subjects in both cases, present or current ADHD and in remitted ADHD cases, with no significant differences between the two groups. The FA did not increase significantly in probands at any brain region [22]. Nagel's team found alterations in brain microstructure in the myelin bundles of frontoparietal white matter, frontolimbic, cerebellar, and temporal corona radiata white matter in 20 patients, mostly medication naïve, compared to controls [23]. Furthermore, the FA was lower in the posterior limb of the internal capsule and fronto-parietal white matter, but greater in fronto-limbic

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white matter. Lower axial diffusion and/or higher radial diffusion were differentially observed for ADHD youth in earlier versus later maturing areas of group FA difference. These findings lead to conclude that abnormal microscopic neural pathways are already present before adolescence and then a delay or reduction occurs in the myelination of fronto-limbic development pathways [23]. A recent systematic review and meta-analysis in DTI showed that white matter integrity is disrupted in children, adolescents, and adults with ADHD in regions and tracts such as the inferior- and superior-longitudinal fasciculus, anterior corona radiata, corticospinal tract, cingulum, corpus callosum, internal capsule, caudate nucleus, and cerebellum [23, 24]. A disruption in fronto-striatal fiber tracts of subjects with ADHD was correlated with lower performance on a go/no go task, suggesting that atypical fronto-striatal circuitry affects cognitive control in children with ADHD [25]. There are also studies with reconstructions of the nerve tracts that showed increased parietal-occipital FA and its association with the severity of symptoms and lower FA in cortico-spinal, prefrontal-parietal (superior longitudinal fasculus) and cingulum bundle. Corpus callosum, the main set of cerebral white matter with functions in inter-hemispheric connection, has also been seen to be affected in patients with ADHD, at least at the level of connections of left-right parietal-temporal regions [24]. In summary, developmentally ADHD structural imaging shows different trajectories in gray matter development predominantly in the prefrontal and parieto-occipital regions, as well as basal ganglia, comprising a biological maturational delay compared with to the development in healthy controls and static or permanent changes over time. The white matter which represents structural connectivity between these areas also appears affected. Some of these alterations correlate with ADHD symptoms, and can improve in part with age and stimulant medication. All this seems to show an approach to the anatomical basis of functional and neuropsychological alterations in fronto-parietal-stritatal systems and the default network, which will be described later.

Brain Function And Connectivity in ADHD: fMRI &rs-fcMRI Functional MRI Functional magnetic resonance imaging (fMRI) adds to anatomical detail the possibility of detecting dynamic blood flow to brain regions that express activation at a given time, and its correlation with tasks performed by the patient. It is an excellent tool for investigating the structure-function relationship of these regions and the degree and pattern of activation. Regional flow changes are measured with BOLD (Blood Oxygen Level Dependent), the CBF (Cerebral Blood Flow), CBV (Cerebral Blood Volume) and MTT (Mean Transit Time) parameters. There are numerous fMRI studies in children with ADHD and most reflect a hypoactivation of the frontal, parietal and striatal regions compared with normally developing children [26-29] that persists into adulthood [30]. Cortese et al., confirmed in a meta-analysis of 55 studies of brain functional resonance imaging (fMRI) in ADHD a hypoactivation of the ventral attentional and frontopariental networks and a hyperactivity in the default mode

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network and in the somatomotor cortex, even in the absence of psychiatric comorbidity and stimulant treatment, suggesting the specificity of this finding in the pathogenesis of ADHD [1, 31]. Another recent meta-analysis shows that there are two main domains that are functionally abnormal in ADHD—attention networks (dorsolateral prefrontal cortex (DLPFC), parietal cortex, and cerebellum) and inhibitory networks (including the inferior frontal cortex and ACC) [32]. Lower activation in the DLPFC has been associated with working memory deficits in adolescents with ADHD [32]. Other networks related with specific functions are also described as impaired in ADHD, such as executive function/cognitive control (prefrontal cortex, dorsal striatum), reward and motivational circuitry (ventral striatum), and stimulus representation and timing (posterior cortex and cerebellum), when Stroop task is performed [33]. For example, in regard to the motivational circuitry, an activity reduction in ventral striatum with an enhanced orbitofrontal cortical activation occurs in adults with ADHD in response to reward outcomes during reward processing [34] The functional hyperactivation in posterior parietal lobe, posterior cingulate and DLPFC could be explained by compensatory mechanisms in response to frontostriatal dysfunction in patients with ADHD. Effects of medication in the frontostriatal brain circuitry have been an important finding in the understanding of frontostriatal abnormalities in ADHD patients. A randomized doubleblind trial in 12 patients aged 10-15 years and 13 medication naive controls showed greater activation during interference inhibition tasks in the group treated with methylphenidate in right inferior prefrontal and premotor cortices and a normalization of activation in right inferior prefrontal and striato-thalamic regions, which in turn were not observed in medial temporal or frontal dysfunction, which suggests the existence of different patterns of activity in different brain regions with methylphenidate [35].

Resting State Functional Connectivity MRI (rs-fcMRI) The study of patterns of temporal correlation or remotely coherent simultaneous neural activation in anatomically distant regions with different neuropsychological events has led to the concept of functional connectivity, which reflects a temporal relationship between different brain regions studied using functional magnetic resonance condition quiescent resting state functional connectivity MRI (rs-fcMRI) [35] and has found support in studies of anatomical pathways by DTI [36]. This technique has been a breakthrough in research on neuroimaging and has served as a very useful tool in the study of functional connectivity of the brain outside the functional study of specific tasks. What used to be a background noise or spontaneous low-frequency (0.1 Hz) blood oxygen LEVEL- dependent (BOLD) signal functionally related fluctuations between brain regions show strong correlations at rest [36] and these signals are related to spontaneous neural activity [37, 38] which cross-correlating the time series of two different regions that are supposed to be ‗‗functionally connected.‖ These findings could reflect human anatomical connectivity [39] that is in charge of maintaining the connectivity of the known specific tasks networks, as well as monitoring functions of internal states and autobiographical memory [40]. The rs-fcMRI has been showing defects in functional connectivity, which seem to underlie the pathogenesis of several neuropsychiatric disorders, such as dementia, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and in particular schizophrenia, considered

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from the start as a disconnection disease [36]. More than 36 intrinsic neural networks have been reported to be associated with brain functions and amongst these networks the frontal network, left and right fronto-parietal, primary motor, visual primary, striate visual, insulartemporal and the default mode network are affected in ADHD [40, 41]. The best known is the default mode network (DMN), described by Andrews-Hanna [42]. This network consists of anterior medial PCF (aMPCF), posterior cingulate cortex (PCC), dorsomedial prefrontal cortex (dMPFC) and medial temporal lobe (MTL), and is related to self-referential cognition and its projection into the future [42]. It shows an inverse temporal correlation or antagonistic (specular activation pattern 180º) with respect to specific activities such as sustained attention, which means that the activation of one of them corresponds to the inactivation of the other. This finding partly explains what is observed in patients with ADHD that fail to suppress the DMN when they need to enable sustained attention networks to complete a specific task proposed to them [43, 44]. Furthermore, after initiating treatment with methylphenidate the patient is able to suppress the DMN and activate areas involved in selective attention to a task thus normalizing the mirror pattern [43, 44]. The development of impairments in DMN connectivity also seems influenced by the clinical course of patients. Mattfeld et al. compared in a study with resonance in resting state, DMN, connectivity in patients with persistent ADHD, patients in remission and healthy controls. The analysis found a lower positive correlation between posterior cingulate and medial prefrontal cortices in patients with persistent diagnosis in adulthood, compared with patients in remission and healthy controls, whereas all patients with persistence and remission, showed a negative functional correlation between medial and dorsolateral prefrontal cortices [45]. Despite the absence of a longitudinal neuroimaging to monitor these changes, the findings reflect the coexistence of irreversible DMN connectivity defects alongside other reversible ones giving us an idea of the dynamic nature and complexity of the neurological changes in ADHD. The fronto-cerebellar and fronto-stritatal connectivity has also been studied in correlation with neuropsychological function, and defects in the connectivity of these networks have been associated with executive dysfunction in children and adolescents aged 6-16 years compared with typically developing controls [46]. In summary, ADHD is characterized by activity and brain dysfunctions in many neural networks, with particular involvement of the fronto-parietal and DMN. These findings partly fixed and partly dynamic/developmental, largely explain the symptoms of inattention, hyperactivity and impulsivity and intra- and inter-variability and could be modified in response to chemical factors such as medication and physical factors such as behavioral patterns and lifestyle changes. However, we still lack sufficient information to assess the longitudinal development and causation of these disorders as well as the relationship with neuropsychological and clinical parameters in patients and their response to treatment. Additional fMRI studies are still needed to further clarify the specific regions that demonstrate the increase in size or the improvement in function or activity after short and long term administration of different doses of stimulant or non-stimulant medications effective in ADHD. Moreover, in addition to its potential diagnostic and prognostic value, knowledge about functional connectivity in ADHD could support therapeutic interventions modulating neural networks [1]. In the study of neural networks, mathematical models, such as Graph Theory, applied in other areas of research for the study of complex networks such as the Internet, flight patterns of airplanes and certain biological systems, are trying to be applied to neuroscience [36, 47].

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With these models we can attempt to determine the characteristics of the networks and the interrelation and hierarchy of the nodes or connected nuclei, in this case brain regions distant from each other and they would allow us to trace neuronal connectivity during development. These techniques and their applicability in neuroscience are currently in development.

Nuclear Medicine Imaging Findings in ADHD PET is a functional imaging technique that involves intravenous injection of radioactivemarked compounds. These compounds consist of radioactive isotopes that bind to glucose or oxygen in the blood and pass the blood brain barrier finally yielding positively charged particles that collide with the related local electrons creating photons capable of being tracked by a PET scanner [48]. Thus, this technique, through the use of specific neuroreceptor imaging agents, provides a general measure of functional activity through glucose metabolism and blood flow to regions of interest and also allows a more specific analysis of the density of the binding site of the neurotransmitter to be studied, the presynaptic and postsynaptic transporter along various regions and binding brain networks. There are numerous studies of PET and ADHD [49], and the majority of these studies have focused on the differences of changes in binding site and neurotransmitter dopamine receptor density [48]. It is postulated that an increase in the number or density of carriers and receivers should probably reflect increased binding potential. Skokaukas et al. summarized the most relevant research findings about children and adults in a review of neuroimaging candidate markers for the prediction of response to methylphenidate [50]. This review included all studies published between 2002 and 2012, performed with SPECT or PET with different tracers for the measurement of Cerebral Blood Flow (rCBF), regional dopamine levels and activity of DAT and D2 receptors. Several studies are consistent in finding a better response to treatment with a higher basal availability of striatal DAT receptor level, one of the target areas of treatment involved in the neuropsychology of motivation and reward [51], although other evidence seems contrary and found no relationship to symptomatology and clinical improvement. It has also been reported that the higher the baseline levels of D2 receptors in the striatum, which reflect less intrasinaptic dopamine, the greater the response to therapy in relation to the decrease in symptoms of hyperactivity but not in relation to the inattention [52]. Although the response of inattention symptoms do not improve with starting doses of methylphenidate, they do seem to improve over time as has been seen in patients with chronic treatment in which the increase in dopamine (DA) in the ventral striatum after administration of intravenous methylphenidate was associated with improvement in symptoms of inattention [51]. The relationship between rCBF in dopaminergic gene polymorphisms and response to treatment have been studied, showing a decrease in cerebral perfusion medial frontal lobe, left basal ganglion and left and right frontal lobes in patients with DAT1 10-repeat allele [53]. In regards to the predictive value of rCBF, it has also been found that decreased basal midbrain, cerebellum and left posterior middle frontal gyrus were associated with a better response of symptoms to the medication [54], while a higher rCBF in left anterior cingulate

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cortex, left claustrum, right anterior cingulate cortex and right putamen had a poorer response [55]. Nuclear Medicine imaging studies provide a wealth of information and have a role in the investigation of neurotransmitters but have the disadvantage of high complexity and teratogenicity associated with the radiation. Although fMRI is safer and rising in the study of cerebral perfusion key in the pathophysiology of ADHD. Alternatively, nuclear imaging are suitable for the molecular characterization of brain dopaminergic activity and therefore are excellent techniques for the study of neurochemical mechanisms of the medication.

Imaging Genetics in ADHD Genetics has widely demonstrated to play a role in the impairment of brain development in ADHD. Although not all ADHD that occurs in the family is genetic, heritability estimates derived from the correlation of ADHD symptoms between monozygotic twins and dizygotic twins reach an average of 76% [56, 57]. In recent decades, research designs have allowed the combination of neuroimaging variables with different genetic polymorphisms. Based on the evidence of the involvement of dopamine and norepinephrine in the circuits of ADHD, research has focused on the genes encoding transmembrane proteins of dopaminergic synapses, whose alterations seem relevant in the pathogenesis of the disorder. Szobot and colleagues evaluated ADHD risk alleles at DRD4 and DAT1 genes and striatal DAT occupancy after treatment with methylphenidate (MPH) [58]. A total of 17 children with ADHD and substance use comorbidity underwent a SPECT at baseline and after three weeks on MPH; the results showed that the combination of DRD4 7R allele and 10R homozygosity at DAT1 was significantly associated with a smaller DAT occupancy in caudate and putamen, bilaterally. On one hand, these associations were lower if genotypes were not included and, on the other hand, striatal DAT occupancy was not significant for each genotype considered separately. What they found is that drug use had an independent effect in all brain areas (except the left putamen) and there was no significant MPH dose effect. It is possible to speculate that there is an additional effect of both DRD4 risk allele and risk genotype at DAT1, leading to a less efficient MPH occupancy [58]. Some studies have demonstrated that MPH induces improvement on prefrontal cortex functioning where NET density is higher. It was postulated that NET could transport dopamine in the prefrontal cortex because dopamine has a greater affinity for NET as compared with its affinity for DAT [59, 60]. MPH also induces an increase in cortical cell excitability, which is mediated by activation of adrenergic alpha2A receptors (ADRA2A) [61]. Shaw et al., studied the development of cortical thickness, and found the best clinical outcomes (lower persistence of ADHD) in the subgroup of patients with DRD4 7-repeat polymorphism at the end of follow up, with a gradual effect of improved clinical outcomes greater genotypic risk [13]. The parietal posterior orbitofrontal right cortices, prefrontal superior-medial were initially reduced in patients compared with healthy controls as well as carriers of the DRD4 allele 7-repeat relative to non-carriers, with a pattern of gradual increase in cortical thickness in the bark right orbitofrontal / inferior-frontal and parietal with sequence: ADHD-carriers; ADHD non-carriers; Controls-carriers; Controls-non-carriers.

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Although the effect of genotype, adjusted for multiple comparisons, was not significant. No significant effect of other polymorphisms (DRD1 and DRD4 and DAT) was found. Indeed, other studies conclude that there is no association between the transporter DAT1 and ADHD [62]. The trajectories of cortical thickness in the right supramarginal / angular gyrus, right orbitofrontal inferior frontal / lateral varied in the subgroup ADHD carrier with respect to the healthy group, and not in the subgroup ADHD no carrier, where it remained parallel but delayed compared with the healthy controls. Similar results were observed in right-angle and orbitofrontal cortices in subgroups of healthy carriers and non-carriers. Cortical thickness, lesser at 7 years in the right orbitofrontal cortex in ADHD carriers, was normal at age 17, in a convergence of paths. The trajectories showed no significant differences for other polymorphisms [13]. In a recent review of genetic association studies, 170 studies had investigated 49 candidate genes of which only 96 studies reported a positive association with ADHD [63]. However, only 14 of these genes have been able to be replicated and only 8 have a greater number of positive than negative reps. Genetic studies conclude that individual risk genes appear to represent only small risk factors to explain the probability of having a disorder like ADHD and could be due to the presence of multiple combinations of polymorphisms and environmental factors [64-66]. The future of genetics is currently in genome wide association studies (GWAS) but samples of 10,000 to 20,000 individuals with ADHD are needed to identify candidate genes associated with the disease [67]. This genetic analysis enables simultaneous genotyping of thousands of single nucleotide polymorphisms (SNPs) throughout the genome. A first preliminary study of GWAS in ADHD failed to detect susceptibility genes and suggests future studies of larger samples in order to identify genetic loci risk [67]. Other gen candidates such as CNTFR, NTF3 y NTRK2 are in study. Despite numerous advances and research, pharmacogenetic studies to identify high-impact genes to predict response and side effects of medications do not yet exist.

Conclusion ADHD is characterized by structure of grey matter, activity and brain connectivity dysfunctions in many neural networks, with particular involvement of the fronto-parietal and DMN. There is also convergent evidence for white matter pathology and disrupted anatomical connectivity in ADHD. In addition, dysfunctional connectivity during rest and during cognitive tasks has been demonstrated. However, the causality between disturbed white matter architecture and cortical dysfunction remains to be evaluated. Both genetic and environmental factors might contribute to disruptions in interactions between different brain regions. Stimulant medication not only modulates regionally specific activation strength but also normalizes dysfunctional connectivity, pointing to a predominant network dysfunction in ADHD [68]. The main findings seem to describe ADHD as a developmental brain disorder characterized by delays and disruptions in the global development of the central nervous system that compromises gray and white matter. This is manifested in lower brain maturation or delays, most evident in the prefrontal cortex, parietal and posterior cingulate cortices, as

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well as basal ganglia, which is associated with alterations in the activity and structural and functional connectivity of various brain networks, especially the fronto-striato-parietal and DMN. Some of these changes seem to correspond to neuropsychological findings and clinical symptoms observed in inattention, hyperactivity and impulsivity, and that define the clinical diagnosis of ADHD. Both those observed in clinical neuroimaging findings as outlined above can be corrected with medication, even with the promise of potential neurotrophic nonpharmacological therapies such as transcranial magnetic stimulation (TMS) etc. To date, efforts to identify which neuroimaging findings may serve as biomarkers for diagnosis [69] or prediction of response to stimulant treatment [50] has not been successful. A good biomarker should be sensitive (i.e., able to detect alterations in individuals with the disorder), specific (able to discard changes that do not really correspond to the disorder), reliable, reproducible, noninvasive, simple, affordable, and it should be replicated in several independent studies. Thome et al., reviewed the literature in search of biomarkers from neuroimaging, neuropsychology and molecular biology suggest that, if no objective alteration to these characteristics has been found to date, the study of the trajectories of cortical maturation (which, according to studies of volume and thickness, appear to relate to the treatment and clinical outcome, as already reviewed) seems promising, with higher specificity to the description of specific findings [69, 70].

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In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 7

Adult Attention-Deficit and Hyperactivity Disorder and Mild Cognitive Impairment: A Case-Control Study Ángel B. Golimstok, María J. García-Basalo, María C. Fernández, Nuria E. Campora, Waleska L. Berrios, Juan I. Rojas and Edgardo Cristiano Department of Neurology, Hospital Italiano de Buenos Aires, Argentina

Abstract In a previous report, we have shown that attention-deficit and hyperactivity disorder (ADHD) often precedes dementia with Lewy bodies (DLB) but not Alzheimer disease type (ADT). As mild cognitive impairment (MCI) is a heterogeneous entity that is a risk factor for developing dementia in general, we hypothesized that ADHD should be frequently associated with it and especially, with the Multiple Domain Non-Amnestic subtype that usually does not evolve to ADT. To confirm this hypothesis we conducted this study. Patients with MCI were recruited from the membership of the Italian Hospital Medical Care Program in Argentina from 2009 to 2013 and were compared with a group of normal controls from our database. The DSM-IV criteria adapted for the identification of adult patients with ADHD and validated to Spanish Wender Utah Rating Scale were used to identify individuals with ADHD criteria during their adult life. Analysis of categorical variables was carried out using chi-square. Mann-Whitney test was used for continuous variables. Statistical significance was p < 0.05. A total of 417 patients with MCI were compared with 160 controls. The percentage of patients with ADHD criteria in MCI cases was 37.41% and 11.87% in the control group. The prevalence of ADHD in 

Correspondence to: Dr. Ángel B. Golimstok, Departamento de Neurología, Hospital Italiano de Buenos Aires, Juan D. Peron 4190, C1181ACH Buenos Aires, Argentina. E-mail: [email protected]

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Ángel B. Golimstok, María J. García-Basalo, María C. Fernández et al. MCI cases was significantly higher compared with the control group (p ≤ 0.001). The Non-Amnestic MCI subtypes was significantly higher in patients with ADHD compared to those without ADHD (p ≤ 0.01). Multiple Domain non-Amnestic was the most frequent subtype found in the ADHD group and Single Domain Amnestic MCI in the other group. We found that ADHD is more prevalent in MCI than in normal controls as we expected. As Non-Amnestic Multiple Domain subtype is predominant in patients with ADHD, it should be done future longitudinal studies to characterize the clinical course and prognosis of this special group.

Keywords: ADHD, mild cognitive impairment, adult

Introduction Attention Deficit Hyperactivity Disorder (ADHD) affects 5%–12% of children in the United States [1] being the most prevalent cause of childhood learning disabilities [2-3]. This disorder is characterized by symptoms of inattention, hyperactivity, and impulsivity. These characteristics persist into adulthood [4-5]. Unfortunately, there are very few epidemiological studies in adulthood and this disorder is usually underdiagnosed [6]. This entity is commonly mistaken with anxiety, depression and other behavioral disorders [7]. As adult ADHD is associated with attention deficit, can be easily mistaken for a late-life degenerative cognitive decline in the geriatric population. Mild Cognitive Impairment (MCI) is the most frequent diagnosis in patients with cognitive difficulties in the geriatric population, and prevalence estimates for this entity range from 5%–40% across studies [811]. There is great variability in operational criteria of MCI. Consensus recommendations for the diagnosis helped recently to estimate the prevalence of MCI more accurately in older population [9-11]. Current consensus recommendations for the diagnosis of MCI [12] from the 2nd International Working Group on MCI, sought to exclude patients without cognitive decline, with lifelong cognitive deficit, which is a clinical characteristic of ADHD, so as not to be confused with this diagnosis that is expected to be an early stage of degenerative dementia. The following inclusion criteria of that consensus: ―Lack of medically identifiable cause for cognitive decline‖ was intended to exclude other etiologies of deficit such as ADHD. However, as ADHD is not usually screened in adults, could be a confounder included in population diagnosed as MCI and in many cases related to cognitive decline [13]. Thus, ADHD may be an overlapped entity with some types of MCI, especially those ―non amnestic.‖ Furthermore, in a previous report we have shown that ADHD often precedes dementia with Lewy bodies (DLB) but not Alzheimer disease type (ADT) [14]. In this chapter, we hypothesized that ADHD should be frequently associated with MCI and especially with the Multiple Domain Non-Amnestic subtype that in most cases does not evolve to ADT. To confirm this hypothesis we conducted this study.

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Methods Participants This study was conducted at the Italian Hospital Medical Care Program (IHMCP) in Buenos Aires, Argentina with approval from the institutional Review Board of the IHMCP research committee. Patients and controls were analyzed after informed consent was signed. In MCI patients, researchers ensured that patients fully understand and appreciate the consequences of their participation throughout the course of the study. Patients with MCI and controls were recruited from the membership of the IHMCP, a large prepaid health maintenance organization model. IHMCP provides comprehensive medical and health services through two medical center hospitals and 24 medical office buildings to over 140 000 members primarily located in the urban areas around the Autonomous City of Buenos Aires, Argentina. Approximately 5–7% of the population in this geographic area is affiliated to the IHMCP. The IHMCP population characteristics are closely representative of the metropolitan population of the Autonomous City of Buenos Aires, as demonstrated by 2001 census data in a series of socioeconomic categories (Table 1). Table 1. Socioeconomic level and ethnic origin of inhabitants of the Autonomous City of Buenos Aires and IHMCP* affiliates, based on the 2001 Argentinean census Socioeconomic level Upper Upper middle Middle Lower middle Lower Total

City of Buenos Aires (%) 10 16 30 21 17 100

IHMCP (%) 5 19.4 37.5 25.6 12.5 100

Ethnic origin Caucasian 92 95.5 Asian 4 2 African American 1 0.5 1 Mestizos 3 2 Total 100 100 *IHMCP, Italian Hospital Medical Care Program. 1 Mestizos: Spanish term used to designate people of mixed European and Amerindian ancestry living in the region of Latin America.

The period of the study was conducted from 2009 through 2013. The sample included two groups of subjects: Each participant was classified as MCI on the basis of the ―typical criteria,‖ adapted by Jak et al., from the criteria outlined by Petersen and Morris [15] operationally-defined objective cognitive impairment for multiple subtypes of MCI. Individuals were classified as MCI if neuropsychological measures fell greater than 1.5 SD below age-appropriate norms on one or more tests within a domain.

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Participants were labeled as Single Domain Amnestic MCI if only the memory domain was impaired, as Single Domain Non-Amnestic MCI if only one non-memory domain was impaired, as Multiple Domain Amnestic MCI if memory and at least one other domain showed impairment, and as Multiple Domain Non-Amnestic MCI if more than one nonmemory domain was impaired. When applying these criteria, individuals were classified as normal if no neuropsychological measure fell greater than 1.5 SD below age-appropriate norms in any cognitive domain. Patients with MCI and controls were matched as groups on a range of demographic variables to ensure comparability. All patients were evaluated and diagnosed by a trained neurologist. Routine clinical investigations were conducted to exclude reversible causes of cognitive impairment. Patients were excluded if formal examination showed evidence of any other brain disorder or physical and/ or mental illness sufficient to contribute considerably to the clinical picture. Patient selection was strictly consecutive and included all the prevalent cases in the center who met previous criteria.

Controls We included as controls, those volunteers of our database, living in the geographic area of residence of patients and with the same age and years of education range. Controls were never duplicated. Records of potential controls were reviewed by a neurologist to exclude those controls in which the presence of dementia of any type or any other neurological disease was suspected before the year of inclusion in database. The list of the entire population from which potential controls were randomly drawn was provided by the record database system of the epidemiological center of the IHMCP, and control subjects were selected for cases using a statistical program.

Ascertainment of Attention-Deficit and Hyperactivity Disorder The DSM-IV criteria adapted for the identification of adult patients with ADHD and the validated to Spanish Wender Utah Rating Scale (WURS) were used as an instrument for retrospective diagnosis of childhood ADHD [16-18] to identify patients and controls with preceding ADHD during their adult life. DSM-IV criteria and the Wender Utah Rating Scale have been successfully adapted for the identification of adult patients with ADHD and have been used in numerous studies in the past [17, 19]. To obtain a full diagnosis of adult ADHD, subjects were required to have the following criteria: (i) fully met the DSM-IV criteria for diagnosis of ADHD within the past years; (ii) described a chronic course of ADHD symptoms from adolescence to adulthood; and (iii) endorsed a mild to severe level of impairment attributed to those symptoms. Participants were also provided with the validated to Spanish Wender Utah Rating Scale for retrospective diagnosis of ADHD in childhood [18]. The validated to Spanish version scale comprises 25 items which are rated on a 5-point scale (0–4) [18]. The total score ranges from 0 to 100. For the retrospective diagnosis of ADHD in childhood, the authors recommended a cutoff score of 32 or higher to obtain a sensibility of 91.5% and specificity of

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90.8%, with a positive and negative predictive value of 81% and 96%, respectively, and a Cronbach coefficient of 0.94. This cutoff score was used because it demonstrated the best behavior (ROC curve) of the validated scale [18]. In patients with MCI, diagnosis was obtained from the patient and a direct informant who had known the patient for at least 10 years and had information obtained from a close relative who knew the patient in childhood, when it was possible. To avoid premorbid symptoms of cognitive impairment, we considered as adult ADHD symptoms only those patients who presented symptoms that fully met the DSM-IV criteria for diagnosis of ADHD and who fulfilled the cutoff score of the Spanish Wender Utah Rating Scale of 32 points or higher during their infancy. For example, if a patient had ADHD symptoms in adult life but he/she did not remember if those symptoms were present during childhood, the patient was not considered as a positive case of ADHD symptoms.

Procedure and Data Analysis The evaluation of cases and controls regarding the identification of preceding ADHD using the DSM-IV criteria and the Wender Utah Rating Scale was performed by a trained neurologist unaware of the objective of the study. Only cases and controls fulfilling ADHD criteria by this kind of evaluator were considered as positive exposure. Raters who collected the information about ADHD symptom status were blind to the MCI subtype and control status. When the evaluation was completed, data were analyzed by an unblinded neurologist aware of the objective of the study. Analysis was performed using Stata 8.0 version. Analysis of differences in the frequency of categorical variables was carried out using the chi-square test. The Mann–Whitney test for independent samples was used for continuous variables. Statistical significance was set up at p < 0.05.

Results We identified 417 patients fulfilling criteria for MCI and 160 with inclusion criteria as controls. All patients authorized the use of their medical records for research. Amongst MCI cases, 38.8% were men, the median age was 71.2 years (range 51–86 years) and the mean years of education was 12.3 (range 3–18). In controls, 40% were men, the median age was 70.4 years (range 51-86) and the mean years of education was 12.8 (range 3-18) (Table 2). There were no significant differences in these variables evaluated between the two groups. Table 2. Demographic and clinical data MCI vs. controls

N (patients) Gender, men (%) Age, mean (years) Education, mean (years) ADHD diagnosis (%)

MCI 417 162 (38.8) 71.2 (range 51-86) 12.3 (range 3-18) 156 (37.4)

Controls 160 64 (40) 70.4 (range 51-86) 12.8 (range 3-18) 19 (11.9)

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The frequency of preceding ADHD symptoms was 37.4% in MCI cases (n = 156), and 11.9% (n = 19) in the control group. The prevalence of ADHD symptoms in MCI cases was significantly higher when compared with the control group (p = 0.001, OR 3.1 95% CI 2.9– 9.4). The Non-Amnestic MCI subtypes were significantly higher in patients with ADHD compared to those without ADHD (p = 0.009) (Table 3) Multiple Domain non-Amnestic was the most frequent subtype found in the ADHD group (n = 118) and Single Domain Amnestic MCI in the non ADHD amnestic group (n = 57). Table 3. Patients with MCI and ADHD diagnosis/ type of MCI ADHD

Non-Amnestic MCI (SD/MD)* Yes 120 No 198 Total 318 *SD: Single Dominium; MD: Multiple Dominium. X² p = 0.009.

Amnestic MCI (SD/MD)* 36 63 99

Total 156 261 417

Discussion In this case–control study, we identified a higher prevalence of ADHD amongst patients with MCI than in the normal control group. Few previous studies have examined the association between ADHD and MCI or dementia. We have reported a study carried out in the same hospital (IHMCP) between 2000 and 2005 [14]. We studied three groups of subjects meeting inclusion criteria for DLB (n = 109), AD (n = 251), and cognitively normal controls matched by age, sex, and year of education to the impaired groups (n = 149). In that study, a retrospective diagnosis of childhood ADHD was performed using adapted DSM-IV criteria and the validated Spanish version of the Wender Utah Rating Scale. But as patients with dementia were the subjects, diagnosis was obtained by a direct informant who had known the patient for at least 10 years, and had information obtained from a close relative who knew the patient in childhood. As this method has not been validated, we considered cases as ADHD symptoms and not as ADHD. We reported an increased frequency of ADHD symptoms (p < 0.001) in DLB group (47.8%), compared with ATD (15.2%), and normal control subjects (15.1%). That study did not evaluate MCI patients but the findings led to speculate that non amnestic type (attentional-executive deficit) should be significant associated with previous ADHD symptoms. This speculation is supported by other publications that demonstrated [20-21] the presence of early attentional deficits in the progression of MCI due to underlying DLB pathology. We found only one previous study assessing ADHD in MCI. In that study, the authors evaluated the WURS in 42 patients with MCI, 18 of them were non-amnestic and 24 amnestic. This study did not find any correlation between childhood ADHD and MCI [13]. The lack of correlation can be explained by the fact that most of the patients studied were amnestic, and it is possible that this kind of patients constitute the less questionable neurodegenerative prodromal group. Thus, ADHD may not be a confounder in that kind of

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subjects. In contrast, in our study with a higher number of non amnestic patients, probably, several cases were ADHD and not ―true‖ MCI. It could be speculated that non amnestic variants were more probably related to underlying pathologies as DLB or frontotemporal degeneration and these etiologies are more susceptible to be confused or preceded by ADHD than Alzheimer´s disease. Recent reports showed structural and functional overlap in degenerative dementia and ADHD using neuroimaging biomarkers. Examples of these kind of changes are reduced activation in frontro-striatal networks [22] in frontotemporal activation [23-24]. These findings demonstrated again that ADHD should be screened routinely during clinical assessment in geriatric population with cognitive decline. In conclusion our findings showed a significant association between ADHD diagnosis and MCI, predominantly non amnestic. This report is consistent with previous findings and should be confirmed in future studies combining neuroimaging and other biomarkers to explain more accurately the clinical and pathophysiological significance of this association. As Non- Amnestic Multiple Domain subtype is predominant in patients with ADHD, it should be done future longitudinal studies to characterize the clinical course and prognosis of this special group.

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In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 8

Attention Deficit Hyperactivity Disorder and Traumatic Brain Injury: Connections, Predictors, and Outcomes Christopher M. Bonfield1, and Joseph B. Stoklosa2 1

Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, US 2 Department of Psychiatry, Harvard School of Medicine, Boston, MA, US

Abstract Attention Deficit Hyperactivity Disorder (ADHD) and traumatic brain injury (TBI) are common pediatric health problems. In the United States alone, a reported 6.4 million children aged 4 to 17 years have received a diagnosis of ADHD, while approximately 500,000 children suffer a TBI annually. Both conditions can lead to significant functional impairment that may persist into adulthood. Furthermore, treatment of these conditions, among hospitalizations, clinic visits, medications, and rehabilitation, creates significant economic costs. Research suggests that there are many links between ADHD and TBI. Due to inattention and impulsivity, children with ADHD engage in more risky behaviors, resulting in more hospitalization and more traumatic injuries, including TBI. Children who have a pre-injury diagnosis of ADHD have worse outcomes after TBI, as well. After TBI, many children are found to have attention and behavior disorders, some with the development of secondary ADHD (S-ADHD). Pre-injury factors and post-injury imaging are being used to predict those at risk for S-ADHD. In this chapter, we explore the links between both pre-injury ADHD and S-ADHD to TBI, investigating pre-injury factors, injury patterns, post-injury imaging characteristics, S-ADHD predictors, rate of development of S-ADHD, treatments, and outcomes after TBI. It is important that children with ADHD and their families be informed about an increased risk of TBI. Also, 

Correspondence to: Dr. Christopher M. Bonfield, Department of Neurosurgery, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213, USA. E-mail: [email protected]

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Christopher M. Bonfield and Joseph B. Stoklosa patients at risk for S-ADHD can be identified at the time of injury, treated accordingly, and their families can be counseled about worse outcomes.

Keywords: ADHD, traumatic brain injury, predictors

Introduction Attention Deficit Hyperactivity Disorder (ADHD) and traumatic brain injury (TBI) are common pediatric health problems. Both conditions can lead to significant functional impairment that may persist into adulthood. Furthermore, treatment of these conditions, among hospitalizations, clinic visits, medications, and rehabilitation, creates significant economic costs. Research suggests that there are many links between ADHD and TBI. ADHD puts a child at risk for increased TBI events, because of the impulsivity, lack of attention, and hyperactivity associated with the condition. These children engage in more risky behaviors, resulting in more hospitalization and more traumatic injuries, including TBI. Children who have a pre-injury diagnosis of ADHD have worse outcomes after TBI, as well. After TBI, many children are found to have attention and behavior disorders, some with the development of secondary ADHD (S-ADHD). Pre-injury factors and post-injury imaging are being used to predict those as risk for S-ADHD. In this chapter, we explore the links between both pre-injury ADHD and S-ADHD to TBI, investigating pre-injury factors, injury patterns, post-injury imaging characteristics, SADHD predictors, rate of development of S-ADHD, treatments, and outcomes after TBI. It is important that children with ADHD and their families be informed about an increased risk of TBI. Also, patients at risk for S-ADHD can be identified at the time of injury, treated accordingly, and their families can be counseled about worse outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) Overview Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood psychiatric disorders, affecting between 3% and 5% of children [1]. In the United States alone, a reported 6.4 million children aged 4 to 17 years have received a diagnosis of ADHD [2]. It is associated with deficits in attention executive functioning, hyperactivity, and impulsivity and often results in problems in school and at home, leading to underachieving academic performance, poor interpersonal relationships, and emotional instability. Other psychiatric conditions, such as oppositional defiant disorder, conduct disorder, anxiety disorder, and depression, are often associated with ADHD, as well. ADHD not only affects the child, but also impacts the immediate family. In families of a child with ADHD, there are more parent-reported problems in terms of emotional-behavioral role function, behavior, mental health, and self-esteem, significant impacts on the parents' emotional health, parents' time to meet their own needs, and interference with family activities and family cohesion [3].

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The deficits seen in ADHD can persist into adulthood. ADHD is associated with higher levels of unemployment. Those who are employed experience workplace impairment and reduced productivity, as well as behavioral issues such as irritability and low frustration tolerance. Indirect effects of ADHD on occupational health include reduced educational achievement and increased rates of substance abuse and criminality. There is also a substantial economic impact as a result of absenteeism and lost productivity. They are at increased risk of accidents, trauma and workplace injuries [4].

Traumatic Brain Injury (TBI) Overview Traumatic brain injury (TBI), a significant public health concern, has an estimated incidence between 250 and 400 per 100,000 per year, with the highest rates among ages 0-4 years old. An estimated 475,000 children aged 0-14 each year in the United States suffer a TBI [5]. TBI results in over 7,000 deaths, 60,000 hospitalizations, and 600,000 emergency room visits annually among American children. TBI is the leading cause of child death and long-term disability, and is one of the most frequent causes of interruption to normal child development [6].

ADHD and TBI: Risk Factor Analysis There is evidence supporting the hypothesis that ADHD is associated with an increased TBI rate. Children with ADHD show increased hyperactivity, impulsivity, attention problems, risk taking behavior, comorbid disorders, diminished motor skills and less coordination, all risk factors in sustaining a trauma, accident, or injury. In preschoolers with ADHD, over half exhibited behavior that placed them at-risk for physical injury [7]. Children with ADHD have a higher incidence of attendance in trauma departments, repeat attendance, head injury, thermal injury, wounding and poisoning [8]. The overall incidence of hospital admissions for injuries is two times higher in the ADHD medication cohort. However, there may be some evidence that the use of ADHD medications has a positive effect on the risk of injury. Van den Ban et al. reported the incidence rate for injuries during exposure to ADHD drugs was lower in the exposed period compared to the period prior to ADHD drug use, although the difference was not statistically significant. However, the relative risk for injuries was almost five times higher in the ADHD medication cohort among those who concomitantly used other psychotropics, which may represent comorbid psychiatric disorders besides ADHD or more severe ADHD [9]. DiScala et al. investigated the injuries to hospitalized children with ADHD compared to a group of controls. They demonstrated that injured children with ADHD were more likely to be male (87.9% vs. 66.5%), to be injured as pedestrians (27.5% vs. 18.3%) or bicyclists (17.1% vs. 13.8%), to inflict injury to themselves (1.3% vs. 0.1%), to sustain injuries to multiple body regions (57.1% vs. 43%), to sustain head injuries (53% vs. 41%), and to be severely injured as measured by the Injury Severity Score (12.5% vs. 5.4%) and the Glasgow Coma Scale (7.5% vs. 3.4%). These patients were also twice as likely to be discharged to

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rehabilitation or extended care instead of to home [10]. Other studies have also shown an increased prevalence of ADHD in patients who suffer TBI [11].

ADHD and TBI: Outcomes Few studies have investigated the neurologic outcome after TBI in children with preinjury ADHD. Bonfield et al. reported outcomes on 48 children with ADHD and 45 without ADHD who sustained mild TBI. In the ADHD group, 25% were moderately disabled and 56% had completely recovered at follow-up, compared to 2% moderately disabled and 84% completely recovered in the control group. The data suggest that patients with pre-injury ADHD who sustained mild TBI were more likely to be moderately disabled than patients without ADHD who sustained mild TBI [12]. Slomine et al. compared performance between children with ADHD and TBI to TBI only. The ADHD group showed worse performance on measures of attention, executive functioning, and memory. Additionally, results suggested greater deficits in memory skills in an S-ADHD group compared with the pre-injury ADHD group, suggesting there may be important neuropsychological differences in children with developmental versus secondary ADHD [13]. Furthermore, treatment with stimulant medication post-injury was more frequently associated with pre-injury ADHD (39% vs. 7% controls). Also, children with ADHD who were treated pre-injury with stimulant medication had fewer total symptoms at 24 months post-injury relative to untreated patients with preinjury ADHD [14]. This information can be used in informing families on what to expect as a child recovers from a TBI, and in emphasizing the importance of TBI-prevention among children with ADHD.

Secondary ADHD (S-ADHD) It has been shown that TBI independently results in deficient response inhibition [15]. Beyond this, however, S-ADHD is a disorder characterized by inattention, impulsiveness, and hyperactivity following TBI without prior history of ADHD. A growing body of literature has demonstrated the increased development of novel psychiatric disorders after TBI compared to controls, with S-ADHD as one of the more common new diagnoses. According to the literature, S-ADHD rate can be as high as 35% after TBI (Table 1). These studies have not only investigated the rate of the development of S-ADHD after TBI, but also explored possible predictive factors including: age, sex, race, socioeconomic status (SES), family psychiatric history, family history of ADHD, preinjury family function, preinjury adaptive function, preinjury lifetime psychiatric disorder, severity of injury, and others. In 1997, Max et al. first published the rates of psychiatric disorders in children and adolescents 2 years after a TBI. After severe TBI, 31% (4 of 13) developed S-ADHD. None of the patients with mild/moderate TBI and no pre-injury psychiatric disorder and 1 with preinjury psychiatric disorder developed S-ADHD. Four of the 16 (25%) mild/moderate TBI had

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pre-injury ADHD. Three of 4 had their ADHD remain stable, while 1 had resolution of ADHD [16]. The following year, Max et al. published a larger study with 50 children and adolescents to investigate the risk factors of disruptive behavior disorders after TBI. Unlike oppositional defiant disorder/conduct disorder (ODD/CD), the development of S-ADHD after TBI was not associated with any variables including: family functioning, severity of injury, family history of alcohol dependence/abuse, performance IQ, language rating, learning disability rating, and age at injury [17]. Table 1. Rate of S-ADHD development after TBI Study

Rate of S-ADHD (n)

Follow-up

Max et al. 1997 [16]

severe TBI: 31% (4/13) overall TBI: 19% (15/80)

24 months

severe TBI: 21% (5/24); mild TBI: 13% (3/24); orthopedic injury: 4% (1/24) overall TBI: 20% (15/76) overall TBI 19% (15/80) overall TBI: 35% (16/46) severe TBI: 54% (7/13); mild TBI: 13% (1/8); orthopedic injury: 0% (0/20) overall TBI: 35%

24 months

premorbid psychosocial adversity, posttraumatic affective lability and aggression, posttraumatic psychiatric comorbidity, overall disability TBI severity

3 months

right putamenal injury

12 months

thalamic and basal ganglia injury

24 months

Levin et al. 2007[ 14]

overall TBI: 17% (7/42) overall TBI: 16% (18/115) overall TBI: 15% (15/103) overall TBI: 21% (17/82) overall TBI: 15%

Levin et al. 2007 [14]

overall TBI: 18%

Gerring et al. 1998 [11]

Max et al. 1998 [18]

Herskovits et al. 1999 [20] Gerring et al. 2000 [23] Bloom et al. 2001 [24] Max et al. 2004 [19]

Schachar et al. 2004 [26] Wassenberg et al. 2004 [25] Max et al. 2005 [21] Max et al. 2005 [22] Max et al. 2005 [22]

12 months

Associated factors

12 months 24 months

TBI severity, intellectual and adaptive functioning, personalty change due to TBI

24 months

6 months

TBI severity, preinjury behaviour disturbance ommission errors and inattention on postinjury PACE test SES, orbitofrontal gyrus lesions

12 months

preinjury adaptive function

24 months

preinjury psychosocial adversity

12 months

SES

24 months

SES

PACE = Paediatric Assessment of Cognitive Efficiency; SES = socioeconomic status; TBI = traumatic brain injury.

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Also, in 1998, Max et al. studied the severity of TBI and the development of psychiatric disorders. Severe TBI was associated with a significantly higher rate of new psychiatric disorders (15/24, 63%) compared with children with mild TBI (5/24; 21%) and orthopedic injury (1/24; 4%). Specifically, 5 of 24 (21%) patients with severe TBI, 3 of 24 (13%) with mild TBI, and 1 of 24 (4%) with orthopedic injuries developed S-ADHD. Pre-injury ADHD remained largely stable across all injuries [18]. This effect of severity of TBI was also shown in another Max study. S-ADHD was seen in 7 of 13 (54%) severe TBI, 1 of 8 (13%) mild TBI and 0 of 20 (0%) orthopedic injuries. Again, pre-injury ADHD remained stable or improved. It was concluded that S-ADHD was significantly associated with TBI severity, intellectual and adaptive functioning deficits, and personality change due to TBI, but not with lesion area or location [19]. Similarly, Gerring et al. reviewed 99 patients with severe and moderate TBI at 1 year follow-up. Premorbid prevalence of ADHD was 20%, significantly higher than in a reference population (5%). Fifteen of the remaining 80 children (19%) developed S-ADHD by the end of the first year. These children had significantly greater premorbid psychosocial adversity, posttraumatic affective lability and aggression, posttraumatic psychiatric comorbidity, and overall disability. There were no differences in age, initial GCS, sex, SES, special education, or pre-injury psychiatric disorders [11]. Numerous other subsequent studies have been published over the last several years on rates of S-ADHD. Overall, the reported rates of S-ADHD development after TBI are 20% at 3 months [20], 16% at 6 months [21], 15% to 35% at 12 months [14, 22-24], and 17% to 35% at 24 months [14, 22, 25-26]. Eme suggests that S-ADHD following TBI is even more common than the 30% average the literature suggests [27]. In general, few pre-injury factors have been associated with the development of SADHD. Although there are no consensus characteristics that predict S-ADHD, some studies have suggested associations. These include TBI severity [19], SES [14, 21, 26], adaptive function [22], psychosocial adversity [22], and behavior disturbance [26]. Other factors, such as age, sex, race, family psychiatric history, family history of ADHD, pre-injury family function, and neurosurgical intervention have not shown association with S-ADHD. Interestingly, other studies have investigated factors seen after the trauma that could predict S-ADHD. Max et al. reported S-ADHD was significantly associated with personality change due to TBI and new onset disruptive behavior disorder [22]. Wassenberg et al. utilized a post-injury Paediatric Assessment of Cognitive Efficiency (PACE) test to predict S-ADHD. They concluded that omission errors after TBI preceded S-ADHD development and inattention (not inhibition) after the injury predicts S-ADHD [25]. Studies have also investigated the association between developing S-ADHD and lesions seen on post-injury neuroimaging, most commonly magnetic resonance imaging (MRI). Gerring et al. obtained an MRI at 3 months and an interview at 1 year after TBI in 4-19 year old patients. In their study, the odds of developing S-ADHD were 3.64 times higher among children with thalamus injury, and 3.15 times higher among children with basal ganglia injury. There was no significant difference in lesion volumes in any of the locations of interest between the group who developed S-ADHD and the group who did not develop SADHD [23]. In a similar study, children who developed S-ADHD had more lesions in the right putamen. However, there were no differences between S-ADHD status and lesion burdens for the right caudate nucleus or the right globus pallidus. There were also no differences in total

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number of lesions or total lesion volume [20]. Another study showed a significant association between S-ADHD and orbitofrontal gyrus lesions [21]. However, other studies were unable to demonstrate an association with lesion area or location [19].

S-ADHD: Mechanisms As both ADHD and TBI can lead to deficits in attention and function, it is thought that similar areas of the brain are involved in both processes. In addition, the immature and developing brain may also be at increased risk to damage compared to the mature adult brain. Children appear to be vulnerable to attentional problems, with these skills developing during childhood. This process of ongoing maturation of attentional skills continues through childhood and into adolescence. If this process is disrupted by a cerebral insult, such as TBI, the child is at risk for lacking complete and mature attention skills as a result. Also, independent of ADHD, attentional skills may be differentially impaired after TBI, with children who have sustained moderate-to-severe TBI exhibiting significant deficits on the following attentional domains: sustain, focus, and response inhibition. Furthermore, cerebral areas related to attentional skills, such as subcortical and anterior areas, are also commonly susceptible to TBI injury, and may also contribute to the link between TBI and S-ADHD [2829]. S-ADHD may largely be a consequence of head injury and brain damage, rather than psychological or demographic factors.

S-ADHD: Treatment Treatment of ADHD ranges from behavioral therapy to medication. S-ADHD treatment is much less proven and very little has been published on the subject. Jin et al. evaluated the use of Methylphenidate (MPH) as medical treatment of S-ADHD. They reported that MPH effects on behavior (hyperactivity, impulsivity) were evident but were not as robust as those typically observed with MPH in primary ADHD, and showed less effect on improving cognition. However, a more favorable outcome was associated with initiation of treatment soon after head injury, and trials with relatively long durations. The authors concluded that there is modest evidence to support the efficacy of MPH in the treatment of S-ADHD [30]. Treatment of S-ADHD is an area in which more studies are needed.

Conclusion ADHD and TBI are common conditions in children that can lead to persistent, significant functional impairment and generate substantial economic costs to affected children, their families, and the healthcare system. Children with ADHD have a variety of predisposing factors that are associated with not only increased rates of TBI, but in some cases more severe TBI and more severe subsequent disability.

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S-ADHD is a disorder characterized by inattention, impulsiveness, and hyperactivity following TBI without prior history of ADHD, with rates as high as 35% after TBI. There are no consensus pre-morbid characteristics that predict S-ADHD, although factors seen after the trauma are being studied, including measurable patient characteristics and imaging findings. S-ADHD may largely be a consequence of head injury and brain damage, rather than psychological or demographic factors. Treatment of S-ADHD currently follows ADHD standards of care, and more work needs to be done to study S-ADHD specific treatment and treatment response.

References [1]

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994. [2] Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, Perou R, Blumberg S. Trends in the Parent-Report of Health Care Provider-Diagnosed and Medicated Attention-Deficit/Hyperactivity Disorder: United States, 2003–2011. J. Am. Acad. Child Adolesc. Psychiatry 2014; 53: 34-46. [3] Klassen AF, Miller A, Fine S. Health-related quality of life in children and adolescents who have a diagnosis of attention-deficit/hyperactivity disorder. Pediatrics 2004; 114: e541-7. [4] Küpper T, Haavik J, Drexler H, Ramos-Quiroga JA, Wermelskirchen D, Prutz C, Schauble B. The negative impact of attention-deficit/hyperactivity disorder on occupational health in adults and adolescents. Int. Arch. Occup. Environ. Health 2012; 85: 837-847. [5] Langlois JA, Rutland-Brown W, Thomas KE. The incidence of traumatic brain injury among children in the United States: differences by race. J. Head Trauma Rehabil. 2005; 20: 229-238. [6] Schneier AJ, Shields BJ, Hostetler SG, Xiang H, Smith GA. Incidence of pediatric traumatic brain injury and associated hospital resource utilization in the United States. Pediatrics 2006; 118: 483–492. [7] Byrne JM, Bawden HN, Beattie T, DeWolfe NA. Risk for injury in preschoolers: relationship to attention deficit hyperactivity disorder. Child Neuropsychol. 2003; 9: 142-151. [8] Hoare P, Beattie T. Children with attention deficit hyperactivity disorder and attendance at hospital. Eur. J. Emerg. Med. 2003; 10: 98-100. [9] van den Ban E, Souverein P, Meijer W, van Engeland H, Swaab H, Egberts T, Heerdink E. Association between ADHD drug use and injuries among children and adolescents. Eur. Child Adolesc. Psychiatry 2014; 23: 95-102. [10] DiScala C, Lescohier I, Barthel M, Li G. Injuries to children with attention deficit hyperactivity disorder. Pediatrics 1998; 102: 1415-1421. [11] Gerring JP, Brady KD, Chen A, Vasa R, Grados M, Bandeen-Roche KJ, Bryan RN, Denckla MB. Premorbid prevalence of ADHD and development of secondary ADHD after closed head injury. J Am Acad Child Adolesc. Psychiatry 1998; 37: 647-654.

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[12] Bonfield CM, Lam S, Lin Y, Greene S. The impact of attention deficit hyperactivity disorder on recovery from mild traumatic brain injury. J. Neurosurg. Pediatr 2013; 12: 97-102. [13] Slomine BS, Salorio CF, Grados MA, Vasa RA, Christensen JR, Gerring JP. Differences in attention, executive functioning, and memory in children with and without ADHD after severe traumatic brain injury. J. Int. Neuropsychol. Soc. 2005; 11: 645-653. [14] Levin H, Hanten G, Max J, Li X, Swank P, Ewing-Cobbs L, Dennis M, Menefee DS, Schachar R. Symptoms of attention-deficit/hyperactivity disorder following traumatic brain injury in children. J. Dev. Behav. Pediatr. 2007; 28: 108-118. [15] Ornstein TJ, Max JE, Schachar R, Dennis M, Barnes M, Ewing-Cobbs L, Levin HS. Response inhibition in children with and without ADHD after traumatic brain injury. J. Neuropsychol. 2013; 7: 1-11. [16] Max JE, Robin DA, Lindgren SD, Smith WL, Sato Y, Mattheis PJ, Stierwalt JA, Castillo CS. Traumatic brain injury in children and adolescents: psychiatric disorders at two years. J. Am. Acad. Child Adolesc. Psychiatry 1997; 36: 1278-1285. [17] Max JE, Lindgren SD, Knutson C, Pearson CS, Ihrig D, Welborn A. Child and adolescent traumatic brain injury: correlates of disruptive behaviour disorders. Brain Inj. 1998; 12: 41-52. [18] Max JE, Koele SL, Smith WL Jr, Sato Y, Lindgren SD, Robin DA, Arndt S. Psychiatric disorders in children and adolescents after severe traumatic brain injury: a controlled study. J. Am. Acad. Child Adolesc. Psychiatry 1998; 37: 832-840. [19] Max JE, Lansing AE, Koele SL, Castillo CS, Bokura H, Schachar R, Collings N, Williams KE. Attention deficit hyperactivity disorder in children and adolescents following traumatic brain injury. Dev. Neuropsychol. 2004; 25: 159-177. [20] Herskovits EH, Megalooikonomou V, Davatzikos C, Chen A, Bryan RN, Gerring JP. Is the spatial distribution of brain lesions associated with closed-head injury predictive of subsequent development of attention-deficit/hyperactivity disorder? Analysis with brain-image database. Radiology 1999; 213: 389-394. [21] Max JE, Schachar RJ, Levin HS, Ewing-Cobbs L, Chapman SB, Dennis M, Saunders A, Landis J. Predictors of attention-deficit/hyperactivity disorder within 6 months after pediatric traumatic brain injury. J. Am. Acad. Child Adolesc. Psychiatry 2005; 44: 1032-1040. [22] Max JE, Schachar RJ, Levin HS, Ewing-Cobbs L, Chapman SB, Dennis M, Saunders A, Landis J. Predictors of secondary attention-deficit/hyperactivity disorder in children and adolescents 6 to 24 months after traumatic brain injury. J. Am. Acad. Child Adolesc. Psychiatry 2005; 44: 1041-1049. [23] Gerring J, Brady K, Chen A, Quinn C, Herskovits E, Bandeen-Roche K, Denckla MB, Bryan RN. Neuroimaging variables related to development of Secondary Attention Deficit Hyperactivity Disorder after closed head injury in children and adolescents. Brain Inj. 2000; 14: 205-218. [24] Bloom DR, Levin HS, Ewing-Cobbs L, Saunders AE, Song J, Fletcher JM, Kowatch RA. Lifetime and novel psychiatric disorders after pediatric traumatic brain injury. J. Am. Acad. Child Adolesc. Psychiatry 2001; 40: 572-579.

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[25] Wassenberg R, Max JE, Lindgren SD, Schatz A. Sustained attention in children and adolescents after traumatic brain injury: relation to severity of injury, adaptive functioning, ADHD and social background. Brain Inj. 2004; 18: 751-764. [26] Schachar R, Levin HS, Max JE, Purvis K, Chen S. Attention deficit hyperactivity disorder symptoms and response inhibition after closed head injury in children: do preinjury behavior and injury severity predict outcome? Dev. Neuropsychol. 2004; 25: 179-198. [27] Eme R. ADHD: an integration with pediatric traumatic brain injury. Expert Rev. Neurother 2012; 12: 475-483. [28] Anderson V, Fenwick T, Manly T, Robertson I. Attentional skills following traumatic brain injury in childhood: a componential analysis. Brain Inj. 1998; 12: 937-949. [29] Fenwick T, Anderson V. Impairments of attention following childhood traumatic brain injury. Child Neuropsychol. 1999; 5: 213-223. [30] Jin C, Schachar R. Methylphenidate treatment of attention-deficit/hyperactivity disorder secondary to traumatic brain injury: a critical appraisal of treatment studies. CNS Spectr. 2004; 9: 217-226.

In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 9

Galenic Formulations of Psychostimulant Drugs Pilar García-García1, Francisco López-Muñoz1,2,3, and Cecilio Álamo1 1

Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, Madrid, Spain 2 Chair of Genomic Medicine and Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain 3 Neuropsychopharmacology Unit, ―Hospital 12 de Octubre‖ Research Institute (i+12), Madrid, Spain

Abstract Psychostimulant drugs are a useful medication tool and the first line therapeutic option for Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate and amphetamine are the classic active substances in this pharmacotherapeutical group. Despite the increase of new active drugs in other pathologies, however, in ADHD, new therapeutic options have come from different galenic formulations. In this sense, there are oral (solid or liquid), transdermal formulation for methylphenidate or prodrugs in case of amphetamines. These different formulations with a pharmacokinetic characteristic are focused to improve efficacy, safety and also the individualized therapy.

Keywords: psychostimulant, galenic formulations, methylphenidate, amphetamine



Correspondence to: Dr. Francisco López-Muñoz, Faculty of Health Sciences, Camilo José Cela University, C/ Castillo de Alarcón, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain. E-mail: [email protected], [email protected]

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Introduction Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder that is estimated to affect 5–12% of children and persists into adulthood in more than half of cases [1-2]. ADHD is characterised by inattention, distractibility, working memory deficits and impulsivity, and as such, subjects with this disorder are particularly unsuited to compliance with rigid dosing schedules [3]. In addition, subjects with ADHD exhibit functional impairments that include poor intrafamily interactions, low academic achievement and conduct problems in children and adolescents. This disorder is also associated, in young adults, with increased risk of lower educational attainment, behavior leading to arrests and traffic violations, unemployment, and divorces [4-10]. Clinical guidelines for the treatment for ADHD generally recommend an individualized, multimodal plan which includes pharmacotherapy, behavioral, and educational interventions [11-14]. For many years, short-acting formulations of the psychostimulants methylphenidate (MPH) and amphetamine (AMP) were the mainstay of ADHD pharmacotherapy. However, despite their well-documented efficacy, durations of action in the range 3–6 h posed significant challenges and limitations in their treatment for ADHD [15]. New formulations of psychostimulant medications for the treatment of ADHD have been and important focus for pharmaceutical industry resesarch and development [16-22]. The longer duration of action of once daily formulation has introduced the possibility of reducing the overall daily burden of ADHD affected individuals [22]. In this sense, the requirement for repeated dosing during the day may cause embarrassment and stigma for the patient, difficulties associated with storing scheduled drugs, especially in a school environment, fragmented coverage, poor adherence, and the potential for the diversion of drug for non-medical use [10, 23-24]. Althoug more expensive, these new psyhostimulant formulations are easier for patients to use the older stimulants, more resistant to abuse or misuse and allow for increased privacy in school or work [22, 25-26].

Psychostimulants in ADHD The use of psychostimulants also referred as stimulants, are increased in last year‘s. The mode of action is a dopamine and norepinephrine reuptake inhibitors, and likely target frontostriatal neurocircuits. These drugs reduce nuclear symptoms of ADHD in 80% of patients approximately [14, 27] and it‘s recommended like first line of treatment for ADHD in main guidelines (Table 1) [28]. Stimulants are indicated in children (ages 6-12) and adolescents (13-17) and also recommended in some guidelines for the treatment of adult with the disorder as an integral part of a total treatment program for ADHD that may include other measures like psychological, educational and social [29]. This group of drugs include dextroamphetamine, d- and d,l-methylphenidate, or mixed salts of amphetamine and lisdexamfetamine [29-31]. In the table has been described the active substances recommended in the main guidelines. Also, when we describe the drug we see the global characteristic of the active substances because the galenic formulation is focused in increased absorption or duration of action or minimizes the adverse reactions.

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Amphetamine / Dextroamphetamine / Lisdexamfetamine Amphetamines are synthetic stimulants, belong to collective groups of amphetamines (beta-phenilethylamines) that includes amphetamine, dextroamphetamine and methamphetamine. The chemical structure is similar of structure of the catecholamine neurotransmitters, noradrenaline and dopamine (Figure 1) [32]. It was first synthesized in Germany 1887. However, its medical use was discovery in 1930s, for its capacity of dilates the bronchial sacs of the lungs. Later amphetamines were prescribing for a whole range of disorder including inability to sleep, epilepsy, migraine, depression and hyperactivity in children (trade name, Benzedrine®). Bradley in 1937 reported the beneficial effects of Benzedrine® in treating children with severe behaviors problems [32]. In the 1950s and 1960s they were widely marketed as slimming tablets [33]. Table 1. First line of treatment of ADHD in the guidelines [32] Drug (1st line) Psychostimulants

Limit dosage children/adolescent -

Guidelines

Year

ACCAP (American Academy of Child and Adolescent Psychiatry) BAP (British Association of Pharmacology) NICE (National Institute for Heath and Clinical Excellence)

2007

Psychostimulants Atomoxetine Methylphenidate* Atomoxetine* Dextroamphetamine*

-

Amphetamines Methylphenidate Dextroamphetamines Atomoxetine Lisdexamfetamine dismesylate Methylphenidate

-

NIMH (National Institute of Mental Health)

2008

0.6-1 mg/kg/d

2009

Stimulant medication Atomoxetine

0.6-1mg/kg/ d-72 mg/d 0.5 mg/kg/d for 1-3 weeks, followed 1-1.8 mg/d 0.5-1 mg/d, max 60 mg/d Max 72 mg/d 0.5-1.4 mg/kg/d

LILAPETDAH (Latin American League for the Study of ADHD) Ramón de la Fuente National Psychiatric Institute, Mexico

National Health System of the Ministry of Health Social Policy an Equality, Catalonia, Spain

2010

CADDRA (Canadian Attention Deficit Hyperactivity Disorder Resource Alliance)

2010

Methylphenidate IR# Methylphenidate ER Atomoxetine

Amphetamine salts& Methylphenidate Atomoxetine Lisdexamfetamine dismesylate

Max. 90 mg/d Max. 80 mg/d Max. 20 mg/d

Max, 30 mg/d Max. 70 mg/d 0.5-1.4 mg/kg/d Max. 70 mg/d

2007 2008

2010

*Pre-schooler no recommended; only for schoolchildren and adolescent with severe deterioration. # Pharmacological treatment >6 years old. & Adolescent: amphetamine salts up to 50 mg/d; methylphenidate up to 90 mg/d; atomoxetine 0.5-1.4 mg/kg/d; lisdexamfetamine dismesylate maximum 70 mg/day.

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Figure 1. Chemical structure of noradrenaline, dopamine and amphetamines.

Figure 2. Chemical structure of amphetamines.

The amphetamine is made up two distinct isomers: dextroamphetamine and levoamphetamine, but dextroamphetamine is more potent than l-amphetamine. Currently, the only use of l-amphetamine in ADHD is in mixed salts/mixed enantiomers amphetamine. The form used are amphetamine salts and lisdexamfetamine with application restricted to ADHD, and also narcolepsy for the first one [32]. Lisdexamfetamine dismesylate is a long-acting, an amphetamine prodrug (therapeutically inactive) that contains and l-lysine amino acid covalently bonded to d-amphetamine via an amide linking group (Figure 2) [32]. This molecule was developed with the aim of providing

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an extended duration of effect that is consistent throughout the day [34] and also, to minimize the potential abuse. After oral ingestion is hydrolyzed to l-lysine, a naturally occurring essential amino acid, converted in an active d-amphetamine [35]. This conversion is unaffected by gastrointestinal pH and variations in normal transit times [34]. Lisdexamfetamine is the first amphetamine ―prodrug‖ to have been approved for use in treating ADHD.

Methylphenidate and Dexmethylphenidate Methylphenidate (MPH) hydrochloride is a basic ester of phenylacetic acid, and its chemical formula is methyl 2-phenyl-2-(2-piperidyl) acetate hydrochloride (Figure 3). Synthesized in 1944, it was licensed in US for treating of hyperactivity and another indication in 1955 [36]. It is formulated as freely soluble hydrochloride salt. The molecular structure of MPH contains a basic phenylethylamine moiety which is common to psychostimulant agents such as amphetamines, and is thought to be responsible for its amphetamine-like action profile. The presence of two chiral centers in the structure of MPH -allows four possible stereoisomers. However, MPH products contain the drug in the racemic form, a 50:50 mixture of the threo-R,R (+)- and threo-S,S (-)- isomers. The threo-R,R (+)-stereoisomer appears to be almost exclusively responsible for the catecholaminergic effects of racemic MPH [10, 37-38].

Figure 3. Molecular structure of methylphenidate hydrochloride and dexmethylphenidate.

Dexmethylphenidate (d-MPH) is the d-threo-enantiomer of racemic methylphenidate, which contains, like we comment previously, a 50:50 mixture of the d-threo and l-threoenantiomers (Figure 3) [38]. When the d-MPH and l-MPH isomers taken orally, the l-isomer is metabolized rapidly via first pass through hepatic circulation, for this reason, it is considered that the d-isomer is likely to be the main pharmacological contributor to the efficacy in the treatment of ADHD [39-40].

Mechanism of Action Psychostimulants like MPH and amphetamine have been show effectivity in the treating ADHD because the increase neurotrasmitter activity in the synaptic cleft. MPH acts as a dopamine-norepinephrine reuptake inhibitor. MFD binds to and blocks dopamine transport and norepinephrine transport. Dexmethylphenidate enantiomers displaying prominent affinity

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for the norepinephrine transporter. Amphetamine is both a realized agent and reuptake inhibitor of dopamine and norepinephrine (Figure 4). Like MPH, d-AMF inhibits uptake of dopamine and noradrenaline with modest potency. Unlike MPH, d-AMF also inhibits 5-hydroxytryptamine (5-HT) uptake. d-AMF also induces the release of monoamines from presynaptic terminals, possibly via mechanisms that include an interaction with vesicular monoamine transporter 2, and the reversal of plasma membrane monoamine transporters [41]. Lisdexamfetamine has no affinity for a wide panel of transporters including DAT and NET (Vyvanse®, US Product Label) or receptors, ion channels, allosteric binding sites and enzymes. This profile is consistent with lisdexamfetamine being pharmacologically inactive.

Figure 4. Mechanism of action of psychostimulants.

Side Effects The adverse event profiles of the two classes of stimulants (amphetamines and methylphenidate) appear to be similar. Some studies suggest that the frequency and severity of adverse events may be somewhat greater with amphetamines than with methylphenidate products when we compared both of them, whereas side effects with methylphenidate may be more common than with amphetamines when both drugs are compared with placebo. Insomnia and appetite suppression were generally reported to be the most common adverse events for both classes of stimulant [41].

ADHD: From Immediate Release to Long-Release The innovations in formulation technology and drug delivery systems have made significant strides forward in improving the clinical management of ADHD [3]. ADHD

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medication has been suffering an evolution mainly in the liberation system (from immediate release to long-release) because all of the stimulants have biological half-lives that require at least twice-daily dosing to deliver efficacy over 12–14 h [3]. In this sense, the immediate release pharmaceutical formulation includes any formulations in which the rate of release of drug from the formulation and /or the absorption of drug is not retarded intentionally by galenic formulation. By the contrary, if it is adapted to provide release of drug we can look for its different terms as ―prolonged‖ ―extended,‖ ―modified,‖ ―controlled,‖ or ―delayed‖ [42]. Tablet is the most popular among all dosage form existing but new galenic form has been introduced in the therapeutical of ADHD, like path or liquid. The development of controlled-release formulations of stimulants and the prodrug LDX has greatly increased the number of pharmacological treatment options for patients with ADHD [21]. The different formulation provide some pharmacokinetic properties and the variation in these properties of the different formulations of long-acting psychostimulant therapies is reflected in Their pharmacodynamic properties including their onset, magnitude, and duration of symptom relief [21]. In this sense, the efficacy and safety of long-acting stimulants appear to be equivalent to short-acting formulations. However, long-acting medications offer several potential benefits to patients [21]. In this sense, the facile metabolic deesterification of methylphenidate [43] to the inactive [44] amino acid ritalinic acid limits the elimination halflife to 2−3 h [45]. This short half-life of MPH conducting to a twice-daily regimen of immediate-release (IR) MPH, given at breakfast and again at lunch or, a three times- daily schedule when the patient need to be concentrate in the afternoon [46]. The extended-release (ER) MPH formulation was developed in the early 1980s using conventional wax matrix technology. The conventional ER dosage form of MPH provides a relatively constant blood concentration over the period between 2 and 6 h after dosing [4647]. Also, the different log-acting formulation of methyphenidate was based on a past postulated that monophasic release profile could be associated with acute tolerance of the first developing of extended release in 1980s [46, 48-50]. The second generation of extendedreleased provide biphasic or pulsed release of MPH. Each of these new products contains a percentage of the total MPH dose as IR-MPH but employing different technologies to obtain their own unique release characteristics [46]. Plasma Cmax values resulting from maintenance doses of ER-MPH formulations for most ADHD patients generally range from 10 to 20 ng/ml [51-55]. However, there are no convincing clinical trials that distinguish any of these formulations are superior to dosage regimens of IR-MPH and all have been shown superior to placebo treatment. Beneficial responses to amphetamine formulations in the treatment of ADHD have also been reported to correlate with the absorption phase of the pharmacokinetic profile. Amphetamine has a rapid elevation in blood and brain MPH concentrations accentuates euphoria [46, 56-58]. The develop of lisdexanfetamine introduce the concept of prodrug, in this sense we need to consider that prodrugs are pharmacologically inactive and are converted by a predictable mechanism to the active drug [59], the aim was to reduce the potential addictive of amphetamine. The choice of a specific drug or regimen for an individual patient should consider pharmacokinetic differences as a therapeutic option based on the shape of the mean plasma drug concentration profiles [46, 51, 54].

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Methylphenidate Galenic Formulations Methylphenidate is the drug most widely employed in ADHD treatment and is one the most investigate for improve its efficacy. MDF has been included in different galenic that permit to modified your absorption, efficacy during the day, this men modified its pharmacokinetic (Figure 5). But when this drug it is on the blood its pharmacodinamic properties are the same despite different formulations (Table 2). All formulation produce plasma concentrations necessary to maintain symptom control during school time in children with ADHD. However, their pharmacokinetic profiles differ with respect to peak plasma levels and the rate at which peak levels are attained and decline. And this contributes to an individualized treatment (Table 3) [26]. We can classify the galenic formulation in various groups depending on duration of action, administration, release delivered system (Table 3) [52, 60-62]. Table 2. Classification of galenic formulation of methylphenidate Duration of action

Administration Release delivered system

Immediate or short-acting formulation (2-4 h) Modified, sustained or intermediate-acting (7-8h) Prolonged release (10-12 h) Oral (solid [tablet, beads, pellets] or liquid) Transdermal (patch) SODAS (Spheroidal Oral Drug Absorption System) Multilayer release bead formulation OROS (Osmotic Release Oral System) Diffucaps Transdermal patch Modified release capsules Continous release

Immediate-Release Methylphenidate (Ritalin®, Rubifen®) This formulation releases 100% of the methylphenidate in the tablet on administration and has a therapeutic effect of 2 to 4 hours, which means that in many cases two or three administrations are necessary to achieve a sustained effect [63]. The abrupt decrease of plasmatic concentrations of MPH can produce a rebound effect [10] and misuse [64]. However, this inmediate formulation has been used for adjustement of methylphenidate´s dosage or to search tolerability of the drug. Moreover, mostly studies of new formulation of methylphenidate has been compared with bioequivalence studies with this methylphenidate immediate release, and it could be consider the reference formula.

Diffucaps Diffucaps thecnology is a multiparticulate bead-delivered system with each bead acting as a drug reservoir [65].

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Diffucaps is characterized by the combination, in a single capsule, of 30% of immediaterelease MPH and 70% of slow-release MPH. In this way a prolonged effect, sustained over 9 hours, is achieved [52, 66-67]. Equasym XL has this technology and other synonymous formulations are Equasym depot, Equasym retard, Equasym XR, Quasym LP, Metadate CD, Metadate ER. The product are availability in Europe, South Korea and USA [29].

Figure 5. Galenic formulations of methylphenidate.

Table 3. Pharmacokinetic characteristic of methylphenidate formulations Parameters

Osmotic system capsule 18 mg

Inmediate release capsule 10 mg

% inmediate release

22

100

Modified, sustained or intermediate-acting capsule 20 mg 50

Diffucaps Capsule 10 mg

PATCH 12.5cm2

WAX MATRIX

SUSPENSION ORAL 20 mg 20

% extended release

78

0

50

70

50

Cmax (ng/mL) Tmax (h)

3.7 6.8

6.4 2.75

41.8

11 1-2 Dose proportional

8 1.5 Dose proportional

0.5-3 2

AUC 0-inf (ng.h.ml-1)

9 1-2 Interindividual variability

Provide a slow, prolonged single pulse 10.8 4.7

163

-

378

T1/2 (h)

3.5

2

3.2

2

3

4-5

4-5

5.2

Duration effects (h)

12

3-4

≥7-8

9

4-6

9

8

12

48.9

30

SODAS Capsule 20 mg 50

Continuous delivered

80 34.4 4.05

*One dose of Concertais equal to three doses of Rubifen; Cmax: Maximum concentration; Tmax; time necessary for attaining maximum concentration; AUC: area under the curve; T1/2: half-life of elimination.

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Multilayer Release Bead Formulation A multi-layered single composition beaded ER- MPH formulation (Biphentin®, Canada). It exhibits a less conspicuously pulsatile pharmacokinetic release profile. It was shown to provide a plasma MPH concentration time course approximating a 2−10 h plateau in ADHD children [53], or found to be only minimally biphasic in a normal adult subject study [55]. Immediate release: extended release ratio (%); 40:60 [29]. Efficacy of this product has been compared against twice daily schedules of IR-MPH [49, 68] in children and adolescents, and versus placebo in adults [46, 69].

SODAS (Spheroidal Oral Drug Absorption System) Methylphenidate administration with the SODAS technology, whose representative is Ritalin LA®, involves the use of a capsule made up of a shell containing half the MPH dose in the form of immediate-release MPH, while the other half has an enteric protection layer that permits release of the active agent after 4 hours. This is a development of the classic formulation, from which the relatively inactive L isomer has been removed. Thus, this product contains only the D isomer, so that with half the dose the same effect is obtained as with the conventional formulation [10, 52, 70-72]. The objective of this formulation is mimetizing, in a single application, the immediate-release administration of MPH twice, separated by 4 hours. The main advantage of this formulation is convenience of administration [52, 66-67]. Ritalin LA is availability in France, Chile and USA. Also Focalin XR is the same technology in Switzerland and USA [29].

OROS (Osmotic Release Oral System) Methylphenidate with OROS (Concerta®) technology consists in an osmotic-release capsule. Each capsule includes a shell of immediate-release MPH and three compartments, two with MPH and another with an osmotic polymer/polymeric agent, coated with a semipermeable membrane. After oral administration, the coating of the capsule provides immediate release of 22% of the dose. From that point on, the osmotic compartment becomes hydrated due to the passing of intestinal juices through the semipermeable membrane, and increases in volume, acting as a plug. The OROS formulation provides two-phase kinetics with two peaks of concentration, corresponding to the two periods of MPH release, with total exposure to the drug equivalent to 3 doses of immediate- release MPH. Fluctuations of plasma concentration of the drug are fewer than in the case of repeated administration of immediate-release stimulants, thus eliminating the daily variation of pharmacological effects associated with the older formulations. MPH with the OROS release system was designed to replace the three-administration regime, morning, midday and evening, since with its use the second peak of plasma concentration occurs later than with other sustained-release systems. This means that the therapeutic effect lasts 12 hours, which can result in insomnia or lack of appetite in the

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evening, with the consequent negative effect on children and secondary effects on the family. In such cases it would be advisable to use a shorter release system [10, 66-67, 70, 73-76]. Other synonymous formulation are Concerta extended release, Concerta LP, Methylphenidate hydrochloride OROS. The product are availability in Africa (Botswana, Brazil, Egypt, Namibia, Nicaragua, South Africa), Asia (Bahrain, China, Hong Kong, Indonesia, Israel, Japan, Jordan, Republic of Korea, Kuwait, Lebanon, Malaysia, Oman, Philippines, Qatar, Saudi Arabia, Singapore, Taiwan Province of China, United Arab Emirates, Yemen), Australia, Europe (Austria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Iceland, Ireland, Latvia, Lichtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, UK), New Zealand, North America (Bahamas, Barbados, Canada, Cayman Islands, Dominican Republic, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Trinidad y Tobago, USA); South America (Argentina, Aruba, Bolivia, Chile, Columbia, Costa Rica, Ecuador, Panama, Paraguay, Peru, Uruguay, Venezuela) [29].

Methylphenidate Modified Release Capsule MFD extended-release capsules consist of two-fractions of active substances; the hardgelatin capsules act like a container and contain two types of pellets in equal proportion 50% immediate-release ate the gastric level (white pellet) and 50% extended-release at the intestinal level, which have a gastro-resistant coating that permits the delayed release of MH (blue pellets). The retard pellet has two layers, one of them, an outer release delaying later, enteric coat, and an inner methylphenidate layer. The enteric coating of the outer layer comprises co-polymers of methacrylic acid and methacrylate containing carboxyl groups, thereby causing sustained release of methylphenidate in vivo. The addition of an alkaline agent to this formulation result in a partial neutralization of the carboxyl groups of the polymer forming the enteric coating, and thus in the formation of small channels in the enteric coating which allow a slight diffusion of the methylphenidate through the coating even at a pH under 5.5 (stomach pH) For this reason, also methylphenidate is absorbed in intestine [10]. The dosage is once a day and the capsule may be opened and the capsule contents sprinkled onto a small amount of applesauce or yoghurt. The capsules and the capsules content must not be crushed or chewed (SPC Medikinet). Medikinet retard and also Medikinet, Medikinet CR, Medikinet EM, Medikinet MR, Medikinet XL are different formulation that include this galenic. These formulations are availability in Europe (Austria, Belgium, Cyprus, Denmark, Estonia, Finland, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, UK), Israel, Korea, South America (Argentina, El Salvador, Guatemala, Honduras) [29].

Methylphenidate Transdermal System or MPH Patch (Daytrana) It is an adhesive-based matrix that is applied to intact skin. Daytrana contains MPH in a multipolymeric adhesive, and its dipersed in acrylic adhesive that is dispersed in silicone adhesive. More detailed the patch of Daytrana contains three layers: first, a polyester/ethylen

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vinyl acetate laminate film backing; a adhesive formulation that include acrylic adhesive; the second layer include a silicone adhesive and methylphenidate based on Inc.´s DOT MatrixTM (Noven Pharmaceuticals) that is the layer in contact to skin, and finally, a fluoropolymercoated polyester protective liner wich is attached to the adhesive surface and must be removed before the patch can be used (www.rxlist.com). The methylphenidate patch is a passive patch technology because once the patch is applied to the skin, a diffusion gradient is established, and the drug moves into the stratum corneum (Figure 5). The pacth should be applied to the hip area 2 hours before an effects is needed and remove 9 hours after application. The differente pacth time (12.5 cm2, 18.75 cm2, 25 cm2, 37.5 cm2), contribute to the titration schedule delivered each 9 hours (10, 15, 20, 30 mg, respectively) (SPC, Daytrana). It exhibits a soothly increasing parmacokinetic profile accrooss dosage streghts, ascending for about 9 hours or until the patch is removed [77]. Other synonymus MPH transdermal system, MethyPatch; MTS is only available in USA [29].

Wax Matrix Ritalin SR is availible in Canada and USA. Wax matrix layer was prepared from physical mixture of excipients to obtain basic propierties for slow release [78]. Ritalin SR is one product in wich methylphenidate is incorporated into a water-insoluble cetyl alcohol was matrix, allowing for the gradual diffusion of methylphenidate as the tablet passes through the gastrointestinal. The water-solouble ingredients, methylphenidate and lactose, are released gradually as the gastrointestinal fluids penetrate the tabler and create pores [79]. This formulation is characterized be a continous-release preparation that include an inmediate release component that ensures a rapid onset of action as well as an extended. Release component that continous to act throughout the course of the day [29].

Methylphenidate Suspension Oral (Quillivant XR) Food and Drug Administration (FDA) has approved a once-daily, extended-release oral suspension of methylphenidate for treatment of ADHD. It is the first liquid formulation of the drug to be marketed for once-daily use. A short-acting oral solution (Methylin, and generics) has been available since 2003. NWP06 (Quillivant XR, NextWave Pharmaceuticals, Cupertino, CA) (methylphenidate hydrochloride) was developed to meet this need. NWP06 is supplied as a powder that is reconstituted with water by the pharmacist prior to dispensing. The resulting ER methylphenidate oral suspension has a concentration of 25 mg/5mL (5 mg/mL) and does not require refrigeration. It is composedof cationic polymer matrix particles that bind d,l-threomethylphenidate racemic mixture via an ion exchange mechanism. A proprietary coating of various thicknesses is applied to the particlesto confer extended release properties. NWP06 is a blend of uncoated and coated particles that is 20% immediate release (IR) and 80% ER methylphenidate [80]. The suspension oral has a grape flavored (SPC, Quillivant XR)

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Amphetamines Galenic Formulations The only use of l-amphetamine in ADHD medications is in mixed salts/mixed enantiomers amphetamine (MES-amphetamine), which consists of a 3:1 enantiomeric mixture d-amphetamine:l-amphetamine salts that is available in both immediate-release (Adderall®, generic) and extended-release (Adderall XR®, generic) formulations [3]. Formulation include 50% inmediate release beads and 50% delayed release beads in a capsule, with a 10-12 h of duration of effect. Dosage: once daily. They can open and sprinkle on food [80]. Dextroamphetamine also include a similar percentage of drug liberation (50:50), but its duration of action is 4-9 h. They need multiple daily dosage and also can open and sprinkle on food [80].

Lisdexamfetamine (Vyvanse, Elvanse) After oral ingestion, LDX is metabolized in the GI tract l-lysine and the active damphetamine. There is no active d-amphetamine in the parent formulation; therefore, manipulation by crushing or extraction will not result in the active drug. In studies of stimulant abusers, there was no difference in abuse-related liking between IV LDX and placebo. Also, likeability was significantly decreased with LDX versus d-amphetamine although that difference disappeared at higher LDX doses.[3, 81-82]. The dosage is once daily and can open capsule and disperse contents in plain waters. Lisdexamphetamine prolonged duration actions is from its properties as a prodrug and not due to a physical delayed release formulation [80-81].

Advantages of Galenic Formulation Treatment strategies should be based on an understanding of the efficacy and safety profile of each formulation, paired with individual patient needs [21]. Inadequate adherence to the ADHD treatment has been observed and the most comment reasons for discontinuation included adverse effects of ADHD medication, treatment ineffectiveness/suboptimal [25]. Galenic formulation has been development to improve the treatment and to provide an individualized therapy. All formulation reviewed in this chapter presents benefits for the patients/physician. For example, the main advantages of immediate release drug delivery system are: improved compliance, stability, suitable for controlled release actives, ability to provide advantages of liquid medication in the form of solid preparations, allows high drug loading, cost-effective, it can be prepared with minimum dose of drug, and this formulation could be used in both initial and final stage of disease [42]. However, the two or three-times-daily MPH schedule carries with it a higher incidence of appetite suppression and insomnia [46, 81-82]. On the other hand, administering a once-daily stimulant medication to a child or adolescent first thing in the morning under parental supervision relieves him/her of the requirement to take additional medication outside of the home, and it also eliminates the need for the patient to take additional medication within strict time-windows. One of the additional

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benefits of these new formulations is their tamper deterrence, making it difficult for abusers to extract amphetamine for self-administration by hazardous routes, such as smoking, ‗snorting‘ or intravenous injection [3]. The convenience of once-daily dosing may contribute to improved adherence of long-acting stimulants compared with short-acting stimulants. Prodrug technology may also provide lower internal intra-patient variability in exposure than mechanical controlled-release systems. Furthermore, long-acting stimulants may be less prone to abuse than their short-acting counterparts. Thus, the development of long-acting formulations of stimulants provides important additional treatment options for the management of ADHD [21].

Figure 6. Galenic formulation of amphetamines.

Table 4. Pharmacokinetic characteristic of amphetamines Parameters Amphetamine salt Lisdexamfetamine % immediate release 50 % extended release 50 Cmax (ng/mL) 80.3 Tmax (h) 7 1 AUC0-ing (ng.h/ml) 5-10 T1/2 (h) 10-13 11 Duration of effect (h) 10-12 13 SPC (Summary Product Characteristic). Amphetamine salts (Adderall) / Dextroamphetamine (Dexedrine Spansules).

The solid form could be a physical barrier limits access to the active compound by resisting chewing, grinding, crushing, or drug extraction. This is accomplished by way of an external shell or by the drug delivery system [42, 81]. The development of transdermal systems has facilitated individualizing the duration of therapy for patients because a patch can be removed, stopping the delivery of medication, unlike orally administered medications which remain in the system once ingested. Transdermal absorption minimizes first-pass metabolism, hepatic side-effects, the attendant potential for drug–drug interactions, as well as the risk of gastrointestinal irritation may be

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reduced [30, 83]. Although there are few data regarding children and adolescents, patch technology does appear to improve adherence to treatment in a large range of these patient groups [84-86]. Prodrugs are biologically inactive substances that are metabolized in vivo to their active form [82]. As a prodrug, LDX needs an enzyme in red blood cells to convert to the active form of amphetamine; therefore, it has less potential for abuse and diversion, and longer effect, as compared with other stimulants [87]. Finally, the psychostimulant formulations are wide and an adequate dosage and individualized treatment could be beneficial for the control of symptoms of ADHD and reduce the adverse effects.

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[85] Molinuevo JL, Arranz FJ. Impact of transdermal drug delivery on treatment adherence in patients with Alzheimer‘s disease. Expert Rev. Neurother 2012; 12: 31–37. [86] Logsdon S, Richards J, Omar HA. Long-term evaluation of the use of the transdermal contraceptive patch in adolescents. Sci. World J. 2004; 4: 512–516. [87] Maneeton N, Maneeton B, Suttajit S, Reungyos J, Srisurapanont M1, Martin SD. Exploratory meta-analysis on lisdexamfetamine versus placebo in adult ADHD. Drug Des. Devel. Ther. 2014; 8: 1685-1693.

In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 10

Antidepressant Drugs in Attention Deficit Hyperactivity Disorder Silvia E. García-Ramos1, Francisco López-Muñoz2,3,4,, Cecilio Álamo3 and Pilar García-García3 1

Hospital Pharmacy, Principe de Asturias University Hospital, Alcalá de Henares, Madrid, Spain 2 Chair of Genomic Medicine and Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain. 3 Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, Madrid, Spain 4 Neuropsychopharmacology Unit, Madrid, Spain.

Abstract The primary goal of drug therapy in ADHD patients is the improvement or control of the disease core symptoms. Stimulant drugs produce clinical improvement both on behavior and cognitive level, and they are the first line treatment for patients with ADHD. In recent years, new drugs have been introduced in the treatment of ADHD; for example, non-stimulant drug atomoxetine, and other like α-agonists and antidepressant drugs are being used off-label to treat ADHD. Atomoxetine is a potent and highly selective inhibitor of the presynaptic norepinephrine transporter. Clinical practice guidelines consider atomoxetine as second line treatment for patients with non-response or intolerance to stimulants. If there is risk of abuse, atomoxetine is considered the drug of choice. Moreover, certain antidepressant drugs, such as reboxetine, bupropion or venlafaxine, are being introduced as a therapeutic alternative to stimulant drugs for treating ADHD. These drugs have proven effective in several clinical trials, placebo

Correspondence to: Dr. Francisco López-Muñoz, Faculty of Health Sciences, Camilo José Cela University, C/ Castillo de Alarcón, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain. E-mail: [email protected], [email protected]

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Keywords: ADHD, antidepressant drugs, atomoxetine, reboxetine, venlafaxine, bupropion

Introducción Attention-déficit hyperactivity disorder (ADHD) is a neurobiological dysfunction affecting the school records and the social and personal development of patients. Available data suggest that between 30% and 70% of children with ADHD continue to manifest symptoms in adulthood [1-5]. ADHD is frequently associated with other psychiatric disorders and has high comorbidity with other diseases [6-8]. The high rate of chronicity, which implies the need for a long-time intervention, and the onset of psychiatric disorders and other comorbidities are aspects to be taken into account when planning a treatment [9]. Multiple studies conducted in children and adult patient population agree that the best treatment option is the multimodal one, combining psychopharmacology with psychotherapy and psychoeducation [10-12]. The primary goal of drug therapy is the improvement or control of the disease core symptoms. At this level, clinical evidence shows that interventions including the use of controlled drugs get better results than if the intervention does not include it [13].

Classic Pharmacotherapy and Need of Therapeutic Alternatives Seventy years ago Bradley observed that stimulant drugs can improve a hyperactive behaviour. These drugs have proven effective in several clinical trials, placebo-controlled and double-blind, in both pediatric and adult patients. Clinical response rates in these clinical trials were between 65% and 85% with stimulant drugs and between 4% to 30% with placebo [14]. The new release formulations have proven as effective as immediate release formulations [15]. Furthermore, these new formulations have important advantages in treatment adherence and convenience, especially in pediatric patients. Stimulant drugs produce clinical improvement both on behavior and cognitive level [1617]. Despite the high response rate, there are circumstances where therapeutic alternatives to these drugs are necessary [18]:    

From 9% to 25% of patients do not respond adequately to treatment [19-20]. Emergence of adverse events, such as mood swings, sleep disturbances, appetite changes and the onset of tics [21]. They are contraindicated in hypertension, hyperthyroidism, glaucoma, symptomatic cardiovascular disorders and hypersensitivity to sympathomimetic amines [21]. Risk of abuse [22].

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In recent years, new drugs have been introduced in the treatment of ADHD; for example, non-stimulant drug atomoxetine, and other like α-agonists and antidepressant drugs are being used off-label to treat ADHD [23-25].

Antidepressant Drugs Used in the Treatment of ADHD As we noted previously, certain antidepressants are being introduced as a therapeutic alternative to stimulant drugs for treating ADHD. Table 1 shows the antidepressant drugs employed in clinical practice for the treatment of ADHD. Table 1. Antidepressant drugs used in the treatment of ADHD Active Atomoxetine Bupropion Tricyclic antidepressant (imipramine, desipramine) Reboxetine Venlafaxine

Licenced On label Off label Off label Off label Off label

Action Mechanism of Drugs Used in the Treatment of ADHD Dopamine (DA) and norepinephrine (NE) play a key role in high-level executive functions [26-27]. These neurotransmitters affect fronto-striatal-cerebellar circuits, frequently affected in patients with ADHD, especially in the prefrontal cortex [28-30]. The action mechanism of the most important antidepressant drugs used in the treatment of patients with ADHD are detailed below. The action mechanism of psychostimulants are also explained briefly, observing the differences between them.

Methylphenidate Methylphenidate hydrochloride is a mild stimulant of the central nervous system (CNS). Methylphenidate blocks the reuptake of NE and DA in the presynaptic terminal, by freezing the transporter at time. Methylphenidate also increase the release of these monoamines to the extraneuronal space. Although affinity for the NE transporter is much higher than for the the DA transporter [31], methylphenidate has activity in the nucleus accumbens; this activity is responsible for the appearance of euphoria, reward, reinforcement and continued abuse.

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Amphetamine Amphetamine produces a competitive blockade of both DA and NE transporter and vesicular monoamine transporter (main difference with methylphenidate). Thus, it enhances the release, blocking the dopaminergic and noradrenergic reuptake neurotransmitters, particularly at high doses.

Atomoxetine Atomoxetine is a potent and highly selective inhibitor of the presynaptic NE transporter. Atomoxetine does not act directly on the DA or serotonin (5-HT) transporters. Atomoxetine operates mainly in the prefrontal cortex, selectively blocking the NE transporter. This transporter also has ability to adsorb DA, and its blockade produces increased levels of DA and NE in the prefrontal cortex and increases its broadcast radio, reinforcing its action. Atomoxetine has a tonic effect, so reset neurons by blocking ongoing NE transporter. The nucleus accumbens has few NE transporters, so that atomoxetine does not alter levels in said core, primarily responsible for the abuse potential.

Bupropion Bupropion is a low potency inhibitor of the reuptake of DA and NE. Bupropion acts by blocking their transporters. This low level of inhibition is responsible for the lack of abuse potential. It has no activity against monoamine oxidase enzyme or on the cholinergic or serotonergic receptors.

Tricyclic Antidepressants These drugs block the binding of NE and 5-HT to its transporter, and they are regarded as dual reuptake inhibitors. Secondary amines such as desipramine, have greater affinity for the NE transporter. Tertiary amines such as imipramine, have greater affinity for the 5-HT transporter; but these tertiary amines suffer demethylation to secondary amines after its administration, so serotonergic and dopaminergic effects appear. On the other hand, tricyclic antidepressants produce changes in receptor sensitization: inhibition of NE reuptake causes a rapid reduction in its metabolism via the presynaptic α2adrenergic autoreceptor, which provides a mechanism for feedback to the presynaptic inhibitory neuron. In the chronic treatment autoreceptor is desensitized, the excitation rate is normalized and the decreased density postsynaptic receptor is canceled, causing a persistent increase of the NE transmission.

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Reboxetine Reboxetine is a highly selective and potent inhibitor of the reuptake of NE, causing increased availability in the synaptic gap and modifying noradrenergic transmission. It is the first selective NE reuptake by blocking its transporter. It has only a weak effect on 5-HT reuptake and does not affect the uptake of DA. Moreover, has no significant affinity for adrenergic or muscarinic receptors.

Venlafaxine Structurally and chemically venlafaxine shows no relationship with tricyclic antidepressants and other antidepressants and anxiolytics. Its neurochemical profile led to the term SNRI (selective reuptake inhibitors of serotonin and norepinephrine), due to its high selectivity for these two neurotransmitters. It does not inhibit monoamine oxidase enzyme and has a very low affinity for muscarinic, cholinergic, histaminergic or α-adrenergic receptors. Unlike dual action tricyclic antidepressants, requiring repeated administration for inducing desensitization of adrenergic receptors, venlafaxine produces a rapid desensitization of the receptor. At low doses, 75-100 mg daily, venlafaxine behaves as an SSRI (selective inhibitor of serotonin reuptake inhibitors), while increasing the dosage its affinity for NE will be increased, becoming a highly selective dual inhibitor.

Therapeutic Positioning of the Antidepressant Drugs in the Treatment of ADHD Most clinical practice guidelines consulted consider atomoxetine as second line treatment for patients with non-response or intolerance to stimulants. If there is risk of abuse, atomoxetine is considered the drug of choice. Guidelines recommend the use of off-label drugs, such as antidepressants, for patients with non-response or intolerance to stimulants and atomoxetine. Specific recommendations for clinical practice guidelines consulted are described below. NICE Guideline for diagnosis and management of ADHD in children, young people and adults [32], recommends psicoestimulants (methylphenidate or amphetamine) and atomoxetine as drug of choice for the treatment of children and young people with ADHD. If the patient does not respond to treatment, recommendation is to increase the dose. If it still fails to achieve clinical response, the guideline recommends the use of off-label drugs such as imipramine or bupropion. For adult patients, guideline recommends methylphenidate as a drug of first choice. If there is poor response or intolerance to methylphenidate, guideline recommends the use of atomoxetine or amphetamine salts. In patients on risk of substance abuse, atomoxetine would be the drug of choice. Canadian ADHD Practice Guideline (CAADRA) [33] recommends long-acting stimulants as drug of choice, atomoxetine and immediate release stimulants as second terapeutic option. The guideline recommends the use of off-label drugs a third line if there

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failure or intolerance to previous drugs. The guideline makes these recommendations for children and young people and for adults. Also it recommends to add antidepressants to treat ADHD in adult patients when there is a comorbid anxiety disorder. Australian Guideline on Attention Deficit Hyperactivity Disorder [34], recommends atomoxetine if there is intolerance, contraindication or lack of response to stimulants in both, adults and children and young people. Atomoxetine is the drug of choice in adult patients with substance abuse problems, tics or comorbid anxiety. Guideline recommends bupropion in adults if not responding to stimulants or atomoxetine; consider that there is insufficient evidence to be used in children and young people. With respect to other antidepressants, they emphasize that there are no antidepressants approved for use in children due to adverse events and they recommend its use in adult patients with severe depression. SIGN Guideline for Management of Attention deficit and hyperkinetic disorders in children and young people [35] recommends the use of atomoxetine in children with intolerance or lack of response to stimulants.

Atomoxetine Main Characteristics Atomoxetine is a non-stimulant and non-addictive drug [36-37] licensed for use in children of 6 years and over and adults for the treatment of ADHD. Atomoxetine dose varies according to age of patients, as shown in the Table 2. The drug tolerance is usually good if the dose is increased slowly [38-39]. The dose should be reduced to a half in patients with moderate hepatic impairment (Child-plugh B) and should be reduced to 25% in patients with severe hepatic impairment (Child-plugh C). It is unlikely that a dose adjustment would be required for atomoxetin in patients with renal impairment. Table 2. Atomoxetine dose CHILDREN AND YOUNG PEOPLE < 70 Kg Start 0,5 mg/kg 7 days after Increase to 1,2 mg/Kg > 70 Kg Start 40 mg 7 days after Increase to 80 mg

ADULTS Start 7 days after

40 mg Increase to 80-100 mg

Clinical Effectiveness of Atomoxetine in the Treatment of ADHD Patients Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI), reducing ADHD symtoms both in children and young people and in adults, as demonstrated by scientific evidence. The following are the most representative findings of research conducted in recent years. Wehmeier et al. administered 1.2 mg / kg / day of atomoxetine in children for 8 weeks. Atomoxetine was effective in reducing hyperactivity, inattention and impulsivity [40].

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Atomoxetine has also proven to be effective in young children, with response rates of 40% in children aged between 5 and 6 years old [41]. This effectiveness was maintained in both patients previously treated with stimulant drugs and untreated patients [42]. There are randomized and placebo-controlled trials demonstrating the effectiveness of both short-term atomoxetine (treatments 12 and 16 weeks) [43-44] and longer term (24 weeks) [45-46]. However, after having corroborated the effectiveness on ADHD symptomatology, Durell et al. demonstrated that the administration of atomoxetine in adults with ADHD produced improvement in patients‘ quality of life [43]. Ni et al. conducted a randomized activecontrolled trial comparing the effectiveness of atomoxetine and methylphenidate in adults with ADHD. The study lasted 10 weeks. There were symptomatic improvements in both treatment groups, with no statistically significant differences between them [47]. Also, other studies assess the effectiveness of atomoxetine as a combined therapy in addition to other drug treatments. Sutherland et al. conducted a randomized double-blind trial comparing the effectiveness of atomoxetine associated with buspirone versus alone atomoxetine and versus placebo. The combination therapy demonstrated superiority over placebo (p < 0.001), but only statistically significant differences were observed compared to alone atomoxetine in a treatment lasting 4 weeks [48]. Gabriel and Violato evaluated the effectiveness of atomoxetine associated to a SSRIs or to a SNRI in adult patients with ADHD and generalized anxiety with poor response to SSRI or SNRI. After 12 weeks of treatment there was a significant improvement in both ADHD symptoms and anxiety symptoms (p < 0.001), including the reduction of disability after 12 weeks [49].

Contraindications and Adverse Events Atomoxetine is contraindicated in patients with glaucoma, cardiovascular or cerebrovascular disorders, pheochromocytoma, and in treatment with inhibitors of monoamine oxidase enzyme. Suicidal behaviors have been detected in patients treated with atomoxetine. The most common side effects are: abdominal pain, headache, loss of appetite, nausea and vomiting, sleep disturbances, and increased blood pressure. These effects are usually transient.

Bupropion Main Characteristics Bupropion is licensed for the treatment of major depression and smoking cessation [50]. The dose commonly used in studies involving patients with ADHD is 150 mg daily. Bupropion should be used with caution in patients with hepatic or renal impairment.

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Clinical Effectiveness of Bupropion in the Treatment of ADHD Patients Bupropion blocks the DA and NE transporters; this action mechanism suggested that it might be a therapeutic alternative to stimulant drugs [51]. Recent systematic reviews published about the effectiveness of bupropion in the treatment of adults with ADHD conclude that it is an effective and well tolerated alternative [52-53]. Wilens et al. evaluated the effectiveness of long-term bupropion in adults with ADHD. They conducted a multicenter, randomized, placebo-controlled and 8-week study. There was a 53% responders compared with 31% in the placebo group (p = 0.004). There was a low rate of discontinuation of treatment and there were no serious or unexpected adverse events [54]. Treatment with bupropion has also been evaluated in pediatric population. Recently, Jafarinia et al. conducted a double-blind randomized clinical trial comparing the effectiveness of bupropion and methylphenidate in the treatment of ADHD in pediatric population. After 6 weeks of treatment (100-150 mg daily of bupropion or 20-30 mg daily of methylphenidate) no statistically significant differences between groups were observed. The response rate was 90% in both groups and there were no differences in tolerance to treatment, except that headache was more frequent in the group of methylphenidate [55].

Contraindications and Adverse Events Bupropion is contraindicated in pacients with seizure disorder, tumor in the CNS, severe hepatic cirrhosis, bulimia or anorexia nervosa, and in treatment with inhibitors of monoamine oxidase enzyme. The most common side effects were hypersensitivity, fatigue, headache, nausea and vomiting, anorexia, insomnia, increased blood pressure, visual disturbances, and tinnitus.

Tricyclic Antidepressants (Imipramine and Desipramine) Main Characteristics Imipramine is licensed for the treatment of depression, anxiety and chronic pain in adults and for the treatment of nocturnal enuresis in children older than 5 years [56]. The recommended doses as antidepressant starts with 25 mg daily and increase up to 150-200 mg daily according to response [56-57]. Treatment should not stop abruptly.

Clinical Effectiveness of Tricyclic Antidepressants in the Treatment of ADHD Patients Years ago, several tricyclic antidepressants were thought be effective in the treatment of ADHD, particularly in patients with psychiatric comorbidities associated, due to its blocking action of 5-HT and NE reuptake transport [58-59]. However, scientific evidence to support its

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use in patients with ADHD is quite limited. Winsberg conducted a study in children with lack of response to methylphenidate. Imipramine effect was compared versus placebo. No clinical response was obtained in any of the 2 groups [60]. There are scientific papers referred to the usefulness of imipramine in patients with ADHD [58,61], but there were no quality clinical trials justifying this recommendation. Regarding desipramine, there are randomized and placebo-controlled trials in children, adolescents [62-63] and adults [64]. However, a recent sistematic review considers that it should be prescribed for treating children with ADHD with a high precaution in view of serious concerns about its safety and lack of enough well-controlled trials providing strong evidence about the efficacy of desipramine [65].

Contraindications and Adverse Events These drugs should not be used with monoamine oxidase inhibitors or in patients in the acute stage of acute myocardial infarction. The most common adverse events include alterations in weight, psychiatric disorders, tremor, headache, somnolence, eye disorders, heart disease, hot flashes, constipation, hyperhidrosis, and fatigue.

Reboxetine Main Characteristics Reboxetine is licensed for the treatment of major depression in adult patients [66]. The dose commonly used in studies involving patients with ADHD ranged from 2 to 8 mg daily. In patients with hepatic or renal impairment it should be started with 2 mg twice a day.

Clinical Effectiveness of Reboxetine in the Treatment of ADHD Patients Because of its inhibitory action of the NE reuptake in the synaptic terminal, it has proven useful in the treatment of other psychiatric disorders, including ADHD [67]. Quintero et al. conducted a study with children diagnosed as ADHD with partial response or intolerance to methylphenidate. After 6 months 90.9% of patients responded to treatment and 72.7% had achieved an overall improvement (as measured by the Clinical Global Improvement Scale CGI-I). During treatment no serious adverse effects appeared. The authors conclude that reboxetine is an effective alternative for long-term treatment of ADHD in children with poor response or intolerance to methylphenidate [68]. Cohen-Yavin et al. compared the effectiveness of methylphenidate and reboxetine in children diagnosed with ADHD. Patients with a history of intolerance to methylphenidate received from 2 to 8 mg daily of reboxetine, while the rest of the patients received 10 to 20 mg daily of methylphenidate. After 8 weeks of treatment, significant symptomatic improvement was observed in both groups and no statistically significant differences were found between them [69].

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Riahi et al. conducted a double-blind and placebo-controlled trial to evaluate the efficacy of reboxetine in adult patients with ADHD. Patients included in the intervention group received 8 mg daily of reboxetine for 6 weeks and obtained significant improvements (p < 0.01) in both the Conners' Adult ADHD Rating Scale-Self-Report (CAARS-S) and the Clinical Global Impression-Severity Scale (CGI-S) [70].

Contraindications and Adverse Events Reboxetine is contraindicated in treatment with inhibitors of monoamine oxidase enzyme. Reboxetine should be administered cautiously in patients with seizure disorders. The most common side effects were insomnia, tachycardia, palpitations, constipation, sweating and urinary tract infections.

Venlafaxine Main Characteristics Venlafaxine is licensed for the treatment and prevention of relapse of major depressive episodes as well as in the treatment of anxiety and panic disorders [71]. The recommended dose for treating depression is 75 mg daily; this dose can be slowly increased up to 375 mg daily. In studies in patients with ADHD there was great variability in the doses administered. The dose should be reduced in a 50% in patients with moderate or severe hepatic impairment or with severe renal impairment. Should be avoided abrupt treatment withdrawal.

Clinical Effectiveness of Venlafaxine in the Treatment of ADHD Patients Venlafaxine inhibits the reuptake of 5-HT and NE; this action mechanism suggests that venlafaxine could be a therapeutic alternative to methylphenidate in the treatment of ADHD [72]. Several systematic reviews confirm its positioning as a therapeutic alternative for the treatment of patients with ADHD and with lack of response or intolerance to stimulants and other drugs (atomoxetine, bupropion, tricyclic antidepressants, etc.), in children, young people [73-74] and adults [75]. Mukkades and Abali conducted a 6-week, open and no-controlled study in children and adolescents with ADHD and without comorbid depression. Venlafaxine was initiated at a dose of 18.75 mg daily and flexibly titrated to 56.25 mg daily. Venlafaxine was significantly effective in reducing the total score of the Conners Parent Scale (p < 0.002) and the CGI severity item (p < 0.05) [76]. Zarinara et al. conducted a 6-week, parallel group, double blind, randomized clinical trial in children with ADHD. Study subjects were randomly assigned to receive venlafaxine at doses of 50-75 mg daily or methylphenidate at a dose of 20-30 mg daily. No significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores (p  =  0.19 and p  =  0.20, respectively). Side effects of headaches and insomnia were observed more frequently in the methylphenidate group [77].

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Amari et al. conducted a double-blind, randomized, placebo-controlled to evaluate the effectiveness of venlafaxine in the treatment of ADHD in drug-naïve adults. Patients in the venlafaxine group received up to 225 mg daily during 6 weeks. Significant decrease was observed in both subscales, total ADHD symptoms score and ADHD index, in both the venlafaxine and the placebo groups. Seventy-five percent of treatment group versus 20% of placebo group met treatment response criteria when defined as a 25% drop in total ADHD score (p  =  0.001). No serious adverse events were reported during the trial [78].

Contraindications and Adverse Events Venlafaxine is contraindicated in treatment with inhibitors of monoamine oxidase enzyme. The most frequent adverse events are headache, insomnia, confusional state, fatigue, loss of appetite, gastrointestinal disturbances, palpitations, high blood pressure, visual disturbances and tinnitus.

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In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 11

Psychological Treatment in ADHD: Clinical and Educational Perspectives M. José De Dios-Pérez, Miguel Ángel Pérez-Nieto and M. Poveda Fernández-Martín Department of Psychology, Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain

Abstract According to DSM-V [1], ADHD is characterised by a persistent pattern of inattention and/or hyperactivity/impulsivity. These symptoms interfere with the development and normal behaviour of children and adolescents. They give rise to serious difficulties both in an academic context and within the family environment. Accordingly, as with assessment, psychological intervention focuses on these three ambits: the actual child, the family environment, and the school context. This chapter will consider the most effective psychological techniques. Thus, for example, regarding intervention with a child and/or adolescent, behavioural and cognitive techniques will be analysed, as well as the combined therapies that have proven to be more effective in the treatment of children and adolescents with ADHD. A review is made of techniques for impulse control and anger management, as well as those focusing on cognitive functions. Intervention with parents complies with the provisions of Parent Management Training (PMT), which include Bandura‘s social learning theory and the analysis of contingencies within the family environment. Presentation is made of some of the programmes with the best results in ADHD, which combine the handling of behaviours and styles of upbringing. Finally, the school context is used to describe the most suitable interventions for the symptoms these children manifest. In line with the theoretical background, intervention is undertaken from an overall perspective of interaction. That is, guidelines are provided for working through the school, through the class that has a child with ADHD, and through 

Correspondence to: Dra. María-José de Dios-Pérez, Department of Psychology, Faculty of Health Sciences, Camilo José Cela University, C/ Castillo de Alarcón, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain. E-mail: [email protected]

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M. José De Dios-Pérez, M. Ángel Pérez-Nieto and M. Poveda Fernández-Martín the actual child. The advantages and drawbacks are listed for each one of the interventions within the various settings.

Keywords: psychological intervention, ADHD, behavioural techniques, cognitive techniques, parent programmes, classroom programmes

Introduction There are different approaches to the treatment of ADHD. Their efficacy depends on the symptoms, the child‘s needs, comorbidity, and the prognosis. Following an assessment from a medical, psychological, educational and social perspective, the decision on the nature of the treatment is made on an individual and multidisciplinary basis, using the information provided by the various professionals and by the family itself. The use of medication, if so required, tends to be established at the beginning of the intervention. Nevertheless, medication alone is not enough. There is different evidence to show that treatment combing medication and non-medicating techniques leads to better results than treatment based solely on medication or on non-medicating techniques [2-3]. Along these lines, Pelham et al., have reported that the best results are recorded when a behavioural-type therapy is used with low doses of stimulant medication [4]. In children, medication helps, but without leading to a significant improvement in academic performance [5], or else there is only a short-term improvement with no sign of any long-term benefits [6]. This may be because the child is undergoing a learning process; medication will provide the child with the prior resources required for that learning -attention, memory, etc. [7], while many other major skills are acquired through training and the implementation of strategies that will permit that learning, which are provided by nonmedicating treatment [5]. Account also needs to be taken of the high comorbidity ADHD, in addition to the disorder‘s main symptoms. Certain authors [8] report that over 85% of patients have an least one comorbidity associated with ADHD involving psychiatric and learning disorders, and compared to the rest of the population they are six times more likely to have another disorder [5]. Hudziak and Todd report that the child population often records comorbidity with bipolar disorder (75%), with dyssocial disorder (50%), with oppositional defiant disorder (35%), and with learning disorders, although in these latter cases, the studies do not agree on the percentage of comorbidity, which ranges from 10% to 92% [9]. In turn, Tannock finds that the probability of an anxiety disorder is three to six times higher in a child with ADHD than in one without another disorder [10]. Likewise, the longitudinal Multimodal Treatment Study (MTS) of Children with ADHD conducted in 1999 found that children aged from 7 to 9 recorded comorbidity with the oppositional defiant disorder (40%), with anxiety disorder (34%), with behavioural disorder (11%), and with depression (4%) [11]. This high comorbidity with other disorders means that psychological intervention in children with ADHD needs to consider other disorders, and not just the symptoms of ADHD. Accordingly, there is evidence to show that non-medicating treatment leads to an improvement in the anxiety disorder, learning disorders, the oppositional defiant disorder, the behavioural disorder, self-esteem, and socio-family issues affecting children with ADHD, as well as the quality of their own and their families‘ lives [12-14].

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Where these does seem to be some consensus among authors is that psychological intervention should be approached from both a clinical and an educational perspective. The bulk of the symptoms appear within a school context and they have a major bearing on the child‘s academic performance [5]. A child with ADHD is fully immersed in a process of physical, cognitive and affective development, in which they still largely depend on adults. These aspects lead to the conclusion that intervention in children with ADHD should focus not only on the child, but also on the environment in order to ease their adjustment. Within this environment, intervention focuses especially on the two scenarios in which the child normally coexists: school and family. This chapter describe the psychological intervention prevailing today in children with ADHD in three scenarios:   

Direct intervention in the child Intervention in the family environment Intervention in the school environment

Psychological Intervention in Children with ADHD Psychological intervention in a child with ADHD may be designed to reduce both the main symptoms of ADHD (inattention, hyperactivity and impulsivity) and the psychological symptoms of other comorbidities [15]. Psychological intervention in children includes a number of different types of therapies:  

Behavioural techniques for mitigating the problems generated by ADHD within the family and school environments. Cognitive therapies that have appeared over time in the treatment of ADHD due to the greater tendency among children with ADHD to internalise negative messages. These therapies are designed to reduce negative thoughts and the emotions that accompany them [15].

There follows a detailed description of each kind of therapy.

Behavioural Therapies Behavioural therapies are especially recommended for reducing the inappropriate behaviour of a child with ADHD. Accordingly, and prior to their application, identification needs to be made of problematic behaviours, their timing and intensity, and possible contingencies, so they can be used to plan the most suitable technique for changing them.

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Specifically, therapy tends to reinforce positive behaviours, showing the children a significant level of change in their behaviour. The most widely used behavioural techniques include the following:     

Positive reinforcement Time out Response cost Overcorrection Extinction

There follows an analysis of each one of them. 

Positive reinforcement is, together with time out, the most commonly used and effective technique for children with ADHD. It is used both for the acquisition of new appropriate modes of behaviour and for the replacement of inappropriate behaviours with other more appropriate ones.

There are many and very different types of reinforcers, which will depend on the nature of the child. In general, the best results are provided by non-material reinforcers, such as praise, giving attention, or encouraging physical contact, provided by people to whom the child is closely attached. Any one of these reinforcers needs to be used as soon as the child reveals the new behaviour that is to be reinforced. It is important to accompany them at all times with positive personal remarks, and ensure they are expressed spontaneously. Specifically, giving attention to the child in response to appropriate behaviour is in many cases a very powerful reinforcer, especially when it is accompanied by expressions of affection by the person providing the reinforcement, such as smiling, doing some activity with the child, or showing an interest in something that the child wants to talk about. 

Together with all the other techniques, time out is a procedure that is used especially for the extinction or reduction of inappropriate or disruptive behaviour, and specifically for disobedience, hyperactivity or aggressive conduct. It is the most commonly used technique among those used to reduce inappropriate behaviours, being especially useful in those cases in which it has been verified that social reinforcements are important for maintaining a certain type of behaviour.

As opposed to positive reinforcement, it involves applying a negative consequence to an inappropriate type of behaviour by the child, such as, for example, isolating the child or the withdrawal of any social reinforcement by removing the child to an isolated and boring place, whether this is a corner or a room without any kind of stimulus, for a brief period of time. The use of this technique in children with ADHD is especially effective for a number of reasons. Firstly, it puts an immediate stop to the inappropriate or disruptive behaviour; secondly, it blocks the social reinforcements that the child may perceive during the performance of that behaviour; thirdly, it reduces the probability of a worsening in the behaviour; and fourthly, it allows isolating the child, enabling them to calm down, or applying other techniques they have learnt and which they can use to reduce their activity

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level. Nevertheless, techniques of this kind should only be used when other measures for stopping the child‘s inappropriate behaviour have failed, although this one has proven to be especially effective in children with high impulsivity and hyperactivity. Concerning its application, it advisable to first issue a warning before it is actually put into effect; when the child returns from their isolation, any appropriate behaviour they may show should be positively reinforced; moreover, it is important to ensure the isolation does not last too long. 

A response cost is a technique that tends to be included in broader programmes together with reinforcement techniques. It involves a punishment, the loss of a specific treat or privilege, which is applied to a child for bad or inappropriate behaviour within the reinforcement programme. This punishment may involve a loss of points, or the surrender of something satisfactory for the child; for example, if they hit another child, they are not allowed to go out to play. It is important to withdraw the treat immediately after the child has behaved in an inappropriate manner. In the case of the loss of points, this will make it more difficult to win a prize for better behaviour.

In the case of this technique, the greatest difficulty lies in suitably establishing a number of points or privileges that are withdrawn from the child for bad behaviour. The punishment needs to be consistent with the intensity of the disruptive behaviour, at the same time as the child must be able to recover the loss as a reward for a specific period of appropriate behaviour. The biggest risk that this type of technique poses is that the cost of recovering the points is too high, whereby the accumulated number of points lost is so high that there is no motivation to earn new points. It is important to combine the response cost with other types of techniques, such as the positive reinforcement of appropriate behaviours, as this will enable the child to replace one kind of behaviour with another one. 



Overcorrection is a suitable technique for dealing with a child‘s inappropriate behaviour. In this case, the child is corrected, replacing the behaviour with another suitable one that occurs more often. This means that the child learns to replace the bad behaviour with another that can lead to reinforcement. The fact that the new behaviour occurs more often helps the child to internalise the new behaviour. Extinction is a technique that is to be found midway between reinforcement and punishment. It is an operational technique that involves the systematic withdrawal of all the positive reinforcements a child may receive after behaving in an appropriate manner. For example, in many cases the child may be seeking to use disruptive behaviour to attract attention; whereby extinction would mean not giving them any attention so as not to reinforce that behaviour. In order to carry it our correctly, it requires identifying all the reinforcers that the child receives after behaving inappropriately; likewise, the person applying this technique needs to have great selfcontrol. Generally speaking, its use is not recommended for stopping aggressive conduct or those behaviours that involve an immediate reward for the child.

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In the case of ADHD, when it is considered that behavioural problems tend to be a major symptom in children, some of these techniques are very often combined in more complex structured behavioural programmes that have proven to be extremely effective in reducing those problems. Two of the most common programmes are the token economy programme and contingency contracts. The token economy programme is a technique based on an immediate reinforcer, such as tokens or points that are awarded to the child as a reward for one or more instances of appropriate behaviour that have been set as a goal. These tokens tend to be physical objects that the child can hold, and which are suitable for that age group (tokens, play money, etc.); it is important to use a physical object so that the child can have palpable proof of their better behaviour. These tokens can be swapped for other privileges or primary reinforcers that have been determined beforehand according to the number of tokens or points required for their achievement. Its correct implementation requires, firstly, carefully defining the specific behaviour to be reinforced; secondly, the number of tokens or points that the child can earn for behaving properly needs to be specified, with their number necessarily being linked to the investment or effort the child needs to make to behave accordingly; thirdly, the primary reinforcements and their cost need to be set. In time, the number of tokens for each achievement will be steadily increased in order to ensure the generalisation of the child‘s target behaviour. It is important to ensure that the child with ADHD understands the entire process, which is to be negotiated and agreed with them, with the aim being to make sure the reinforcements are truly motivating for the child. Their performance needs to be very well organised and consistent with the reinforcers established previously, being realistic and varied for the child. The efficacy of the token economy technique has been amply proven. However, its effectiveness depends largely on the fact that the rules for earning the tokens, or losing them, if and when deemed appropriate, are very clear and set from the start, as well as being understood by the child. Once the target behaviours have appeared and the programme is in place for their acquisition, consideration then needs to be given to their maintenance and generalisation, with the aim being to ensure their effects do not disappear. In general terms, any relatively straightforward behaviour that can be observed by others may be subject to this technique, although it is important to value the appearance of these behaviours in natural situations. As soon as the child performs the action in the proper manner, they are to be given one or more tokens, accompanied by a social reinforcement and acknowledgement of the effort the child has made in carrying it out. As time passes and the patterns of behaviour become consolidated, they can gradually be replaced with other more complex ones, slowly withdrawing the reinforcement for those already achieved. In the case of older children, whose symptomology enables them to adapt more readily to a reinforcement that is not immediate but instead delayed, use may be made of another technique called the contingency contract. This technique is very similar to the token economy, albeit without the need for an immediate reinforcer such as tokens or points. The arrangement of this contract involves agreeing with the child on the behaviours to be achieved or those that are to disappear from the child‘s behavioural repertoire. Once these have been established, a negotiation is held with the child to decide upon the rewards that may be earned for appropriate behaviour.

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For contingency contracts to be effective, they need to fulfil the same requirements as the token economy technique. It is vital to negotiate the target behaviours, as well as the rewards, with the child to ensure they do indeed constitute an incentive, and they may be changed on a fairly frequent basis [16]. Furthermore, and as in the previous case, the target behaviours are to be realistic, and may be performed easily within the child‘s natural context. The basic difference with the token economy technique is that in this case there are no immediate reinforcements, as with the contingency contract the child obtains the reinforcement on a delayed basis. Nevertheless, it is important not to overly delay this reinforcement or reward, as this would render it ineffective. The application of all these techniques requires the professional to teach those people closest to the child how to apply the programme in a reliable manner; furthermore, it is advantageous if the programme can be applied in all those contexts in which the child lives, especially at home and at school, being undertaken by the child‘s carers and teachers [5]. This means boosting the chances of the successful appearance of new target behaviours, as well as the disappearance of unwanted ones. To conclude, it should be noted that behavioural therapy has certain clear advantages in the treatment of ADHD in children. One of the main ones is that it has proven to be especially effective in children with disruptive behaviours that systematically need help to behave in a more adjusted manner. Children who receive this type of therapy clearly improve their behaviour [5]. On the other hand, certain authors [15] have pointed out some of the limitations in the behavioural treatment of ADHD. Firstly, it needs to be noted that although it improves disruptive behaviours, it does not have a clear impact in terms of improving cognitive abilities. Secondly, mention should be made of the difficulty of applying the treatment. Behavioural therapies are often perceived as being easy to apply, but if they are to be effective, they require an extremely thorough assessment of the minor, of their problematic behaviours and of those aspects that may be driving them; the therapy‘s goals need to be well focused in order to ensure it is effective, being ideally implemented in all those ambits in which the child lives, especially at home and at school; this means that parents and teachers need to be well versed in its correct implementation, as it is vital to suitably decide upon the reinforcement and punishments. A third limitation is that it has a greater impact over the short term than over the long term. This may have a double reading: on the one hand, the change in the child is seen very soon after the beginning of the application, which is motivating for the people who are assisting in the application, as well as for the child, who sees that these changes in behaviour quickly modify their relationships both at home and at school, yet on the other hand, it is often difficult to maintain these rewards over the long term, whereby the intervention needs to involve another kind of therapies. The fourth and last limitation is that not all children with ADHD respond well to behavioural treatment [5, 17]. It has been verified that behavioural therapy is less effective in children with a very low level of selfcontrol and a high level of frustration. According to Green, this is because the child does not have the skills to know what is expected of them and what they need to do to earn rewards, with their control of frustration being very underdeveloped, which stops them behaving in the expected way [17]; in such cases, it may be necessary to focus the therapy on a handful of behaviours, and then gradually increase the demands placed upon the child in step with their improvement.

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Cognitive Therapies As with behavioural techniques, numerous cognitive techniques are applied to children with ADHD. Their main purpose is to boost the development of certain cognitive skills in children, especially in those that appear to be most seriously affected; specifically, the cognitive processes that receive the most attention are those that affect attention, and selfregulation and self-control processes [18]. The applicability of each one of them depends on the patient‘s characteristics. The following are the ones most widely used:    

Problem-solving techniques Self-control techniques involving self-instructions Instruction in social skills Working on self-esteem

These details are now explained in detail: 

Training in problem-solving is a technique that helps a child to be conscious of the causes and consequences of their behaviour, dispelling mistaken beliefs [15]. Moreover, it helps with the learning of appropriate behaviour when the child manages to correctly process all the steps into which such behaviour can be divided: deciphering social codes, interpreting those codes, setting goals, building a response and making a decision on the response, and assessing and selecting suitable strategies for doing so [19]. It is especially effective for resolving social problems and conflicts, which normally pose a major difficulty in children with ADHD. Its use is recommended in children with high levels of aggressiveness, impulsivity or behavioural problems, as they tend to make mistakes in the interpretation of social codes, which leads them to commit errors because they do not think things over or look for alternative solutions, besides being hampered by being overly sensitive, which blocks them when seeking to find solutions for interpersonal problems.

Training in problem-solving involves four steps. Firstly, the child is taught to recognise the problem and identify the signs indicating it exists. Secondly, the child is taught to analyse the problem, identifying those aspects of the situation that may be influencing the problem, and the level of difficulty for overcoming each one of these aspects. Thirdly, the child is taught to find alternative solutions in order to respond to the problematic situation and assess the consequences of each one of them. It is important at this point to generate all the possible solutions in principle, without judging them beforehand, because if the child generates their own different solutions, they are more likely to find the right solution for the problem. When a sufficient number of alternative solutions have been generated, the child is shown how to evaluate each one of them according to their possible ramifications. Such ramifications should consider behavioural and affective aspects both for

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the child and for the environment. This means that the most effective option is chosen, which is therefore the one with more positive outcomes and fewer negative ones. Fourthly and lastly, the child is shown how to behave in the desired manner, which is planned beforehand. There is often a need to teach the child new repertoires of behavioural responses that they are unfamiliar with and which are required for successfully solving the problem. 

Techniques for the self-control of thoughts through self-instructions. Selfinstructions are a self-control procedure referred to as talking to oneself, self-talk or inner speech [20]. According to the model for the development of thought proposed by Vygotsky, the utility of inner speech is that the child uses language to internalise their own thoughts based on social interaction [21]; in other words, by interacting with others, the child gradually appropriates, or assimilates, the strategies prompted by others. Initially, the child uses language as a tool for regulating their own action. The child speaks out aloud to regulate their behaviour; this speech features elements that have appeared previously in their action with others, which the child includes in their own repertoire through language. In time, that language becomes internalised, constituting a self-regulating inner speech. Self-instructions are based on making that speech explicit, whereby the child internalises and assimilates the instructions prompted by others for resolving different situations.

Training in self-instructions aims to make the most of this phenomenon that appears naturally and spontaneously in children aged between 3 and 7 [21] to favour the internalisation of certain elements of self-control that help to alleviate deficits of attention, impulsivity and distraction in children with ADHD. Through the use of speech, children are taught to talk to themselves in order to analyse the situation, reflect upon possible response options, and assess their consequences before acting. This training consists of five steps that correspond to the language internalisation process propounded by Vygotsky. In the first step, the child interacts with a model to learn how to react to a situation; the model proceeds to read out the steps to be taken, clearly and concisely specifying the instructions to be followed. In the second step, the child does exactly the same as the model, but using their own language to repeat the instructions in the same way as the model, with the latter acting as an independent guide to assist with the repetition of those steps. In the third step, the child takes responsibility for regulating their behaviour, whereby they repeat the instructions on their own, without being guided by the model. In the fourth step, the child internalises those instructions, without having to repeat them out aloud, but instead does so in a semi-internalised way, whispering them and repeating them under their breath. In the final step, the child carries out the actions using self-talk or inner speech as their guide. This means that the instructions become internalised and the child makes them part of their inner dialogue, regulating their own behaviour and avoiding impulsive behaviour. Training in self-instructions has become a useful tool for behavioural control; nevertheless, its effectiveness depends on it first being applied to straightforward behaviours with short, succinct instructions, and then it can be applied to more complex behaviours that

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require more instructions. Furthermore, it is important that once the training has been completed, the child can apply this process to natural processes as and when required. 

Training in social skills. The symptoms of ADHD mean that many of the children diagnosed with it have problems with their social skills, generally due to two reasons: on the one hand, their impulsivity, whereby they fail to analyse the social situation or abide by social conventions in their interaction with others, and on the other hand, their inattention, which hinders their learning of appropriate social behaviours. From this perspective, it is assumed that social skills are behaviours that are learnt through social interaction, whereby this type of training does not need to apply techniques to help the child learn them, to acquire either new skills or those that have not been properly learnt. The type of training in social skills will depend largely on the repertoire the child has acquired and on a prior analysis of those social behaviours that the child uses inappropriately. Generally speaking, the following are the most common skills in which children with ADHD are instructed: o Conversation skills: how to start a conversation, greetings, taking leave, waiting for one‘s turn to speak, listening, answering when prompted to do so, etc. o Friendship skills: meeting other children, making friends, offering help, cooperating with them, undertaking both cooperative and competitive group activities, etc. o Skills in difficult situations: taking one‘s turn when waiting, making and accepting criticism in a constructive manner, following other people‘s instructions, obeying, reacting responsibly in situations of conflict, avoiding tense situations, etc.

When providing instruction in these skills, the procedure generally used involves modelling. The child is first exposed to a situation in order to perform the skill in the proper way, being explained what they have to do, placing particular emphasis on the positive ramifications that this skill may have in the social situation. Whenever necessary, the action is divided up into steps that the child is taught separately, and then as an overall sequence. The model then performs the skill in an appropriate manner, while the child watches, with clarification of any doubts that may arise. The second step involves the actual child, who performs the skill, when necessary using the verbal instructions they need to internalise. Once the skill has been performed, the child is given feedback on what they have done well, with further instruction on those parts of the sequence that have not been performed properly. If necessary, the model‘s example is repeated. 

Working on self-esteem: when they are conscious of their behavioural problems and the issues they have in their relationships with others as a result of their hyperactivity, children with ADHD tend to suffer from a lack of self-esteem; this is compounded by a low tolerance to frustration and oversensitivity to criticism. In many cases, this calls for a therapy designed to improve the child‘s self-esteem, which favours their treatment in all aspects, while at the same time preventing future complications in their socio-emotional development.

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The building of self-esteem, although it may be influenced by the way other people view the child, is linked to the child‘s own ability to cope with situations and correctly assess their own behaviour. It is often the case that children with ADHD have a distorted view of their own behaviour, which has a major impact on their self-esteem as they do not understand what is going wrong. In order to reinforce self-esteem, there are two aspects that are worked on with the child. On the one hand, working on the child‘s proper self-assessment; through self-registers, recordings, the assessment of pre-set targets, etc. The child is made aware of their own behaviour, of the extent to which they have reached their proposed targets, providing them with feedback on both positive and negative aspects, with the latter being accompanied by possible solutions for achieving the desired behaviour. On the other hand, working on the handling of the causal attributions of their behaviour. During childhood and adolescence, children steadily develop an attributional style, seeking the causes of their actions either in internal factors (their own skills, their own effort, etc.) or in external factors (other people, luck, etc.); likewise, these attributions may be down to causes that the child can control by themself (such as their effort) or those that are beyond their control (such as their intelligence). There are certain attributional styles that do not favour children‘s self-esteem; specifically, attributing successes to external causes and failures to internal ones that are uncontrollable compromise a child‘s self-esteem, as from this perspective they do not think they can use their behaviour to feel better, as they cannot control the situation and it does not depend on them. In these cases, the child needs to be helped to make an objective assessment of the situations, attributing the results to internal causes that can be controlled, such as their own behaviour, which may be modified in order to achieve their goal. In addition, this attributional change needs to be accompanied by a change in the child‘s approach, whereby they do not focus so much on attributing the consequences of their behaviour to one cause or another, but instead focus on the process. This is what is referred to as instrumental messages, which help the child to concentrate less on the final outcome of their behaviour and the reasons for it, and more on the entire behavioural process, assessing the different factors that may render such behaviour appropriate or inappropriate, leading to success or failure in a given situation. Messages of this kind help the child to make progress in learning skills, rather than become fixated with the ultimately positive or negative outcome of certain behaviour. These cognitive treatments have for years been the most widely used psychological treatment in the care for children with ADHD, especially those programmes based on selfinstructions, as several studies have reported how effective they are for reducing impulsivity [22-23], improving social relations [24], and increasing planning ability [25]. Nevertheless, there also studies that do not support this improvement [26-27]. These differences may be due to the way the therapy has been implemented, in which different types of teaching have been used and at different rates, which seems to have a bearing on its efficacy. These limitations led to the consideration of the need to introduce programmes that combine cognitive and behavioural techniques that merge their benefits in the treatment.

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Cognitive-Behavioural Programmes In many cases, the most effective intervention directly involving a child with ADHD consists of a blend of cognitive techniques and behavioural techniques. Most of these programmes focus on directly changing the children‘s behaviour and cognitive patterns, although in some cases, when younger children are involved, this intervention needs to be undertaken through the parents. A review of the studies on these treatment programmes reveals their effectiveness [28], although this may vary depending on the nature of the children, their symptoms, and their comorbidities, as well as on the techniques included in the programme and the actual application process itself. In general, these programmes are designed to favour the child‘s development, doing away with disruptive and aggressive behaviours. Some of them, however, also focus on the emotional anger response, with these being the programmes that record the best results. The techniques included in these programmes differ greatly, ranging from those based on deactivation, such as meditation and the use of behavioural timetables [29] to programmes based more on cognitive-behavioural techniques [30]. There follows a detail of some of the programmes arranged from this perspective that are now used in the treatment of children with ADHD. As in the case of the previous techniques, some of these programmes are not exclusively for children with this pathology, as they are also used in other disorders, such as problems of behaviour, aggressiveness or impulsivity. One of the specific programmes for children with this disorder is the one developed by Orjales, which includes the application of sundry techniques, and specifically the following [31]:         

instruction in self-assessment instruction in identifying feelings solution of cognitive, academic and social problems social reinforcement positive self-reinforcement modelling tortoise technique instruction in relaxation training in self-instructions and a specific programme for the generalisation of the training in self-instructions [32].

Other programmes that focus on intervention in core aspects of ADHD are those centred on attention. Nowadays, these interventions are combined with visual therapy, cortical activation, and training with activity banks for improving sustained and selective attention ability [33]. As regards the symptoms associated with impulsivity and hyperactivity, there are interventions that focus on reducing activation based on the adaptation of anxiety reducing programmes, as well as interventions centred on the control of impulses. One of these programmes of proven efficacy in children with ADHD is the one developed by Kendall and Braswell, which basically focuses on the control of impulsivity,

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and specifically on reducing the impulsive response to the appearance of a problem, combining this technique with the use of self-instructions [34]; the merger of these two techniques increases its efficacy in children. The programme consists of steps in the resolution of a problem: the first step requires acknowledging the problem and defining it, analysing those aspects that have a bearing on it; the next step involves developing options for resolving the problem, evaluating their advantages and drawbacks; thirdly, attention needs to be focused on the problem‘s keys components for its proper evaluation; fourthly, a choice needs to be made of the best solution by taking into account the possible consequences it may have; and finally, once the chosen behaviour has been implemented, self-reinforcement is achieved through the use of the technique and evaluation of its utility. This programme deals with coping with conflictive situations, and therefore refers to a specific aspect of the child‘s response. Nevertheless, other programmes focus more on the regulation of the emotional and cognitive process in social interaction, and not so much on regulating the situation. Another programme pursues this same line, namely, the one developed by Greenberg and his group, being referred to as Promoting Alternative Thinking Strategies (PATHS) [35]. This programme aims to enhance pro-social behaviours through three learning models. The first of these models involves reinforcing positive social behaviours in the child; this is achieved through the following learning processes:   

Learning skills for making and keeping friends Developing rewarding social interactions Developing skills for expressing opinions and listening when interacting

The second module focuses on self-control and emotional regulation, by means of the following strategies:  

Recognising affective extremes and their assessment Differentiating emotional responses to different behavioural responses

The third and final module addresses the child‘s development of problem-solving strategies through the following actions, amongst others:   

Stopping and thinking before acting Considering multiple alternatives for solving a problem, analysing both their positive and their negative ramifications Applying the solution and performing the assessment of the process undertaken and its utility

Other behavioural cognitive programmes focus on other symptoms that also appear frequently in children with ADHD, such as anger and aggressiveness. Such is the case of the programme designed by Lochman and Wells, which considers the most effective strategies for coping with anger and the lack of control over it [36]. The following are its key points:

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    

Impede the possible secondary advantages derived from the presence of reactions of aggressiveness and anger through behavioural techniques such as extinction, the response cost or time out. Increase the recognition of the physiological signs that precede anger in order to prevent its onset. Identify the discriminatory impulses that trigger aggressive behaviour. Block the impulse that sets off an aggressive response through techniques involving self-instructions. Provide social skills that allow handling problematic situations in a more adaptive way. Promote the use of problem-solving strategies.

All these programmes can be readily adapted to timeframes and users, although they are usually undertaken over a few weeks in sessions lasting between 40 and 80 minutes. The proper implementation of all these programmes requires the professional to be well trained in their use. If possible, it would be convenient to instruct the adults closest to the child, such as their parents, so that the application of the techniques can be supervised in everyday settings. Nevertheless, this aspect is not always feasible, and may restrict the efficacy of these techniques. On the other hand, a further restriction is to be found in the child‘s attitude when starting or continuing the treatment; when an adult is involved, there is an agreement between the psychologist and the person seeking help, but in the case of children, the assistance is generally sought by the parents, and not by the actual child. This sometimes hinders the pursuit of the treatment, especially in adolescents, who may prove to be uncooperative; this is compounded by the fact that children with ADHD have little control over their impulses and an attention deficit that reduces the efficacy of these interventions [37]. In other cases, it is important to begin by holding awareness sessions with the child to enable them to identify the problems that the disorder is causing them in their everyday lives, and then, based on the problems singled out and on the evaluation the child makes of them, begin the application of these treatments.

Intervention within the Family Environment In addition to individual intervention with the child, it should be remembered that the symptoms of ADHD tend to be the cause of conflict both at home and at school. This calls for intervention within the family environment in order to reinforce the parenting skills need to help the minor develop in the most appropriate way. The family environment plays a vital role in the development of ADHD, and may either alleviate the symptoms or even exacerbate them [15]. Bearing in mind that one of the main problems in children with ADHD is their behaviour within the family environment, therapies have been developed designed to instruct parents from a behavioural perspective in order to ensure parental orders are obeyed and rules are kept, as well as to ease aggressive and defiant behaviour and other symptoms of ADHD [38]. The training of parents, referred to generically as ―Parent Management Training‖ – PMTis the method most widely used and accepted amongst all the techniques designed for the

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treatment of behavioural problems in children, being specifically used on a systematic basis in children with ADHD. The focus of its intervention is centred on the development in parents of structured contingency patterns within the home that allow teaching the child to temper their conduct by modulating the consequences of the same [37]. The systems for handling contingencies have proven their efficacy in the modification of behaviours that were proving to be highly unstable over time and involving different situations [39]. These programmes involving the instruction of parents with a view to improving the behaviour of children with ADHD are based on two theoretical models: on the one hand, on Bandura‘s social learning principles, as these children face major difficulties in their social relations within the family, either through a lack of social learning skills or because of a mistaken interpretation of social situations; and on the other hand, on an analysis of contingencies in the interactions that arise within the heart of families, above all when the child with problems is involved [40]. They are applied either individually or in a group with the parents of children with similar pathologies. Their aim is to encourage more pro-social behaviour among the children, while at the same time forging a stronger link between parents and their children, with the ensuing improvement in the atmosphere at home; these changes reduce the child‘s behavioural problems within the family environment. There are several different types of intervention in this case. On the one hand, there are behavioural training programmes for parents, which are designed to teach parents the behavioural principles for dealing with a child‘s behaviour within the family environment, and on the other, programmes based on interpersonal relationships [41], which adopt a more humanist perspective and focus on family interaction processes and on the communication across it members. Nevertheless, in recent years the boundary between these two types of intervention programmes has gradually disappeared, with there now being an increasing number of programmes that combine both elements. The programmes based on the instruction of parents from a behavioural perspective seek to teach parents the basic principles of the techniques used to modify behaviour that are described in the preceding section, for their application within the family environment. Their efficacy depends largely on the fact they are implemented by all the adults or carers within the child‘s family environment. Almost all the programmes arranged along these lines are a modified version of the original programme for parents proposed by Barkley [42]. This programme shows parents how to apply simple procedures for modifying behaviour and handling contingencies, being designed to increase the child‘s attention and obedience, adapting them to the characteristics of each specific child. The techniques featuring the most are the handling of praise, extinction, the use of rewards, isolation, response cost, the token economy, and the contingencies contract. Nevertheless, the contingent and ongoing application by parents of the reinforcement and punishment system may prove difficult, whereby this aspect, that is, the implementation of contingency patterns within the family environment on a sustained basis, becomes a key feature of the instruction of parents. Contingency patterns are obviously based on the consistent punishment of inappropriate behaviour and the reinforcement of appropriate or positive behaviour, always giving specific priority to the use of reinforcement, which is always more effective in the modification of behaviour [43]. There follows a description of two programmes that have been validated as examples of training programmes for parents: one by Forehand and McMahon [44], and the other by Hembree-Kigin and McNeil [45]. The first of these, referred to as ―Helping the noncompliant

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child,‖ contains certain points that have subsequently become accepted standards in interventions of this nature, and which quickly recorded positive results. The second one, called ―Parent-Child interaction therapy‖ –PCIT-, includes a treatment of the time variable in view of the importance of consistency in reinforcement patterns. Table 1 presents the modules that make up each programme. Table 1. Parent training programmes ―Parent-Child interaction therapy‖ –PCITHembree-Kigin and McNeil (1995) [45] 1. Introduction: description of the programme 2. Briefing and behavioural instruction on therapeutic skills for parents a. Use of dedicated times for interacting with the child b. Use of selective attention strategies 3. Briefing and instruction on skills for maintaining reinforcement patterns a. Emphasis on consistency, predictability and monitoring b. Giving children clear and concise instructions c. Using praise as a reinforcement d. Using time out for disruptive behaviours e. Adjusting timetables with routines f. Applicable also to public behaviours

―Helping the noncompliant child‖ Forehand and McMahon (1981) [44] 1. Introduction: description of the programme 2. Use of differential attention for the behaviours to be instilled a. Use of attention in direct interaction b. Use of attention in the handling of behaviours c. Use of reinforcements d. Ignoring inappropriate behaviour e. Provide guidelines on specific contingencies for specific behaviours 3. Training in appropriate behaviours a. Specific instructions b. Reinforcing adaptive behaviour c. Use of time out d. Emphasis on consistency

In general, parent management training programmes may be administered in a flexible way, although they tend to have a limited time format, usually ranging from eight to ten sessions per week, which involve a family or a small group of parents. They tend to be accompanied by prior working sessions with the parents designed to make them realise how gratifying positive interaction between parents and child can be, as well as to work with them on the problem‘s share of responsibility, to avoid focusing exclusively on the child. One of the main difficulties that may be encountered in the application of these programmes lies in the degree of engagement, not only of the parents but also of any carer responsible for a child with ADHD, as everyone‘s involvement is required to uphold the contingency patterns developed. The research into the impact of training parents shows it has a greater effect on the child‘s functional outcome than on the specific symptoms of ADHD, above all in cases of comorbidity with other disorders [46]. Its efficacy has been especially noticeable in behavioural disorders, with positive results being recorded in both children and adolescents [47]. In addition to these programmes, other family-based interventions focus on instructing parents in the use of suitable disciplinary strategies, whereby they adapt their parenting style

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to adapt more closely to the difficulties faced by a child with ADHD. The aim of these programmes is to provide parents with guidelines that will help to improve the child‘s behaviour. These measures include the following highlights [48]:       

Keep to a stable daily timetable, with a clear organisation of activities. Avoid distractions when performing an activity. Provide specific and suitable places for the child to perform each type of activity, whether this involves homework, play, getting dressed, etc. Use lists to help the child organise their tasks. Limit the choices when the child has more than one option. Organise activities with the child that they find pleasant and in which they may perform well, such as sports, games, hobbies, etc. Apply discipline consistently, implementing the therapeutic measures already described.

Intervention at School Interventions at school come in all shapes and sizes, but they are vital for improving the academic performance of a child with ADHD. The behaviour of a child with ADHD within the classroom may be challenging, as their symptoms may include problems of attention and understanding, difficulties for completing tasks, behavioural issues that may be manifested in the form of passivity or aggressiveness, etc. Furthermore, this is often compounded by the frustration they feel when facing the difficulties the disorder entails. Studies with children diagnosed with ADHD report a need to make adjustments at school level, both in programming and in the need for authorisation and support within the classroom. In most cases, children can take part in normal everyday classes, but in some cases there is a need for some subjects to be taught following an inclusion model, either inside or outside the class with specific support [48-50]. Psychoeducational intervention within a school context should consider the inclusion of these interventions as part of a multidisciplinary treatment that also involves parents and other professionals. The coordination between them is essential for the efficacy of the therapies applied. Furthermore, and strictly within a school context, attention needs to be paid to the pupil‘s cognitive and affective development, apart from purely academic considerations. Regarding these interventions, special mention should be made of those measures that the school takes to adapt to children with these issues, those taken by teachers and which affect the entire class, those designed solely for the child, and the intervention undertaken in groups, which may benefit other pupils without ADHD.

Interventions by the School At school level, the educational response to ADHD targets all the pupils studying there and is designed for all kinds of pupils. Nevertheless, the school‘s regulations may explicitly provide for special measures for children with ADHD or for other measures, which although

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applicable to children with ADHD may favour the student body as a whole, such as the measures used to mitigate behavioural problems. On the one hand, the school‘s educational projects and its goals may help to pay special attention to certain problems that might appear, not only in other children but also in those children with ADHD. These may include the following highlights:   

The school‘s operating regulations have a more educational than disciplinary nature, which will help to prevent the appearance of behavioural problems. Give importance to harmony within the school, favouring supportive interpersonal relationships. Foster cooperation across different sectors in the community, both within the school itself (between teachers and pupils) and outside it (with parents, social services, health centres, etc.), making decisions and undertaking actions in a coordinated manner that benefit the entire student body, and in this case those children with ADHD.

On the other hand, the school‘s curriculum involves making a series of decisions in which the educational response may be adjusted to suit children with ADHD. These include the following highlights:      

Regarding curricular goals, prioritise the capabilities of integration and interpersonal relationships, fostering collaboration and cooperation among pupils. Regarding content, reinforce attitudinal content, dedicating a significant amount of time to it within the school timetable. Regarding assessment, emphasise the aforementioned goals and content. Regarding the learning methodology, prioritise participatory methods, peer learning, and group dynamics. Regarding the mainstream learning that is inherent to all the subjects, emphasise moral and civic values. Regarding the authorisation of pupils, implement programmes that foster the development of harmony and the prevention of violence.

Interventions by Teachers That Affect All the Pupils within a Group The classroom provides the setting for most of a child‘s learning activities; furthermore, it is the place where children learn to interact with their peers. The structuring of classroom times and activities may be more or less beneficial or detrimental for a child with ADHD. The approach to the planning of the syllabus in class and the tutoring of pupils should cater for certain aspects that may help to avoid some of the problems present in ADHD. Generally speaking, there are certain strategies that favour pupils with ADHD [15]:

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

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Performance of the more difficult tasks that require greater attention early on in the day. Intersperse among the more difficult tasks moments of practical work, and take breaks to stop the pupils from becoming tired or distracted. Break complex tasks down into smaller steps, in which the pupils can achieve interim goals and assess their own progress. Reduce the number of distracting features within the classroom. For example, place these pupils in the front row, where they are less likely to be distracted by their classmates. Maintain an environment that is structured, motivating and predictable, with stable routines, which help pupils to feel more secure within the classroom. It is advisable to use visual material to help pupils anticipate the next tasks.

When one considers that some the most prevalent problems within a classroom with children with ADHD involve problems of behaviour, the classroom may also provide the setting for the implementation of techniques for modifying behaviour that help a child with ADHD to self-regulate their conduct. At the same time,it constitutes a learning process for all the other pupils, regardless of whether or not they have issues with their behaviour. These techniques follow two paths: on the one hand, they reinforce the appropriate behaviour expected in the classroom, and on the other, they avoid disruptive and inappropriate behaviours. Regarding the promotion of the behaviours expected in class, the most widely used and effective procedure for fostering appropriate conduct involves the systematic and meticulous application of positive reinforcements, such as tangible prizes, points, praise or special privileges, in a manner contingent to the performance of the behaviours expected [51]. Ensuring their efficacy requires the teacher to specify the precise nature of the behaviour expected and apply the reinforcement immediately, while focusing attention solely on that behaviour. Concerning the positive reinforcements a teacher may use, tangible prizes should only be awarded immediately after the expected behaviour, and never before; they are to be awarded consistently, in response to the behaviour, and they are to be changed frequently to avoid them losing their effectiveness through habituation. Furthermore, they should be balanced, in the sense that they correspond to the importance and difficulty of the target behaviour. Reinforcement in the form of praise or other kinds of positive acknowledgement, such as smiling, are the most basic ones available to a teacher, but no less effective because of that. Praise should also be made immediately in response to the behaviour, being sincere and highlighting the appropriateness of the behaviour. Regarding the suppression of the inappropriate, disruptive or disturbing behaviour that may appear within the classroom, the tendency is to combine the positive reinforcement of incompatible behaviours with techniques such as extinction, positive punishment, the cost response, and time out. All these techniques, already explained at the beginning of this chapter, should be applied immediately after the episode of the behaviour that is to be stopped, being more effective when there is a close relationship between the agent applying them, in this case the teacher, and the receiving pupil.

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Interventions by Teachers Involving Solely Children with ADHD It often happens that following the implementation of other measures in the school or in the classroom with all the pupils as a whole, the need arises for the teacher to apply certain interventions that are designed solely for children with ADHD, with the aim being to improve their learning and wellbeing in class. The type of measures that focus solely on children with ADHD may be very varied, ranging from minor adjustments of the physical medium to more or less significant changes to their curriculum. One aspect to be considered is that a teacher does not normally have specific training for dealing with the difficulties posed in the classroom by a child with ADHD, and tends to adopt an overly permissive attitude or, on other occasions, an authoritarian approach involving an angry response. In both cases, such responses by the teacher may reinforce some of the symptoms manifested by a child with ADHD, such as hyperactivity, or trigger the appearance of disruptive behaviours [52], which is detrimental to the actual child in terms of both their emotional development and their education [53]. In addition, it is vital for teachers to coordinate with each other to bring out the best in a child with ADHD. The school should guarantee the sharing of information between teachers, especially when the child changes year or level, with the aim being to ensure there is continuity in the established guidelines that are favouring the pupil‘s development. The need to consider one or other type of measures will depend on the nature of the child. In most cases, minor adjustments usually need to be made to the physical medium to cater for a child with ADHD, and thereby also improve their performance [15]. It should be remembered that children with ADHD learn more easily in ordered environments and routinebased situations, with clear, reasoned and consistent rules, so the teacher should show a particular interest in favouring these conditions. The following are some of the more common measures that tend to be taken with children with ADHD: 

        

Reduce possible distractions, seating the child as close as possible to the teacher, in the front row, and not next to a window or with a lot of other children when performing a task. Seat them next to pupils that provide positive models of behaviour. Provide a study area that is isolated and quiet for use by pupils with ADHD and those with similar conditions. Leave a wider gap between the tables where the child with ADHD is seated. Maintain eye contact with the pupil whenever they are required to pay attention to some specific information. Provide visual and verbal cues, especially when changing from one activity to another. Issue brief, concise instructions. When complex tasks are involved, divide each one into successive steps, with specific instructions on each one of them. Lay down clear rules on behaviour in the classroom that are always to be followed. Empathise with the pupil. Address the pupil often in order to hold their attention and reinforce their motivation, even use a ―code‖ or ―secret signal‖ with a pupil's problems of attention and behaviour, which may be used whenever their attention appears to wander.

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In those cases in which the symptoms of ADHD do not allow a child to follow the normal learning process in class, special curricular planning needs to be introduced to favour their performance. In this case, too, the measures may be very varied; on a general basis, the child needs to be helped with their organisation and, if necessary, the school syllabus may need to be adapted to the child‘s specific characteristics. The most common measures in this case are as follows:  

 

Organise the tasks to be performed in as much detail as possible, dividing them up so that the pupil has many to do, but they are all short. Set aside areas for resting, where the child may go if they notice symptoms of impulsivity or aggressiveness; these spaces may involve play areas where the pupil can calm down. Organise their homework, teaching the child to use their diary, making sure a note is always made in the same place and that the pupil has their corresponding copy. Break down tasks into short, simple activities, using visual aids and spoken instructions. It is important not to overburden the pupil with tasks.

When attention problems are very severe, it is advisable to proceed as follows:     

Reduce the number of tasks assigned. Structure the tasks specifically for this pupil into short time spans. Adjust the time to the pupil‘s needs, giving them more time to complete tasks or tests. Alternate activities to avoid boredom. Study those subjects that the child finds more difficult out of class, with a smaller group of pupils in order to increase their attention and concentration.

Intervention in a Group Finally, there are certain specific types of intervention for children with ADHD that are undertaken in a group in the classroom, either during the school day or as an extracurricular activity. These kinds of group intervention are good for all the pupils, and especially those with impulsivity or behavioural problems. One of the more common group interventions involves peer intervention. As Rickel and Brown describe, these are interventions that are applied to a group of pupils, either during the school day or as an extracurricular activity [15]. They may serve a variety of purposes, although they are generally designed to teach pupils social skills and problem-solving, help them improve their behavioural skills, and reduce their aggressiveness. In these interventions, the pupil‘s peers provide the model for behaving appropriately in different situations. Several studies have shown how effective these interventions are when they are combined with other interventions either within the family or at school.

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Conclusion Children with ADHD have difficulties with attention, impulsivity and hyperactivity that impact negatively upon their adjustment to the different contexts in which they develop, and in addition to this there is high comorbidity with other disorders involving, for example, behaviour, anxiety, mood swings, etc. The intervention with this population may be undertaken, as outlined in this handbook, from a medical, psychological and educational perspective. The literature review singles out three approaches that have proven to be especially effective in dealing with ADHD: the use of psychostimulant medication, the modification of behaviour and, more recently, cognitive behavioural therapy. This chapter has considered the psychological approach and its associated techniques. In view of the disorder‘s variability (in terms not only of its frequency rate, whether this involves hyperactivity, impulsivity or inattention, but also of its evolution in step with the child‘s development) and its high comorbidity with other disorders, it is important to build an accurate explanatory model to help specialists choose the most appropriate therapy or therapies for addressing the problems an individual with ADHD has to face. It is important to maintain an open, two-way relationship between specialists and the people who interact with the child with ADHD, as this facilitates not only a systematic assessment but also the finetuning or modification of the techniques being applied. Once ADHD has been diagnosed, the intervention should revolve around the development of skills for the child‘s behavioural and emotional regulation, using cognitivebehavioural techniques, or around the development of contingency patterns that reinforce appropriate behaviour and reduce any that is inappropriate, while training parents to handle reinforcements in a contingent and consistent manner. Behavioural therapies are especially recommended for young children, and seem to be the techniques that best deal with the symptoms of ADHD, as well as of certain comorbidities, focusing on functional disabilities [23]. Nevertheless, some studies indicate that they do not lead to any improvement in cognitive skills. It is therefore important to include these techniques in the treatment of these children, which means programmes need to be revised to include training in self-instructions, problem-solving, or the focusing of attention. The research into the effects of training parents reveals that it has a greater impact on the child‘s functional outcome than on the specific symptoms of ADHD, above all when there is comorbidity with other disorders, such as, for example, behavioural problems. Intervention in the classroom is essential, not only for the child or adolescent with ADHD but also for all their other classmates, as well as for the acquisition of knowledge and prosocial interaction skills. It is important for teachers to know and implement actions linked to the planning of the syllabus, the time distribution of tasks, the handling of disruptive behaviours in the classroom, as well as to executive functions, that is, attention, problemsolving, and memory. Furthermore, teachers have to control the need to be constantly moving that these children have. As noted in the chapter, the correct use of these interventions requires not only their mastery and control by the attendant professional, but also suitable awareness and training on the part of those agents involved in the life of the child or adolescent.

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A further limitation lies in the child‘s willingness to begin and continue the treatment; in the case of adults, there is an agreement between the psychologist and the person asking for help, whereas in the case of children, such assistance is generally sought by the parents, and not by the actual child. In some cases, this may hinder the continuity of the treatment, especially when adolescents are involved, as they may be reluctant to cooperate. When we link attention deficit to the control of impulses, the efficacy may be reduced even further. In short, for treatments to be effective they need to consider the level of cognitive development, the needs of the child-adolescent, and the changes they are undergoing, as well as be implemented wherever the difficulty manifests itself over a protracted period of time.

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[29] Oldfield RR. The effects of meditation on selected measures of human potential. Dissert Abstr Int 1982; 42-11A: 4717. [30] Sukhodolsky DG, Solomon RM, Perine J. Cognitive-behavioral anger-control intervention for elementary school children: A treatment-outcome study. J. Child Group Ther. 2000; 10: 159-170. [31] Orjales I. Eficacia diferencial en técnicas de intervención en el síndrome hipercinético. Unpublished Doctoral Thesis. Madrid: Universidad Complutense, 1991. [32] Orjales I. Tratamiento cognitivo en niños con trastorno por déficit de atención con hiperactividad (TDAH): revisión y nuevas aportaciones. Ann. Clin. Health Psychol. 2007; 3: 19-30. [33] Álvarez L, González-Castro P, Núñez JC, González-Pienda A, Álvarez D, Bernardo AB. Programa de intervención multimodal para la mejora de los déficits de atención. Psicothema, 2007; 19: 591-596. [34] Kendall PC, Braswell L. Cognitive-behavioral therapy for impulsive children. New York: Guilford, 1985. [35] Bierman KL, Greenberg MT. Social skills training in the FAST track program. In: Peters RD, McMahon, RJ, eds. Preventing childhood disorders, substance abuse and delinquency. Thousand Oaks, CA: Sage, 1996, pp. 65-89. [36] Lochman JE, Wells KC. A social-cognitive intervention with aggressive children: prevention effects and contextual implementation issues. In: Peters RD, McMahon RJ, eds. Preventing childhood disorders, substance abuse, and delinquency. Thousand Oaks, CA: Sage, 1996, pp. 111-143. [37] Frick PJ. Conduct disorders and severe antisocial behavior. New York: Plenum Press, 1998. [38] Anastopoulos AD, Shelton TL, Barkley RA. Family-based psychosocial treatments for children and adolescents with attention-deficit/hyperactivity disorder. In: Hibbs ED, Jensen PS, eds. Psychosocial treatments for child and adolescent disorders: Empirically based strategies for clinical practice. Washington DC: American Psychological Association, 2005, pp. 327-350. [39] Kazdin AE. Conduct disorders in childhood and adolescence (2nd ed.). Thousand Oaks, CA: Sage, 1995. [40] Reid JB, Patterson GR, Snyder J. Antisocial behaviour in children and adolescents. Washington, DC: American Psychological Association, 2002. [41] Barlow J, Coren E, Stewart-Brown S. Meta-analysis of the effectiveness of parenting programmes in improving maternal psychosocial health. Brit J. Gen. Pract. 2002; 52 (476): 223-233. [42] Barkley RA. ADHD and the nature of self-control. New York: Guilford Press, 1997. [43] Ross AO. Child behavior therapy: Principles, procedures and empirical basis. New York: Wiley, 1981. [44] Forehand R., McMahon RJ. Helping the noncompliant child: A clinician`s guide to parent training. New York: Guilford, 1981. [45] Hembree-Kigin TL, McNeil CB. Parent-child interaction therapy. New York: Plenum Press, 1995. [46] Lundahl B, Risser HJ, Lovejoy CM. A meta-analysis of parent training: Moderators and follow-up effects. Clin. Psychol. Rev. 2006; 26: 86-104.

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[47] Brown RT, Antonuccio DO, DuPaul GJ, Fristad MA, King ChA, Leslie LK, McCormick GS, Pelham WE. Childhood Mental Health Disorders: Evidence Base and Contextual Factors for Psychosocial, Psychopharmacological, and Combined Interventions. Washington DC: American Psychological Association, 2007. [48] American Academic of Pediatrics. Understanding ADHD. Information for parents about attention-deficit/hyperactivity disorder. Grove Village, IL: ELK, 2001. [49] Goldman LS, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment of attentiondeficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA 1998; 279: 1100. [50] Miller KJ, Wender EH. Attention deficit/hyperactivity disorder. In: Hoekelman RA, ed. Primary Pediatric Care, 4th ed. St. Louis: Mosby, 2001, p. 756. [51] Webber J., Scheuermann B. Accentuate the positive... eliminate the negative! Teach Except Children 1991; 24: 13-19. [52] Martin AJ, Linfoot K, Stephenson J. How teachers respond to concerns about misbehavior in their classroom. Psychol Schools 1999; 36: 347-358. [53] Wheldall K. Managing troublesome classroom behavior in regular schools: a positive teaching perspective. Int. J. Disabil. Dev. Ed. 1991; 38: 99-116.

In: Attention Deficit Hyperactivity Disorder (ADHD) Editors: F. López-Muñoz and C. Álamo

ISBN: 978-1-63483-128-4 © 2015 Nova Science Publishers, Inc.

Chapter 12

Is It Possible to Prevent ADHD? Javier Quintero1,2,3,*, Josefa Pérez-Templado3 and Patricia Alcindor1 1

ADHD Across Life Spam Program, Psychiatry Department, Universitary Hospital Infanta Leonor, Madrid, Spain 2 Psychiatry Department, Faculty of Medicine, Complutense University, Madrid, Spain 3 Psiformacion Fundation, Madrid, Spain

Abstract ADHD is a disorder that emerges early in the neuro-developmental process and it persists during adolescence and young adulthood. The identification of children ―at risk‖ could prevent the development of emotional, social, academic and work difficulties in the future. The authors describe in this chapter aspects related to primary, secondary and tertiary prevention. Primary and secondary prevention is the target of new research projects and therapeutics challenges in psychiatry. In ADHD these actions or approaches are based on the essential idea of neuro-development and brain plasticity. There is also a complex body of information that suggests many and heterogeneous biochemical causes for ADHD in relation to diet, such as allergies to additives, heavy metal toxicity (lead), mineral unbalances (like zinc, iron and magnesium), the new role of essential fatty acids and/or vitamin B deficit. There are also new studies that connect the role of physical exercise or cognitive stimulation programmes with ADHD prevention. There are many actions that have focused towards the tertiary role of prevention, namely, minimize evolutionary risks that imply an ADHD focused in minimizing co-morbidities and psychosocial risks.

Keywords: ADHD, prevention, drug use, cognitive stimulation programmes, physical exercise, nutrition *

Correspondence to: Dr. Javier Quintero, Psychiatry Department, Universitary Hospital Infanta Leonor, Av. Gran Vía del Este, 80, 28031 Madrid, Spain. E-mail: [email protected].

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Introduction ADHD is a disorder that emerges early in the neurodevelopmental process and persists during adolescence and young adulthood in many affected individuals [1-2]. In addition to inattention, impulsivity and hyperactivity symptoms that define this disorder, neurocognitive deficits, psychiatric comorbidity and social and emotional difficulties should also be added [3-4]. One of the diagnostic difficulties is based on the fact that symptoms must be present before the age of 12 years old [5], which not necessarily means that there is an impairment from the beginning, as many symptoms may be considered ―normal‖ during the preschool period. There is important evidence that psychopharmacological treatment and psychosocial interventions are effective in the treatment of target symptoms and, to a lesser extent, the rest of traits associated with ADHD. Stimulants and non stimulant drugs [6-7] reduce severity of ADHD symptoms and oppositional and defiant behaviours. Parental and school behavioural interventions have also shown positive effects on symptomatology [8-10]. New treatment development for ADHD has been centred in school age [11], as this is when it is most diagnosed and when the brain is supposed to be more ―plastic‖ [12]. Moreover, through the identification of children ―at risk,‖ it could be prevented the development of emotional, social, academic and work difficulties in the future, tackling the treatment of ADHD as something more than only the control of core symptoms [13].

Epigenetic Model Research centred in ADHD causes have shown that the most likely theory is that one which brings together gene interaction, pre-natal and post-natal environment exposure (Figure 1). From this perspective, ADHD has been conceptualized through an epigenetic model with these three factors interacting to influence in the brain development [14].

Adapted from Halperin et al. [12]. Figure 1. Epigenetic model in ADHD.

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Genetic Factors Family studies, twins and adoption cases show that the genetic component is a risk factor for ADHD, being the average inheritability attributed to genetic factors of 76% [15]. There is an important genetic heterogeneity so different genes may lead to the same phenotype. Moreover, each capable gene may have a low penetrance and therefore not everybody that carries the genes will develop the disorder. It would support the theory of a complex multigene inheritance in ADHD.

Pre-Natal Environment Environmental factors are important factors in complex diseases such as ADHD and its role in the aetiology is more significant than in Mendelian genetic transmission diseases [1617]. Maternal exposure to tobacco, alcohol, caffeine and some psychotropic drugs during pregnancy may increase ADHD risk in the newborns [14, 18]. Other factors that have also been involved are: an inadequate maternal nutrition (obesity, iron and essential fatty acids deficits [19-21]), maternal stress during the organogenesis [22], gestational diabetes [23] and exposure to chemicals and heavy metals [14, 18].

Post-Natal Environment Although it is highly unlikely that post-natal environment alone may cause ADHD, it seems important its role in the severity of this disorder. Several factors, very related among them, have been published in earlier studies: an unfavourable environment at home, a poor model of upbringing, socioeconomic status, institutionalization, and exposure to trauma and violence [14].

What Is Prevention? Primary Prevention Primary prevention is carried out removing those factors that may cause damage before they become effective. Interventions take place before the disease appears; its main target is to prevent or delay the illness. The most usual actions in this sort of prevention are: •

Promoting health focused on people. It is the promotion of public health through actions that influence individuals of a community. For instance: anti-smoking campaigns to prevent lung cancer and others tobacco-related illnesses or campaigns to promote healthy diets or physical exercises for overweight prevention.

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Promoting health focused on the environment. It is the promotion of public health through the actions that influence the environment. As for instance, environmental health and food hygiene.

For ADHD, measures directed to increase maternal care during pregnancy, such as no smoking, use of drugs, decrease exposure to heavy metals like mercury and lead, could all be understood as actions with primary preventive potential.

Secondary Prevention Secondary prevention consists of detecting and treating diseases in early stages. Intervention takes places at the beginning of the illness, being its main target to avoid or delay the development of disease. It could be divided in two types of actions: passive and active. a) Passive - the screening: in general practice, the most common strategy is the active search of cases where a number of tests are carried out according to age, sex and possible risk factors present in the individual that consults for any other reason. A special interest population when making a diagnosis and early intervention is one where there are ADHD cases in relatives. Studies of families indicate a risk for first-grade relatives 4-10 times higher than general population, with prevalence in these relatives of 2050% [24]. Therefore, in studies of clinical samples children with an ADHD diagnosis have high rates of childhood-onset ADHD in their parents, with a risk between 2 and 8 times higher [25]. Biederman et al. studied 84 children at risk of showing ADHD for having a parent affected of this disorder. It was found that 57% of children of parents with ADHD also had an ADHD. Of the 84% of parents that had children, at least one showed ADHD and 52% had at least two children affected [26]. Although the existence of ADHD is very much deep-rooted in child and adolescent psychiatry practice, and it is usually part of the differential diagnosis in clinic in ―nearly‖ any motive for consultation, at adult clinical practice it is underdiagnosed. In fact, it is known that ADHD is present in around 10%-20% of people with common mental health problems, according to data from clinical and epidemiological research [27-32]. The clinical experience shows that, as opposed to what psychiatric research tells us, ADHD is not diagnosed nor is it present as a comorbidity diagnosis in those frequencies. On that respect, Mannuzza et al. found that in 91 patients with ADHD, a third of cases versus 15% control cases (without ADHD) a psychiatric disorder diagnosis was made during the follow-up [33]. On the contrary, Hofstra et al. analysed the psychopathology in a sample selected 14 years earlier. Child behaviour scales were used in order to test how child psychopathology was predictive of psychiatric disorders in adulthood. Attention problems, detected in 67 boys and 55 girls, did not predict any psychiatric disorders 14 years later, when it was adjusted with other categories of child behaviour scale [34]. On the other hand, in those subjects with an ADHD diagnosis in childhood, the persistence of the disorder should be ruled out and the need of a specific pharmacological treatment should be considered. Kessler et al. carried out an epidemiologic research on a general population sample and using the clinical scale of adult ADHD diagnosis, examined symptoms stability from

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childhood to adulthood [35]. 45.7% of the sample that had criteria for ADHD in children, persisted fulfilling criteria for ADHD in adulthood, with 94.9% of people with an inattentive profile and 34.6% with a hyperactive/impulsive profile. Namely, persistence is higher in inattention than hyperactivity. Moreover, persistence of executive dysfunction symptoms was included, turning out to be a specific value of ADHD diagnosis and incorporation in the DSM-5 was considered, but not imcluded. In a study of Mental Health World Organization [36] carried out in 10 countries over a 629-adult total sample with childhood-onset ADHD found that up to 50% children with ADHD fulfil criteria of ADHD persistence in adulthood. Moreover, what predicts in childhood the persistence of symptoms in adulthood is: having more symptoms of inattention in childhood than hyperactivity/impulsivity ones, greater severity of symptoms, showing a comorbid depression, harmful psychosocial factors and parental psychopathology. Biederman et al. had already pointed out these factors, also finding comorbidity with conduct disorders and anxiety as persistence predictors [37]. b) Actives: auto-examinations or auto-explorations are auto-administered actions to detect some illnesses. In this sense, actions to increase awareness of what ADHD is among general population may result in a better ability to detect this problem. It is also of special importance actions directed to the Educational System, as it is a largely dysfunctional habitat for patients with ADHD and where symptoms may be easily measurable. Therefore we often see that the first suspicion of ADHD diagnosis in adults is carried out by the subject after reading information about this disorder in a newspaper article and identifying with what it is described there. This situation, particularly important in the USA, where adult ADHD has become topical, has managed to estimate an auto-diagnosis rate of 5% in general population.

Tertiary Prevention Tertiary prevention is carried out when the disorder has already been established, being its main target to eliminate or decrease consequences of the development of this disorder. An example for ADHD is the treatment with stimulants. It decreases ADHD symptoms and, additionally, the emergence of complications and comorbidities. In relation to the family genetic load, there is an increasing recognition of the importance of diagnosing and treating the disorder of parents of children with ADHD [38], since around 20% parents of children with ADHD suffer ADHD themselves [24] and many of them were not diagnosed or treated in childhood [39]. Recent national guidelines recommend that ADHD should be diagnosed and treated appropriately throughout the entire life [40-43]. This is controversial due to the prejudice that usually exists among professionals to treat ADHD in adults [44], in spite of finding it contradictory that a treatment could be effective in children but harmful in adults [45].

What Kind of Prevention Usually Occurs in the ADHD? We will first focus on the need of a tertiary prevention, which is being carried out in one way or another, or at least it is being considered, mainly based on consequences or risks more

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frequently related to ADHD, where comorbidity with other mental disorders are excluded in a more specific way. Research studies have classically focused on the study of ADHD evolution by means of retrospective and prospective design studies. In the last decade, research has been dedicated to comorbidity studies in adult ADHD, whereas in previous decades it was dedicated to prospective follow-up studies in children who had been seen in different centres for suffering ADHD. Therefore it would be an intervention focused on the tertiary prevention and based on the diffusion of possible comorbidities and risk associated to ADHD to the consultant and patient. One of the main features of ADHD is impulsivity, which initially is shown as disorganized, without a clear purpose and of a motor kind. However, impulsivity modulates with age; it becomes more verbal than behavioural while hyperactivity can be expressed as inner tension [46]. It is then when it begins to show usual comorbidities of ADHD, namely those ones related to impulse control disorders (antisocial disorder and substance abuse disorder are the most frequent). Drug Use It has been estimated that the prevalence of substance abuse in ADHD patient samples is around 45% - 55% [47]. On the other hand, ADHD prevalence in populations with substance abuse disorder fluctuates between 11% [48] and 54% [49], according to studies. Moreover, this relationship is harmful since patients with ADHD begin this misuse earlier, continue for longer and switch from alcohol to hard drugs earlier and quicker [50]. Alcohol [49, 51] and cannabis are the most common substances, followed by cocaine and amphetamines [52-53]. Nicotine dependence is also more frequent in subjects with ADHD than in general population (40% vs. 26%, respectively) and smoking and cannabis use begins at an earlier age than in subjects without ADHD [54]. At the same time, it is known that smoking is a risk factor for developing substance use disorder in adulthood. Moreover, patients with substance use disorder are less likely of continuing treatment programmes, less remission rates of substance use disorders and longer periods of substance use disorder [52], as well as more severe conditions of this disorder [55-56] with an earlier beginning, greater damage and a faster transition from use to dependence. Given therefore the high prevalence of ADHD in patients that seek treatment for substance use disorder and its role in having a worse prognosis, the presence of ADHD in this population should be routinely ruled out. It is therefore essential to have ADHD screening programmes in population of patients with substance use disorders [57]. On the other hand, it could be thought that pharmacological treatment for ADHD may be a risk factor for substance use disorder in adolescence or adulthood. The fact is that, according to new researches in this matter [58], ADHD treatment is not a risk factor for developing substance use disorder and in addition, treatment of childhood ADHD prevents the development of substance use disorder, including nicotine dependence in adulthood [5960]. Stimulants Abuse Causes of this comorbidity are complex, but it could be said that in ADHD there are three factors that predispose stimulant abuse:

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An altered reward system A greater exposure to psychosocial risk factor Treatment of ADHD with stimulants without any medical follow-up.

The most highly regarded paper that analyses the relationship between stimulant treatment and development of substance abuse disorder is Faraone and Wilens‘s paper, where a revision of this topic was carried out [61]. They found that the inadequate use of pharmacological treatments for ADHD was minimal, and in any case, those patients with conduct disorders or substance abuse disorders were the most inclined to inappropriate use. On that respect, 75% adolescent patients that make an inadequate use of these drugs have comorbidity with substance abuse disorder [47]. Nevertheless, research field is open on that respect and in a recent paper, using a population survey in the United States of America (National Survey on Drug Use and Health) try to analyse the kind of adult without ADHD that use stimulant drug with prescription, concluding that there is a heterogeneous subgroup which not necessarily uses other substances [62]. Stimulant drug use is also worrying among the university population [63-64]. It has been estimated that on a population basis, there is a stimulant drug abuse between 5% and 35% in university students and between 5% and 10% in adolescents. Even though prevalence does not seem to be very high among adolescents, it increases to 23%-31% if we focus on adolescents that abuse of other substances and among those adolescents and adults that receive treatment for ADHD it increases to 14%. These numbers increase even more in case of university students treated for ADHD (up to 45%) [64]. Therefore supervision of ADHD treatment is needed, mainly in populations at risk and in cases where there is a suspicion of abuse, atomoxetine could be a safer alternative of treatment [65]. Traffic Accidents/Road Accidents There are more road accidents among young adults with ADHD, as a result of being inattentive and impulsive, as they have a greater need of seeking new sensations [66-68]. This leads to a very necessary and uncomfortable question; do we carry out any type of intervention in our patients with ADHD who drive? [69]. In this respect, it has been stated that pharmacological treatment has shown its efficacy in reducing risk of road accidents in drivers with ADHD [70]. School and Job Failure Subjects with ADHD have usually a low academic and labour performance [71]. Efforts directed to improve academic results of children with ADHD are the warhorse for parents of these children. Stimulant drug use and behavioural techniques have shown its efficacy in improving their attention ability and executive dysfunction in children with ADHD. The risk of school failure associated with non-treated ADHD increases. However there is much to do in adulthood. It is known that subjects with ADHD have usually a low labour performance. Often, jobs are for a short duration [72], either because they are fired or get bored and change. Due to their attention deficit, they show a difficulty to finish tasks, resulting in a low performance at school, when studying and at a job place, in comparison with control subjects with equal cognitive abilities. In fact, many see reduced

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their financial resources [73]. This precariousness in relation to the plenitude of professional development is independent of their intellectual ability [74]. Aggressive Behaviour and Criminality Impulsivity is an usual behaviour in children with ADHD and it is not unusual that it turns into aggressive behaviours and even dissocial. This relationship has its origin in family, environment and family factors [75-76]. In addition, criminality in adulthood is predicted by ADHD. Subjects with ADHD are more frequently arrested, convicted and imprisoned in comparison with control subjects, and ADHD is increasingly diagnosed among adults in the field of forensic psychiatry and in prospective studies [76-78]. It is not necessary to suffer from an antisocial disorder in adulthood or childhood to develop criminal behaviour in patients with ADHD, but criminal behaviour is related to having suffered conduct problems in childhood [77]. The development of an antisocial personality disorder or substance abuse disorder has shown to be independent from the comorbid diagnosis of childhood conduct disorder, even though both comorbidities certainly increase criminality rates. It has been demonstrated that an adequate treatment, plus psychosocial intervention, decrease aggressiveness, disruptive behaviours and commission of offences significantly [7980]. From that we could infer that pharmacological treatment decreases criminality in adult patients with ADHD properly diagnosed and treated. Obesity ADHD has also been associated with obesity [19, 81], so screening and treatment of ADHD in children has been suggested with the specific target of avoiding morbid obesity in childhood [82]. Several explanatory hypotheses have been proposed regarding this relationship [83]: •

• •

It is possible that obesity is associated with breathing problems and sleep troubles, so this daytime fatigue would cause the symptoms similar to ADHD, such as inattention. It is possible that there is a common biological relationship between both disorders, for example, in relation to altered brain areas connected through dopamine. ADHD itself contributes to obesity. One reason could be that obesity is helped by a chaotic and disorganized life rhythm, or because anxiety and depression secondary to suffering ADHD, could lead the patient to use food as a mean of breaking anxiety (as it is understood in eating disorders, ―using food for things that is not for eating‖).

Besides, ADHD is therefore the cause of obesity and it has been suggested that it also involves an extra difficulty in slimming programmes with worse results than in subjects without ADHD. On the other hand, it seems that pharmacological treatment for ADHD could help strategies of weight loss in these subjects [84].

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Traumatic Brain Injuries It is known that subjects with ADHD are more likely of having accidents, such as dog bites, stings, burns and an unhealthy lifestyle secondary to inattention and impulsivity, which are the main features of this disorder. In this regard, there is a new research on athletes where the high tendency of suffering falls with consciousness loss is analysed in comparison to athletes without ADHD and emphasizing the need of intervention on the prevention of these falls [85].

Risky Sexual Behaviours It is also known that subjects with ADHD have a higher number of sexual partners, risky behaviours and unwanted pregnancies [86]. It has been suggested that this association is more important in cases of ADHD who are marijuana users, too. Risky sexual behaviour prevention in ADHD could improve family stability.

Suicidal Risk Alley carried out a revision on 14 papers published on this topic, finding an association between suicidal risk and ADHD [87] and encouraging in depth research of this aspect. Both deliberate self-harm [88] and suicide attempts [89] have been reported in subjects with ADHD. There are studies which suggest that suicidal risk on people with ADHD persists on even intensify up to young adulthood [90], in relation to strains associated with developmental changes that occur in an existing immature premorbid disposition, together with insufficient coping strategies that make the adaptation to changes difficult. In this respect, impulsivity and deficits in executive functions and behaviour self-regulation could affect subjects with ADHD and have a critical role in a suicidal behaviour, particularly when they face changes, frustrations and stress at the beginning of the adulthood [91]. Adolescence is characterized by higher levels of emotional reactivity, an increase of risk behaviours and desire for autonomy. All this may lead to conflicts and a tendency to move away from previous sources of support, such as parental figures [90]. In this context, risk for a suicidal attempt may increase, especially associated to adolescents with greater emotive nature and/or impulse control (greater disinhibition). This is the case of adolescents with ADHD, where characteristic clinical symptoms coincide with this profile. However it has also been suggested that familial aggregation could be at the origin of the relationship between suicide attempts and ADHD, so that a genetic component, in addition to environmental one, could exist. Therefore opening a new field in the suicidal behaviours prevention for these more vulnerable subjects [92-93]. Barkley and Fischer [91] found that young adults diagnosed with ADHD in childhood, were more likely of suicidal attempts and were associated with greater severity, past depressive episodes and conduct disorders. The relationship between suicidal attempts and depressive episodes in ADHD samples, particularly women, has been replicated in other studies [94-95].

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That is to say, it seems there are some combinations of disorders that increase suicidal behaviours: poor behavioural inhibition together with tendency of irresponsibility towards problems associated with ADHD, may trigger a deliberate self-harm in the context of a depressive episode. In this sense, several studies have associated suicidal tendencies in ADHD through comorbidity with depression. It is important to have these studies in mind, given that in many non-accomplished suicidal attempts attended in A&E Department, the existence of depression or substance abuse is explored and the possibility of an ADHD diagnosis is overlooked. Manor study is worth mentioning (despite its methodological limitations) [96]. In 23 adolescents who come to A&E Department for non-accomplished suicidal attempts, it was found that 65% met criteria for ADHD. On the other hand, a controversial issue is whether there are differences depending on the adult ADHD subtype; there is little research in this respect [97-98].

What Kind of Prevention Could Be Carried out in ADHD? Primary and secondary prevention is certainly the target of new research projects and therapeutic challenges in Psychiatry generally and in ADHD in particular. In ADHD, these actions or approaches are based on the essential idea of neurodevelopment: brain plasticity and its windows of opportunity. Brain reaches almost full size at the age of 5 [99]. Nevertheless 80% of adult-age size is established at the age of 2 [100] and is also at this age when most number of intra-uterus initiated synapses are generated [101]. Therefore, toxins in the brain could have a great impact at that age. However, brain maturation continues during childhood and up to adulthood, where the process of ―neuron pruning‖ is highlighted. Brain re-organizes these intercommunications to give sense to its needs. On the other hand, we know that the prefrontal area is the last part to mature. These are an array of questions that could become windows of opportunities. The following prenatal risk factors have been studied: exposure to alcohol, nicotine, drugs, high blood pressure, maternal stress during pregnancy, premature delivery and low birth weight [102]. There is also a complex body of information that suggests heterogeneous biochemical causes for ADHD in relation to diet: food and allergies to additives, heavy metal toxicity (such as lead), mineral unbalances (in the case of zinc, iron and magnesium) and the new role of essential fatty acids or deficits of B vitamin complex [19]. In these cases, primary prevention would have controlled these toxins to minimize the risk of development of ADHD. An even newer aspect of primary and secondary prevention would have to do with the implementation, in an active fashion, of measures that modulate the brain plasticity to avoid or minimize ADHD symptoms. In this respect there are new studies that connect the role of physical exercise, diet with supplement of essential fatty acids or cognitive stimulation programmes with ADHD prevention. Cognitive Stimulation Programmes Those programmes orientated to exercising attention and cognition in school-age children with ADHD have shown functional and structural brain changes [103-104] and many of these studies have obtained improvements in inhibitory response measures, sustained attention, working memory, executive function, academic attainment and specific ADHD symptoms.

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Similar studies in pre-school children have obtained positive results in those areas [12]. New interventions have been developed [12], designed to improve behavioural control in children with ADHD through the improvement of neurocognitive functions [12,105-106] characterized by the use of games: TEAMS, ―Training Executive, Attention and Motor Skills‖: is a programme developed for 4-5 year-old children with ADHD and its target is the inhibition, sustained attention, memory, planning, visual-spatial and motor tools. It takes place in groups of children and parents, where the latter are training to incorporate these tools in their day to day lives. An open study has shown efficacy in decreasing ADHD symptoms [107]. ENGAGE, ―Enhancing Neurocognitive Growth with the Aid of Games and Exercise‖: a programme developed for 3-4 year-old children: an open trial has found improvement in ADHD symptoms [106]. ETAM, ―Executive Training of Attention and Metacognition‖: is for 3-7 year-old children. An open study has shown efficacy in measures of executive function [105]. Physical Exercise Helps Many Patients with ADHD But Could It Help Control the Occurrence of These Symptoms? It is known that physical activity increases brain neurotrophic factor levels, proteins at the synapses, glutamatergic receptors and availability of insulin-like growth factor, and all contribute to cellular proliferation and neuron plasticity. In rodents, exercise leads to behavioural change, improving the ability of learning and memory [108]. Exercise promotes essential changes in the early development, in that way it makes particularly interesting to practise sport in the early childhood. Aerobic exercise in children predicts changes in brain function according to the results of functional magnetic resonance and improves cognitive abilities [109]. Although there are some studies that analyse the relationship between physical exercise and its role in ADHD, more studies in this field are needed and specially controlled trials [110-111]. Family Intervention Programmes It is known that certain child rearing models (or the absence of these) favour the beginning or maintenance of disruptive behaviours and of ADHD symptoms. We refer to physical punishment, inconsistent discipline, parental positive behaviour, etc. [112].Therefore, a way of prevention would be trying to decrease ADHD symptoms (or even make them disappear?) through the adoption of different educational models in patients with risk factors for ADHD or emerging symptoms of this disorder. Studies of intervention programmes in relatives of pre-school children have given evidence of behavioural improvement and ADHD symptoms in these children [113]. This has also been replicated in preschool children [114]. Moreover, specific intervention programmes have been developed for teachers with positive results in decreasing behavioural problems and ADHD symptoms in children with this disorder [115]. Intervention with at-Risk Groups It is important to observe patients at special risk in order to try to prevent problems applying measures to minimize or avoid developing ADHD symptoms. Offspring of parents

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with this disorder, bipolar disorder and those people with history of physical or emotional trauma are kinds of special interest groups to prevent ADHD [116]. Screening ADHD questionnaires for teachers and parents in pre-school children have also been developed with good results [117] and even screening tools for teachers which discriminate between groups of risk for future health problems [118]. The Role of Nutrition in Preventing ADHD. What Essential Fatty Acids Can Do There are studies that support the hypothesis that an abnormal contribution of essential fatty acids (EFA) in the diet may be implied in the aetiology of ADHD [119]. Changes in the diet during the last century have had important nutritional impacts [120]. One of the most important is that currently, vegetable fats and oils dominate in markets and they are devoid of the essential fatty acids omega-3 (ALA, EPA y DHA). This problem has been aggravated by the fact that vegetable fats and oils contain unusual high quantities of linoleic acid omega-6, predecessor of the omega-6 essential fatty acids family, and its important metabolite arachidonic acid (AA), which is a well-known inflammatory factor. Traditional fats and oils used to have a healthy ratio of omega-6 and omega-3 of 4 to 1 or less, with a wide quantity of fatty acids omega-3, while new fats and vegetable oils are deficient in omega-3, contain a high quantity of omega-6, reaching a relationship between the two of approximately 20:1 [19]. There are also theories that relate ADHD with a congenital defect caused by deficiencies in maternal DHA supply during pregnancy and/or breast-feeding, as well as the absence of DHA and AA in child milk formula. DHA and AA are needed as building blocks for the newborn‘s brain and eyes [121]. Brain begins its growth very quickly during the third trimester of pregnancy and carries on growing for 24 months after delivery. DHA and AA are supplied directly from mother to child during pregnancy and through the mother‘s milk during breastfeeding. When the mother or child‘s diet is deficient in DHA and/or AA, brain and eyes can‘t develop adequately. Nowadays, a DHA supplement is recommended during the pregnancy as a protective factor in this regard [122]. As for the possibility of using essential fatty acids for ADHD treatment, these findings have been very contradictory, with reviews which conclude that its use compared with placebo is not superior [123-124]. However, there are many methodological difficulties when comparing the different studies among them: trials do not have the same duration and there are a lot of formulas used. Due to this, we can‘t conclude which kind, what quantity or how much time would be the most effective. In this regard, it is under discussion whether an excess of DHA and /or EPA supply could be harmful in the brain and could be the reason why some studies have found that it is beneficial in low doses but without any results in higher dosages [125]. Breastfeeding Beyond the role it has in the development of bonding, breastfeeding presents other important advantages. It is better than milk formula with regard to adequate nutritional supply to the newborn. WHO (World Health Organization) and UNICEF (United Nations Children's Fund) recommend breastfeeding during the newborn‘s first six months. The American Academy of Paediatrics recommends maintaining breastfeeding at least for the first year, even though not exclusively.

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In relation to ADHD there are studies that analyse children with ADHD and compare them to children without ADHD, and conclude that the group with ADHD were breastfed for a shorter time or not at all [126-128]. Smoking during Pregnancy There is enough scientific evidence that smoking during pregnancy is related with higher risk of ADHD in the newborn baby and even though the mechanisms involved are not known, studies with brain magnetic resonance imaging have pointed out that smoking may affect the same inhibitory control related neuroanatomic areas in ADHD [129]. Effects of Toxins on Neuro-Development and Especially on ADHD Environment contamination with heavy metals has turned in a global problem. Creation of fast and accessible systems to reliably predict the concentrations of these elements in polluted places is necessary. Heavy metals are a 65-element group with very heterogeneous physical, chemical and biological features. They may become pollutants if its distribution in the environment is altered by human activity: liberation of industrial effluents, vehicle emissions, agricultural activities, extraction of minerals are the sources of contamination of land, aquatic and air ecosystems. In relation with its role in ADHD, metals such as lead, mercury, bisphosphonates, arsenic and toluene have been the most studied ones [130-131]. New ones also appear, such as manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane, tetrachloroethylene and polybrominated diphenyl ethers [132]. Lead is probably the metal that has raised more discussion nowadays due to its content in fish and whether it is beneficial or not to consume during pregnancy with no consensus; given that it has high levels of essential fatty acids [133]. Prematurity and Other Obstetric Factors Preterm newborn babies have a higher risk of suffering development disorders and among them, the most prevalent are ADHD, with rates of up to 4 times more than term newborn babies [134], mainly the inattentive subtype [135]. It is thought that brain inflammatory processes are involved in the later development of attention problems, so the application of measures orientated to decrease the inflammation as a preventive measure is suggested for the later development of inattention symptoms [136]. Prenatal interventions in preterm mothers with corticoid, antibiotics or magnesium sulphate have not received any positive results in reducing inattentive symptoms. Maternal obesity may have an inflammatory role in the newborn and therefore weight loss programmes during pregnancy should be initiated in order to decrease inattention symptoms [137]. Other obstetric factors, such as having had an induced delivery have been related with ADHD [138] and in the last few years it is wining popularity between in vitro fertilization and ADHD, where the combination of biological and emotional factors need to be studied. Other Factors ―Everything is possible under Florida‘s Sun.‖ There is a low prevalence rate for ADHD in very sunny areas, being related with the circadian rhythms in ADHD [139] and the role that melatonin plays in the control of sleep troubles in ADHD.

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It has also been related with the appearance of eczemas in the breastfed babies with the later appearance of ADHD in a possible relationship by the liberation of cytokines in that pathology and its inflammatory role that would predispose to ADHD. Treating the eczema we could avoid ADHD and this could be considered primary prevention [140].

Conclusion The list of possibilities associated with ADHD in the field of prevention can be very long. There are many actions that have focused towards the tertiary role of prevention, namely to minimize evolutionary risks that imply ADHD, focused on minimizing comorbidities and psychosocial risks. Some actions are getting acceptance for early screening and the greater knowledge of ADHD in general and in school population, such as the PANDAH programme, carried out in Spain. However, those actions orientated to a true Primary Prevention are scarce. Those actions that are directed to reduce ADHD incidence should preferably approach perinatal aspects in the first years of life of higher risk populations.

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[127] Pérez Ruiz JM, IribarIbabe MC, Peinado Herreros JM, Miranda León MT, Campoy Folgoso C. Breastfeeding and cognitive development; interference evaluation by "5 digits test." Nutr Hosp 2014; 29: 852-857. [128] Sabuncuoglu O, Orengul C, Bikmazer A, Kaynar SY. Breastfeeding and parafunctional oral habits in children with and without attention-deficit/hyperactivity disorder. Breastfeed Med 2014; 9: 244-250. [129] Holz NE, Boecker R, Baumeister S, Hohm E, Zohsel K, Buchmann AF, Blomeyer D, Jennen-Steinmetz C, Hohmann S, Wolf I, Plichta MM, Meyer-Lindenberg A, Banaschewski T, Brandeis D, Laucht M. Effect of prenatal exposure to tobacco smoke on inhibitory control: neuroimaging results from a 25-year prospective study. JAMA Psychiatry 2014; 71: 786-796. [130] Kim S, Arora M, Fernandez C, Landero J, Caruso J, Chen A. Lead, mercury, and cadmium exposure and attention deficit hyperactivity disorder in children. Environ Res 2013; 126: 105-110. [131] Chopra V, Harley K, Lahiff M, Eskenazi B. Association between phthalates and attention deficit disorder and learning disability in U.S. children, 6-15 years. Environ Res 2014; 128: 64-69. [132] Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol 2014; 13: 330-338. [133] Sagiv SK, Thurston SW, Bellinger DC, Amarasiriwardena C, Korrick SA. Prenatal exposure to mercury and fish consumption during pregnancy and attentiondeficit/hyperactivity disorder-related behavior in children. Arch Pediatr Adolesc Med 2012; 166: 1123-1131. [134] Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Psychiatric disorders in extremely preterm children: longitudinal finding at age 11 years in the EPICure study. J Am Acad Child Adolesc Psychiatry 2010; 49: 453-463. [135] Anderson, PJ, De Luca C R, Hutchinson E, Spencer-Smith M, Roberts G, Doyle L W. Attention problems in a representative sample of extremely preterm/extremely low birth weight children. Dev Neuropsychol 2011; 36: 57-73. [136] O'Shea TM, Downey LC, Kuban KK. Extreme prematurity and attention deficit: epidemiology and prevention. Front Hum Neurosci 2013; 7: 578. [137] Leibowitz KL, Moore RH, Ahima RS, Stunkard AJ, Stallings VA, Berkowitz RI, Chittams JL, Faith MS, Stettler N. Maternal obesity associated with inflammation in their children. World J Pediatr 2012; 8: 76-79. [138] Silva D, Colvin L, Hagemann E, Bower C. Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics 2014; 133: e14-22. doi: 10.1542/peds.2013-1434. Epub 2013 Dec 2 [139] Arns M, van der Heijden KB, Arnold LE, Kenemans JL. Geographic variation in the prevalence of attention-deficit/hyperactivity disorder: the sunny perspective. Biol Psychiatry 2013; 74: 585-590. [140] Buske-Kirschbaum A, Schmitt J, Plessow F, Romanos M, Weidinger S, Roessner V. Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. Psychoneuroendocrinology 2013; 38: 12-23.

Index # 10q24, 84, 191 20th century, 14, 15

α α2-adrenergic agonists, ix

A Abraham, 242 abuse, ix, 23, 37, 141, 160, 168, 169, 171, 172, 240, 285, 292, 295, 304, 305, 306, 308, 310, 313, 314, 315, 316, 317, 325, 360, 361, 371, 372 academic performance, 47, 48, 51, 56, 66, 282, 330, 331, 345, 351 academic progress, 2, 30 access, 51, 56, 305 accounting, 15, 75, 81, 129 acetaminophen, 237 acetic acid, 169 acetylation, 148, 188 acetylcholine, 115, 125, 181, 221, 248 acid, 85, 131, 142, 150, 153, 154, 164, 166, 168, 184, 185, 236, 249, 295, 297, 366 acquisition of knowledge, 350 action potential, 101 active compound, 305 activity level, 29, 333 adaptability, 50 adaptation, 47, 340, 363 adaptive functioning, 285, 286, 290 ADD syndrome, vii additives, 154, 355, 364 adenoma, 88

adenosine, 114, 142, 181, 225 ADH, 153, 188 adhesion, 84, 87, 90, 112, 119, 120, 129, 130, 143 adiponectin, 112, 166, 224, 242 adipose, 31 adipose tissue, 31 adjunctive therapy, 14, 173, 246 adjustment, 2, 4, 5, 6, 23, 50, 56, 92, 152, 318, 331, 350 adolescent boys, 99 ADR, 167, 168 adrenal gland, 193 adrenal insufficiency, 133, 232 adrenaline, 31, 32 adrenoceptors, 246 adulthood, vii, 15, 22, 24, 25, 26, 29, 37, 40, 66, 67, 70, 80, 98, 127, 168, 205, 225, 229, 252, 257, 259, 261, 272, 274, 277, 281, 282, 283, 292, 314, 355, 356, 358, 359, 360, 361, 362, 363, 364, 370, 371, 373 advancement, 168 adverse effects, 154, 173, 177, 181, 184, 185, 186, 253, 304, 306, 321, 323, 328 adverse event, 166, 169, 171, 172, 173, 174, 175, 176, 179, 180, 181, 296, 314, 318, 320, 321, 323 aetiology, 2, 214, 357, 366 affective disorder, 40, 86, 102, 110 Africa, 189, 302 African Americans, 157 African-American, 130, 193 aggregation, 81, 363 aggression, 99, 108, 153, 176, 177, 247, 285, 286, 373 aggressive behavior, 124, 151 aggressiveness, 50, 336, 340, 341, 342, 345, 349, 362 agonist, 102, 146, 164, 173, 175, 178, 179, 180, 181, 243, 248

382

Index

agoraphobia, 32, 80 air pollutants, 155 albumin, 145 albuminuria, 167 alcohol consumption, 157 alcohol dependence, 86, 87, 110, 207, 224, 285 alcohol use, 156, 157, 161, 168, 239 alcoholism, 129 alertness, 114, 151 algorithm, 14, 20, 240 allele, 89, 91, 92, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 115, 119, 120, 129, 130, 131, 149, 157, 192, 193, 200, 202, 203, 217, 218, 226, 239, 252, 262, 263 allergy, 65, 82, 215 alpha activity, 72 ALS, 260 alternative treatments, 205 alters, 217, 218, 233, 243 American Psychiatric Association, vii, 2, 17, 25, 35, 58, 288, 351, 368 American Psychological Association, 353, 354 AMF, 296 amine(s), 99, 129,197, 198, 199, 230, 314, 316 amino, 77, 85, 92, 94, 142, 164, 166, 194, 221, 294, 297 amino acid(s), 77, 85, 92, 94, 142, 194, 221, 294, 297 amphetamine(s), 4, 5, 6, 92, 94, 111, 142, 147, 150, 160, 161, 162, 163, 164, 168, 170, 172, 194, 195, 200, 201, 241, 244, 291, 292, 293, 294, 295, 297, 304, 305, 306, 317, 360 amplitude, 69, 149, 186 amygdala, 139, 147, 165, 234 amyotrophic lateral sclerosis, 260 anatomy, viii, 256, 258 anger, 51, 95, 329, 340, 341, 342, 353, 373 angiotensin II, 145 anisotropy, 67, 68, 98, 202, 258 annual rate, 23 anorexia, 82, 84, 86, 320 anorexia nervosa, 84 antagonism, 142, 149, 181 anterior cingulate cortex, 66, 142, 263 antidepressant(s), ix, 74, 110, 150, 152, 179, 188, 237, 247, 313, 314, 315, 317, 318, 320, 328, 371 antigen, 130 antioxidant, 168, 185 antipsychotic, 19, 176, 177, 209, 246, 247, 248 antipsychotic drugs, 19, 209 antisense, 109 antisocial behavior, 71, 72, 86, 98, 152, 353 antisocial personality, 23, 66, 156, 362

antisocial personality disorder, 23, 66, 156, 362 anxiety disorder, 21, 23, 47, 49, 64, 66, 74, 80, 89, 90, 96, 100, 126, 250, 282, 318, 330, 370 APA, 2, 25, 35, 39, 40, 351 aphasia, 137 apoptosis, 75, 109, 111, 122, 165, 242 appetite, 166, 169, 171, 172, 180, 181, 182, 242, 296, 301, 304, 314 Argentina, 271, 273, 302 aripiprazole, 177, 183 arithmetic, 51, 56 aromatic hydrocarbons, 155 arousal, 114, 140 arrest(s), 75, 292, 373 arrhythmia, 175 arsenic, 84, 151, 236, 367 aryl hydrocarbon receptor, 113 Asia, 19, 206, 302 aspartate, 148, 164, 166, 204 assessment, vii, 3, 13, 33, 36, 39, 45, 47, 48, 49, 51, 52, 53, 54, 55, 57, 58, 59, 60, 62, 65, 82, 125, 126, 174, 205, 239, 258, 307, 311, 325, 326, 329, 330, 335, 339, 341, 346, 350, 368 assessment tools, vii, 3 asthma, 84, 135, 153 asymmetry, 72, 113, 208 ataxia, 82, 84, 85, 112, 150 athletes, 363, 374 atmosphere, 343 atomoxetine, ix, 3, 4, 5, 6, 14, 15, 64, 98, 105, 130, 141, 146, 160, 161, 162, 164, 167, 171, 172, 173, 181, 182, 195, 199, 204, 222, 235, 241, 242, 243, 244, 245, 253, 254, 293, 307, 313, 314, 315, 316, 317, 318, 319, 322, 325, 326, 361 atopic eczema, 377 ATP, 192, 193, 251 atrophy, 175 attachment, 103, 105, 204 Attention Deficit Hyperactivity Disorder, i, iii, vi, 17, 19, 20, 37, 39, 41, 60, 207, 212, 225, 242, 248, 250, 272, 281, 282, 289, 291, 293, 307, 313, 318, 324, 370 Attention Deficit/Hyperactivity Disorder, 56, 210, 237, 238 Attention-Deficit/Hyperactivity Disorder, v, 18, 19, 21, 22, 26, 27, 61, 62, 63, 207, 208, 219, 224, 235, 247, 249, 257, 288, 309, 311, 327, 351, 352, 369 attitudes, 35, 240 Austria, 302 authority, 47, 51, 56 autobiographical memory, 260 autonomic neuropathy, 87

Index autonomy, 363 autosomal dominant, 233 autosomal recessive, 84 awareness, 17, 53, 342, 350, 359 axons, 147

B BAC, 134 background noise, 260 bacteremia, 65 bacterial artificial chromosome, 134 Bahrain, 302 banks, 340 Barbados, 302 barriers, 251 basal ganglia, 66, 141, 178, 234, 256, 259, 265, 285, 286 base, 75, 91, 101, 209 base pair, 75, 91 basic research, 14, 352 BBB, 193, 194, 195 BED, 170 behavior modification, 352 behavior therapy, 353 behavioral change, 82 behavioral dimension, 200 behavioral disorders, 84, 86, 153, 272 behavioral problems, 99, 112, 121, 125, 135, 165 behavioral sensitization, 243 behaviors, 33, 71, 77, 95, 101, 105, 108, 109, 125, 127, 129, 145, 148, 149, 150, 151, 214, 224, 230, 236, 242, 249, 281, 282, 293, 319, 369 behavioural techniques, 330, 332, 336, 339, 340, 342, 350, 361 Belgium, 302 beneficial effect, 140, 184, 185, 187, 293 benefits, 30, 245, 304, 305, 330, 339 benign, 79, 85 bias, 4, 97 bibliometry, 2 bilateral, 67, 159, 182 bilirubin, 159, 235 bioavailability, 310 biofeedback, 187 bioinformatics, 139 biological markers, 269 biological processes, 125 biological systems, 261 biomarkers, ix, 34, 65, 140, 205, 207, 256, 265, 277 biomedical knowledge, 255 biomolecules, 166

383

bipolar disorder, 14, 47, 48, 73, 78, 81, 88, 89, 90, 92, 94, 101, 102, 104, 105, 111, 118, 124, 137, 142, 148, 156, 176, 184, 213, 222, 224, 330, 366 birth weight, 128, 158, 239, 240, 364, 377 blame, 256 blood, 30, 31, 32, 33, 34, 89, 94, 96, 100, 104, 110, 121, 145, 151, 152, 157, 162, 167, 168, 170, 171, 172, 180, 181, 183, 193, 237, 251, 259, 260, 262, 269, 297, 298, 319, 320 blood flow, 259, 262, 269 blood group, 89 blood pressure, 145, 162, 167, 170, 171, 172, 180, 319, 320 blood-brain barrier, 251 body mass index (BMI), 120, 143, 166, 167, 170 body weight, 166 Bolivia, 302 bonding, 366 bone, 126, 136, 143, 234 bone age, 126 bone mineral content, 143 borderline personality disorder, 80, 214, 370 boredom, 349 Botswana, 302 brachydactyly, 131 brain abnormalities, 209, 268 brain activity, 71, 95, 218, 256 brain asymmetry, 72, 210, 258 brain damage, 36, 40, 54, 287, 288 brain functioning, 70 brain functions, 103, 261 brain structure, 182, 209, 256, 265 brain tumor, 82 branching, 258 Brazil, 16, 26, 94, 302 breast cancer, 192 breast milk, 154 breastfeeding, 366 breathing, 362 breeding, 144 brothers, 82, 133, 134 buffalo, 31 building blocks, 366 bulimia, 84, 320 bulimia nervosa, 84 bupropion, ix, 3, 179, 247, 313, 314, 317, 318, 320, 322, 326 buttons, 54

C Ca2+, 76 CAD, 130

384 cadmium, 377 caesarean section, 239 caffeine, 32, 37, 181, 248, 357 calcium, 101, 105, 143, 151, 175 campaigns, 357 cancer, 101, 129 candidates, 100, 115, 117, 125, 133, 139, 264 cannabis, 360 capsule, 150, 258, 259, 300, 301, 302, 304 car accidents, 2 carbonyl groups, 168 carboxyl, 302 carboxylic acid, 154 carcinogenesis, 84 carcinoma, 88 cardiac autonomic function, 162 cardiovascular disease(s), 80 cardiovascular disorders, 314 cardiovascular function, 117, 183, 248 cardiovascular risk, 167, 243 cardiovascular system, 179 cascades, 187 case study, 212 catalytic activity, 93 cataplexy, 131 cataract, 123 catecholamines, 140, 163, 197 cation, 88, 93, 109, 251 Caucasians, 95, 193, 251 causal attribution, 339 causal relationship, 23 causality, 112, 264 causation, 74, 75, 261 cell cycle, 75 cell division, 90, 125, 129 cell line(s), 79, 104, 107, 222, 251 cell surface, 92, 94 central nervous system (CNS), 93, 103, 106, 125, 129, 145, 186, 203, 209, 264, 315, 375 cerebellum, 66, 77, 165, 208, 255, 259, 260, 262 cerebral blood flow, 268, 269 cerebral cortex, 196, 197, 257 cerebral hemisphere, 82, 113 cerebral palsy, 36, 158, 376 cerebrospinal fluid, 104, 251 cerebrum, 66 challenges, 17, 292, 307, 355, 364 changing environment, 54 chemical(s), 140, 189, 261, 293, 295, 357, 367 Chicago, 82 child abuse, 36 Child Behavior Checklist, 48, 59, 155 child development, 283

Index child rearing, 365 childhood disorders, 63, 353 childhood history, 214 Chile, 301, 302 China, 11, 12, 16, 103, 151, 160, 205, 206, 302 Chinese medicine, 184, 186, 249, 250 chiral center, 295 chirality, 309 cholesterol, 167, 188, 193 chromosome, 75, 77, 82, 115, 120, 121, 122, 123, 124, 128, 130, 131, 132, 135, 137, 227, 228 chromosome 10, 75, 132 cigarette smoke, 151 cigarette smoking, 372 cingulate region, 257 circadian rhythm(s), 66, 132, 211, 367 circulation, 295 cirrhosis, 320 classes, 129, 152, 192, 296, 345 classification, 19, 40, 41 classroom, 43, 45, 50, 52, 311, 330, 345, 346, 347, 348, 349, 350, 351, 354 classroom programmes, 330 cleavage, 169 cleft lip, 136 cleft palate, 124 clients, 29 clinical assessment, 33, 34, 61, 277 clinical diagnosis, 30, 34, 51, 124, 265 clinical presentation, 23, 116, 124 clinical symptoms, 31, 265, 363 clinical trials, 3, 171, 172, 177, 185, 245, 297, 313, 314, 321 cloning, 77, 213 clozapine, 177 cluster of differentiation, 113 clusters, 68, 73, 192 CNS, 18, 26, 37, 90, 111, 118, 119, 167, 188, 193, 205, 209, 234, 241, 243, 244, 245, 249, 277, 290, 307, 308, 311, 320, 324, 326, 370 cocaine, 88, 142, 151, 164, 178, 242, 360 coding, 77, 91, 92, 93, 95, 97, 113, 120, 123, 130, 188, 203, 204, 217, 218, 219 codon, 77 cognition, 102, 117, 143, 146, 148, 163, 164, 175, 181, 184, 205, 222, 246, 249, 261, 278, 287, 364 cognitive abilities, 53, 335, 361, 365 cognitive associations, 257 cognitive deficit(s), ix, 66, 97, 102, 106, 108, 111, 123, 221, 272 cognitive development, viii, 138, 185, 351, 377 cognitive dysfunction, 223 cognitive flexibility, 46, 53, 55, 101

Index cognitive function, 46, 58, 74, 90, 112, 118, 133, 146, 181, 223, 329 cognitive impairment, viii, 44, 65, 133, 144, 180, 207, 214, 271, 272, 273, 274, 275, 277, 278 cognitive level, 313, 314 cognitive performance, 146 cognitive process, 45, 336, 341 cognitive skills, 336, 350 cognitive tasks, 66, 164, 264 cognitive techniques, 329, 330, 336, 340 cognitive testing, 135 cognitive therapy, 187 coherence, 67, 73 coherence measures, 73 collaboration, 346 collateral, 33 college students, 59, 60, 161, 240, 310 combination therapy, 182, 319 combined effect, 248, 351 combustion, 155 commercial, 144 common symptoms, 82, 101 communication, 343 community, 25, 27, 60, 76, 183, 237, 323, 346, 357 comorbidity, 21, 23, 25, 39, 58, 63, 72, 74, 78, 80, 81, 94, 98, 105, 108, 144, 160, 178, 212, 213, 214, 260, 263, 269, 277, 278, 285, 286, 314, 327, 330, 344, 350, 351, 356, 358, 359, 360, 361, 364, 375, 377 compensation, 182 complement, 58 complexity, 55, 261, 263 compliance, 127, 292, 304, 311 complications, 36, 88, 182, 194, 338, 359, 375 composition, 301 compounds, 129, 154, 193, 262 comprehension, 42 compulsion, 207 computed tomography, 93, 217 computer, 52, 53, 54, 58, 325 concordance, 75 conditioning, 147, 148, 149 conduct disorder, 18, 23, 51, 66, 74, 81, 99, 122, 156, 176, 177, 182, 239, 247, 269, 282, 285, 359, 361, 362, 363, 371, 372 conductive hearing loss, 136 conference, 3 conflict, 33, 338, 342 conflict resolution, 33 confounders, 156 congenital heart disease, 121, 122, 126, 136, 137, 229 congenital malformations, 121, 122, 124

385

congestive heart failure, 83 conjugation, 188 connectivity, 67, 68, 70, 98, 124, 140, 144, 147, 150, 164, 165, 202, 208, 219, 242, 252, 255, 256, 258, 259, 260, 261, 262, 264, 265, 267, 268, 269 connectivity patterns, 67 consanguinity, 143 consciousness, 40, 363 consensus, 19, 20, 36, 39, 193, 269, 272, 278, 286, 288, 308, 331, 367, 371 constipation, 112, 171, 321, 322 construction, 192 consumption, 5, 6, 8, 15, 157, 377 contamination, 367 contingency, 334, 335, 343, 344, 350 continuous performance tests, 53 control group, 93, 100, 113, 116, 145, 166, 187, 271, 276, 284 controlled studies, 172, 178 controlled trials, 171, 174, 178, 184, 245, 247, 250, 319, 321, 326, 328, 365 controversial, 29, 93, 156, 182, 359, 364 controversies, 29, 278 convergence, 205, 264 cooperation, 346 coordination, 40, 69, 148, 150, 208, 283, 345 coping strategies, 23, 363 coronary artery disease, 88 coronary artery spasm, 88 coronary heart disease, 86 corpus callosum, 66, 67, 259 correlation(s), 2, 6, 12, 15, 16, 73, 94, 97, 99, 101, 102, 103, 114, 118, 131, 143, 144, 153, 157, 165, 186, 235, 258, 259, 260, 261, 263, 276 correlation coefficient, 2, 6 cortex, 66, 67, 68, 69, 109, 127, 144, 147, 164, 165, 175, 178, 242, 257, 260, 261, 263, 264, 265, 266, 267, 316 cortical asymmetry, 266 cortical neurons, 79, 148 corticosteroids, 186 cortisol, 31, 165, 186 cost, 2, 48, 151, 304, 332, 333, 334, 342, 343, 347 Costa Rica, 302 covering, 5, 18, 39, 50 CpG sites, 82 CPT(s), 53, 54, 57, 60, 99, 100, 104, 155, 183, 186 criminal acts, vii criminality, 23, 127, 129, 283, 362, 373 criticism, 338 Croatia, 302 cross-sectional study, 160, 210, 240 CSF, 131

386

Index

CST, 166 cues, 55, 348 curriculum, 346, 348 Cyprus, 302 cytochrome, 165, 171, 188 cytokines, 368 cytokinesis, 129 cytoplasmic tail, 147 Czech Republic, 302

D dark matter, 233 data set, 180 database, 3, 4, 12, 32, 139, 166, 189, 245, 251, 271, 274, 289 DBP, 155 deaths, 283 decay, 116 defects, 61, 63, 87, 112, 124, 126, 131, 150, 205, 260, 261 defence, 37 deficiency(s), 40, 84, 85, 87, 100, 128, 131, 132, 143, 149, 151, 162, 184, 211, 231, 234, 366 degenerative dementia, 272, 277 degradation, 99 DEHP, 154, 155 delinquency, 353 delinquent behavior, 72, 151, 209 Delta, 182 delusions, 48 delusions of grandeur, 48 dementia, 192, 251, 260, 271, 272, 274, 276, 278 demographic factors, 287, 288 dendrites, 175 dendritic spines, 140, 246 Denmark, 161, 167, 232, 302 depolarization, 94 depressive symptoms, 68 deprivation, 369 depth, 363 derivatives, 189 desensitization, 317 desorption, 153 destruction, 172 detectable, 79, 154 detection, 21, 32, 65, 138, 154, 310 deterrence, 305 developing brain, 70, 151, 257, 287 developmental change, 363, 374 developmental disorder, 29, 39, 40, 73, 74, 78, 151, 185, 212, 213, 326 developmental dyslexia, 68, 208

developmental process, 355 developmental psychology, 375 deviation, 68 diabetes, 88 Diagnostic and Statistical Manual of Mental Disorders, viii, 288 diagnostic criteria, vii, viii, 2, 14, 21, 24, 25, 30, 39, 47, 51, 52, 82, 126 diaphragmatic hernia, 124 diarrhea, 30 diastolic blood pressure, 172 dibenzo-p-dioxins, 154 diet, 355, 364, 366 dietary intake, 185, 249 differential diagnosis, 30, 34, 48, 57, 358 diffusion, 10, 14, 17, 68, 184, 207, 256, 259, 266, 302, 303, 360 diffusivity, 67, 68, 95 dimensionality, 97 direct action, 197 direct observation, 58 disability, 2, 73, 75, 82, 109, 112, 116, 120, 121, 122, 123, 124, 127, 128, 130, 131, 132, 133, 134, 135, 136, 137, 147, 154, 185, 225, 228, 230, 283, 285, 286, 287, 319, 377 discharges, 72, 73, 209, 210 discrimination, vii diseases, vii, viii, 2, 75, 83, 84, 86, 88, 103, 111, 116, 118, 119, 128, 129, 130, 138, 184, 193, 250, 314, 357, 358 disequilibrium, 98, 107, 113, 117, 118, 203 dispersion, 156 disposition, 193, 251, 309, 363 disruptive behaviours, 335, 344, 348, 350, 362, 365 dissociation, 146 dissociative identity disorder, 33 distress, 64, 136, 369, 374 distribution, 3, 10, 12, 13, 31, 72, 95, 98, 103, 154, 179, 289, 350, 367 diversity, 47 dizygotic, 75, 263 dizygotic twins, 263 dizziness, 171, 175, 180 DNA, 75, 76, 82, 91, 106, 110, 115, 118, 138, 139, 204, 212, 223, 225, 233 DNA sequencing, 110 docosahexaenoic acid, 184, 185 dominance, 52 Dominican Republic, 302 dopaminergic, ix, 63, 89, 92, 93, 94, 96, 99, 104, 105, 111, 128, 129, 141, 142, 148, 149, 158, 198, 211, 219, 224, 243, 257, 262, 263, 316 dorsolateral prefrontal cortex, 67, 99, 111, 260

Index dosage, 107, 119, 132, 136, 137, 186, 205, 223, 293, 297, 298, 302, 303, 304, 306, 310, 317 dose-response relationship, 151, 162 dosing, 160, 163, 171, 178, 181, 292, 297, 305, 311, 325 DOT, 303 double-blind trial, 260, 319 Down syndrome, 81 down-regulation, 108, 146 draft, 325 drawing, 52 DRD4 gene, 96, 218 Drosophila, 85, 112 drug abuse, 104, 156, 361 drug delivery, 296, 304, 305, 309, 311, 312 drug dependence, 32, 166 drug discovery, 168, 233 drug efflux, 203 drug interaction, 168, 174, 192, 251, 305 drug metabolism, 187, 188, 192 drug reactions, 162, 166, 203, 205 drug resistance, 193 drug seeking behavior, 165 drug therapy, 313, 314 drug treatment, viii, 18, 35, 96, 138, 161, 162, 172, 240, 258, 319 drug use, 26, 152, 161, 215, 237, 263, 283, 288, 306, 310, 355, 361, 372 DSM, viii, 30, 34, 40, 42, 43, 44, 45, 47, 110 DSM-IV-TR, 42, 43, 44, 47, 50 DTI, 255, 256, 258, 259, 260 dyslexia, 68, 79, 214 dyslipidemia, 176 dysmenorrhea, 171 dyspepsia, 171 dystonia, 85, 88, 128

E East Asia, 95 eating disorders, 81, 214, 362 ECG, 175, 246 Ecuador, 302 eczema, 368 EDAH, viii, 25 editors, vii education, 45, 81, 103, 274, 275, 276, 348 educational attainment, 292 educational background, 47 educators, 45 EEG, ix, 36, 70, 71, 72, 73, 82, 106, 123, 159, 164, 187, 209, 210, 240, 250, 327 EEG patterns, 123, 164

387

effluents, 367 efflux transporters, 192 egg, 82 Egypt, 215, 302 eicosapentaenoic acid, 184 El Salvador, 302 elaboration, 147 electrodes, 72, 187 electroencephalogram, 187 electroencephalography, 70 electromagnetic, 187 electron(s), 146, 262 elementary school, 353 elucidation, viii, 69 emergency, 164, 177, 283 emission, 93, 217, 268 emotion, 55, 57, 67, 80, 96, 140, 164, 175, 214, 219, 376 emotion regulation, 67 emotional disorder, 82 emotional functioning, vii emotional health, 282 emotional problems, 138, 236, 376 emotional responses, 140, 341 emotional stimuli, 96 emotionality, 101, 221, 369 empathy, 49 enantiomers, 294, 295, 304, 309 encephalitis, 31 encoding, 75, 96, 101, 113, 116, 117, 130, 263 encopresis, 47, 74, 164, 242 endocrine, 138, 153, 154, 162, 205 endocrinology, 162, 223 endophenotypes, 66 endothelial cells, 192 endurance, 170 energy, 51, 56, 153, 193, 237 enlargement, 66, 135 enuresis, 47, 74, 79, 320 environment(s), 39, 45, 47, 48, 49, 51, 95, 101, 140, 146, 148, 151, 159, 225, 236, 292, 329, 331, 337, 342, 343, 347, 348, 356, 357, 358, 362, 367, 369, 375 environmental conditions, 90 environmental effects, 139 environmental factors, 63, 64, 75, 95, 114, 135, 138, 139, 150, 205, 264 environmental influences, 149, 157, 239 environmental tobacco, 156, 238 enzymatic activity, 98, 148 enzyme(s), 96, 99, 101, 110, 113, 130, 136, 140, 157, 180, 187, 188, 189, 191, 192, 194, 203, 251, 296, 306, 316, 317, 319, 320, 322, 323

388

Index

EPA, 184, 366 epidemiologic, 358, 374 epidemiology, 17, 24, 26, 377 epigenetic modification, 138 epigenetics, 233 Epigenomics, 138, 233 epilepsy, 4, 66, 73, 78, 87, 88, 109, 117, 121, 122, 123, 125, 128, 129, 131, 134, 135, 148, 167, 189, 190, 191, 213, 228, 250, 293 equipment, 58 erythrocyte membranes, 184 essential fatty acids, 355, 357, 364, 366, 367 ester, 295 Estonia, 302 ethanol, 168, 243 ethnic background, 131 ethnic groups, 108 ethnicity, 95, 111 etiology, 74, 76, 77, 80, 90, 91, 95, 99, 101, 120, 124, 137, 145, 147, 148, 219, 255, 256 eukaryotic, 76 euphoria, 48, 168, 204, 297, 315 Europe, 22, 169, 173, 189, 299, 302 event-related potential, 35, 223 everyday life, 55 evolution, 3, 5, 6, 8, 13, 17, 133, 258, 297, 350, 360 examinations, 34, 359 excitability, 41, 102, 141, 142, 164, 263, 269 excitation, 51, 142, 146, 316 excitatory synapses, 132, 145, 146 excretion, 194 executive function(s), 39, 46, 53, 55, 59, 61, 62, 68, 69, 81, 114, 140, 143, 158, 170, 171, 181, 208, 244, 248, 260, 282, 284, 289, 315, 326, 350, 363, 364, 365, 368, 375 executive functioning, 56, 59, 170, 181, 282, 284, 289 exercise, 184, 249, 365, 375 exocytosis, 103, 166 exons, 77, 110, 112, 128, 188, 191, 192 exposure, 31, 106, 114, 138, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159, 161, 167, 168, 171, 174, 175, 178, 233, 236, 237, 238, 239, 243, 275, 283, 301, 305, 356, 357, 358, 361, 364, 377 externalizing behavior, 26, 71, 157, 209, 238 externalizing disorders, 66, 79, 207 extinction, 332, 333, 342, 343, 347 extracellular matrix, 90 extraction, 304, 305, 367 extraversion, 114 extrovert, 32

F facies, 82 faecal incontinence, 79 failure to thrive, 132 families, 55, 75, 87, 108, 109, 112, 120, 121, 128, 132, 133, 137, 140, 194, 226, 239, 281, 282, 284, 287, 330, 343, 358 family environment, 45, 57, 59, 329, 331, 342, 343 family factors, 362 family functioning, 59, 285, 326 family history, 49, 157, 239, 284, 285, 286, 327 family life, 24 family members, 129, 135, 137, 146 family relationships, 22 family studies, 77 fat, 179 fatty acids, 37, 184, 185, 193, 206, 249, 366, 376 FDA approval, 14 fear, 49, 50, 56, 95, 148, 149, 218, 236 feelings, 41, 43, 48, 103, 340 female rat, 23, 64, 75 ferritin, 143 fertilization, 367 fetal growth, 139 fetus, 157, 233 fever, 34, 86, 153 fiber(s), 256, 258, 259 financial, 362 financial resources, 362 Finland, 302 fish, 184, 367, 377 fish oil, 184 fitness, 375 flexibility, 101 flight, 33, 261 fluctuations, 69, 73, 260, 267, 268 fluid, 158, 239 fluid intelligence, 158, 239 fluoxetine, 110, 178, 183, 247 fMRI, 159, 175, 177, 240, 246, 255, 259, 261, 263, 267, 268 focal seizure, 78, 137 folate, 108, 193, 223, 369 follicle, 135 follicle stimulating hormone, 135 food, 65, 82, 184, 215, 304, 358, 362, 364 Food and Drug Administration (FDA), 14, 72, 160, 163, 168, 171, 303 force, 269 Ford, 206 formation, 75, 123, 258, 302 formula, 295, 298, 310, 366

Index frameshift mutation, 112, 132 France, 11, 12, 16, 23, 26, 301, 302 freezing, 315 frontal cortex, 66, 69, 109, 111, 178, 202, 208, 260 frontal lobe, 19, 31, 36, 61, 84, 178, 262 functional architecture, 67, 208 functional imaging, 66, 262 functional MRI, 256 fusion, 77, 105, 213

G GABA, 75, 76, 142, 234 gait, 112 galenic formulations, 291 ganglion, 262 gender differences, 23 gender factors, 21, 25 gene expression, 92, 115, 138, 139, 145, 192, 202, 204, 217, 233, 235, 253 gene regulation, 178, 231, 247 general intelligence, 49 generalized anxiety disorder, 37, 64, 80, 82, 214 Generalized Anxiety Disorder, 32, 80 generalized seizures, 78 genetic background, 89, 107, 144 genetic components, 90, 106, 216 genetic defect, 75, 118, 205 genetic factors, vii, 75, 81, 105, 357 genetic linkage, 79 genetic load, 90, 359 genetic marker, 92, 200 genetic predisposition, 70 genetic screening, 65 genetic studies, viii, 116, 205, 370 genetic syndromes, 131 genetic testing, 125 genetics, 14, 17, 117, 138, 145, 212, 215, 216, 226, 233, 264, 269, 369 genome, 73, 75, 79, 82, 83, 89, 90, 100, 105, 110, 115, 118, 119, 120, 122, 124, 127, 129, 138, 141, 168, 202, 205, 211, 214, 215, 216, 227, 233, 264 genomics, viii, 217 Genomics, v, 63, 73, 83, 90, 206, 209, 210, 235, 251 genotype, 70, 73, 90, 93, 94, 96, 99, 100, 101, 102, 103, 104, 106, 114, 115, 117, 120, 155, 160, 176, 200, 201, 202, 203, 204, 217, 219, 220, 221, 222, 227, 252, 253, 263, 264 genotyping, 91, 95, 96, 206, 251, 264 germ cells, 157 Germany, 2, 10, 11, 12, 16, 79, 293, 302, 325, 352 gestation, 158 gestational age, 128

389

gestational diabetes, 357, 369 ginseng, 186, 250 glaucoma, 129, 314, 319 glia, 111, 148, 224 glial cells, 257 glioma, 137 globus, 69, 147, 286 glucocorticoid, 139, 158 glucocorticoid receptor, 158 glucose, 93, 262 glutamate, 100, 119, 120, 125, 142, 146, 148, 164, 166, 194, 202, 221, 226, 237, 242, 253 glutathione, 188 graph, 11 gray matter, 64, 107, 175, 208, 256, 258, 259, 265 Greece, 302 gross domestic product (GDP), 2, 4, 11, 12 group activities, 338 growth, 2, 3, 4, 6, 13, 15, 31, 36, 68, 87, 111, 116, 123, 137, 159, 160, 162, 164, 183, 241, 307, 365, 366 growth factor, 87, 164, 365 growth hormone, 31, 36, 162, 241 growth rate, 2, 4, 6 GTPases, 129 guanine, 129 Guatemala, 302 guidance, 371 guidelines, ix, 17, 34, 58, 65, 172, 207, 292, 293, 308, 313, 317, 323, 325, 329, 344, 345, 348, 359, 370, 371

H habitat, 138, 359 habituation, 243, 347 hair, 151, 236 half-life, 163, 204, 297, 300 hallucinations, 171 haplotypes, 99, 106, 109, 110, 117, 200 harbors, 75 harmful effects, 81 harmony, 346 hazards, 160 head injuries, 283 head injury, 283, 287, 288, 289, 290 headache, 82, 169, 171, 173, 174, 180, 185, 319, 320, 321, 323 health, vii, 2, 4, 10, 11, 12, 16, 22, 41, 47, 62, 126, 152, 153, 160, 161, 162, 176, 184, 205, 234, 237, 249, 273, 281, 282, 310, 346, 353, 357, 358, 366 health care, 126, 161, 176 health care costs, 176

390

Index

health expenditure, 12, 16 health problems, 153, 281, 282, 366 health services, 273 hearing impairment, 86 hearing loss, 137 heart disease, 121, 227, 321 heart rate (HR), 162, 167, 171, 172, 175, 182, 243 heavy metals, 151, 357, 358, 367 height, 135, 162, 168, 170, 171, 232, 243 hemiplegia, 133, 232 hemoglobin, 143, 164 hepatitis, 167 hepatitis a, 167 hepatocytes, 191 heritability, viii, 24, 90, 91, 157, 263, 277 heroin, 151 herpes, 31 heterogeneity, 71, 79, 89, 97, 116, 145, 200, 216, 278, 357 heterozygote, 149 high blood pressure, 323, 364 high school, 161 hippocampus, 68, 77, 109, 110, 147, 148, 158, 165, 204, 208 histamine, 188 histone, 138, 148, 236 history, 32, 33, 47, 65, 96, 118, 123, 124, 125, 134, 141, 144, 157, 175, 226, 230, 284, 286, 288, 321, 327, 366, 375 HIV, 36 HLA, 82, 130, 131, 231 homeostasis, 76 homework, 45, 127, 206, 345, 349 homovanillic acid, 109 Honduras, 302 Hong Kong, 302 hormone(s), 30, 31, 88, 108, 162 hospitalization, 281, 282 hostility, 153 hot spots, 22 human, 40, 61, 63, 76, 77, 83, 90, 92, 93, 94, 101, 105, 107, 113, 116, 118, 127, 129, 138, 147, 154, 162, 169, 178, 181, 192, 205, 208, 217, 221, 230, 251, 260, 265, 267, 353, 367, 375 human activity, 367 human behavior, 113 human brain, 40, 77, 90, 127, 147, 208, 265, 267 human genome, 63, 83, 118, 205 Hunter, 231 hybridization, 119, 134, 136, 137 hydrocele, 136 hydrolysis, 169, 188, 243 hygiene, 358

hyperactivity-impulsivity, 40, 49, 50, 56, 67, 101, 120, 152, 201, 227 hyperarousal, 80 hyperbilirubinemia, 65, 143 hyperhidrosis, 321 hyperlipoproteinemia, 84 hypermethylation, 138 hypersensitivity, 314, 320 hypertelorism, 135 hypertension, 144, 145, 167, 171, 175, 235, 314 hyperthyroidism, 314 hypogonadism, 133, 232 hypospadias, 82 hypothalamus, 173 hypothesis, 72, 93, 115, 118, 165, 200, 202, 210, 268, 271, 272, 283, 366 hypothyroidism, 109

I IASP, 372 iatrogenic, 182 Iceland, 302 ideal, ix, 17 identification, ix, 89, 90, 91, 92, 94, 106, 131, 216, 227, 271, 274, 275, 331, 355, 356 identity, 33, 192 idiopathic, 123, 162 idiosyncratic, 192 image(s), 95, 289 imbalances, 93, 94 immediate gratification, 129 immune function, 185 immune response, 122 immunization, 102 immunodeficiency, 129 immunoglobulin, 123 impairments, 62, 74, 75, 101, 126, 132, 170, 181, 184, 261, 292, 373 improvements, 130, 164, 169, 172, 181, 183, 186, 319, 322, 364 impulse control, viii, 19, 40, 139, 178, 329, 360, 363 impulses, vii, 40, 140, 340, 342, 351 impulsive, 23, 24, 40, 48, 49, 58, 63, 66, 68, 83, 95, 99, 105, 139, 146, 154, 155, 156, 161, 165, 178, 203, 208, 220, 222, 225, 230, 247, 337, 341, 352, 353, 359, 361 impulsiveness, ix, 67, 95, 108, 284, 288 in situ hybridization, 134, 136 in utero, 76, 138, 154 in vitro, 92, 106, 132, 179, 193, 367 in vivo, 92, 107, 132, 193, 218, 253, 269, 302, 306, 325

Index incidence, 17, 23, 65, 66, 78, 132, 135, 153, 157, 159, 171, 207, 278, 283, 288, 304, 368 income, 103 index case, 137 indexing, 19 India, 11, 12, 16, 99 indirect effect, 172 individual differences, 81, 101, 157, 203 individualization, ix Indonesia, 302 inducer, 123 induction, 149, 192 industrial chemicals, 151 industry, 14, 292 ineffectiveness, 304 infancy, 29, 41, 133, 152, 237, 275, 375 infants, 143, 154, 157, 159, 185, 249, 375 infection, 36, 181 inferences, 258 inflammation, 184, 367, 377 informed consent, 273 infrared spectroscopy, 172, 242 ingestion, 295, 304 ingredients, 186, 303 inheritance, 75, 138, 357 inhibition, 56, 69, 92, 94, 95, 100, 106, 114, 146, 149, 171, 177, 186, 199, 201, 208, 225, 260, 267, 284, 286, 287, 289, 290, 316, 364, 365, 368 inhibitor, 14, 86, 130, 169, 171, 178, 180, 194, 195, 196, 197, 198, 199, 201, 204, 295, 313, 316, 317, 318 initiation, 55, 76, 160, 162, 172, 287, 372 injury(s), viii, 80, 111, 131, 158, 244, 250, 258, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290 inner tension, 360 insertion, 75, 95, 132 insomnia, 74, 168, 169, 170, 171, 172, 180, 185, 247, 301, 304, 320, 322, 323 institutions, 12, 13 insulators, 129 insulin, 365 integration, 184, 255, 257, 290, 346 integrin, 90 integrity, 68, 92, 94, 98, 142, 208, 256, 259 intellect, 123 intellectual ability, viii, 362 intellectual disabilities, 124, 125, 158 intelligence, 33, 78, 98, 100, 108, 111, 125, 134, 152, 222, 339 intelligence quotient, 100, 108, 134 interaction process, 343 interest groups, 366 interference, 51, 54, 56, 235, 260, 267, 282, 377

391

internalised, 49, 56, 337 internalizing, 68, 73, 101, 103, 151, 222 International Classification of Diseases, 4, 37 International Narcotics Control, 5, 8, 15, 16, 19 interneuron(s), 128, 129, 142, 147 interpersonal relations, 40, 50, 282, 343, 346 interpersonal relationships, 50, 282, 343, 346 intervention, 61, 65, 70, 183, 187, 205, 234, 249, 269, 286, 314, 322, 329, 330, 331, 335, 340, 342, 343, 345, 349, 350, 353, 358, 360, 361, 362, 363, 365, 375, 376 intestine, 192, 302 intoxication, 32 intron(s), 77, 91, 92, 94, 109, 110, 113, 193 invasions, 192 inversion, 75, 136 investment, 14, 16, 334 ion channels, 140, 296 ionization, 153 Iowa, 179 IQ scores, 121 Iran, 64, 206, 207, 247 Ireland, 302 iron, 143, 234, 235, 355, 357, 364 irritability, 51, 168, 169, 176, 183, 201, 283 Islam, 309 islands, 145 isolation, ix, 34, 49, 65, 333, 343 isomers, 294, 295, 308 Israel, 16, 302 issues, x, 40, 47, 65, 121, 132, 163, 195, 227, 283, 323, 330, 338, 345, 347, 353, 375 Italy, 11, 12, 16, 64, 302

J Jamaica, 302 Japan, 11, 12, 16, 302 jaundice, 159, 240 Jordan, 302 juveniles, 2

K K+, 109, 175 kidney(s), 31, 193 kill, 352 kindergarten, 376 kinetics, 301 Korea, 64, 206, 302, 374 Kuwait, 302

392

Index

L labeling, 153 lack of control, 341 lactose, 303 laminar, 79 landscape, 233 language development, 143 language impairment, 113, 120, 131, 227, 231 latency, 53, 57, 180 Latin America, 223, 273, 293 Latvia, 302 lead, 2, 21, 31, 34, 47, 90, 95, 140, 148, 151, 152, 154, 184, 236, 237, 259, 281, 282, 287, 331, 333, 350, 355, 357, 358, 362, 363, 364, 367 leadership, ix, 50 learning, vii, 33, 37, 39, 40, 47, 48, 50, 53, 56, 61, 66, 73, 95, 96, 125, 134, 135, 136, 137, 146, 147, 148, 154, 173, 205, 235, 250, 272, 285, 330, 336, 338, 339, 341, 343, 346, 347, 348, 349, 365, 377 learning difficulties, 33, 37, 40, 53, 135, 136, 137 learning disabilities, 96, 137, 272 learning process, 330, 341, 347, 349 learning skills, 339, 343 Lebanon, 302 legs, 74, 88 leisure, 41, 43, 45 leptin, 166, 242 lesions, 36, 147, 178, 247, 285, 286, 289 lethargy, 48 leucine, 119, 137, 147 liberation, 297, 304, 367, 368 libido, 171 life cycle, 252 life experiences, 138 lifestyle changes, 261 lifetime, 80, 126, 159, 284 light, 33, 149, 175, 371 linoleic acid, 366 lipid metabolism, 132 lipids, 188 lisdexamfetamine dimesylate, ix, 160, 169, 170, 174, 244, 307, 308 Lithuania, 302 liver, 153, 167, 188, 191, 192, 193 liver cells, 191 liver failure, 153, 167 liver transplant, 167 liver transplantation, 167 localization, 116, 134 loci, 75, 82, 89, 106, 119, 120, 121, 122, 124, 130, 131, 214, 215, 231, 264 locomotor, 94, 141, 142, 145, 146, 148, 149, 235

locus, 50, 75, 76, 79, 91, 95, 115, 119, 120, 122, 129, 131, 135, 139, 144, 157, 192, 200, 203, 214, 216, 226, 227, 229, 230 longitudinal study, 225, 241, 258 loss of appetite, 166, 319, 323 LTD, 149, 236 lumen, 109 lung cancer, 357 Luo, 148, 215, 224, 236 luteinizing hormone, 135 lysine, 169, 294, 304

M machinery, 105, 107, 119 magnesium, 143, 249, 355, 364, 367 magnetic field, 143, 256 magnetic resonance, 36, 99, 128, 165, 177, 208, 209, 234, 242, 256, 259, 260, 265, 267, 268, 286, 325, 365, 367 magnetic resonance imaging, 99, 128, 177, 208, 209, 256, 259, 265, 267, 268, 286, 325, 367 magnetic resonance scanning, 36 magnetic resonance spectroscopy, 165, 234, 242 magnetism, 256 magnitude, 4, 22, 81, 175, 297 major depression, 66, 88, 101, 102, 140, 142, 152, 184, 234, 319, 321, 370 major depressive disorder, 73, 80, 89, 90, 105, 118, 156, 222 majority, 2, 91, 132, 138, 182, 185, 186, 262 Malaysia, 302 MALDI, 153 malingering, 240 mammals, 147 management, ix, 18, 29, 51, 55, 56, 57, 168, 183, 296, 305, 307, 317, 325, 329, 344, 352 manganese, 150, 151, 236, 367 mania, 66, 171, 181, 244 manic, 33, 37 manipulation, 130, 304 manufacturing, 373 MAOI, ix mapping, 70, 71, 118, 129, 138, 205, 257 marijuana, 161, 182, 363 marketing, 170 MAS, 170, 201 mass, 85, 153, 167, 179 mass spectrometry, 153 materials, vii maternal care, 358 maternal smoking, 149, 156, 238, 239 mathematics, 215

Index matrix, 153, 297, 302, 303, 311 matter, 4, 24, 54, 66, 68, 98, 154, 155, 202, 207, 208, 252, 255, 258, 259, 264, 266, 309, 360 MCI, viii, 65, 271, 272, 273, 274, 275, 276, 277 measurement(s), 161, 257, 262, 269, 277, 326 mechanical stress, 80 median, 78, 154, 160, 175, 275 mediation, 75, 80, 152, 215 medical, 2, 25, 34, 47, 50, 56, 57, 60, 65, 72, 74, 152, 160, 162, 170, 176, 177, 237, 240, 273, 275, 287, 292, 293, 330, 350, 361 medical reason, 74 medicine, ix, 34, 168, 184, 207, 250 melatonin, 74, 185, 211, 250, 367 mellitus, 369 membership, 271, 273 membranes, 76, 184 memory, 46, 54, 79, 84, 98, 108, 112, 115, 121, 135, 147, 149, 150, 166, 167, 175, 184, 202, 219, 236, 274, 284, 289, 330, 350, 365 memory performance, 150, 175 mental disorder, 25, 58, 64, 73, 90, 114, 115, 130, 178, 206, 207, 210, 216, 250, 306, 351, 360 mental health, vii, 126, 156, 185, 233, 238, 282, 358, 371 mental health professionals, vii mental illness, 101, 110, 128, 230, 274 mental processes, 49 mental retardation, 66, 76, 84, 85, 117, 119, 124, 126, 136, 178, 189, 190, 191, 226, 229, 232 mercury, 151, 152, 237, 358, 367, 377 MES, 304 messages, 331, 339 messengers, 187, 256 meta-analysis, 18, 60, 62, 71, 89, 93, 95, 111, 120, 152, 161, 170, 184, 187, 201, 206, 209, 216, 217, 218, 224, 237, 239, 240, 244, 246, 250, 258, 259, 260, 266, 267, 310, 312, 326, 353, 372, 373, 374 Metabolic, 176 metabolic pathways, 138, 231 metabolic syndrome, 84, 170 metabolism, 93, 111, 113, 153, 155, 157, 168, 171, 180, 184, 185, 188, 189, 192, 196, 197, 198, 199, 203, 204, 223, 237, 238, 243, 262, 305, 316 metabolites, 31, 104, 142, 154, 155, 192, 203, 204, 309 metabolized, 168, 188, 192, 295, 304, 306 metabolizing, 115, 225 metals, 151, 236, 367 methacrylic acid, 302 methadone, 372 methamphetamine, 195, 198, 293 methodology, 21, 228, 346

393

methylation, 76, 82, 138, 139, 188, 212, 233 Mexico, 110, 224, 293, 302 mice, 75, 81, 94, 101, 105, 106, 107, 108, 109, 111, 124, 129, 139, 142, 146, 147, 148, 149, 150, 158, 168, 175, 214, 222, 224, 235, 236, 246 microcephaly, 135 micronutrients, 184 microRNA, 76, 106, 139, 222, 233 microstructure, 67, 68, 208, 258, 266 midbrain, 262 Middle East, 189 migraine headache, 158 migration, 90, 127, 129 Minimal Brain Dysfunction, viii missions, 45 misuse, 161, 240, 292, 298, 360, 372 mitochondrial DNA, 138 mitogen, 85, 120 mobile phone, 160, 240 modelling, 338, 340 models, 34, 68, 75, 103, 111, 116, 119, 133, 138, 144, 145, 147, 153, 156, 158, 181, 184, 212, 235, 261, 341, 343, 348, 365 moderates, 101, 201, 221, 230 moderators, 201 modifications, 40, 138, 148 modules, 344 MOG, 131 molecular biology, 211, 265 molecular structure, 295 molecular weight, 149 molecules, 119, 130, 132, 189, 194, 258 monoamine oxidase inhibitors, 321 monosomy, 132, 137, 232 monozygotic twins, 263 mood change, 99 mood disorder, 23, 74, 122, 126, 158, 204, 213 mood states, 51 mood swings, 314, 350 Moon, 245, 250, 311 morbidity, 22, 219, 223, 323 morphogenesis, 129 morphology, 113, 141, 146 morphometric, 150, 375 mortality, 80, 127, 130, 214 mortality risk, 80 motif, 87, 88, 109, 120 motivation, 47, 55, 57, 72, 262, 333, 348 motor activity, 45, 81, 173, 214 motor restlessness, vii motor skills, 48, 283, 375 motor system, 68 movement disorders, 128

394

Index

MRI, 31, 67, 68, 69, 70, 93, 143, 150, 208, 209, 248, 255, 256, 257, 258, 259, 260, 267, 286, 375 mRNA, 77, 104, 110, 116, 129, 145, 158, 164, 204 mtDNA, 138 MTS, 303, 308, 330 multiple sclerosis, 260 muscarinic receptor, 317 mutagenesis, 236 mutant, 93, 101, 105, 147, 148, 149 mutation(s), 74, 75, 77, 81, 91, 94, 97, 108, 109, 110, 112, 116, 128, 129, 131, 132, 133, 134, 135, 137, 147, 148, 157, 218, 221, 231, 232, 233, 236 myelin, 258 myelomeningocele, 108, 223 myocardial infarction, 166, 321 myocarditis, 176, 246

N Na+, 109 NAD, 87 Namibia, 302 narcolepsy, 131, 163, 231, 294 National Institute of Mental Health, 15, 293 National Survey, 361, 372 nausea, 169, 171, 172, 173, 181, 319, 320 NCS, 17 negative outcomes, ix, 127 neglect, 36 negotiation, 334 neocortex, 127 neonates, 159, 376 nerve, 111, 197, 259 nervous system, 85 Netherlands, 2, 3, 10, 11, 12, 16, 24, 302, 307 networking, 233 neural connection, 148 neural development, 184, 249, 257 neural function, 149 neural network(s), 256, 261, 264 neural system(s), 67 neuroanatomical abnormalities, 67, 147 neurobiology, 17, 165 neurodegeneration, 93, 117, 138, 184, 249 neurodegenerative disease, viii, 65 neurodevelopmental disorder(s), vii, 41, 57, 63, 64, 65, 77, 82, 91, 107, 112, 119, 120, 123, 125, 127, 133, 134, 135, 137, 138, 142, 145, 151, 155, 205, 215, 232, 233, 238, 255, 256 neuroimaging, 14, 46, 65, 111, 205, 209, 255, 256, 258, 260, 261, 262, 263, 265, 268, 277, 286, 377 neurokinin, 105, 110, 175, 222 neuroleptics, 188

neurological disease, 223, 274 neurologist, 274, 275 neurons, 104, 105, 111, 116, 119, 128, 141, 147, 148, 164, 178, 196, 236, 242, 316 neuropharmacology, 168 neurophysiology, 70 neuroprotection, 153, 192, 230 neuropsychiatric disorder, vii, 14, 17, 30, 35, 70, 73, 76, 77, 89, 93, 94, 102, 121, 148, 205, 216, 235, 260, 376 neuropsychiatric research, vii neuropsychiatry, 207 neuropsychology, 262, 265 neuroscience, 261, 266, 267, 375 neurotransmission, 89, 92, 94, 103, 141, 145, 148, 151, 153, 256 neurotransmitter(s), 63, 88, 99, 105, 109, 114, 117, 132, 142, 145, 150, 153, 171, 172, 193, 204, 235, 253, 262, 263, 293, 315, 316, 317 neutral, 96 New England, 152 New Zealand, 302 NHANES, 238, 243 Nicaragua, 302 nicotine, 84, 149, 360, 364 Nigeria, 213 nitric oxide, 104, 119, 222 nitric oxide synthase, 119, 222 nitrogen, 155 NMDA receptors, 242 node of Ranvier, 84 nodes, 262 non-pharmacological treatments, 160 noradrenergic, ix, 63, 89, 104, 146, 163, 164, 204, 269, 316, 317 norepinephrine, 97, 98, 99, 141, 145, 146, 150, 155, 163, 164, 168, 171, 180, 196, 197, 198, 199, 200, 202, 203, 204, 219, 236, 242, 253, 263, 269, 292, 295, 313, 315, 317, 318, 325, 328, 371 normal children, 19, 60, 73, 98 North America, 22, 302 Norway, 182, 302 novelty seeking, 95 nuclei, 258, 262 nucleotides, 106, 193 nucleus, 66, 98, 139, 145, 146, 164, 259, 286, 315, 316 null, 125, 149, 192 nutrient(s), 185, 249 nutrition, 355, 357 nutritional deficiencies, 184

Index

O obedience, 343 obesity, 84, 85, 86, 105, 120, 123, 125, 170, 222, 227, 357, 362, 367, 369, 374, 377 observed behavior, 109 obsessive-compulsive disorder, 76, 78, 86, 121, 122, 142, 213, 227 obstructive sleep apnea, 65 occipital regions, 259 occupational health, 283, 288 OCD, 76, 77, 78, 122, 127, 134, 213 ODD, 64, 72, 79, 97, 99, 177, 183, 285, 323 OECD, 5, 12, 19 olanzapine, 177 omega-3, 184, 185, 206, 366 omission, 53, 57, 98, 100, 106, 154, 155, 286 onset latency, 185 opportunities, 364 oppositional behaviour, 41, 42, 50, 56 optimization, 64, 205 organ(s), 131, 364 organelles, 90 originality, 95 osteoporosis, 85 outpatient(s), 80, 177, 213, 214, 328 ovarian failure, 85 overlap, 71, 90, 118, 120, 124, 125, 229, 277 overweight, 105, 357 ownership, 160 oxidation, 84, 122, 188 oxidative damage, 168 oxidative stress, 122, 243 oxygen, 100, 260, 262

P Pacific, 19 pain, 131, 153, 169, 171, 180, 319, 320 pairing, 53 palate, 136 palpitations, 322, 323 Panama, 302 panic disorder, 85, 90, 322, 370 Paraguay, 302 parallel, 16, 71, 169, 170, 200, 257, 264, 307, 322 paraneoplastic syndrome, 31 parent programmes, 330 parenting, 59, 103, 127, 183, 222, 230, 342, 344, 352, 353, 374 parents, viii, 22, 45, 46, 47, 48, 49, 50, 51, 55, 56, 57, 60, 82, 96, 109, 121, 125, 126, 127, 151, 156,

395

157, 161, 177, 179, 200, 230, 240, 256, 282, 329, 335, 340, 342, 343, 344, 345, 346, 350, 351, 354, 358, 359, 361, 365, 370, 371 parietal cortex, 260 parietal lobe, 140, 260 parkinsonism, 93, 218 paroxetine, 171 participants, 22, 23, 68, 71, 82, 96, 108, 114, 126, 153, 156, 158, 164, 174, 204 pathogenesis, 64, 76, 77, 98, 111, 115, 142, 145, 148, 157, 186, 187, 260, 263 pathology, 2, 14, 19, 148, 264, 276, 340, 368 pathophysiological, 67, 118, 145, 277 pathophysiology, x, 17, 68, 92, 94, 97, 108, 110, 112, 113, 140, 148, 151, 164, 204, 234, 256, 263, 325 pathway(s), 66, 77, 104, 109, 111, 116, 119, 122, 125, 127, 129, 132, 140, 147, 159, 178, 180, 219, 226, 234, 247, 256, 258, 259, 260, 265, 269 PCBs, 151, 237 PCDD/Fs, 154, 237 PCR, 77, 115 pediatrician, 74 pedigree, 102, 370 peer relationship, 50 penetrance, 115, 121, 135, 136, 357 penis, 82 peptidase, 77, 243 peptide, 169 per capita expenditure, 2, 4 percentile, 49, 154 perfusion, 262, 263 perinatal, 75, 233, 237, 240, 368 peripheral blood, 34, 104 peripheral neuropathy, 131 permit, 3, 45, 51, 298, 330 personal development, 314 personal hygiene, 49 personality, 21, 23, 37, 39, 47, 50, 85, 88, 114, 127, 129, 152, 214, 225, 230, 237, 286, 371 personality disorder(s), 21, 23, 39, 47, 127, 129, 214, 371 personality traits, 88, 127, 129, 152, 237 Peru, 302 pesticide, 154, 238 PET, 93, 98, 217, 255, 262, 310 PET scan, 262 pH, 109, 295, 302 pharmaceutical(s), 14, 15, 168, 181, 292, 297 pharmacogenetics, 113, 188, 194, 195, 196, 252 pharmacogenomics, v, viii, 63, 64, 187, 189, 193, 205, 209, 217, 226, 233, 251, 252, 253

396

Index

pharmacokinetics, 84, 168, 171, 187, 204, 251, 254, 308, 309, 310, 326 pharmacological research, 3 pharmacological treatment, 1, 3, 4, 5, 10, 13, 15, 64, 65, 101, 130, 161, 203, 205, 297, 358, 360, 361, 362 pharmacology, 37, 129, 230, 308, 309 pharmacotherapy, ix, 11, 14, 18, 20, 165, 168, 246, 292, 309, 311, 324 phenotype(s), 63, 65, 73, 74, 75, 77, 90, 92, 94, 102, 108, 111, 112, 116, 121, 123, 124, 125, 126, 127, 128, 133, 134, 135, 136, 137, 138, 139, 144, 147, 150, 159, 162, 188, 189, 191, 192, 224, 228, 229, 231, 232, 233, 235, 269, 357 phenylalanine, 181 phenylketonuria, 181, 248 pheochromocytoma, 36, 319 Philadelphia, 4, 36 Philippines, 302 phobia, 64 phosphate, 86, 120 phosphorous, 143 phosphorylation, 92, 94 photons, 262 phthalates, 154, 155, 238, 377 physical activity, 143, 365, 375 physical aggression, 373 physical exercise, 355, 357, 364, 365 physical well-being, 22 physiology, 32, 143, 146, 222 pilot study, 60, 179, 187, 218, 223, 230, 242, 251, 268, 370, 374 pineal gland, 185 PKU, 181 placenta, 139, 193 plants, 186 plasma levels, 154, 298 plasma membrane, 92, 94, 105, 149, 150, 296 plasticity, 89, 90, 95, 129, 134, 139, 146, 148, 149, 165, 216, 355, 364, 365, 375 platform, 3, 4 play activity, 42 playing, 43, 45, 160, 180 PM, 36, 62, 114, 174, 189, 190, 191, 204, 207, 210, 211, 212, 220, 239, 251, 265, 310, 325, 326 point mutation, 77, 130, 132 Poland, 302 polarity, 90 policy, 16 pollutants, 153, 367 pollution, 155, 238 polybrominated diphenyl ethers, 367 polychlorinated biphenyl(s) (PCBs), 151, 154, 236

polycyclic aromatic hydrocarbon, 155, 238 polydipsia, 66, 74, 212 polymer, 301, 302, 303 polymer matrix, 303 polymerization, 129 polymers, 302 polymorphism(s), 89, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 110, 111, 113, 114, 116, 155, 160, 200, 201, 202, 203, 204, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 230, 251, 252, 253, 254, 258, 262, 263, 264 polypeptide, 84, 87, 133 polyunsaturated fat, 184, 249 polyunsaturated fatty acids, 184, 249 poor performance, 57, 152 population control, 125, 131 Portugal, 302 positive correlation, 97, 101, 157, 183, 261 positive reinforcement, 332, 333, 347 positron, 219, 268 positron emission tomography, 219, 268 posterior cortex, 260 postnatal exposure, 155 postpartum depression, 159 posttraumatic stress, 37, 80 potassium, 109 potential benefits, 297 poverty, 167 PPP, 12 predictability, 344 prefrontal cortex, 13, 61, 66, 91, 98, 129, 140, 141, 145, 146, 148, 164, 166, 171, 175, 178, 199, 221, 223, 234, 235, 237, 242, 246, 247, 260, 261, 263, 264, 315, 316 pregnancy, 47, 128, 138, 152, 153, 156, 159, 167, 238, 239, 243, 357, 358, 364, 366, 367, 369, 377 prejudice(s), vii, 359 prematurity, 377 premutation carriers, 114, 225 preparation, 163, 174, 303 preschool, 201, 214, 356, 365, 375, 376 preschool children, 214, 365, 375 preschoolers, 20, 62, 218, 250, 283, 288 prestige, 4 preterm infants, 185 prevalence rate, 24, 75, 367 prevention, 37, 185, 239, 284, 322, 346, 352, 353, 355, 357, 358, 359, 360, 363, 364, 365, 368, 375, 377 priapism, 171 principles, 187, 343 prisoners, 184 probability, 264, 330, 332

Index proband(s), 79, 80, 81, 92, 94, 97, 98, 100, 104, 108, 109, 113, 115, 117, 122, 134, 135, 200, 217, 219, 220, 223, 258 Problem Behavior, 376 problem drinking, 157, 239 problematic alcohol use, 157 problem-solving, 55, 57, 336, 341, 342, 349, 350, 352 problem-solving strategies, 341, 342 prodrug stimulant, ix, 160 prodrugs, 291, 297 producers, 12 productivity rates, 16 professional development, 362 professionals, 330, 345, 359 progenitor cell(s), 116, 193, 225 prognosis, 17, 30, 137, 256, 272, 277, 330, 360 programming, 138, 233, 345 project, 240 prolactin, 177 proliferation, 79, 109, 365 promoter, 76, 92, 94, 101, 106, 110, 115, 145, 201, 218 prostaglandin, 145 protection, 301 protective factors, 37, 102 protein analysis, 204 protein family, 120 protein folding, 153 protein kinase C, 92, 94, 175 protein kinases, 234 proteins, 75, 90, 117, 129, 132, 146, 147, 148, 153, 158, 188, 192, 194, 204, 256, 263, 365 proteomics, 234 protons, 109 pruning, 257, 364 pseudogene, 123 psychiatric diagnosis, 65 psychiatric illness, 182 psychiatric morbidity, 126, 130 psychiatric patients, 104 psychiatric side effects, 308 psychiatry, vii, 3, 19, 34, 35, 163, 248, 355, 358, 362 psychoeducational intervention, 352 Psychological intervention, 330, 331 psychological variables, 161 psychologist, 342, 351 psychometric properties, 51, 60 psychopathology, 58, 59, 99, 126, 157, 206, 215, 239, 267, 358, 359 psychopathy, 129 psychopharmacology, 3, 14, 314 psychoses, 265

397

psychosis, 102, 107, 111, 117, 121, 126, 166, 176, 177, 189, 190, 191, 247 psychosocial factors, 359 psychosocial functioning, 81, 278 psychosocial interventions, 65, 161, 187, 356 psychosocial stress, 101 psychosocial treatments, viii, 187, 352, 353, 368 psychosomatic, 50, 56, 250 psychostimulant(s), vi, viii, 2, 14, 15, 146, 163, 174, 209, 218, 235, 246, 257, 266, 291, 292, 296, 315, 324, 352 Psychostimulants, ix, 3, 241, 242, 292, 293, 295 psychotherapy, ix, 314, 326 psychotic symptoms, 33, 48 psychotropic drugs, 203, 205, 357 psychotropic medications, 20 PTEN, 75, 124 PTSD, 37, 80 public health, 22, 74, 82, 170, 283, 357, 358 punishment, 333, 343, 347, 365 pyramidal cells, 140

Q QT interval, 175 quadratic curve, 257 quality of life, 24, 34, 80, 288, 306, 319 Queensland, 29 questionnaire, 23, 34, 49, 50, 51 quetiapine, 176, 177 quinone, 188

R race, 167, 284, 286, 288, 295, 303 radiation, 263 radio, 316 radioactive isotopes, 262 random assignment, 372 rating scale, 58, 59, 60, 108, 202, 245 RBC, 185 reaction time, 53, 57, 72, 130, 183, 218 reactions, 49, 168, 187, 188, 243, 253, 292, 342 reactivity, 148, 363 reading, 51, 54, 56, 81, 121, 206, 214, 335, 359 reading comprehension, 206 reading difficulties, 81, 214 reasoning, 54 reboxetine, 178, 247, 313, 314, 321, 322, 327, 328 recall, 51, 56 receptor sites, 197 recognition, 14, 15, 94, 108, 166, 342, 359

398

Index

recombination, 75 recommendations, 26, 65, 250, 272, 317, 318 recovery, 106, 289 recreational, 310 recurrence, 75 recycling, 109, 151, 237 red blood cells, 169, 243, 306 redistribution, 92, 94, 142 redundancy, 192 reflexes, 82 regeneration, 230 regions of the world, viii Registry, 152, 153, 161 regression, 17, 187 regression analysis, 17 regulations, 345, 346 rehabilitation, 281, 282, 284 reinforcement, 52, 61, 315, 332, 333, 334, 335, 340, 341, 343, 344, 347 reinforcers, 332, 333, 334 relatives, viii, 80, 81, 215, 358, 365 relaxation, 340 relevance, 3, 72, 125, 140, 146, 148, 192, 218, 234, 235 reliability, 30, 55 relief, 297 remission, 70, 128, 161, 174, 204, 246, 261, 308, 360 repetitive behavior, 78, 148 replication, 277 representativeness, 17 requirement, 147, 160, 292, 304 requirements, 39, 335 researchers, 144, 258, 273 residues, 92, 94 resistance, 52, 108, 192, 193 resolution, 141, 187, 256, 285, 341 resource utilization, 176, 177, 288 resources, 2, 22, 64, 140, 330 response time, 54, 98, 104, 155, 203, 253 responsiveness, 80 restitution, 175, 246 restless legs syndrome, 125, 143, 212 restoration, 102 retardation, 84, 85, 88, 89, 119, 136, 137 reticular activating system, 197 reticulum, 188 retina, 185 reversal learning, 101 rewards, 334, 335, 343 rhythm, 105, 115, 362 right hemisphere, 140

risk factors, 25, 63, 81, 123, 128, 154, 158, 160, 167, 206, 239, 240, 264, 283, 285, 358, 364, 365, 374, 377 risk taking, 283 risperidone, 176, 177, 182, 183, 248 RNA, 120, 158, 188, 191, 192, 234, 235 ROC, 275 rodents, 178, 184, 365 Romania, 302 Rouleau, 211 routes, 305 routines, 344, 347 rules, 52, 54, 140, 334, 342, 348

S sadness, 203 safety, 15, 55, 65, 162, 166, 169, 170, 172, 173, 174, 176, 180, 181, 182, 194, 195, 234, 241, 244, 245, 291, 297, 304, 307, 308, 310, 321, 324, 327, 352 salts, 5, 6, 160, 170, 171, 201, 244, 292, 293, 294, 304, 305, 317 SAS, 147 saturation, 2, 14 Saudi Arabia, 302 schizophrenia, 33, 73, 78, 81, 84, 85, 86, 87, 89, 90, 93, 99, 100, 101, 102, 104, 105, 111, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 129, 135, 138, 139, 140, 142, 145, 148, 149, 158, 184, 209, 213, 222, 225, 226, 234, 260, 265 school failure, 361 school work, 45 science, 4, 10, 12, 19, 168, 251, 375 scientific knowledge, vii scientific papers, 321 scientific publications, 1, 6, 13, 15 scoliosis, 131 scope, 25, 35 second generation, 153, 176, 297 secretion, 105 sedatives, 152 seed, 106 segregation, 77, 226 seizure, 320, 322 selective attention, 73, 78, 95, 146, 173, 203, 222, 235, 261, 340, 344 selective serotonin reuptake inhibitor, 178 selectivity, 168, 171, 179, 310, 317 selenium, 151, 236 self-assessment, 339, 340 self-confidence, 50 self-control, 52, 60, 333, 335, 336, 337, 341, 352, 353

Index self-esteem, 2, 40, 50, 282, 330, 336, 338, 339 self-evaluations, 351 self-regulation, 40, 52, 55, 57, 336, 363 semi-permeable membrane, 301 senescence, 249 sensations, 50, 361 sensitivity, 21, 30, 34, 73, 84, 131, 175, 256 sensitization, 316 sensorimotor gating, 148 sensory symptoms, 74 septum, 147 sequencing, 55, 77, 131, 233 serine, 84, 92, 94 serotonin, 75, 86, 99, 101, 116, 141, 142, 146, 150, 158, 160, 178, 193, 198, 221, 234, 239, 316, 317, 328, 376 sertraline, 183 serum, 112, 143, 151, 159, 224, 236 serum ferritin, 143 services, 176 SES, 284, 285, 286 sex, 66, 68, 73, 104, 114, 116, 130, 135, 167, 188, 276, 284, 286, 358 sex differences, 135 sexual behaviour, 363 shape, 54, 55, 225, 256, 297 short-term memory, 108, 131 showing, 14, 54, 79, 95, 104, 105, 121, 122, 145, 164, 169, 173, 181, 260, 262, 332, 358, 359 siblings, 75, 81, 82, 94, 128, 134, 158, 230, 232 side effects, ix, 161, 166, 183, 201, 204, 264, 296, 319, 320, 322 signaling pathway, 122, 124, 165, 242 signalling, 119, 125, 153, 226, 237 signals, 79, 103, 111, 140, 260 signs, 72, 78, 82, 112, 162, 164, 167, 169, 173, 336, 342 simulations, 93 Singapore, 207, 302 single cap, 299 SIP, 74 skills training, 353 skin, 74, 136, 172, 302, 303 SLE, 31, 114 sleep disorders, 74, 143, 182 sleep disturbance, 131, 185, 212, 314, 319 sleep latency, 74 sleeping pills, 152 sleeping problems, 111 Slovakia, 302 small intestine, 169, 193 smoking, 102, 156, 238, 305, 319, 357, 358, 360, 367

399

smoking cessation, 319 SMS, 131, 231 SNAP, 105, 106, 149, 202, 222, 253 SNP, 79, 82, 89, 95, 97, 98, 102, 104, 105, 106, 108, 111, 113, 115, 116, 117, 120, 124, 130, 159, 203 sociability, 153 social adjustment, 352 social anxiety, 74, 114 social behavior, 144, 149 social behaviour, 50, 56, 132, 338, 341, 343 social competence, 49, 56 social context, 45, 113 social impact, vii, 3 social impairment, 64, 75, 106, 127 social interaction(s), 47, 51, 74, 148, 149, 337, 338, 341, 350 social learning, 329, 343 social learning theory, 329 social phobia, 64, 80 social problems, 49, 151, 336, 340 social relations, 49, 66, 339, 343 social relationships, 49, 66 social services, 346 social situations, 343 social skills, vii, 50, 183, 336, 338, 342, 349 social stress, 50 social withdrawal, 201 society, 34 socioeconomic status, 284, 285, 357, 369 sodium, 93, 106 software, 256 solution, 303, 336, 340, 341 solvents, 154 somatomotor, 68, 260 somnolence, 171, 173, 174, 181, 321 South Africa, 16, 206, 302 South America, 302 South Korea, 152, 258, 299 Spain, 1, 2, 10, 11, 12, 16, 21, 22, 25, 39, 63, 116, 251, 255, 291, 293, 302, 313, 329, 355, 368 spatial learning, 180, 248 spatial memory, 243 special education, 286 specialists, 45, 46, 57, 350 specialization, 13 species, 77, 138, 147, 168 speculation, 276 speech, 75, 112, 121, 122, 123, 127, 128, 134, 135, 143, 337 spending, 15, 20 sperm, 139, 233 spiders, 226 spine, 178

400

Index

spleen, 188 spontaneous abortion, 167 Spring, 222 stability, 170, 304, 358, 363 stabilization, 75 standard deviation, 49 state(s), 25, 47, 48, 67, 68, 69, 72, 84, 98, 140, 144, 164, 165, 193, 200, 209, 211, 219, 260, 261, 267, 268, 278, 323, 326 statistics, 62 steroids, 31, 188 stigma, vii, ix, 256, 292 stimulation, 70, 118, 141, 168, 175, 186, 246, 265, 267, 355, 364 stimulus, 14, 53, 140, 149, 260, 332 stomach, 302 stress, 101, 109, 138, 139, 153, 158, 159, 166, 175, 211, 214, 221, 224, 233, 239, 246, 357, 363, 364 stressful life events, 114 stressors, 33, 96 striatum, 66, 91, 93, 146, 149, 150, 158, 159, 163, 165, 173, 178, 184, 200, 204, 221, 237, 249, 255, 260, 262, 268 stroke, 145, 166, 235 structural defects, 100 structure, 59, 61, 68, 98, 115, 153, 193, 257, 259, 264, 266, 293, 294, 295 structuring, 346 style(s), 47, 183, 329, 339, 344, 374 subgroups, ix, 169, 176, 183, 264, 351 substance abuse, vii, 21, 23, 37, 171, 182, 283, 317, 318, 353, 360, 361, 362, 364, 372 substance use, 81, 215, 225, 263, 269, 360, 371, 372 substance use disorders (SUD), 81, 215, 225, 360, 371 substitution, 92, 94, 95, 97, 137 substrate(s), 2, 68, 92, 93, 94, 130, 172, 188, 191, 192, 193, 194, 195, 203, 251 SUD, 81, 116, 371 suicidal behavior, 140, 172, 214, 234, 374 suicidal ideation, 124, 162, 171, 172, 245 suicide, 79, 80, 162, 166, 245, 363, 374, 375 suicide attempters, 375 suicide attempts, 80, 363, 374 sulfate, 130 Sun, 111, 213, 215, 224, 236, 248, 249, 367 supervision, 44, 51, 55, 304, 361 supplementation, 37, 184, 185, 249, 376 suppression, 72, 183, 296, 304, 347 surface area, 141, 257, 258, 266 survival, 104, 158 survival rate, 158

susceptibility, 77, 83, 88, 90, 91, 94, 100, 102, 103, 110, 120, 125, 131, 137, 148, 149, 204, 221, 223, 224, 234, 264 Sweden, 16, 23, 26, 113, 114, 128, 151, 155, 158, 162, 214, 302, 374 Switzerland, 16, 163, 301, 302 sympathomimetics, 196, 197, 198 symptomatic treatment, ix symptomology, 39, 40, 334 synapse, 75, 101, 128, 132, 141, 146, 197 synaptic gap, 317 synaptic plasticity, 117, 119, 130, 139, 142, 148, 149 synaptic transmission, 90, 125 syndrome, vii, 2, 30, 31, 33, 34, 40, 64, 73, 74, 75, 76, 77, 78, 81, 82, 84, 85, 86, 87, 88, 89, 107, 110, 121, 122, 123, 124, 125, 126, 131, 132, 133, 134, 135, 137, 154, 185, 186, 212, 213, 214, 223, 224, 225, 228, 229, 231, 232 synthesis, 101, 188 syphilis, 31 systemic lupus erythematosus, 36 systolic blood pressure, 172

T tachycardia, 30, 182, 322 Taiwan, 111, 158, 159, 302 tandem repeats, 91, 93, 95, 200 TAP, 193 target, 53, 76, 98, 107, 115, 123, 132, 150, 200, 222, 223, 262, 292, 334, 335, 347, 355, 356, 357, 358, 359, 362, 364, 365 task conditions, 71 task difficulty, 70 Task Force, 37 TBI, viii, 170, 281, 282, 283, 284, 285, 286, 287, 288 teachers, 22, 46, 47, 48, 49, 50, 51, 52, 55, 57, 96, 151, 161, 177, 179, 335, 345, 346, 348, 350, 354, 365, 366 techniques, 3, 140, 255, 256, 262, 263, 329, 330, 331, 332, 333, 334, 335, 336, 338, 339, 340, 341, 342, 343, 347, 350, 361 technology(s), viii, 12, 19, 69, 118, 124, 145, 255, 296, 297, 299, 301, 303, 305, 306, 326 teeth, 124, 131 telencephalon, 116 temperament, 101 temperature, 211 temporal lobe, 96, 137, 233, 261 temporal lobe epilepsy, 137, 233 tendon, 82 terminals, 94, 197, 296

Index termination codon, 116 testing, 31, 60, 90, 91, 92, 128, 134, 149, 159 testis, 154 testosterone, 31, 154 thalamus, 159, 165, 182, 286 therapeutic approaches, 146 therapeutic effect, 201, 298, 301 therapeutic interventions, 261 therapeutic targets, 129, 165 therapeutics, 65, 130, 142, 205, 355 Therapeutics, v, 63, 160 therapy, ix, 2, 5, 18, 36, 126, 162, 172, 177, 181, 182, 186, 187, 202, 213, 241, 243, 250, 251, 256, 262, 287, 291, 304, 305, 307, 308, 319, 330, 331, 332, 335, 338, 339, 340, 344, 350, 351, 352, 353, 374 therapy interventions, 187 thigmotaxis, 147 thimerosal, 152 thinning, 257, 258, 266 thoughts, 77, 331, 337 thyroid, 30, 108, 130 thyroid gland, 30 thyrotoxicosis, 88 thyrotropin, 108 tic disorder, 23, 74, 102, 221, 244, 324, 327 tics, 76, 77, 108, 134, 171, 201, 314, 318 time series, 260 time use, 161 tinnitus, 320, 323 tissue, 109 tobacco, 102, 156, 221, 239, 357, 377 tobacco smoke, 156, 377 tobacco smoking, 102, 221 toddlers, 38, 156 toluene, 367 tones, 53 tonic, 316 top-down, 175 total product, 10 toxicity, 193, 355, 364, 377 toxicology, 37 TP53, 123 trace elements, 151 trade, 293 traffic violations, 2, 292 trafficking, 92, 94, 142, 217, 234 training, 72, 177, 210, 247, 330, 337, 338, 340, 342, 343, 344, 348, 350, 352, 353, 365, 375 traits, 32, 97, 99, 105, 107, 114, 115, 118, 120, 139, 219, 223, 225, 227, 234, 356 trajectory, 30, 32

401

transcription, 77, 84, 90, 107, 112, 115, 128, 130, 132, 139, 253 transcripts, 77, 89, 116, 188, 191, 192, 193, 213 transesterification, 243 translation, 76, 251, 253 translocation, 76, 77, 107, 112, 134, 213, 232 transmission, 63, 92, 97, 98, 100, 103, 108, 109, 119, 132, 138, 139, 146, 164, 200, 204, 214, 215, 230, 257, 316, 317, 357 transplant, 243 transport, 92, 94, 143, 169, 184, 188, 192, 193, 194, 195, 200, 203, 263, 295, 320 trauma, 33, 37, 38, 80, 164, 242, 283, 286, 288, 357, 366 traumatic brain injury, viii, 62, 158, 170, 239, 281, 282, 285, 288, 289, 290 tremor, 85, 135, 321 trial, 20, 36, 161, 169, 170, 180, 203, 205, 243, 244, 245, 248, 249, 250, 252, 253, 306, 308, 311, 319, 320, 322, 323, 324, 325, 326, 327, 328, 352, 365, 368, 369, 375 trichotillomania, 74, 77 tricyclic antidepressant(s), ix, 316, 317, 320, 322 trigeminal nerve, 186 triggers, 39, 131 Trinidad, 302 trisomy, 81, 137 trypsin, 103 tryptophan, 101, 142, 221 TSH, 108 tumor, 75, 320 tumours, 36 Turkey, 23 turnover, 157 tutoring, 346 twins, 75, 76, 114, 133, 155, 157, 212, 238, 239, 357 type 2 diabetes, 83 tyramine, 129 tyrosine, 87, 88, 125

U ubiquitin, 87 umbilical cord, 151, 236 underlying mechanisms, 372 unemployment, vii, 24, 283, 292 United Kingdom, 2, 10, 12, 16, 122 United Nations, 5, 15, 16, 19, 366 United States, 2, 10, 11, 12, 15, 16, 23, 26, 122, 272, 277, 278, 281, 282, 283, 288, 306, 361, 370 updating, viii upper respiratory tract, 181 urban, 155, 273

402

Index

urban areas, 273 urea, 193 urethra, 82 urinary retention, 171 urinary tract, 65, 322 urinary tract infection, 65, 322 urine, 31, 151, 154, 155, 238 Uruguay, 302 USA, 3, 4, 11, 22, 65, 173, 185, 257, 266, 281, 299, 301, 302, 303, 359 uterus, 193, 364

V Valencia, 25 validation, 62 valuation, 377 variable expressivity, 121 variables, 52, 54, 263, 271, 274, 275, 285, 289 variations, 21, 25, 52, 73, 76, 77, 90, 112, 115, 119, 203, 226, 295 vasculature, 192 vasomotor, 199 vector, 145, 235 vegetable oil, 366 Venezuela, 302 venlafaxine, ix, 313, 314, 317, 322, 323, 328 vesicle, 103, 105, 143 violence, 346, 352, 357 violent behavior, 184 violent behaviour, 48 vision, 256 visual acuity, 185 visual attention, 185 vitamin D, 143, 234 vitamin D deficiency, 143 vitamins, 185 vitiligo, 168, 172, 243 vomiting, 171, 319, 320 vulnerability, 102, 110, 157 Vygotsky, 337, 352

W Washington, 17, 25, 35, 58, 59, 288, 324, 351, 352, 353, 354, 368 waste, 151, 237 watches, 338

water, 150, 256, 258, 303 wealth, 263 web, 12, 145 Wechsler Intelligence Scale, 38, 54, 61 weight gain, 176, 177, 182 weight loss, 30, 166, 169, 171, 362, 367 well-being, 24 Western countries, 152 wheezing, 153 white matter, 66, 67, 68, 95, 98, 219, 256, 258, 259, 264, 266 wild type, 81, 112, 149, 236 windows, 156, 304, 364 Wisconsin, 54, 55, 62 withdrawal, 32, 50, 164, 322, 332, 333 workers, 23, 26, 373 working memory, 51, 53, 54, 56, 57, 60, 61, 62, 67, 78, 92, 95, 99, 103, 114, 128, 141, 146, 149, 154, 164, 170, 175, 183, 184, 201, 207, 208, 217, 220, 221, 260, 292, 364 workplace, 42, 283, 373 World Health Organization (WHO), 5, 11, 12, 19, 23, 26, 35, 41, 58, 366, 370, 373 worldwide, vii, 6, 8, 15, 17, 21, 22, 25, 30, 35, 58, 62, 64, 73, 153, 158, 162, 205, 206, 277, 306

X X chromosome, 99, 136 XYY syndrome, 232

Y Yale University, 351 yeast, 89 Yemen, 302 yield, 32, 34, 168 young adults, 171, 230, 239, 240, 244, 267, 292, 310, 326, 361, 363, 371, 374 young people, 36, 160, 177, 307, 317, 318, 322, 325 young women, 214

Z zinc, 111, 123, 132, 224, 355, 364 ziprasidone, 177