Mineral Lithium: Inorganic Pharmacology and Psychiatric Use 1852211113, 9781852211110

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LITHIUM: INORGANIC PHARMACOLOGY AND PSYCHIATRIC USE Edited by N J Birch

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WW NY | RC483.5 .L5 B75 1987 Lithium: Inorganic Pharmacology and

IRLFE © OXFORD - WASF

Psychiatric

Use

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Spring Valley Library

Cdiorado Mountain College

20)0 County Road 114 enwood Springs, CO 8160)

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IRL Press Eynsham Oxford England

© IRL Press Limited First Published

1988

1988

All rights reserved by the publisher. No part of this book may be reproduced or transmitted in any form by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission in writing from the publisher. British Library Cataloguing

British Lithium Congress

in Publication

Data

(2nd : 1987 : Wolverhampton

Polytechnic) Lithium. 1. Man. Mental disorders. Drug therapy. |. Title ll. Birch, Nicholas J. 616.89'18

ISBNGWES5221

ities

ao

Library a Conese

Ser

arty

4

SDb

@

Cataloging in Publication

British Lithium Congress Polytechnic)

Data

(2nd : 1987 : Wolverhampton

Lithium : inorganic pharmacology Includes index.

and psychiatric

1. Lithium. Therapeutic use. Congresses. 2. Lithium. Metabolism. Congresses. |. Birch, Nicholas J. Il. Title {[DNLM: 1. Lithium —pharmacology —congresses. therapeutic use — congresses.

W3 BR447 2bd 1987L / QV 77.9 B862 1987L] RC483.5.L5B75 1987 615’.2381 ISBN

1 85221

use.

2. Lithium —

88-6787

111 3 (soft)

Publication of these Proceedings was made possible by generous sponsorship of Delandale Laboratories Limited, manufacturers of Priadel.

Printed by Information

Printing Ltd, Oxford,

England.

CONTENTS xiii

Introduction

xvii

Principal authors

xxiii

Co-authors

1

Lithium reflections | M.Schou

5

Lithium reflections P.C.Baastrup

II

CLINICAL USE IN CURRENT

PRACTICE

11

The epidemiology of lithium usage and its implications for health economics R.G.McCreadie

15

Review of significant side effects J.R.King

19

Morbidity and mortality of lithium patients D.P.Srinivasan R.P.Hullin

23

Does lithium prevent suicides and suicidal attempts? B.Causemann B.Muller-Oerlinghausen

25

The relationship lithium dosage M.T.Abou-Saleh

29

Expressed emotion lithium prophylaxis

between

morbidity index and

and hospital admission

in

S.Priebe C.Wildgrube B.Miuller-Oerlinghausen 33

Lithium dose reduction trial P.T.S.Milin C.Patch

35

Double blind trial of lithium carbonate resistant depression G.S.Stein M.Bernadt

37

Quality of interepisodic periods in manicdepressive patients under lithium long-term

treatment J.Volk B.Miuller-Oerlinghausen

in tricyclic

39

Lithium in aggression S.P.Tyrer

DRUG INTERACTIONS MIXED THERAPY 45

Lithium interactions J.W.Jefferson J.H.Greist J.A.Carroll

49

Lithium and clonazepam G.M.Dempsey

55

Problems

AND

USE IN

with other drugs

of combined

in atypical bipolar patients

lithium neuroleptic

toxicity

G.K.Spring

oi,

Combination therapy with lithium and carbamazepine T.D.Brewerton

K.G.Kramlinger R.M.Post

61

Carbamazepine and lithium: endocrine biochemical aspects

and

R.M.Post

65

The syndrome neurotoxicity Adityanjee

67

Cerebellar damage following lithium toxicity K.Balasubramaniam

69

Is there a negative interaction between and lithium? S.K.Ahmed G.S.Stein

of irreversible lithium effectuated

NON-PSYCHIATRIC LITHIUM THERAPY

73

77

Lithium and dental M.E.J.Curzon

SEQUELAE

ECT

OF

caries

Lithium/bipolar disorder: their effects on salivary disease A.H.Friedlander flow, dental caries and periodontal

79

Cutaneous side effects in patients on long-term lithium therapy G.H.Albrecht

83

Effect of lithium salts on the replication of viruses and non-viral microorganisms A.Buchan S.Randall C.E.Hartley G.R.B.Skinner A.Fuller

91

Antiviral activity of the lithium ion with adjuvant

agents R.O.Bach S.Specter

93

Lithium and granulopoiesis: lithium action V.S.Gallicchio

mechanisms

of

LITHIUM AND IMMUNOLOGY

99

103

Immunopharmacologic aspects of lithium: one aspect of a general role as a modulator of homeostasis D.A.Hart Failure of lithium to influence cellular immune function in long-term treated patients with affective disorders J.Albrecht B.Miuller-Oerlinghausen K.RUuggeberg-Schmidt J.Volk

ABSORPTION AND BIOAVAILABILITY LITHIUM PREPARATIONS

107

OF

Lithium transport in isolated epithelial preparations R.J.Davie 1.P.L.Coleman

S.Partridge

113

The uptake of lithium by rat glycocalyx after oral administration of lithium carbonate G.Farrar 1.P.L.Coleman Bioavailability of lithium preparations R.K.Shelley

119

Formulation

and other factors affecting serum

lithium kinetic profiles

J.D.Phillips 125

Estimation

J.D.Phillips N.J.Birch

of lithium

tablet dissolution

rate

129

The prospective prediction of individualized lithium concentrations in acute mania P.J.Perry B.Alexander

133

Validation of Cooper-Simpson adolescents

technique

serum

in

B.M.Karajgi A.Rifkin V.Boppana

E.Perl

135

Serum lithium: the importance of peak values, minimum values and mean values P.Plenge E.T.Mellerup

139

Clinical significance of lithium pharmacokinetics and RBC lithium transport J.Rybakowski W.Lehmann R.Kanarkowski

THE COURSE

OF LITHIUM THERAPY

143

Predictors of response M.T.Abou-Saleh

145

Characteristics of recurrencies during ten years of lithium prophylaxis? B.Miuller-Oerlinghausen B.Kossmann J.Volk H.Herrmann

147

Routine and course outpatient clinic R.Wolf Ch.Simhandl K.Thau G.Lenz A.Lovrek J.Wancata A.Topitz E.Denk

documentation

Lithium

reactions

149

withdrawal

to prophylactic

W.Greil St.Schmidt

155

vi

Lithium withdrawal: L.Tondo G.Floris C.Burrai P.P.Pani

an outcome

lithium

of the lithium

157

Side effects (self rating and objective rating) in

265 patients under lithium long term therapy

Ch.Simhandl K.Thau Ch.Spiel E.Denk G.Lenz A.Lovrek A.Topitz J.Wancata R.Wolf

159

161

Reliability of lithium related side effects J.Wancata Ch.Simhandl E.Denk G.Lenz A.Lovrek K.Thau A.Topitz R.Wolf Ch.Spiel

Lithium

withdrawal

study in schizoaffective

patients

G.Lenz A.Lovrek K.Thau A.Topitz E.Denk Ch.Simhandl

J.Wancata R.Wolf

163

Lithium in clinical use J.L.Crammer

—

the next step

MECHANISMS: ENDOCRINOLOGY NEUROTRANSMITTERS

AND

169

The switch process in periodic affective disorder: aldosterone and AVP M.J.Levell R.P.Hullin

173

Lithium effects on essential fatty acid and prostaglandin metabolism D.F.Horrobin D.K.Jenkins J.Mitchell M.S.Manku

Vii

177

Investigations of lithium effects on neuroendocrine function in man E.Grof P.Grof G.M.Brown

183

Serum thyroglobulin and thyroid volume during administration of lithium carbonate to healthy young subjects H.Perrild U.Feldt-Rasmussen L.Hegedus P.C.Baastrup

185

Antibodies directed against determinants in the pituitary gland in lithium treated patients H.Perrild A.Moller P.C.Baastrup S.Kastberg L.Hegedus

189

The influence of lithium on blood and cerebral serotonin and on renal elimination of sodium, water and potassium in normal rats and those susceptible to audiogenic convulsions M.Uluitu C.Rodica G.Petec

noi

A clinical trial of demethylchlortetracycline lithium-like

agent in excited

as a

psychoses

R.H.Belmaker G.Roitman

195

Influence of lithium on adaptability membrane receptors A.Geisler

and function of

A.Mork R.Klysner

PHOSPHOINOSITIDE

viii

METABOLISM

201

Lithium and inositol lipid turnover S.B.Shears

205

The inhibition by lithium of inositol(1,4)bisphosphate metabolism C.1.Ragan N.Gee R.Jackson G.Reid

209

Effects of lithium ions on the accumulation of inositolphosphates in PC-12 cells and human granulocytes D.Van Calker W.Greil

213

Lithium effects on cyclic AMP and phosphatidylinositol metabolism may adrenergic — cholinergic balance S.S.Avissar

promote

G.Schreiber A.Danon R.H.Belmaker

TETRAHYDROBIOPTERIN 219

The effect of lithium on in vitro synthesis of tetrahydrobiopterin in human brain preparations J.D.Cowburn J.A.Blair

INORGANIC 225

PHARMACOLOGY

The inorganic pharmacology N.J.Birch

of lithium

THE KIDNEY 231

The renal excretion K.Thomsen

235

Lithium effects on renal function and morphology S.Christensen

241

The effects of i.v. theophylline infusion versus i.v. sodium bicarbonate infusion on lithium clearance in normal subjects S.G.Holstad P.J.Perry R.G.Kathol R.W.Carson S.J.Krummel

245

Interaction between lithium elimination steroidal anti-inflammatory drugs J.L.imbs J.M.Danion M.Schmidt M.Welsch L.Singer

of lithium

and non-

249

Evaluation of renal lesions of lithium patients by non-invasive methods Ch.Simhandl S.Kircher E.Denk G.Lubec R.Plohberger

PSYCHOBIOLOGY

AND

NEUROPHYSIOLOGY

255

Lithium and information F.N.Johnson

259

Effects of lithium on neurophysiological B.Miuller-Oerlinghausen

263

Motor and cognitive performance relationship to thyroid function J.H.Kocsis E.D.Shaw J.Hatterer J.J.Mann

265

Discrimination of responders and non responders towards lithium prophylaxis by auditory evoked potentials U.Hegerl

processing

functions

on lithium:

G.Ulrich J.Volk B.Miuller-Oerlinghausen

CELLULAR DISTRIBUTION ISOTOPE STUDIES 271

PATLT|

AND TRANSPORT,

Methods for studying the distribution transport of lithium M.Thellier J.-C.Wissocq A.Monnier Noninvasive

measurement

and

of tissue lithium in man

by 7-Li NMR spectroscopy P.F.Renshaw S.Wicklund J.S.Leigh,Jr

279

NMR studies of lithium in bipolar depression J.S.Rosenthal A.Winston S.G.Sullivan

281

“Li NMR studies of lithium transport in red cells of

manic-depressive

patients

and normal

controls

D.Mota de Freitas M.C.Espanol R.Ramasamy

285

Multinuclear

NMR

studies

M.S.Hughes

289

in lithium pharmacology

Studies of lithium ion transport in isolated rat

hepatocytes using 7Li NMR

G.M.H.Thomas R.Olufunwa

293

Effects of membrane membrane

surface charge on Lit:

interactions

and on Li* transport

mediated by monensin studied by 7Li NMR spectroscopy F.G.Riddell S.Arumugam B.G.Cox

297

A method for in-vivo measurement the body D.Vartsky A.LoMonte S.Yasumura K.J.Ellis S.H.Cohn

299

Lithium-6 isotope: toxicological, behavioural effects G.J.Alexander K.W.Lieberman J.A.Sechzer

303

Preliminary clinical and animal lithium-7 isotope

of lithium in

physiological and

experience

with

P.E.Stokes P.M.Stoll M.Okamoto E.Triana

305

New methods for the determination of the extent and stability of interaction of Li* with further solute species D.R.Crow

309

Trace element patients

serum

levels in lithium treated

C.A.Campbell M.Peet N.1.Ward

xi

ANIMAL 313

MODELS

Lithium and animal Table’ discussion

models:

introduction

to ‘Round

H.Steinberg E.A.Sykes

317

Animal models P.Plenge

319

Lithium differentially alters selective attention to novelty in rats depending on length of treatment and state of withdrawal — a possible role for 5-HT

and

lithium treatment

receptor sub-types

P.E.Harrison-Read

325

Lithium the rat

effects on memory

for food location in

G.Hines

329

Cognitive effects in offspring of rats treated the Li-6 isotope J.A.Sechzer K.W.Lieberman G.J.Alexander

331

Acute effects of LiCl upon M.E.Otero Losada M.C.Rubio

333

Molecular

mechanisms

seizures

in the rat

of action of lithium:

on the stereoselectivity of rat-brain

MAO.

D.F.Smith

335

Closing address: R.P.Hullin

339

The message: M.Schou

xii

341

Author

343

Subject index

index

a review of the Congress

an epilogue

with

effect

INTRODUCTION

Lithium was introduced into psychiatry in 1949 by John Cade. We were fortunate at the first Lithium Congress in 1977 to have him give a personal account of the discovery of the use of lithium in psychiatry. Sadly he is no longer with us, but the 2nd British Lithium Congress has tried to build and

extend on the fine foundation which is his legacy to us. The first Congress was held at the University of Lancaster under the chairmanship of Dr Neil Johnson and it is a great privilege to acknowledge his assistance in the original planning of the second conference ten years later in Wolverhampton. The 2nd British Lithium Congress was long overdue and, in fact, there had been no major Congress on lithium since about 1982. Much progress has been made, particularly in the biochemical, pharmacological and psychophysiological areas and in the range of clinical use to which lithium has been put. It was hoped that the choice of Wolverhampton as a location for this Congress would be appropriate because of its central position and easy travel facilities and because of its pleasant Conference Centre at Compton Park on the edge of the town. Wolverhampton Polytechnic is a new generation institution of higher education founded in the late sixties and now coming of age in the international academic world. The organizers received much encouragement from the Polytechnic and Civic authorities and it is a pleasure to acknowledge particularly the roles of the Director of the Polytechnic, Mr M.J.Harrison and the Mayor of Wolverhampton, Councillor Mrs D.Seiboth. Why then should we need to have a Congress on lithium at all? Conflicting views appear in the first few papers of the Congress. Professor Schou’s thoughtful introduction provides us with a number of clinical justifications for our concern with lithium. His close friend and colleague, Dr Baastrup, takes a much more iconoclastic viewpoint and questions whether we should not, in fact, allow patients to act out their disease process rather than try to suppress it. Dr McCreadie gives us some insights into the financial implications of the use of lithium and provides figures which, if calculated on a global, or even European, basis are truly staggering. We are, of course, unable to measure the cost of suffering or the cost in terms of disruption to the family, but purely in terms of savings in hospital

xiii

costs we must recognize, and broadcast, the information that lithium is a major contributor to the health economy. From the scientific viewpoint, of course, lithium is an interesting substance. It is very simple,

small and inexpensive, but it has powerful effects on biological systems at low concentration. The molecular details of these interactions are but sketchily known and the boundaries of our knowledge are frequently limited by the boundaries of other disciplines and our ability to communicate with the practitioners of these disciplines. Wittgenstein said ‘the limits of my speech determine the limits of my world’ and this is ever true in science. True interdisciplinarity requires a multi-lingual attitude and a willingness to try to comprehend the modus operandi of other disciplines. Lithium is, after all, of prime interest to very few scientists and, in fact, it is its use by other scientists as a tool to interfere with other processes which provides much of the experimental information known about the metal ion. It is this collection of sundry experimental information from a variety of sources which is the essence of the core of lithium knowledge at the molecular and mechanistic level. It seems clear to me that there have been major advances in the area of hormone receptors and second messenger systems which go some way to explain the endocrinological results reported. The clinical uses of lithium have been expanded to encompass some areas which were considered psychopharmacological curiosities; for instance, the use in aggression. Combination therapy with drugs such as carbamazepine is now an exciting new prospect. Conversely, the nature of the interactions with other psychotropic and nonpsychotropic drugs to give toxic side effects is being steadily defined to lead to safer practice. The techniques of studying large cohorts of lithium patients have been valuably exploited in several centres and these have given us a new insight into side effects and the ways in which these side effects are perceived, both by patients and by their physicians. Research studies on information processing and on the application of neuro/psychophysiological techniques are beginning to yield knowledge of the psychophysiological substrates on which lithium plays its part. Finally we have some new, exciting techniques for investigating the location

Xiv

and interactions of lithium at the intracellular level, both in humans and in animal and ex vivo models. Much has been heard of nuclear magnetic resonance

spectroscopy

as it has been

applied to

other branches of diagnostic medicine and it is clear that this technique has its own special role in biological psychiatry. The structure of the present volume is deliberately concise. It was decided that within the constraints of the pages allocated there was no justification for inclusion of long review chapters since it was more important to allow the whole range of participants at the Congress to make brief but adequately documented statements of the recent work in their area. In this way we hope that it is as up-to-date and comprehensive a coverage of the subject as is possible in a volume of manageable size. Many major reviews are cited and these may be consulted for detailed evidence and for historical aspects. | wish to acknowledge the large debt | have in the organization of the Congress to the sponsors, whose generosity made the meeting possible. Lithium is not a drug which is a very large commercial earner in the same sense that benzodiazepines and other psychotropic drugs can be. It is therefore all the more creditable that the two major lithium producing companies in the UK, Delandale Laboratories Ltd and Norgine Ltd, together with the world’s major producer of lithium ore, Lithium Corporation of America and its European subsidiary, provided much of the support base which was required. Essential financial support was also received from Foote Mineral Co. Inc., Heyden & Son Ltd, Janssen Ltd, Pergamon Press, S.K. & F.Foundation and Georg Thieme Verlag. Particularly, | wish to thank my colleagues on the Organizing Committee, Drs |.P.L.Coleman and S.Partridge and Messrs R.J.Davie, M.S.Hughes, J.D.Phillips and G.M.H.Thomas, whose work throughout the year of organization was careful and painstaking and mainly very tedious. Their efforts during the running of the Conference were seen by all, though perhaps because of the efficiency of their operation the amount of effort may not have been appreciated. Thanks to Susanna and Catherine Birch for their editorial assistance. Thanks also go to the editorial staff of IRL Press for their prompt attention to queries and helpful advice and guidance in the preparation of

XV

this volume. Finally, | wish to thank Mrs Sue Sydenham, who was secretary to the Congress from the beginning of its organization and who held the whole arrangement together. She has borne the changes of direction, bad hand-writing, irate telephone calls and intermittent faults with the word-processor with great fortitude and always with a smile. Very many thanks from all of us. This volume is, therefore, presented as an up-todate summary of lithium research as it was in September 1987. It is hoped that it will act as a springboard for further ideas and for further progress in the area of lithium in psychiatry and in inorganic pharmacology. Nicholas J. Birch

Xvi

Biomedical Research Laboratory Wolverhampton Polytechnic

PRINCIPAL

AUTHORS

M.T.Abou-Saleh

University Department of Psychiatry, Royal Liverpool Hospital, PO Box 147, Liverpool

L69 Adityanjee

3BX,

Department

UK of Psychological

Medicine,

Medicine, University of Malaya, Lumpur, Malaysia

59100

Faculty of

Kuala

S.K.Ahmed

Hayes Grove Priory Hospital, Preston Road, Hayes, Kent BR2 7AS, UK

G.Albrecht

Department of Dermatology, Krankenhaus Spandau, Lynarstrasse 12, 1000 Berlin 20, FRG

J.Albrecht

Psychiatrische Klinik und Poliklinik d. FU B, Eschenallee 3, D 1000 Berlin 19, FRG

G.J.Alexander

722 West

S.S.Avissar

Beer-Sheva Mental Beer-Sheva, Israel

P.C.Baastrup

Busmedjen Denmark

R.O.Bach

44 Old Post Road, Lake Wylie, SC 29710,

K.Balasubramaniam

Senior Registrar in Psychiatry, North Wales Hospital, Denbigh, Clwyd LL16 5SS, UK

R.H.Belmaker

Ben Gurion University Faculty of Medicine, POB 4600, Beer-Sheva, Israel

N.J.Birch

Biomedical Research Laboratory, Centre for Health Sciences, The Polytechnic, Wolverhampton WV1 1DJ, UK

J.A.Blair

School of Molecular Sciences, Aston University, Birmingham B4 7ET, UK

T.D.Brewerton

Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, 171 Ashley Avenue, Charleston, SC 29482, USA

A.Buchan

Department of Medical Microbiology, University of Birmingham, Birmingham B15 2TJ, UK

C.A.Campbell

David Rice Hospital, Drayton High Road, Norwich, Norfolk NR8 6BH, UK

S.Christensen

Department of Pharmacology, University of Copenhagen, 20 Juliane Maries Vej, 2100 Copenhagen, Denmark

168 Street,

New

Health

23, Tebbestrup,

York, NY Center,

POB

10032,

USA

4600,

8900 Randers,

USA

xvil

J.L.Crammer

South Grange, 35,°UK

Fenway,

Steeple Aston,

Oxon

OX5

D.R.Crow

School of Appliéd Sciences, The Polytechnic, Wolverhampton WV1 1LY, UK

M.£.J.Curzon

Department of Child Dental Health, School of Dentistry, Clarendon Way, Leeds LS2 9LU, UK

R.J.Davie

Biomedical Research Laboratory, Centre for Health Sciences, The Polytechnic, Wolverhampton WV 1

1DJ, UK G.M.Dempsey

715 Grand Avenue, NM 87102, USA

G.Farrar

Department of Molecular Sciences, Aston University, Birmingham B4 7ET, UK

A.H.Friedlander

Brentwood

Dental

203 Albuquerque,

Service,

Administration Medical CA 90073, USA

Veterans

Center,

West

Los Angeles,

V.S.Gallicchio

University of Kentucky

Medical Center, Medical Center Annex 2, Lexington, KY 40536-0080, USA

A.Geisler

Department of Pharmacology, University of Copenhagen, 20 Juliane Maries Vej, 2100 Copenhagen, Denmark

W.Greil

Psychiatric Hospital, University of Munich, Nussbaumstrasse 7, D 8000 Munich 2, FRG

P.Grof

Departments of Psychiatry and Neurosciences, PO Box 585, McMaster University, Hamilton, Ontario, Canada L8N 3K7

P.E.Harrison-Read

Mental Health Unit, St Charles Street, London W10 6DZ, UK

D.A.Hart

Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, 3330 Hospital Drive N.W., HSC Calgary, Alberta, Canada T2N 4N1

U.Hegerl

Psychiatrische

D G.Hines

XViill

126

Hospital,

Klinik d. FU B, Eschenallee 1000 Berlin 19, FRG

Exmoor

3,

Department of Psychology, University of Arkansas at Little Rock, 2801 South University, Little Rock, AR 72204, USA

D.F.Horrobin

Efamol

Research

Guildford,

M.S.Hughes

Meadows,

UK

1DJ, UK

Regional Metabolic Hospital, Menston,

J.-L.Imbs

1BA,

Biomedical Research Laboratory, Centre for Health Sciences, The Polytechnic, Wolverhampton

WV1 R.P.Hullin

Institute, Woodbridge

Surrey GU1

Research Unit, High Royds Ilkley LS29 6AQ, UK

Institut de Pharmacologie,

Strasbourg,

11 rue Humann,

67000

France

J.W.Jefferson

Department of Psychiatry, University Hospitals, 600 Highland Avenue, Madison, WI 53792, USA

F.N.Johnson

Department of Psychology, Bailrigg, Lancaster, UK

B.M.Karajgi

Mount Sinai Services, Department of Psychiatry, C11-26, City Hospital Center at Elmhurst,

Elmhurst, NY 11373, J.R.King

USA

Barnsley Hall Hospital,

B61

The University,

Bromsgrove,

Worcs

OEX, UK

J.H.Kocsis

Payne Whitney Clinic, 525 East 68th Street, New York, NY 10021, USA

G.Lenz

Psychiatric Clinic, University of Vienna, Wahringergurtel 18-20, A-1090 Vienna,

Austria

M.J.Levell

Division of Steroid Endocrinology, University of Leeds, 26 Hyde Terrace, Leeds LS2 9LN, UK

R.G.McCreadie

Crichton

P.Milln

Department of Psychiatry, Royal South Hants Hospital, Graham Road, Southampton

SO9 D.Mota

de Freitas

Royal Hospital,

4PE,

Dumfries,

UK

UK

Department of Chemistry, Loyola University of Chicago, 6525 N. Sheridan Road, Chicago, IL 60626, USA

B.Miuller-Oerlinghausen

Psychiatrische Klinik d. FU B, Eschenallee 3, D 1000 Berlin 19, FRG

M.E.Otero

Instituto de Investigaciones,

Farmacoldégicas

(CONICET) Argentina

(1113) Bs.As.

Losada

Junin 956 5°P°,

xix

H.Perrild

Department of Medicine E, Frederiksberg 2000 Copenhagen, Denmark

P.J.Perry

College of Pharmacy, The University of lowa, lowa City, IA 52242, USA

J.D.Phillips

Biomedical

Research Laboratory, Centre for Health Sciences, The Polytechnic, Wolverhampton WV1 1DJ, UK

P.Plenge

Psychochemistry

Institute, Rigshospitalet, 9, 2100 Copenhagen, Denmark

Blegdamsvej R.M.Post

Building 10, Room 3N212, 9000 Bethesda, MD 20892, USA

S.Priebe

Psychiatrische

Eschenallee C.1.Ragan

Rockville

Pike,

Klinik und Poliklinik d. FU B, 3, 1000 Berlin 19, FRG

Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex

CM20 P.F.Renshaw

Hospital,

2Q0R, UK

504 Goddard Laboratories, 37th and Hamilton Walk, University of Pennsylvania, Philadelphia,

PA

19104,

USA

F.G.Riddell

Department of Chemistry, The University, FK9 4LA, UK

J.Rybakowski

Department of Psychiatry, Academy of Medicine, 85-863 Bydgoszcz, ul-comzynska 54, Poland

M.Schou

The Psychiatric Hospital, Skovagervej DK 8240, Denmark

J.A.Sechzer

Bourne Behavioral Laboratory, Cornell University Medical Center, Bloomingdale Road, White Plains, NY 10605, USA

S.B.Shears

Department of Biochemistry, University of Birmingham, Birmingham B15 2TT, UK

R.K.Shelley

St Brigid’s Hospital, Ardee, County Louth, Ireland

Ch.Simhandl

Department of Psychiatry, University of Vienna, WahringergUurtel 18-19, A-1090 Vienna, Austria

D.F.Smith

Psychopharmacology Research Unit, Psychiatric Hospital, Skovagervej 2, 8240 Risskov, Denmark

G.K.Spring

11311 Shaker Boulevard, OH 44118, USA

XX

Cleveland,

Stirling

2, Risskov,

D.P.Srinivasan

Garlands Hospital, Carlisle, Cumbria CA 3SX, UK

G.Stein

Post-Graduate Centre, Farnborough Hospital, Farnborough Common, Orpington, Kent BR6 8ND, UK

H.Steinberg

University College, Gower Street, London WC1, UK

P.E.Stokes

New

York Hospital-Cornell

East 68th M.Thellier

Street,

New

Faculté des Sciences

Medical

York,

NY

de Rouen,

Center,

10021,

525

USA

Laboratoire

Echanges Cellulaires, BP 67-76130, Aignan, France

des

Mont Saint

G.M.H.Thomas

Biomedical Research Laboratory, Centre for Health Sciences, The Polytechnic, Wolverhampton WV1 1DJ, UK

K.Thomsen

The Psychopharmacology Research Unit, The Psychiatric Hospital, Skovagervej 2, 8240 Risskov,

Denmark L.Tondo

Via Cavalcanti

S.P.Tyrer

Department of Psychiatry, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP, UK

M.Uluitu

Baladei Street, 2 Bloc 61, sc.2 ap.49, Sector 4, 73252 Bucharest, Romania

D.van

Psychiatric Hospital, University of Munich, Nussbaumstrasse 7, D 8000 Munich 2, FRG

Calker

32, 09100

Cagliari, Italy

D.Vartsky

Soreq Nuclear Research Israel

J.Volk

Psychiatrische Klinik d. FU B, Eschenallee 3, D 1000 Berlin 19, FRG

J.Wancata

Psychiatric Clinic, University of Vienna, WaAhringergutrtel 18-20, A-1090 Vienna, Austria

A.Winston

Beth

R.Wolf

Psychiatric Clinic, University of Vienna, Wahringergtrtel 18-20, A-1090 Vienna,

Israel Medical

Place, New

York,

Center, Yavne

Center,

NY

10 Nathan

10003,

70600,

Perlman

USA

Austria

xxi

:

=

ae

wstitelye

a

its

DSSuto

~wabe -Lifes

ere

he

aed

aa

CO-AUTHORS B.Alexander

College of Pharmacy, University of lowa, lowa City, |A 52242, USA, and lowa City Veterans Administration Medical Center

S.Arumugam

Department of Chemistry, The University, Stirling FKQ 4LA, UK

M.Bernadt

King’s College Hospital, London,

V.Boppana

Mount Sinai Services, Department of Psychiatry, C11-26, City Hospital Center at Elmhurst, Elmhurst, NY 11373, USA

G.M.Brown

Departments of Psychiatry and Neurosciences, PO Box 585, McMaster University, Hamilton, Ontario,

Canada C.Burrai J.A.Carroll

L8N 3K7

Clinica Psichiatrica, Universita di Cagliari, Italy Department

of Psychiatry,

600 Highland Avenue, R.W.Carson

B.Causemann

1.P.L.Coleman

Hospitals,

WI 53792,

USA

The University of lowa,

lowa City, IA 52242,

USA

Psychiatrische

1000

Berlin

Soreq Nuclear Israel Biomedical

Klinik d. FU B, Eschenallee

Department University,

3,

19, FRG Research

Research

Center,

Yavne

Laboratory,

Sciences, The Polytechnic, WV1 1DJ, UK J.D.Cowburn

University

Madison,

College of Pharmacy,

D S.H.Cohn

UK

of Pharmacy, Birmingham

70600,

Centre

for Health

Wolverhampton

Biology Division, Aston

B4 7ET,

UK

B.G.Cox

Department of Chemistry, FK9 4LA, UK

J.M.Danion

Service France

E.Denk

Psychiatric Clinic, University of Vienna, Wahringergurtel 18-20, A-1090 Vienna, Austria

K.J.Ellis

Soreq Nuclear Israel

M.C.Espanol

de Psychiatrie,

Department

Research

The University,

CHRU,

Center,

of Chemistry,

Chicago, 6525 N. Sheridan 60626, USA

67091

Yavne

Stirling

Strasbourg,

70600,

Loyola University of

Road, Chicago,

IL

XXII

U.Feldt

Rasmussen

Department

of Medicine

2000 Copenhagen,

E, Frederiksberg

Hospital,

Denmark

G.Floris

Centro

‘Bini’, Cagliari, Italy

A.Fuller

Department of Medical Microbiology, University of Birmingham, Birmingham B15 2TJ, UK

N.S.Gee

Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK

J.H.Greist

Department of Psychiatry, University Hospitals, 600 Highland Avenue, Madison, WI 53792, USA

E.Grof

Departments of Psychiatry and Neurosciences, PO Box 585, McMaster University, Hamilton, Ontario, Canada L8N 3K7

C.E.Hartley

Department of Medical Microbiology, University of Birmingham, Birmingham B15 2TJ, UK

J.Hatterer

Cornell University Medical New York, USA

L.Hegedus

Department of Medicine E, Frederiksberg 2000 Copenhagen, Denmark

Hospital,

H.Herrmann

Department of Biometrics and Statistics, School of Hannover, FRG

Medical

S.G.Holstad

College of Pharmacy,

The University of lowa,

lowa City, IA 52242,

USA

College,

R.G.Jackson

Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 20R, UK

D.K.Jenkins

Efamol Research Institute, Woodbridge Guildford, Surrey GU1 1BA, UK

R.Kanarkowski

Department of Psychiatry, Academy of Medicine, 85-863 Bydgoszcz, ul.Lomzynska 54, and Department of Biopharmaceutics, Medical Centre of Postgraduate Education, Bydgoszcz, Poland

R.G.Kathol

College of Pharmacy, The University of lowa, lowa City, IA 52242, USA

S.Kastberg

Department of Medicine E, Frederiksberg 2000 Copenhagen, Denmark

S.Kircher

Institute of Medical Chemistry, University of Vienna, A-1090 Vienna, Austria

XXiV

Meadows,

Hospital,

R.Klysner

Department of Pharmacology, University of Copenhagen, 20 Juliane Maries Vej, 2100 Copenhagen, Denmark

B.Kossmann

Psychiatrische

K.G.Kramlinger

Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, 171 Ashley Avenue, Charleston, SC 29482, USA

S.J.Krummel

College of Pharmacy,

The University of lowa,

lowa City, IA 52242,

USA

Klinik d. FU B, Eschenallee 1000 Berlin 19, FRG

$}, |D)

W.Lehmann

Department of Psychiatry, Academy of Medicine, 85-863 Bydgoszcz, uldomzynska 54, Poland

J.S.Leigh

Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA

19104,

USA

K.W.Lieberman

New York State Psychiatric Institute, Columbia University, NY 10032 and Bourne Behavioral Laboratory, Cornell University Medical Center, Bloomingdale Road, White Plains, NY 10605, USA

A.LoMonte

Soreq Nuclear Research Israel

A.Lovrek

Psychiatric Clinic, University of Vienna, Wahringergurtel 18-20, A-1090 Vienna, Austria

G.Lubec

Pediatric Department, University of Vienna, A-1090 Vienna, Austria

M.S.Manku

Efamol

Research

70600,

Institute, Woodbridge

Guildford, Surrey GU1 J.J.Mann

Center, Yavne

Meadows,

1BA, UK

Cornell University Medical

College, New

York,

USA E.T.Mellerup

J.Mitchell

Psychochemistry Institute, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark Efamol

Research

Guildford,

Institute, Woodbridge

Surrey GU1

1BA,

Meadows,

UK

A.Moller

Department of Medicine E, Frederiksberg 2000 Copenhagen, Denmark

A.Monnier

Faculté des Sciences de Rouen, Laboratoire des Echanges Cellulaires, BP 67-76130, Mont Saint Aignan, France

Hospital,

XXV

A.Mork

Department of Pharmacology, University of Copenhagen, 20 Juliane Maries Vej, 2100 Copenhagen, Denmark

M.Okamoto

New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA

P.P.Pani

Clinica Psichiatrica,

C.Patch

Department of Psychiatry, Royal South Hants Hospital, Graham Road, Southampton SO9 4PE,

Universita di Cagliari, Italy

UK M.Peet

Northern

General

E.Perl

Mount Sinai Services, Department of Psychiatry, C11-26, City Hospital Center at Elmhurst, Elmhurst,

NY

Hospital,

11373,

Sheffield,

UK

USA

G.Petec

Baladei Street, 2 Bloc 61, sc.2 ap.49, Sector 4, 73252 Bucharest, Romania

R.Plohberger

Institute of Medical Chemistry, University of Vienna, A-1090 Vienna, Austria

R.Ramasamy

Department of Chemistry, Loyola University of Chicago, 6525 N. Sheridan Road, Chicago, IL 60626, USA

S.Randall

Department Birmingham,

G.G.Reid

Merck

of Medical

Sharp & Dohme

Terlings Park, Eastwick CM20 20R, UK A.Rifkin

Microbiology,

Birmingham

B15

2TJ,

Research

University of UK

Laboratories,

Road, Harlow,

Essex

Mount Sinai Services, Department of Psychiatry, C11-26, City Hospital Center at Elmhurst,

Elmhurst,

NY 11373,

USA

C.Rodica

Baladei Street, 2 Bloc 61, sc.2 ap.49, Sector 4, 73252 Bucharest, Romania

J.S.Rosenthal

Beth Israel Medical Center, 10 Nathan Place, New York, NY 10003, USA

M.C.Rubio

Instituto de Investigaciones,

Farmacoldgicas

(CONICERM Argentina

(1113) bs-As

XXVIi

Sunin S56 SoP27

Perlman

K.RUggeberg-Schmidt

M.Schmidt

Department of Dermatology, Krankenhaus Spandau, Lynarstrasse 12, 1000 Berlin 20, FRG Institut de Pharmacologie,

11

rue Humann,

67000

France

Strasbourg,

S.Schmidt

Psychiatric Hospital, University of Munich, Nussbaumstrasse 7, D 8000 Munich 2, FRG

E.D.Shaw

Cornell University Medical

College, New

York,

USA L.Singer

Service de Psychiatrie,

CHRU,

67091

Strasbourg,

France G.R.B.Skinner

Department of Medical Microbiology, University of Birmingham, Birmingham B15 2TJ, UK

S.Specter

University of South Florida Medical Center, Department of Medical Microbiology, Florida, USA

Ch.Spiel

Department of Psychology, A-1090 Vienna, Austria

P.M.Stoll

New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA

S.Suilivan

Beth Israel Medical Center, 10 Nathan Place, New York, NY 10003, USA

E.A.Sykes

School of Psychology, Middlesex, UK

K.Thau

Psychiatric Clinic, University of Vienna, Wahringergurtel 18-20, A-1090 Vienna, Austria

A. Topitz

Psychiatric

E.Triana

New

G.Ulrich

Psychiatrische

Polytechnic,

18-20,

A-1090

Vienna,

Austria

York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA

1000

Berlin

Department Guildford,

M.Welsch

Middlesex

Perlman

Clinic, University of Vienna,

Wahringergurtel

N.1.Ward

University of Vienna,

Klinik d. FU B, Eschenallee

of Chemistry,

University of Surrey,

UK

Institut de Pharmacologie, Strasbourg,

3, D

19, FRG

11 rue Humann,

67000

France

XXVIII

S.Wicklund

Department of Biochemistry and Biophysics, University of Pennsylvania Philadelphia, PA 19104, USA

C.Wildgrube

Psychiatrische Klinik und Poliklinik d. FU B, Eschenallee 3, 1000 Berlin 19, FRG

J.-C.Wissocq

Faculté

des Sciences

Echanges Cellulaires, Aignan, France S.Yasamura

XXVill

de Rouen,

Laboratoire

BP 67-76130,

Soreq Nuclear Research Israel

Mont

Center, Yavne

des

Saint

70600,

Mogens Schou

Lithium reflections | The Psychiatric Hospital, Skovage2, rvej Risskov, DK 8240, Denmark

In

his

about

inaugural

"Lithium

-

lecture

past,

ten

present

years and

ago

John

future"

Cade

(1).

talked

Also

later

treatises have dealt with lithium's past, for example Johnson's "The History of Lithium Therapy" (2). There is accodingly no reason now to delve into the more distant past. During the last decade the interest in lithium, as reflected in the number of publications about its biology, pharmacology and clinical use, has not waned (3). Approximately 600 articles and books about these topics have appeared each year. The number is in fact higher, but I have incorporated into my lithium reference database only some of the papers that deal with lithium effects on blood formation. The frequency of lithium publications will presumably decrease sooner or later, but there is as yet no clear indication of a fall of interest. This

last

decade

has

not

seen

as

dramatic

developments

as

the previous one, when lithium prophylaxis became established. It has rather been a period of consolidation and steady growth, and it is my impression that lithium treatment today is used with better insight and more skill and conscientiousness than it was ten years ago. This has undoubtedly to do with a higher level

of

information,

and

the

decade

has

seen

a

number

of

initiativesin this direction. There was a lithium congress in New York in 1978 (4) and a symposium on the mechanism of action of lithium in 1981 (5). Several books have surveyed and updated our knowledge, in English (6,7), Japanese (8) and German (9). In Japan a special lithium branch of the psychiatric association meet at yearly intervals. And now we are gathered here again in England. Equally important as information to physicians is information and instruction of patients and relatives. If long-term treatment is to yield satisfactory results, it must be based on close and confident cooperation between doctor, patient and family, and such cooperation requires that full and sober information is given to the latter both verbally and in written form. Information books written specifically for patients and relatives are available in several languages (10-16). They should not replace personal contacts, but may form the basis for enlightened discussion. The congress ten years ago took place in the shadow of fear generated by observation of morphological changes in the kidDid we perhaps buy their neys of lithium-treated patients. mental health at the expense of their kidney function? Would long-term treatment lead to progressive deterioration of glomerular filtration with eventual azotemia? On the basis of both transversal and longitudinal, extensive function studies, It does not. But the events these fears can now be put to rest. have

focussed

our

attention

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch Deen eee eee

eee

on

long-term

effects

in

general,

and Psychiatric Use

eee

© IRL Press Limited, Oxford, England.

eee

es

M.Schou a a

aT

and systematic prospective studies are in mental and somatic, progress in several places. At the Psychiatric Hospital in Risskov we have fora number

of

with

treated

patients

of

a group

following

been

years

after 6 and They are examined before treatment starts, lithium. At at yearly intervals. and thereafter 12 months of treatment,

the lithium exposure time for the Publications about patient years.

is

period

treatment

individual

longest

the

present

seven

years;

group as a whole is about 550 the cohort have dealt with

effects of long-term the effect of age on dosage requirements, erythrofunction, renal lithium treatment on thyroid function, cyte folate concentration, fasting blood sugar, seasonal of blood pressure, variations and prediction of noncompliance (17-24). Future publications will include additional exami-

nations bolism, our

of kidney function as well as studies on water metatremor, weight gain, and psychological complaints.

An important experience own treatment practice

lowering

of

lithium

of is

dosages

recent years, concerned, is

and

serum

at least as far that a general

lithium

as

concentrations

to

averages of about 24 mmol/day and 0.7 mmol/l does not seem to have lowered prophylactic efficacy substantially, while many side effects have become markedly less frequent and troublesome. Today, for example, we find no significant difference between average urine volumes during and before lithium treatment, and polyuria complaints are infrequent. It is my

impression that also intoxications have become rarer, but I do not at the present time have quantitative documentation of this, and possible causative factors may include improved observance of precautions and guidelines. With

a

prospective

increasingly

cohort

valuable

with

project

time.

We

the

data

shall

bank

continue

becomes

to

follow

the patients according to gradually revised schedules, and plan to cooperate with research groups similarly active in Germany, Austria, Canada, and possibly Sweden.

We sible but

do not yet know for the effects

research

in

the

intrigued

in

of

the

order

the biological mechanism that is responof lithium on manic-depressive illness,

area

particularly

is

by

0.5-1

very

the

mmol/l

active.

ability to

regulatory

feedback

Personally

of

exert

inositol messenger system which stimulating or inhibitory. That of

we

lithium

actions

I have

on

the

phospho-

according to circumstances is at least a model of the

mechanism

we

are

looking

been

concentrations

are kind

for.

The main obstacle in trying to study mood-modifying drugs experimentally is the difficulty of knowing whether the changes we produce in our experimental systems, be they healthy rats or brain cortex slices or neuroblastoma clones, are in any way connected with what happens when the same drugs or procedures

are

used

former

to

and

heal the

extrapolation ridiculous. A

helpful

the

sick

latter

or

deduction

procedure

human

systems

may

could,

mind.

is

so

seem

The large

distance that

farfetched

however,

be

to

between

attempts

and

group

the

at

even treatment

modalities into categories which are reasonably distinct as regards their effect on manic-depressive illness. In the first category one might place electroconvulsive therapy and lithium, both of them treatments of well documented efficacy, with a good deal of diagnostic specificity, and acting on the manic as well as the depressive manifestations of the illness. Carbann

2

ee

mazepine

should

depressant

possibly

drugs

might

be

placed

constitute

in a

the

same

second

Lithium

ee

group.

category.

reflections | eee

The

anti-

They

share

with the treatments in the first group considerable efficacy and diagnostic specificity, but they act on depressions only, not on manias. A third category might then contain the neuroleptics and drugs with hypnotic-sedative-anxiolytic action. some of the symptoms of mania These agents can alleviate anxiety), restlessness, agitation, (violence, depression

and but

their action is not specific for manic-depressive illness. Now, if we exposed our experimental system to appropriate representatives of all the groups or categories, we might find that none of them had any effect, and then there would be no evidence of a connection with mood modification. Or we might find that the experimental system was affected similarly by all

the groups, and in that case evidence of specificity would be lacking. But we might also be lucky enough to find that the experimental change was produced by ECT and lithium (and perhaps carbamazepine), that it was or was not produced by antidepressant

drugs,

neuroleptics

and

it

be

would

not

and

that

the

barbiturates entirely

system

and

absurd

to

was

quite

unaffected

benzodiazepines. assume

that

In

the

by

that

case

phenomenon

under investigation might somehow, however indirectly, be related to manic-depressive illness and mood normalization. My suggestion is therefore that rather than exposing our experimental systems to same or different

ten different antidepressants, whether generations, we should investigate the

of

the

effects of widely differing psychotropic agents and procedures and then compare clinical similarities and dissimilarities with experimental similarities and dissimilarities. Such a procedure might give us indications of validity and a clue to further progress. And

what

about

the

more

distant

future?

If

research

should

at one time succeed in clarifying the cerebral mechanisms which govern levels of mood, activity and mental speed, this would seem to open possibilities of not only normalizing but also manipulating mood. It might, for example, become possible through chemical or a particular level, perhaps become able

electrical procedures to adjust the mood to one's own mood and that of others. One may to choose a life in chronic hypomania, a

state subjectively more attractive than even the most pleasant marihuana or alcohol euphoria. Is that a happy vision? Or is it a frightening one? It is at any rate a possibility which has wide

perspectives

issue:

Should

and

which

scientists

forces

under

all

us

to

ponder

circumstances

the

central

reveal

the

secrets of nature, or are there doors which they should from opening because of the possible consequences?

abstain

REFERENCES

1.

Cade,J.F.J.(1978) in Lithium in Medical Practice, Johnson,F.N.,Johnson,S.) pp 5-16. MTP, Lancaster.

2.

Johnson,F.N.(1984) Millan, London.

3. 4.

Schou,M.(1986) Hum.Psychoparmacology, 1, 51-55. Cooper,T.B.,Gershon,S.,Kline,N.S.,Schou,M.,eds. (1979)

Lithium: Med.,

The

Controversies

Amsterdam.

History

and

of

Lithium

Unresolved

Therapy.

Issues.

(eds.

Mac-

Excerpt.

M.Schou

Emrich,H.M.,Aldenhoff,J.B.,Lux,H.D.,eds. (1982) Basic Mechanisms in the Action of Lithium. Excerpt.Med., Amsterdam.

Johnson,F.N.,ed. (1980)

Handbook

of

Lithium

Therapy.

MTP,

Lancaster. Jefferson,J.W.,Greist,J.H.,Ackerman,D.L.,Carroll,J.A.

(1987) Lithium Encyclopedia for Clinical Practice,2.ed. Am.Psychiatr.Press, Washington. Watanabe,S.(1983) Lithium: Research and Clinical Use. (In Japanese).

14.

MDP,

Tokyo.

Muller-Oerlinghausen,B.,Greil,W.,eds.(1986) Die Lithiumtherapie. Springer, Berlin. Schou,M.(1980) Litiumbehandling av mano-depressiv sjukdom. Astra, Sddertalje. Schou,M. (1983) Lithiumbehandling af manio-depressiv sygdom. 2.ed. Arkona, Aarhus. Schou,M. (1984) Lithium Treatment of Manic-Depressive Illness. (In Japanese). Igakushuppan-Sha, Tokyo. Schou,M. (1984) Le Lithium. Press.Univ.France, Paris. Schou,M. (1986) Lithium Treatment of Manic-Depressive Illness. 3.ed. Karger, Basel. Schou,M. (1986) Lithium-Behandlung der manisch-depressiven Krankheit. 2.ed. Thieme, Stuttgart. Schou,M. (1986) Il trattamento con litio della malattia maniaco-depressiva. Athena Editrice, Roma. Vestergaard,P.,Schou,M.(1984) Pharmacopsychiatry, 17, IES PA(OM0)

Maarbjerg,K.,Vestergaard,P.,Schou,M. (1987)

psychiatr.scand.,

75,

Acta

217-221.

Lassen,E.,Vestergaard,P.,Thomsen,K.(1986) Psychiatry, 43, 481-482.

Arch.Gen.

Schou,M.,Thomsen,K.,Vestergaard,P.(1986) Clin.Nephrol., ZOO =e ar Schou,M.,Mortensen,E.,Vestergaard,P.(1986) Human

Psychopharmacology,

1,

29-33.

Vestergaard,P.,Schou,M. (1987)

Neuropsychobiology,

in

the press. Vestergaard,P.,Schou,M. (1986)

Pharmacopsychiatry,

19,

73-

74.

Vestergaard,P.,Maarbjerg,K.,Nielsen,N.,Aagaard,J. (1986) Inte .Neurosei., Silly) 12),

P.C.Baastrup

Lithium Busmedjen

LITHIUM

reflections

II

23, Tebbestrup, 8900 Randers,

Denmark

REFLECTIONS

In 1967 Professor Schou and I published a joint paper entitled "Lithium as a prophylactic agent". We both considered the title a good one — what we intended to demonstrate was that continuous lithium treatment made it possible to change the course of a manic-depressive illness in such a way that the patients no longer experienced psychotic episodes. The use of that title was a grave mistake! And - having been brought up in a country where modesty is considered the prime virtue, we ought to have known better. We had been pretentious enough to claim that we could present a method for the preven-— tion of mental illness. Our claim was interpreted as improper selfassertion and invited criticism which was not altogether objective. Ten years later, however, everyone knew that lithium was effective in the prevention of psychotic episodes with a nucleus of manic-depressive patients, though only a minority of the diagnostically rather vaguely defined group of patients who suffer from affective disorders. And ten years ago attention was focused on the side treatment, especially the effects of lithium on the

effects of lithium kidney function.

What about the present situation? Professor Schou has sought to give an objective answer to that question on the basis of his thorough knowledge of scientific literature. My intention is to give an answer based on a clearly subjective experience of a more superficial knowledge of the same literature combined with my clinical experience. In my opinion we are faced with a situation where therapeutic enthusiasm motivates too many patients for lithium treatment. I think that the selection of patients for lithium treatment is often made indiscriminately. A claim which is partly based on my study of the case records of several hundred patients undergoing lithium treatment, and the fact that approximately 25 per cent of the patients cease lithium treatment within the first six months substantiates

I also

"The

think

History

my

that

claim.

therapeutic

of Lithium

enthusiasm

Therapy"

presents

- I quote:

itself

"Lithium

in the great majority of cases for the treatment of what manic-depression or more accurately recurrent endogenous

and

— I quote

again:

"If affective

simple expedient of administering that the basis of these disorders

disorders a chemical might take

could

are

gamut

prologue

of

prescribed

is commonly called affective disorders."

be eliminated

substance, a chemical

that; might affect, mood, emotion and the whole experience be translated into chemical terms?"

in the

salts

by the

did this not suggest form? And not only of human

conscious

Looking back on the history of psychiatry we all recall times where therapeutic enthusiasm dominated a more detached critical attitude. I do not think it necessary to give examples to this Congress - examples which were not to the advantage of the patients.

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

Fe ee © IRL Press Limited, Oxford, England.

eS

P.C.Baastrup ne

EEE EEE

EEE

Such therapeutic enthusiasm has the: result that patients who may well be manic-depressive but do not need preventive treatment are submitted to lithium treatment. That patients who are actually lithium non-responders continue lithium treatment supplemented with sundry antidepressiva and neuroleptica. That patients continue lithium treatment in spite of disabling side effects, apparently in conformity with the Hippocratic principle that the best way to treat a disease is to give the patient another disease. My intention with this lecture is not to emphasize truisms but to call attention to circumstances which have to the best of my knowledge been disregarded. Lithium is effective as a prophylactic agent if the indication is correct — but lithium is a double-edged sword in the psychiatric armoury; to some manic depressive patients the acceptance of lithium treatment can be costly.

Although lithium is effective in the prevention of psychcticepisodes - and should thus be considered beneficial by the patients - it is primarily a drug with effects that are satisfactory to the surroundings of the patients. Manic-depressive patients undergoing lithium treatment become less of a burden to society. The patients may find that they no longer have periods of serious illness, but they also experience interference with their manic-— depressive personality. They frequently see themselves as less enterprising they feel that their creativity is restricted and that their lives become less colourful. They are deprived of options of reaction which were formerly natural to them. They have to give up being the persons they used to be, manic-depressives for better or for worse. In other words: They have to pay a price, and some find it too high. Of course it would be nice if clinical facts could always be translated into scientific data which could be shown in tables and treated statistically. But often that is just not possible, especially where psychiatry is concerned. So the best I can do is to describe the problem in question by means of two case histories.

A 55-year-old woman has been under successful lithium treatment for twelve years. She says that it may well be that she has had no psychotic episodes for twelve years, but she has lost her self. She wants to bear the consequen-— ses of her manic-depressiveness, to retrieve her old self, and to cope with her manic—depression. Since the patient was determined to cease lithium treatment, I offered her psychotherapeutic assistance, which she accepted as the lesser of two evils. I know perfectly well that psychotherapy cannot cure manic-depressive patients - nor can lithium treatment, by the way — but one can help the patients. After a lapse of two years during which she had been hospitalized five times in manic as well as depressive phases, the patient concluded firstly that she experienced herself as the personality she used to be, secondly that although she continued having manic and depressive phases she had learned how to control them during her treatment: For instance, she could handle her sense of guilt and did not experience suicidal impulses. Nor did she need hospitalization, but managed at home, also in her manic phases where she had previously had a tendency to be self-destructive. She was very proud when she stopped treatment after three years and said, "Now I‘m living as the person

I am on my own hospitalization,

terms"

and

she

has

done

so ever

since

without

the

need

for

Lithium

The other undergone

patient lithium

treatment.

Some

twenty.

He went

I wish to mention is a 60-year-old man who treatment for nine years. He has been very

years to

ago

a party

he told with

me:

some

"We only had one friends

and

smoked

child,

reflections

has successfully content with his

a son

cannabis.

aged

Under

the

influence of the drug he fell out of the window and was killed. I think it’s my fault that it happened, it would never have happened if I had given him a better upbringing. I can*‘t bear this situation and it would be natural for me to become depressive, but because of lithium I don‘t. I know that depression is an escape from reality, but being the person I am, I have no alternative but to escape, to hide away for some time." He wanted to cease lithium treatment, which was, however, prevented by his wife.

Two weeks later I saw him again and he told me that now he understood everything. During the war he had been very active in the resistance movement and after the war he had been threatened by a Nazi group. Now this group had taken revenge by killing his son. The patient developed a clear paranoid psychosis, in which the police became involved since they did not take his allegations about his son‘s assasination seriously. He is still under lithium treatment, he has had no manic or depressive periods, but he continues to be more or less paranoid, that is constantly trying to escape. A natural depression might have been better for him. There are many patients who experience successful lithium treatment as an interference in their personality. But they rarely talk about it for that might be interpreted as criticism of a treatment which is otherwise successful.

I should like to propose, therefore, that therapeutic that the enthusiasm be left to the patients; and that to the price the patients have to pay.

enthusiasm be shelved; more attention be paid

II

——E—

a M6

ee

-

ae

ee

m>>]o

|

aw

=:

Grice

Clinical Use in Current Practice

= | 7

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-

7

remix

(4 Gell tral

a

Ss 7

R.G.McCreadie

The epidemiology of lithium usage and its implications for health economics Director of Clinical Dumfries,

UK

Research,

Crichton Royal Hospital,

This paper examines lithium usage in four ways, namely the production of lithium, the cost of lithium, the cost benefits of lithium and the cost to the patient. Two previous papers have already examined these areas in some detail (lt 2) THE

PRODUCTION

OF

LITHIUM

The element lithium occurs as a readily available natural salt. It is cheap to produce in a formulation suitable for Profits and it cannot be patented. human consumption, therefore from this drug will not be great, and it is not

Surprising that although five pharmaceutical firms produce lithium in the United Kingdom, four of them are very small. if a product can make little profit then it is likely it will A review made of all drug adverts not be widely advertised. in the five years to March 1986 in the British from March 1981 Journal of Psychiatry found that of the 623 adverts, antipsychotics accounted for 35%, antidepressants 41%, but The most widely advertised lithium products only 3%. drugs were prothiaden, individual clopixol and depixol. Priadel and litarex came 19th and 26th out of a total of 34; camcolit and liskonum were not advertised at all. phasal, Although all trained psychiatrists are aware of the existence of lithium, they are presumably no less immune to the powers than other people; that is, if lithium were of advertising then probably it would be more widely more widely advertised used. THE

COST

OF

LITHIUM

The cost of different lithium products to the consumer, that is the National Health Service or the patient if he receives the drug on private prescription, varies from 2.7 pence for a 250 mg tablet to 3.9 pence for a 450 mg tablet (Monthly Index of Medical Specialties (MIMS), March 1986). The cost to hospital pharmacists is slightly less. In an attempt to assess the national cost per annum, figures have been taken from a review carried out in 1982 of all patients receiving lithium in South West Scotland (1). This study found that the average daily dose was 800 mg; the average daily cost of lithium per patient is therefore about 7-8 pence. It was also found that 77 people per 100,000 of the general population were taking lithium. If these figures hold good throughout the United Kingdom then at any given time about 40,000 people are taking lithium. Therefore the approximate annual cost of

Lithium:

Inorganic Pharmacology

and Psychiatric Use

Edited by Nicholas J.Birch

© IRL Press Limited, Oxford, England.

R.G.McCreadie

lithium at MIMS prices is about £1.1 million. If lithium were not available patients might receive alternative maintenance therapy. This would cost approximately the same as lithium for outpatients; for example, maintenance antidepressant therapy with, say, amitriptyline 75 mg daily would cost 7.5 pence per day, and with oral antipsychotics such as chlorpromazine, 6 pence per day. If both drugs were used in combination, maintenance therapy would of course be more expensive. Hospital pharmacists pay substantially less for both these drugs; the cost of maintenance therapy to inpatients therefore would be considerably less than if they received lithium. COST

BENEFITS

OF

LITHIUM

It is very difficult to assess accurately the cost benefits of lithium. In the South West Scotland survey the course of the patient's illness before and after the patient was started on lithium was examined. After the introduction of lithium there was a substantial reduction in the number and length of admissions to inpatient care, and in the number of ECT administered to patients. There was however no change in the amount of time patients spent on antidepressant or tranquillising drugs. The average length of stay dropped from 25 days a year before lithium was introduced to 1l days a year after its introduction. The cost of inpatient care in March 1986 at Crichton Royal Hospital which serves South West Scotland was £290 per week. This is probably typical for psychiatric hospitals in the United Kingdom, and if so the saving in inpatient costs per year for the 40,000 patients receiving lithium is approximately £23 million. Against this saving must be balanced the costs of lithium, serum lithium estimations and outpatient care. An American study (3) attempted to assess the economic impact of lithium in the United States. It assessed not only the costs of lithium and the saving in inpatient costs, but

also

examined

the

"productivity"

of

manic

depressive

patients

before and after the introduction of lithium. It was estimated that in the 10 years from 1969 to 1979 the United States saved at least $2.88 billion in medical costs and gained

these THE

COST

In

and

$1.28

billion

savings,

May

TO

THE

1986

a yearly

while

in

production.

speculative,

The

were

authors

believed

extremely

conservative.

PATIENT

an

individual

"season

ticket"

prescription

£33.50;

this

cost

is

a

in

patient

fact

£2.20

more

than

the cost of a year's supply at MIMS prices (e.g. priadel £27, liskonum £28). Some patients may need lithium indefinitely. If this were so, might it not be reasonable for this drug to be exempt from charges - much as drugs for epilepsy are exempt? Paradoxically groups which are totally exempt from prescription charges include the young, the pregnant and Se caees - the very groups that are not likely to be taking

ithium.

Epidemiology

of lithium usage

CONCLUSION The economics of lithium therapy is a neglected area. It is probably under-advertised, and therefore possibly underused. Further research into its cost benefits is required. More detailed information might persuade the United Kingdom Gevernment to add it to its list of drugs exempt from prescription charges. REFERENCES

1. 2. 3.

McCREADIE,

R.G.

Journal

Psychiatry,

of

and

MORRISON, 146,

D.P.

(1982).

British

70-80.

McCREADIE, R.G. (1987). The economics of lithium therapy. In Modern Lithium Therapy (ed. Johnson, F.N.). In press. REIFMAN, A. and WYATT, R.J. (1980). Archives of General Psychiatry, 37, 385-388.

J.R.King

Review

of significant side effects

Consultant Psychiatrist, Barnsley Hall Hospital,

Bromsgrove,

The

success

of lithium

the

facilitated

study

treatment

of its

side

over

Worcs

the

B61

past

OEX, UK

thirty

psychiatrically well, motivated subjects. Now that the damage has been largely settled, we are in a position to appraisal of these side effects. They may throw light action, and are of particular importance in determining

areas will tremor.

be considered

PSYCHOLOGICAL

in more

psychological

detail:

years

large

by providing

effects,

has

of

cohorts

question of renal form a more balanced on lithium's mode of compliance. Three

effects,

thirst,

and

EFFECTS

A cherished concept of lithium's action has been that of a specific prophylactic agent against manic-depressive illness, restoring normality without significantly affecting normal mental function(1). Several lines of evidence challenge the completeness of this idea, suggesting that lithium may also have a non-specific sedative or emotionally stabilising effect:

1. Withdrawal drawal

efficacy the

Syndrome.

syndrome,

than

existence

psychosis

or

2. Controlled

but

Early withdrawal

they were

detecting

Trials.

phenomena,

related

(7,8,9)

studies(2,3)did

concerned

such a syndrome.

of withdrawal of anxiety

more

with

More which

not detect

demonstrating

recent

may take

any with-

clinical

reports(4,5,6)confirm the

form of a rebound

symptoms.

have

shown

that

processing and induces a feeling of "withdrawal effects which may relate to its anti-aggressive

lithium

slows

cognitive

from environmental action.

demands",

3. Anti-Aggressive Action. Pathological impulsive aggressiveness is the other main established psychiatric indication outside manic depressive disorder and may reflect a separate mode of action.

4. EEG evidence

(10) indicates

that

lithium

has a hypnotic

effect.

These findings add weight to anecdotal reports of patients and volunteers that lithium induces a lowered emotional responsiveness. Anecdotal reports need to be interpreted with caution since emotional blunting in patients is easily confused with residual depression or with loss of hypomanic zest. True effects of lithium on the normal mind are probably weak but nevertheless important because quantitatively, it is on the normal mind that prophylactic lithium has the majority of its effect. In the author's experience they are also a powerful factor determining compliance; some patients feel "less natural" on lithium whilst others credit the drug with improving their self-control and ability to remain calm.

THIRST Thirst and polyuria have long been recognised as common and troublesome side effects. The incidence of gross polyuria has fallen along with other side effects since lower maintenance levels were introduced in the 1970's, thirst remains a surprisingly common complaint, affecting about 70% of

patients

but

in one study in 1985 (11).

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

© IRL Press Limited, Oxford, England.

15

J.R.King LLL

Mechanism. Tt is not

vasopressin

to renal

this

to explain

easy

(AVP)

7 symptom

purely

has

which

resistance,

in terms

due

of dehydration

view.

the conventional

been

An alternative hypothesis postulates increased osmoreceptor sensitivity resulting both in an increased AVP output and in the production of thirst at normal On this basis, increased drinking in lithium patients plasma osmolalities. would constitute a form of primary polydipsia, thirst being effectively stimSupport for such a mechanism comes from work in ulated directly by lithium.

animals

(12,13)

and in man

Elucidating the importance in view

(14).

precise mechanism has practical of the putative function of AVP

implicated in the antidepressant response recently confirmed that plasma AVP levels

plasma osmolality

in lithium-treated

as well as theoretical as a neurotransmitter,

Gold and his co-workers (15,16). rise sharply with small increases

patients

(17);

it follows

that

in

the mood-

stabilising action of lithium could be affected by minor variations in water balance. Our advice to patients regarding their fluid intake hence becomes important. Any advice to resist feelings of thirst is, however, potentially dangerous for lithium treated patients: it would only be appropriate where the thirst were based primarily on the direct mechanism outlined above. Hullin's group attempt to clarify the significance of thirst and related symptoms, by studying 87 patients and 52 controls in the normal free-drinking Sapuacaone lps Subjective symptoms were rated by questionnaire whilst the measures of reciprocal urinary creatinine and V/C Li were chosen to give as accurate an indication as possible of urine flow and distal tubular water excretion,

the serum

respectively.

lithium

level

The

finding

that

these

measures

and with the length of treatment

correlated

both

(independently

with

of age)

is consistent with the operation of a dual mechanism in the genesis of thirst, i.e. there is probably a contribution from primary polydipsia and from renal concentrating deficit. Other evidence (18) indicates that the latter may be incompletely reversible in some cases, leading to the worsening of side effects with length of treatment, although it may be conjectured that with the use of lower maintenance levels this will occur less often in the future. Advice to Patients. The presence of a renal concentrating deficit in some patients means that advice to patients to resist feelings of thirst, in an attempt to improve lithium's effectiveness or to avoid troublesome polyuria and weight gain, eannot be justified. On the other hand, advice to drink more, which was given in former years, is equally inappropriate and the guidance has to be a compromise: thirst should not be neglected but should be quenched in moderation, by low calorie drinks. A more sparing use of tricyclic antidepressants may also be helpful since their combination with lithium was almost invariably associated with thirst (often severe) in the above study.

TREMOR The prevalence of hand tremor varies widely in different studies but it is one of the commoner side-effects, especially in older males (19,20). It isa cause of occupational interference and a source of social embarrassment since it resembles anxiety-induced tremor. Like anxiety tremor it is alleviated by

betablockers and

in low dosage

in view also

elimination, tered

"for

(21).

of a possible

Schou

However,

interference

and Vestergaard

the occasion"

rather

(22)

than

this

effect

may wear

by betablockers

suggest

that

off with

with

propranolol

renal

time

lithium

be adminis-

chronically.

Lithium tremor may also be reduced by lowering the dosage (23) may not always be possible without loss of clinical efficacy.

although

this

Review

of side effects

SIDE EFFECTS AND COMPLIANCE The author's experience endorses an opinion expressed by Van Putten and Jamison (24) that the physician's sensitivity to side-effects influences

compliance; by explaining them to the patient in advance, he is less likely to discontinue lithium when they occur. In many cases they can be reduced or eliminated by fine adjustment of the dosage, which may make all the difference

life quality

to the patient's

(25).

Verbal explanation about side effects and all other aspects of lithium therapy should be backed up by written material as a part of involving the

patient

as fully as possible

in his treatment

(25).

The information

should

preferably pay attention to the principles of the therapy rather than being The success of lithium treatment confined to a list of do's and don'ts. continues to depend crucially upon the co-operation and education of the patient and his family, and it is salutary to remember that without these it remains

safeguards,

a potentially

hazardous

undertaking.

REFERENCES

1. Schou,

M.J.

(1980)

Lancaster:

2. Grof,

MIP

P., Cakuls,

of patients

In Handbook

of Lithium

Therapy

(ed.

F.N.Johnson).

Press.

who

P. & Dostal, discontinued

T.

copsychiatry, 5, 162-169. 3. Baastrup, P.C., Poulsen, J.C., Prophylactic lithium recurrent depressive

(1970)

Lithium

prophylactic

Schou,

dropouts.

treatment.

M., Thomsen,

A follow-up

International

K. & Amdisen,

: double blind discontinuation in manic disorders. The Lancet, ii, 326-330.

study

Pharma-

A.

(1970)

depressive

and

4, Lapierre, Y.D., Gagnon, A. & Kokkinidis, L. (1980) Rapid recurrence of mania following lithium withdrawal. Biological Psychiatry, 15, 859-64. 5. Klein, H.E., Broucek, B. & Greil, W. (1981) Lithium withdrawal triggers psychotic

states.

British

Journal

6. Margo, A. & McMahon, P. (1982) British Journal of Psychiatry, 7. Judd,

L.L.

function

(1979)

Effect

in normal

of Psychiatry,

Lithium withdrawal 141, 407-10.

of lithium

subjects.

on mood,

Archives

139,

cognitive

of General

255-6.

triggers and

psychosis. personality

Psychiatry,

36, 860-5.

8. Muller-Oerlinghausen, B., Bauer, H., Girke, W., Kanowski, S. & Goncalves,N. (1977) Impairment of vigilance and performance under lithium treatment: studies in patients and normal volunteers. Pharmakopsychiatrie Neuro-

psychopharmakoligie,

10, 67-8.

9. Glue, P.W., et al (1987) Selective Effect of Lithium ance in Man. Psychopharmacology 91: 109-111.

on

Cognitive

Perform-

10. Chernik, D.A., Cochrane, C. and Mendels, J. (1974), Effects of Lithium carbonate on sleep. J.Psychiat. Res., 10, 133-146. 11.King, J.R., Aylard, P.R., Hullin, R.P. (1985). Side-effects of Lithium Lower

Therapeutic

Medicine, j2.Smith,

1985,

D.F.

lithium

Levels:

Toxicologica

Significance

of Thirst.

at

Psychological

15, 355-361.

& Amdisen,

levels,

The

body

A.

(1983).

weight

Central

and water

effects

intake.

Acta

of lithium

in rats:

Pharmacologica

et

52, 81-85.

13.Christensen, S. (1983). Effect of lithium on water intake and renal concentrating ability in rats with vasopressin-deficient diabetes insipidus (Brattleboro strain). Pflugers Archiv fur die gesamte Phsyiologie der

Menschen 14.

und der Tiere D.B.,

Morgan,

Penney,

396,

106-109.

M.D.,

Hullin,

R.P.,

Thomas,

T.H.

& Srinivasan,

The responses to water deprivation in lithium-treated (1982). Clinical Science 63, 549-554. with and without polyuria.

15. Gold,

P.W.,

(1979).

Ballenger,

Effects

J.C.,

Weingartner,

of 1-desamo-8-D-arginine

H.,

Goodwin,

vasopressin

F.K.

D.P.,

patients

& Post,

on behaviour

R.M.

and

a AG

J.R.King

cognition

in primary

affective

disorder.

Iversen, S.D. (1981). Neuropeptides: Nature (London) 291, 454. Gold,

P.W.,

Robertson,

D. & Goodwin, arginine

F.K.

G.L.,

(1983).

vasopressin

irreversible

R.M.,

The effect

secretion.

Metabolism 156, 295-299. Hwang, S. & Tuason, V.B. possible

Post,

ii,

Kaye,

992-994.

Ballengar,

J.,

Rubinow,

Endocrinology

maintenance

Journal

body and brain?

on the osmoregulation

of Clinical

Long-term

damage.

W.,

of lithium

Journal

(1980).

renal

Lancet

do they integrate

lithium

of Clinical

of

and

therapy

Psychiatry

and

41,

11-19. Bech O.J.

P., LNOMSenilie,, ERYyicZasices) The profile and severity

healthy

subjects.

Neuropsychobiology

Vestergaard, P., Amdisen, A., effects of lithium treatment.

treatment. Kirk,

Acta Psychiatr

L.,

Laneet Schou,

P.C.

Baastrup,

1979:5:160-166.

Schou, M. A survery

Seand

Clinically significant side of 237 patients in long-term

1980:62:193-200.

M.Schou:

Propranolol

and

lithium-induced

tremor.

I (1972) 839. M., Vestergaard,

P. (1987). Use of Propranolol During Lithium : An Enquiry and a Suggestion. Pharmacopsychiat. 20 (1987),131.

Treatment Persson,

G.

gradients

Lithium

of lithium

Van Putten, ance

VCHOSDORS. 8Pa Deg ail etorh kK .naracrsen, of lithium-induced side effects in mentally

Therapy

side

effects

in plasma.

T., and Jamison, by the

Patient.

in relation

Acta

K.R. In:

to dose

Psychiatr

Seand

(1980).

Rejection

Handbook

of Lithium

Johnson). Lancaster : MIP Press. Schou, M. (1986). Lithium Treatment Journal of Psychiatry, 149, 541-547.

: A Refresher

and

to levels

and

1977:55:208-213.

of Lithium Therapy,

Course.

Mainten(Ed.

British

F.N.

D.P.Srinivasan

Morbidity and mortality of lithium

R.P.Hullin

patients Consultant

Psychiatrist, Garlands Hospital, Carlisle,

Cumbria CA1 3SX, and 'Department University of Leeds, Leeds, UK

Since

its

introduction

in

1949,

lithium

has

of Biochemistry,

revolutionised

tine treatment On Varreciuive WWdasorderns. SSWeieil xu @iaieal sesys studies soon established that lithium was effective in the prophylaxis) of “mecumment abmhectawve disorders, thus prompting the MinUSyiG al 1D eeltey a of long term medication in hundreds’ of jokelagalysvalnetsy Special lithium clinics were set up around the world to monitor and follow up these patients and the collective Conte UG hom Om Sthese clingcs,, am tenmme lof volindeal experience and research, has been unparalleled in the history of medicine. Morbidity and mortality of lithium patients were studied retrospectively from casenotes of one such lithium clinic, COVCi sae Co DIG aOCe Noli a moieo ZOMmnyiccin Sis Thais) iciimnae has) peen running as a regional clinical and research facility in the Kingdon, United accepting from Pieuine de culuss a wide area. Rhetermvals came “from mainly for patients they Psychtatrasts, before, to start treated on or to them and lithium known had had remained patients see Wey WwlSahie in Many “Wyss WEISS NASA Ciuc ie Coke u nic sion 2 ON wears | con toi | Ole iS claiuntice eC OMsad not usually intervals at medication wela\esak ie of monitoring records good had maintained clinic The CxXCe eda pauline. monddirs:. WSL FAIS) 15) parts. three in The done study Glico atines elataLsy yo\eusalalroyel was ve an was survey outcome sample random conducted a on dethawulitexs:. Secondly, reviewed was the morbidity psychiatric on a term group and on long who of lithium patients were Eheieeraelhmsye: ioeysahlilemallnis 5 “gickes Swe aia, Eb yy Grae alee ely ellalicialie, was conducted on all patients reported deaths known of to the kemc. weres notes whakch) or lemiverie the during Cimmnuc peritod Derauiitexish: Heme Ce mMOsiue (One had had an established disorders,

it

was

felt

ine spiatdeMinsr history of

that

an

aremmenImed «oO! recurrent

outcome

survey

of

ebines cleadnane affective defaulters

would be interesting. GCasenotes of defaulterns for the Last 20 year period are available at thie ClmimunCes Rani stormed Sepawavendiv. 30 casenotes were randomly chosen from this group and there (doctors “contvacced throwsh a postal (questionnarne. it wes. icGecided not “ho contact Gchie patwents: shemsielves,, ior thiemn

Mmiext

om

Kin,

“bo

Javoud

wpsets*

or

embarrassmenusi.

The

questionnaire placed emphasis on the current position of the joeneabinene ewe\el” ieee al elelGY “inesleyeticleb ign “forse aeleWe) AbigigieeoNeenaialinyes jeyeniatal (oyel & Diora t WOM OWwehtlic iuiceds aime wnen sinc wspiac Wenn Wasi spine SieimiG day One ec LunN Or menOl was cause On death. Of 30 letters sent, in

Table

I

Men 26

awe ll were

sor

ain

returned.

below.

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

© IRL Press Limited, Oxford, England.

hospmitads

and

wat

Results

sdeceased, are

shown

D.P.Srinivasan

Table

and R.P.Hullin

I

OUTCOME

ell and yukaL feyal

im

SURVEY

Hos pa tad

OF

DEFAULTERS

Dead

Not

nes

Known

Well and Won. oi hee haem

Ish qelorslate

6

2

3

GLAS)

7

8

When surveyed, “sim patients were =oril) jon leaphaum medication alGewenl las Two were in “hospital fea Vong) term “caxe. Tires Datienus were déad, two from natural causes and one by suicide. The whereabouts of seven was not known. However, (gabsedgire patients had come off lithium and were reported to be keeping Wicmlelens It was possible that all the eight patients happened to be well when the questionnaire was returned and their outcome “could pe Sdittermens uf “surveyed jab a “Lwiime dace. Little is known about the long term outcome of such patients who had come off lithium propylaxis after a period and further Re Seawmehy LS WatimahayCd aici iss) cee Clan. Morbidity Survey: Morbidity survey was conducted on about 40 patients who were on long term lithium medication and Bos cnaelsijeyer agles. “(ell alvaialye “akveg “aeteyenolilelar GAG lon) — abs) Lo study their DS VEC Meena sin, morbidity retrospectivly, a scoring system was devised for entries im ther casenotes. Scoring was determined DYs Cita SiC tf tine: Olllowwalrnp.. a) Reported complaints by patients such as subjective mood changes or sleeplessness. fal )) Observation by the clinician such as tearfulness or DME SsStiive Om ms Die eo dr. leteete) Adjustments made in medication, if any, like addition of neuroleptics or anti-depressants. iv) Hospital admission for psychiatric reasons. Scoring was done on a five point scale, above or below the base line. Hospital admissions always scored maximum DiOmehie Ss. Thais Ss en Order sGormmet lect morn only the failure of out-patient treatment but also the disruption such an admission would have the to routine. patient's caused Majority of patients were good responders to Tse Dieta,

producing adequate scores produced a

stability of mood so that their morbidity straight line when plotted on a graph. The NOI One Ahavaslavseabyg) Sige WelaNe proplylaxis of recurrent mood disorders has been well documented and our morbidity survey clearly same. the confirmed of to the In when CHUTS

been

Two further observations could be made from the results our morbidity survey. Hirs6, €Ven in patients. who farled respond completely to lithium, changes could be seen in

frequency, duration or severity of their mood Swings. such cases, mood changes occured at longer intervals or they occured they were Tess severe and of shorter ee Ona Such moderation in the course of the illness has

also

noted

by

other

workers

(1).

Hence

caution

bie exercised Mot to See Witham prophylaxis as an phenomenon and the course of the illness monitored

eS 20

‘all for

should or none! a period

Morbidity and mortality of lithium patients

MRS.

M.B.

DiOib

24-4518

MORBIDITY

SURVEY

1s

4 3 2 ile

O

1

= —

|

4

oa


+—

_14 yrs. ——_______»

Figure | before the responders. responded optimum

future of lithium medication was secondly, though majority quickly to lithium medication

level

of

mood

stability

in

a

decided in joehio wal er Ons the patients by reaching their

matter

of

weeks,

some

patients continued to show mood changes to a varying degree Hom “several jmontuhc. When response was achieved, the mood stability and the straight line graph they produced were as good as the early responders. This time lag in a small group cannot be readily explained with our current understanding. However this finding that some patients show a time lag before showing a good response has been mentioned aera a iaedoteUr

literature

before

(2).

Figure I shows the morbidity scores of one of our patients to illustrate the above point. Mrs M. B. was a manic depressive and had had 10 hospital admissions in 12 years before starting Onna at hainuimy. She had 3 further hospital admissions in the 18 months after starting lithium prophylaxis before finding hospital no further had She sitabila ty. sof mood hen level own mur. AMeWabsS) Sevie mary cars) ot acon Mlon during the admissions

hugh

igh cs

elinician

the or

the

meed

) tom

patient

wallow

fon

wan

tame

lithium

evaluates

lar)

befone

— the

medication.

Mortality eolim ve ys clinic patients were

keeping. Casienotesi. Ore Hanmi shown ave Taibite:

ovine reported siaGina —amiviolivamion sdeathis MISS um record for entire studied of the period was ascertained death Cause either of the from Tavatlablie,, ors if) by TG lP. “contactine mellevant ‘the Prac bistaonerm eCOmmlG cee. Of) Live muhies isu viey, Sweswitss Whi. sin: Labite

ii

MORTALETY

MI

CVA

9

4

Cancer

pe

SURVEY

=

CAUSES

OP

DRATH

Other

Unnatural

3

9

n

Not

=

34

Known

yf

21

D.P.Srinivasan

and R.P.Hullin

Except for unnatural causes, other causes of deaths namely myocardial infarction, cerebro vascular accidents, cancer ete. Gund MONG seem to be Salen aseremai ley; lin Se eeu avevianse compared to non Luthaum patients: lon jseneral Spopula tion Of “te 9° deaths from unnatural causes, 3 were Vie bams of murder. uiiaycuess Spams cal amomoly Was euOlaMmecm OC ei Mcine cuicin Gil mes see msiet -Tcalnice GOwbhsl |e) TSEC! Ainge) Teles}, The Gther 6 were suicidal deatbhs,, 3 by Slelf podsonmne, 2 by drowname “and i by hangin. Gonsuderinig the) iach that. tie ssUrvey scomemed a0) ba cra sis group of patients numbering several hundred over a period of lip Go 20) yearns, the Number of “sulcidal “deaths as “small — reflecting the beneficial effects of lithium prophylaxis and wie seStsplilieakiayes aovoyel Spwetevoa dlaliGAy « Omer notable fact from wae sie wey Was that evem Gn the 3 cases of sumecilde by selt poisoning, Liehium Was Mets anivelwed am “the Voverdoses . lt was possibile Piece ce Wicks! sl cUNNEC MiclinGle sur tuaiiclasaien. Other explanations include Deere Dp Gomes iy —piatasem ts that Insc: Arey. ber np eas ami | ex Glsbatimabionveibig Geror syieidl ike; stiae Jelsevere. ielwlo ener oe eae Elio sho) Bese) eS) iy, acy “niot, adiembadaed wali) ‘secdahimes Or Emamcdudl Waren as | daar ina am my Mion joe Ikeiginail aia Aa wweiAClosS «

Conclusion: Liebewine see ai SeneCc rine Spiro phiy Vac tec Meme nai MOGs jMewalGins. Wail mee wuewen guru ege wae Glisyouevl Sins Long term lithium medication does not seem to expose patients to any Elclclaiesiemeill jolniy/issal@ell aeakiges| ENS} Gieie clia. O@Ule Wei ipeulcl sy, sebe yey 5 On the ‘other hand psychiatric risks have been considerably iessemed “by Iithvum prophylexrs anid “by 2egular Montvorins or woe Meduveatlon.

Acknowledgement. Wewtsh to express our apprectatton and gratitude and Glenda Furness for thetr tnvaluable help of this manuscript.

to Andrea Jones in preparation

References.

dhe

PuCO HAS

Zio

2

hake TOnnsvon

BOUMOWi, ike of ltthtum

tn

HOnd

Havin

BOOK

ie Ulee

Ara, treatment.

"Om “hati eunl.s Umerary as pr Press

(CRS Zi Bee ve

irda.

The EO SO

ise

ets

geo),

practtcal UC Cima (Oe

management 2) ee OO

B.Causemann

Does lithium prevent suicides and

B.Miuller-

suicidal attempts?

Oerlinghausen

Department

of Psychiatry,

Free University of Berlin,

FRG

Strong evidence exists from animal and human studies that subchronic or chronic administration of lithium (Li) results into increased central serotonergic activity, possibly related to effects on preSynaptic functions. We have also shown recently that prophylactic response of lithium long-term treated patients with affective disorders is correlated with an increased cortisol secretion after fenfluramine challenge. On the other hand, anti-aggresive effects of Li have been clearly shown in animals and humans. The antiaggresive and serotonin-agonistic actions of Li would fit well within concepts developed in recent years by Asberg (1) and others relating violent Suicidal and aggressive behaviour to "lowered serotonin" in the CNS. The question, thus, arises, whether Li may also possess specific antisuicidal properties not necessarily connected to its general prophylactic effect in pats. with affective disorders. Surprisingly, this question has found very little attention as yet in the abundant literature on the clinical effects of Li (2-5). We have attempted to assess a possible suicide-preventing pats. of our Li clinic operating now examined as to violent or non-violent

effect of Li prophylaxis in for 20 years. Patients files were suicides (S) and suicidal at-

tempts (SA) as well as to number, quality, and duration of manic-depressive episodes resulting into hospital admissions. From these data the Morbidity Index (M.I.) acc. to Coppen was calculated in order to assess

the

prophylactic

response

of

individual

pats.

RESULTS Among a total of 411 pats. entering the lithium clinic at various times we selected 31 males and 47 females, who had at least one SA in their history before onset of prophyiaxis (1.8 SA/pat; 61% nonviolent, 33% violent, 6% unknown), and had been treated with Li for at least 1 year. Their age at the first episode of their disease was 27.3 (16-44) ys. in the males, and 30.3 (17-61) in females. The diagnostic distribution (ICD 9) was as follows: 296.2/3: 61.5%, 296.1:14.1%, was of the disease duration the 295.7: 16.7%, others:7.7%. In 64%, occurred in the total period episodes/pat. 5.734+3.5 ys.(1985). 11-30 iS) was before and during Li treatment. Av. duration of Li treatment periods of equal length before and after observational When +3.3. ys. of number intraindividually,the compared were onset of Li treatment i.e. hospitalizations, had decreased by 58.9 % on the relapses, severe of ratio to the acc. average during Li treatment. Ranking the pats. for the years after and before start of lithium treatcalculated M.I. cut-off as ratio of this (0.29) value ment, and setting the mean we were left with 59 responders (R) and 19 non-responders (nonpoint, in their pat. per resp., SA, R) having suffered from 1.88 and 1.58 | history before onset of Li medication. committed violent Sang pat. 3 bipolar treatment Li regular During of S time pats. showed 11 SA. The av.duration of Li medication at the 2 ys. The av.Li blood level shortly before S or SA was 0.78 SA was or Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

a UEaEyEEEEESEEEISS SSS ne

© IRL Press Limited, Oxford, England.

23

B.Causemann

and B.Muller-Oerlinghausen

mmol/l (in one of the pats.with S, however, it was only 0.05 mmol/1.). Taking equal observational periods into account the av.number of SA/ pat. dropped from 1.17 before to 0.18 (incl.S) after onset of Li prophylaxis. Remarkably, all SA were non-violent. ICD diagnoses of the 9 DatSewluiesny werner 29 672/-siealims tos 29 Ollie nimi 29 50/ seats Seen cise mmITUSs schizoaffective psychoses seem to be overrepresented in this sample. However, SA and S were equally distributed between R and non-R. In addition, 5 S(2 violent, 3 non-violent), and 12 SA (2 violent, 10 non-violent; 10 pats.from a total of 18 with occasional withdrawl) occurred

after

Li medication

had been

interrupted:

before,

these

pats.

had been treated for 2 ys. on the average, 75% of them being rated as R. 11 pats. were bipolar, 3 pats. had schizoaffective or schizophrenic psychosis. Taking the total of 8 pats.with S as one sample, it turned out that their diagnostic distribution more or less corresponds to that of the whole sample. The av.number of SA/pat.in these pats.before

Li was

even

lower

(1.5)

than

the

corresponding

figure

of

the

total

sample. The mean interval between the last preceding SA and the final S amounted to 5.5 ys. Only 2 of these 8 pats.were classified as non-R, which corresponds to the percentage of non-R in the overall sample. The frequency of all SA in pats.under continuous and occasionally

interrupted

Li treatment

had

decreased

by 94.64

in R, and

by

56.3%

in

non-R aS compared to the figures before start of Li prophylaxis. In conclusion, these preliminary findings suggest that Li treatment exerts a S/SA preventing effect which may not just be the natural consequence of the effective prophylaxis of depressive episodes, since the small number of S/SA preventive failures occurred in prophylactic R as well as non-R. An international collaborative effort should be taken to further elucidate this important issue.

REFERENCES 1.

ASBERG,

te

Om po &w

M. et al.,

(Meltzer,

in:

Psychopharmacology,

H.Y.

et

al.,

Eds.).

the Third

Raven

1986). BARRACLOUGH, B., Brit.J.Psychiat. 121(1972), 391. HANUS, H., ZAPLETALEK, M., Cesk.Psychiatr.90 (1984), JAMISON, K.R., Ann.NY Acad.Sci.487, 301. WEEKE, A., in: Origin, Prevention and Treatment (M.SCHOU, E.STROMGREN, Eds.). Academic Press, London

Generation

Press,

of

New York

97. of Depression. (1979).

M.T.Abou-Saleh

The relationship between morbidity index and lithium dosage University Department of Psychiatry, Royal Liverpool Hospital, PO Box 147, Liverpool L69 3BX, UK

ABSTRACT The relationships between lithium dosage, affective morbidity, side-effects, thyroid and renal functions and biological markers for depression were examined in the context of a prospective

double-blind lithium reduction study in patients receiving prophylactic lithium. Unipolar and bipolar patients receiving prophylactic lithium were randomly allocated, either to continue with their usual dose of lithium or receive up to 50% reduction in lithium dosage for one year. Biological markers investigated included Dexamethasone Suppression Test (DST) and 5-HT transport in

platlets

(Vmax).

Results

showed

no

association

between

affective morbidity and lithium dosages/levels. There was an however association between lower of dosages/levels lithium gain. including and weight tremor There side-effects and lower waS an association TSH and lower lower dosages/levels between lower volume urinary hour 24 patients. in these and levels greater experienced however, significantly patients Elderly There was an lithium dosage. morbidity upon reduction of their transport 5-HT and of Vmax increased a between association reduction with associated was non-suppression DST in morbidity. for the whole period of the study. lower mean weight

INTRODUCTION Little attention has been devoted to ascertaining dosage/plasma level of lithium during prophylaxis affective disorders. The empirically determined

the optimum of recurrent therapeutic range of 0.8 - 1.2 mmol/l 12 hrs after the last dose has been shown to be unnecessarily high for the majority of patients and Jerram and McDonald (1978) in a prospective open study have found that lithium levels as low as 0.4 mmol/l were as effective as the higher ones. Against this background we have carried out the first prospective double-blind trial over one year in which the

affective morbidity, side-effects, thyroid and renal functions were examined in 90 patients who were randomly allocated to either continue with their usual dose of lithium or to receive either a 25% or 50% reduction in lithium dosage. Contribution of personality

transport METHODS

characteristics

in

AND

platlets)

to

and

biological

outcome

were

also

variables

(DST,

5-HT

investigated.

PATIENTS

Ninety patients attending the MRC Neuropsychiatry Laboratory at Epsom were randomly allocated to either remain on their previous dosage or to receive approximately a 25% or 50% reduction of lithium.

Lithium:

The

reduction

Inorganic Pharmacology

of

lithium

dosage

was

approximate

as

the

and Psychiatric Use

Edited by Nicholas J.Birch

© IRL Press Limited, Oxford, England.

spring Valley Library

3000 County Road 114

3

Glenwood Springs, CO areon”

aa

M.T.Abou-Saleh

smallest

Unit

of

Jah

tium= secarbomate

Msisitaineds

me lease

preparation; Priadel Delandale Laboratories, Canterbury) was half tablet of 250 mg. No patient was allowed to have a dose that would give a 12 hr plasma lithium concentration of less than 0.45 mmol/l. Different amounts of lithium carbonate were packed into identically looking capsules to maintaine the double-blind nature of

the

trial.

A

research

co-ordinator

(who

was

not

involved

in

the clinical assessment of patients) monitored the plasma levels of lithium. The patients affective morbidity over the trial period was assessed using the Affective Morbidity Index (AMI) (Coppen et al 1973) for the year preceding and the year on the trial. Morbidity was also measured by calculating the time each patient had spent as an in-patient and by calculating the mean Beck Depression Inventory Score for the year preceding and the year on the trial. The number and severity of side-effects were assessed using a checklist that was completed by the patient ac each) Visit to the clinic. = Lhe mean total side—-ertecesscore was calculated for each patient both during the trial and for the same period preceding the trial. The patients' weight was measured in the same way. Thyroid function was assessed by estimating the plasma concentration of T4 and TSH and renal function was assessed by estimating 24 urinary volume both before and after starting the trial. DST and 5S-HT transport were similarly performed before and during the trial. Unipolar patients were classified on the Newcastle Diagnostic Scale and personality was measured on the Eysenck Personality Questionnaire and the Marke-Nyman Temprament Scale during a euthymic phase of their illness. The patients, for the purpose of analysis, were classified into three groups according to their percentage reduction ani dosage (group L

Pesearch

Rubinow,

D.R.

Psychiatry Research,

in

Post,

D.R.

Riedie a

UGC a LW

Psychiatry

R.M.,

Uo

Rubinow,

Weyeluigiay

ONES A ARPS, ROSIE Gold), 2 eWee (1986)

Big

mciCunWi@ tere

paiva.

UMN

and Huggins,

a,

{LQ

7/ey)

press.

IO,

and

Ballenger,

J.C.

(1986)

Wealo2oal-

Tallini Balvenger; Vin Compe Oa ice Acta “Psychiatrica Scandinavica

eratCl 73, 524-

Bice SeEUOL

LC

Gold,

MERE

P.W.

LOS te, miele mb Allenicgers mills Con mtxe cis,

(1986)

Epilepsia

27,

salou

TCL

156-160.

Cee

Dee LUCal wt. AieaO)e tlie, Pandalle, ly 7 SANGECUIS EME), MiGs 7 Benvenga, S. and Trimarchi, F. (1986) European J. Pedtatraicsel4> . wij—79e8 Clinicals Endocranollogyels, 2475252.

7.

Roy-Byrne, (1984)

P.P.,

Archives

Joffe, of

R.T.,

General

Uhde,

T.W.

Psychiatry

44,

and

Post,

R.M.

1150- 1153.

63

R.M.Post

ROS Uhde, 1987,

Reh seca Langer ecke Gey wOLie,. helen GOL 7sla Whee ccaricl T.W. (1987) A.P.A. Symposium, Chicago, May 9-14,

Abstract

Ghose,

K.

RUDUNOW

(1984)

#104-D,

(1978) De Rey

pg.

hOSitc,.

Rebs

Psychopharmacology

Rubinow,

D.R.,

142.

Pharmacopsychiatry

Post,

Gola.

Bulletin

R.M.,

Gold,

11,

PW

snc

20,

P.W.

241-245. Uncle isii. Wee

590-594. and

Uhde,

T.W.

(1986) Psychopharmacology 88, 115-118. Rubinow, D.R., Post, R.M., Gold, P.W., Ballenger, J.C. Reach in, S) (19'85) Psyvchopharmacology 185, 2005215" Steardo, L., Barone, P. and Hunnicutt, E. (1986) Acta Neurologica Scandinavica 74, 140-144. Katz, R.J. and Schmaltz, K. (1979) Psychopharmacology 65-63). Bernasconi,

R.

Lithium,

183-192.

POSE;

pp

(1982)

in

Basic

Excerpta

Niollilspy IeybIksioncisse,

WolGap,

Mechanisms

Medica,

Winsle,

EM,

in

the

and

65,

Action

of

Amsterdam. Sinlwelsi,

I< -

Rubinow, Dok. wand Bunney,, Wie, Wire (L982) Brolagnents Psy— Glnavences, Ui, MOST aiOes Post, R.M. (1987) in Psychopharmacology: A Third Generation O£ Progress, (ed. Meltzer, H.)" pp. 567-576. Raven Press, New

York.

Pratt,

JeA.,,

Jenner,

Reynolds, E.H. Meyyeldakeimey Cy, Weiss, S.R.B., (1985)

Life

2. , wonnson,

Anak. , sHoOrvol,

Science

Bip

Basses)

Willow, M., Kuenzel, E.A. and Catterall, Molecular Pharmacology 25, 228-234.

64

ob.)

and

(1984) J. of Neurology, Neurosurgery and asta ils} Post, R.M., Patel, J. and Marangos, P. W.A.

(1984)

Adityanjee

The syndrome

of irreversible lithium effectuated neurotoxicity Department of Psychological Medicine, Malaya, Kuala Lumpur, Malaysia

University of

Long before lithium was used in psychiatry, Cleaveland in an experiment conducted on himself described for the first time acute severe neurologic disturbance resulting from lithium ion intoxication, emphasizing its occurrence in absence of any

gastro-intestinal tion

symptoms

psychiatry

the

also

(1).

The

seventies,

witnessed

year

of

several

cases

a series

lithium's

were

of

reports

introduc-

its neurotoxicity and occasional lethality. The possibility of persisting neurologic sequelae, however, has not been given much thought till recently (2) despite evidence to contrary (3, 4, 5). In

to

reported

in

on

which

severe

neurotoxicity occurred with 'therapeutic' lithium levels. Although the first report on persistent sequelae of lithium intoxication appeared in 1965 (6), it did not arouse much interest. The report by Cohen & Cohen on irreversible brain damage caused by a combination of lithium and haloperidol, despite generating controversy, focussed attention on irreversible neurotoxicity (7). Forty cases were included in a review in 1984 by Schou (4). The author encountered two such cases and identified fifty-five cases of persistent sequelae of lithium treatment in the literature. Persistent sequelae of lithium have been described either alone or in combination with other drugs including antipsychotics like haloperidol, thioridazine and chlorpromazine. The emergence of neurotoxicity does not correlate with serum lithium levels and threshold of sensitivity to effects shows wide individual variations. Individuals with pre-existing neurologic illness or cerebral impairment are more likely to develop persistent sequelae after lithium intoxication as well as more frequent acute intoxications. Somatic illness may precede the intoxication and fever from any cause has been implicated in a large

number

of

cases.

Fever,

however,

has

been

reported

as

part of the syndrome of lithium-induced neurotoxicity both clinically and experimentally. Presence of high grade fever in all the four cases reported by Cohen & Cohen (1974) has generated some scepticism as to the typicality of presentation and issue of similarity to neuroleptic malignant syndrome was raised on the same grounds. Besides

other

factors,

the

duration

of

exposure

to

elevated

serum lithium levels is important in determining the outcome. In a typical presentation, acute lithium poisoning precedes the sequelae and the acute phase is generally without cerebellar symptoms (4). As the consciousness returns, the neurologic sequelae, chiefly cerebellar signs and symptoms, become more prominent though there are signs of damage at multiple sites in the nervous system. However, in four cases I reviewed cere-

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric

© IRL Press Limited, Oxford, England.

Use

65

Adityanjee

bellar signs were present from the beginning of the acute phase. Besides persistent cerebellar dysfunction, persistent extrapyramidal syndromes, persistent brain-stem dysfunction and organic mental syndromes including dementia may be seen. Atypical presentations may include persistent papilloedema, optic neuritis, isolated down-beat nystagmus, peripheral neuropathy and myopathy. Those with atypical presentations are unlikely to have undergone an acute organic brain syndrome, a fact hitherto unrecognised. In such cases, symptoms develop insidiously while on long-term lithium therapy and persist after discontinuation for varying periods. The author identified four such cases of insidiously developing neurotoxicity in which neurologic signs resolved in less than two months after discontinuation. However,

these

cases

cannot

be

termed

as

long-lasting

according

to

criteria laid down by Schou (4). Complete neurologic recovery is uncommon and some cases may remain unchanged and irreversible. In general spontaneous recovery in varying degrees may occur over a period of time. Some patients may respond to rehabilitative measures with significant functional gains and may return to previous living arrangements. I propose to the Syndrome of

name these persistent sequelae of lithium as Irreversible Lithium Effectuated Neuro-Toxicity (SILENT). Extensive demyelination has been found on biopsy in peripheral nerves so involved. It is likely that toxic demyelination at various sites in the central nervous system especially in the cerebellum may be the mechanism involved in the etiology of SILENT. Experimental evidence available also favours this hypothesis. REFERENCES (1)

Cleaveland,

(2)ebditoriale (3)

Donaldson,

S.A.

(1913)

JAMA,

(LIS melancet, I.M.,

60,

722.

424\e

Cuningham,

J.

(1983)

Arch

Neurol,

40,

747-751. (4)

Schou,

(5)

Adityanjee

(6)

Verbov,

(7)

Med J, Cohen,

66

M.

(1984)

Acta

(1987)

J.L.,

Psychiatr

Lancet,

Phillips,

41, 190-192. W.J., Cohen,

N.H.

1,

Scand,

70,

594-602.

866-867.

J.D.,

(1974)

Fife,

JAMA,

D.G.

230,

(1965)

Postgrad

1283-1287.

K.Balasubramaniam

Cerebellar damage following lithium toxicity Senior registrar in Psychiatry,

Denbigh, Clwyd LL16

Cerebellar

damage

following

Lithium

is

a

established

prophyl

axis

range

not

Manic

could

if

toxicity do

of

which

However

well

the

be

show

easily

Most

any

reported

cases

EOD SNCS?

(dla) 3

of

residual of

in

the

levels

the

by

it

serum

exceed

patients

damage,

persistent

treatment

Psychosis,

monitcred

Lithium

Hospital,

Toxicity.

drug

Depressive

serum

appears.

Lithium

North Wales

5SS, UK

however

therapeutic

toxicity

are

damage

assays.

m.mol./L.,

suffered

there

Cerebellar

a

Lithium

1.2

who

and

has

a

few

following

Casemaws rorya Mrs.M.J

is

a

stabilised 50

mg

on

t.d.s,

evidence

a

of

two

weeks clear.

-ria

before

with

later months

a

she

did

speech The

not

The

confirmed was

into

and

Tomography

show

any

a

Lithium transfered

and

remained

so

for

the

toxicity

was

ataxia,

not

by

clinical

immediately

nystagmus,

clinical

did

with

coma

reason

other

symtoms

previously

Chlorpromazine

She

severe

was

presented

was

went

with

Computerised

later

that

who

t.d.s,

nocte,

3.38m.mol/L.

left

damage.

400mg mg

recovering.

slurred

and

20

toxicity

where

was

depressive

carbonate

read

unit,

She

Manic

Temazepam

Lithium

cerebellar

old

Lithium

that

medical

not

years

and

estimation to

67

evidence

improve

Scan

abnormalities

in

five

out the

dysarth-

of

even

carried

for

months

three

brain.

Discussion:-—

The

as

serum

the

excrete

Lithium

dose ,

particular or

case

a

of

levels

Lithium

hydration, case

the

combination

of

of

and

Myopathy

are

governed

taken,

and

the

interaction

reason several

for

several

of

with

toxicity

syndrome

the

other

may

factors.Julien

Cerebellar

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

by

ability

be

factors

such

kidneys

to

drugs(3).In a

single

etal(2),

during

acute

any

factor

reported

a

poisoning

and Psychiatric Use

© IRL Press Limited, Oxford, England.

67

K.Balasubramaniam

with

Lithium

carbonate.

that

Lithium

toxicity

sequele,

in

with

one

Computerised

damage

is

Begar(1),

can

showing

in

evidence

Tomography

a rare

reported

result

scan.

3 cases

permanent of

Cortical

However

sugesting

neurological Cerebellar

irreversible

atropy

brain

occurence.

References:1)Begar.

J.M.,

toxicity. 2)Julien.J, cerebellar carbonate

Cerebellar

Cllanacal

degeneration

WNeuropharmacology

Vallat.J.M.,Lagueny.A, syndrome

(Letter).

3) hLoudon.J.B.

during Muscle-

,Waring.H.,

acute

Toxic

The

4)West.A.P.,

induced

brain

damage,

Lithium a

possible

JOUBNaAlINOfGiinwcale

68

1979,

and

Lithium

to

Lithium

Vol.2(3),240 and

1088.

neurotoxicity and

Lithium

9=—Sioa) es

Myopathy with

June,

reactions

mechanism

acute

May-

Lancet(1976),2,

PSYChtatry—

to

Vital.C, poisoning

Nerve,

Haloperidol(letter),

due

U9 S5yes/ 457

and

irreversible

antidote(letter).

hoe 5). witli

VOlesa cay jp SOG

S.K.Ahmed

Is there a negative interaction

G.S.Stein

between ECT and lithium? Hayes Grove

Priory Hospital,

Preston

Road, Hayes,

Kent BR2 7AS, and 'Farnborough Hospital, Kent and King’s College Hospital,

a

UK

ig

A 57 year old woman with a history admitted to hospital following the father

London,

had

also

suffered

with

of recurrent death of her

depressions,

depression husband.

but

later

was Her

died

of

Alzheimer's disease. She was admitted to hospital but was intolerant of a variety of antidepressants, including amitriptyline, mianserin and tranylcypromine but was able to tolerate dothiepin. Lithium was added to her regime and although it resulted in an initial improvement, she later developed severe ataxia and confusion. Medication was stopped but because of severe depression ECT was started. The first ECT appeared to help, apart from mild myalgia, and she took to her bed but recovered. However, after the second ECT she became severely confused, was rambling and disorientated in time and place, and had a reversal of her sleep rhythm, She was nursed in bed for one month afterwards and thereafter made a gradual recovery. This is the first description of an ECT induced confusional state following an episode of lithium toxicity (with a normal serum lithium level). There are three other cases of a confusional state arising from ECT in lithium treated subjects: l.Hoenig (1977) reported a patient who developed an encephalopathy with ECT while on lithium. 2.Remick (1978) reported a patient who developed severe confusion and incontinence following the 4th ECT while on lithium, 3.Weiner (1980) reported a case where ECT caused fluctuating confusion in a patient on lithium. Small (1980) studied 25 subjects and found that the ECT/lithium group had more severe memory loss, atypical neurological features and a poorer response to ECT than a matched control group. There is therefore a suggestion that there may be a negative interaction between lithium and ECT in some individuals, although the case is not yet proven.

REFERENCES

Hoenig, J., Chaulk, Delirium associated

R. (1977) with lithium

therapy.

Medical Association Journal,

Remick, Acute

Canadian

R.A. brain

therapy

and

electroconvulsive

116,

837

(1980)

838.

oe

syndrome

associated

hiatri

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

-

Lati

and Psychiatric

© IRL Press Limited, Oxford, England.

fe)

with

Ble

72n

ECT

IW)

and

>

lithium.

Alsi)

Use

69

S.K.Ahmed

Small"

and

G.S.Stein

d.Gy,

Kellans,

J.0.,

Millstein,;.v.,

small,

Lor.

(19380)

Complications with electroconvulsive treatment lithium, Biological Psychiatry, 15, 103 - 111.

combined

Weiner,

W.P.

R.D.,

Prolonged concurrent

LS,

70

aS 2 —

Whanger,

confusional ECT

and

14 53).

A.D.,

Erwin,

state

and

lithium

use.

C.W.,

EEG

Wilson,

seizure

American

activity

Journal

of

with

(1980)

following Psychiatry,

Non-psychiatric Sequelae of Lithium Therapy

M.E.J.Curzon

Lithium

and dental caries

Department of Child Dental Health, School of Dentistry, Clarendon Way, Leeds LS2 9LU, UK

Lithium (Li), among several trace elements, may affect teeth ina number of ways. Li could be deposited in tooth enamel during development, could affect the metabolism of bacteria in the mouth or act as part of the oral environment affecting the prevalence of By deposition in tooth enamel the subsequent ability of a tooth resist acid dissolution may be altered, which might affect the subsequent resistance of in teeth has, therefore,

the

carefully

at

HUMAN

ANIMAL

AND

possible

teeth to promoted

role

of

decay. a number

Li

on

decay. to

The presence of Li element of researchers to look more

teeth.

STUDIES

Studies at the Sydney Research Institute in Australia(!) indicated that children living in communities in South Australia with high Li levels, derived from artesian water, had significantly lower dental decay than a comparable group of children drinking surface or river water, which was low in Li (Table 1).

Table 1 Caries prevalence in 10-11 year old Australian children related to the levels of lithium and fluoride (mg/ml) in the drinking water

supply.

FE

Mean number of decayed tooth surfaces examined (DMFT)

Town

Water supply

Li

n

Brewarrina

R

0.0002

0.20

129

3.8

& Walgett Goodooga

W

0.1321

0.59

52

2.3

Previously an epidemiologic dental survey in Papua, New Guinea had also shown a low incidence of dental decay associated with Li when present in saliva(2). In this case the subject population was a tribe of New Guinea natives living mainly on a diet of sago. Analysis of many materials, teeth, saliva, urine, plaque, food, water and soils revealed that high concentrations of Li in enamel and saliva were related

to

low

levels

of

tooth

decay.

It

should

also

be

noted,

however, that these people were also in the habit of chewing betel nut with lime, which would be full of many other elements such as calcium, strontium and barium, which also have an effect on decay. Li occurs naturally in water supplies and often associated with gypsum deposits. One such area in Texas (USA) provided a further dental study using towns with high and low Li levels (and high and low fluoride) in their water supplies. The dental decay status of 12 to 14 year old children who were life-long residents revealed no beneficial

Lithium:

Inorganic

Pharmacology

and Psychiatric

Use

Edited by Nicholas J.Birch

© IRL Press Limited, Oxford, England.

73

M.E.J.Curzon eT

Table 2 Relationship of and fluoride in drinking

caries prevalence water supplies

in

Texas

children

to

lithium

Mean

Town

Water supply

Li

F

number of decayed tooth surfaces examined (DMFT)

n

Farwell Hereford Wichita Falls Lamesa Levelland

W W W WwW W

0.049 O.L65) 0.000 0.039 OnjO39

1.9 15) 0.6 0.5 065)

46 eZ 105 106 5 127

Big

Ww

OOLS

0.20

102

6.9

W

0.038

0.2

46

Tied:

Spring

Paducah

effect of the Li at all (Table 2). Rather any in the drinking water was offset by the Li(3), findings on Li and dental caries in humans are

229 4d 5.3 Giod, O05

effect of the fluoride The epidemiologic at present only

equivocal with no clear causative effect. Animal studies have similarly been unclear with various studies showing either no effect, a reduction in decay and even an increase in decay(4). These various experiments have tried adding Li to the foods, to the drinking water or given by injection. High doses of Li when given to rats cause problems with salivation leading to an increase results.

in

dental

POSSIBLE

MECHANISMS

decay.

OR

Low

ACTION

doses

OF

do

not

seem

to

give

consistent

LITHIUM

The chemistry of Li would not suggest any possible effect on tooth enamel. Other elements shown to affect dental decay such as strontium or zinc, are generally those that can easily replace calcium in tooth enamel structure. Others such as fluoride can be fitted into the enamel apatite by replacing the -OH group in the apatite and so alter the chemistry of the tooth. Li is a very small atom therefore it is not logical that it could affect enamel in the same way. However, there is also the possibility that Li might affect bacteria in the mouth and so indirectly influence dental decay. A review of all the available information by Eisenberg (4) came to the conclusion that there was no evidence that Li has an effect on oral bacteria. Although there is some evidence that Li could reduce baterial growth rates it only seems to occur with a few strains of oral bacteria under very selected conditions. If, therefore, there is no scientific evidence that Li affects dental decay on the basis of chemistry, epidemiology, animal or bacterial

experiments

why

do

people

who

take

or

consume

quantities of Li develop high levels of dental decay? consists of enamel, dentine and cementum held into the fibrous

periodontal

continually the

mouth

Dental

hygiene

74

membrane

by saliva. is

decay

with

lost

and

starts

diet

with

Without stagnation

and

progresses

counselling

can

the

crown

saliva of

the

food

such

the

tooth

bathed

self-cleansing

debris

rapidly

keep

of

large

The human tooth jaws by a

and

occurs only

action

round

rigorous

a situation

under

the

of teeth.

oral

control.

Lithium

EFFECT

OF

LITHIUM

ON

SALIVA

and dental

caries

SECRETION

The effect of Li on teeth is, therefore, an indirect one by bringing about a change in the natural mechanism of oral cleansing. When the Li intake to the body increases, as might occur in Li therapy, the salivary glands are affected producing a gradual reduction in salivary flow. Under these circumstances the mouth becomes drier and the subject eventually complains of the condition and has difficulty eating. With the loss of salivary flow there is increasing difficulty in keeping the teeth clean and removing food debris. The antibacterial effect of the saliva, and also its ability to remineralise the tooth surface by calcium and phosphorous ions is removed. Without the protection of the saliva cavities start up in teeth within only a few weeks. Studies by Clarke(5) noted that the metabolism of calcium and phosphorus were changed during Li therapy. Calcium depletion in saliva by Li can occur and altered calcium and phosphorus secretion might also change the remineralising potential of saliva. A common reaction to the dry mouth effect of the Li is to drink more, often sweet, soft drinks. While relieving the dry mouth, tooth decay is increased. Instead water, sugar free drinks or saliva substitutes should be used, formulated to have the slightly thicker consistency of natural saliva. Therefore, the effect of Li on the teeth is an indirect one. There is no evidence of any direct effects of the element on tooth structure or on oral bacteria. The major effect of Li is by a reduction of salivary flow which can be easily be offset by good dental care, the use of saliva substitutes and fluoride mouthrinses. REFERENCES

1.

2.

3.

Schamschula, R.G., Cooper, M.H., Agus, H.M. and Un, P.S.H. (1981) Oral health of Australian children using surface and artesian water supplies. Community Dentl. Oral Epidemiol. 9: 27-31. Schamschula, R G., Adkins, B.L., Barmes D.E et al (1978) WHO Study of dental caries aetiology in Papua New Guinea. WHO Publications No. 40, Geneva. Curzon, M.E.J., Richardson, D.S. and Featherstone, J.D.B. (1986) Dental caries prevalence in Texas schoolchildren using water supplies with high and low lithium and fluoride. J. Dent. Res. 65, 421-423

4,

Eisenberg, Dental

5.

A.D.

Disease.

Bristol, U.K. J.F. and Clarke, lithium therapy. Nebraska, U.S.A.

(1983) (ed.

Kies, M.S.

Lithium, Curzon

Chapter

M.E.J.

and

17

in Trace

Cutress

T.W)

Elements John

and

Wright,

implications C. (1985) Nutritional/dental Thesis University of Nebraska, Lincoln,

of

US

en _

re

-

_

ee

:

.

ieee

0 s

ae pee

DOSS a

aes ———

©

4S

CG)

=> a6

» =

:

=

=> Onnk® ‘

SO

=

& & Lom

-

as

Cr

0s

she ®@

;

> #4,

2

==> oer

, die

«©

en

ee)

ane ged pe We

- ofits

Si

an ©

mo) 7

SPE =e

a

mm

136

ay

tae

. we

a

oo Silene 5 Goe

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aa 63 a

|

ope, Gud

A210

Gj are

p pn i) ied

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Cogs. fre SONS? s79 etiam

exam

PPI.

ay (78)

4+@

er ay

Sh e2 Gam

“= Cela

P2'Pidtead

tide

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se0tee . ot

ao aa o

amumal

ake

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1aty the-geSePhatdeae

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pee

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“le =

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(ee Gy pees

se eaiae Se

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eee

Bike errr

ay

ee,

ee

a -

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a

_ :

4 pus>-esteal _

oo) arte

Goa

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| rane stom PP ang Pts Ses h

ak) ee

=

-

we

aul eine

~~

Gas

»

owes —

wand

.0.7 mmol/l) and low (S) IAL PERMEATION THEL LITHIUM TRANSEPI

uumoles Li+/g final wet weight tissue

70

50

30

10

Buffer

Figure 1. Kinetic serosal direction the

sets

mean

of

equimolar

Results be

)

of

at

plot of lithium absorption in the mucosal in isolated guinea pig jejunum. Each value

least

six

experiments basis,

and

[Li+] (mM)

(up

observations

lithium to

a

maximum

+

SEM

replaced of

(r=0.99,

sodium

to is

p.>0.001).

on

an

50mM).

Discussion

Lauterbach Isolated Epithelia Technique Lithium permeation and tissue uptake were studied in the absorptive (mucosal to serosal) direction. Several tests of tissue viability were performed, including LDH release (0.01). Q,;9 values were calculated for both

108

a

Lithium transport in epithelium

ee

TISSUE LITHIUM

ABSORPTION

umoles Li+/g final wet weight tissue

10

n=5 (+ SEM) [1

Oo

10 Buffer

ae

20

yee aL

30

40

[Li+] (mM)

EGU rewe2 Tissue lithium accumulation over the range luminal concentrations 0-30mM. Each value is the mean of least six observations + SEM (r=0.99,p.>0.001).

of at

percentage transepithelial substrate movement

120

LITHIUM

GLUCOSE

100

Figure 3. The effect of 2.4-dinitrophenol, 10°C temperature rie Guic taco nemaGuaam ilo nd dic Ones tt ham, san desc lanc Ose absorption in guinea pig jejunum. Each value is the mean of at least three observations + SEM (p.>0.05=%,

De

0 sO

> 3)

109

R.J.Davie,

|.P.L.Coleman

and S.Partridge

ET

Efflux

The

of

from

PEG

and

Lithium

Preloaded

Rings.

Everted

16

30

‘ Buffer

ees i

a

2

20

eee |:12 ——

[

Hi

2

ay

Brak

Buffer

ate

pas

[PEG]

9

©

=

Z

i

a

=

6. =

te

=

2

a

aN

1 H i

Tissue

1 ig

ol

eee

;

ee ak eee ;

32

ae

Tissue [PEG]

10

20 Time

Each

4.

[Lit]

eee

O

Figure

m

2 rane

ae

g

z

S

poem

a

14

i

i\

o

[Li]

point is the mean

Efflux

of lithium

(mins)

of at least 5 observations

and

loaded everted rings of rat concentration was 20mM. Each least five observations + SEM,

40

30

7H-PEG

(+SEM)

900 with

jejunum. value is

time

from

Buffer lithium the mean of at

lithium (0.64) and glucose transport (2.30). The data obtained for lithium are characteristic of passive diffusion; by contrast glucose absorption was shown to be an active process. The rate of lithium transfer is proportional to the initial lithium concentration in the mucosal compartment. Amiloride had no effect on lithium transport suggesting that the amiloride sensitive sodium Chiannelise do note ipilay™ aaisaonlficant sod e ain siena um absorption in the jejunum. Lithium transport probably occurs via the paracellular pathway formed by the tight junctions and lateral intercellular spaces. 2)

_

110

Everted Ring Study The suggestion that lithium movement was occurring through the extracellular spaces led to a comparison of lithium and PEG efflux from preloaded rat everted jejunal rings. The tigsue was loaded in KHBB containing 20mM lithium and luci 24pgc-900 as an extracellular marker for 30 minutes. SS

erer

SO

ee

Lithium transport in epithelium Xe

After

this

Krebs

buffer,

lithium

and

measured,

time PEG

the

tissue

initially

over

(Fig.4).

was PEG

varying Lithium

washed

and

placed

in

fresh

and

lithium

free.

Efflux

time

periods

(0-30

mins.)

movement

can

be

of

was

seen

to

correlate closely with that of the extracellular marker. Initial efflux was extremely rapid, followed by a slower, more constant decline. Thus the interaction of lithium with intestinal tissue may reflect a diffusion into the extracellular space and deposition on to the cell membrane. However this does not exclude the possibility that transcellular transport may also be involved to a limited extent.

Conclusions

Lithium absorption from guinea pig jejunum appears to be a passive process occuring primarily through the paracellular pathway. Absorption was shown to be unaffected by metabolic

inhibition

and

exhibited

kinetics

indicative

of

a

diffusion

system. The amount of lithium absorbed was dependant upon luminal lithium concentration and intestinal permeability. Studies with extracellular markers suggest lithium is predominantly associated with the extracellular fluid.

References

(Qi)

eeBasnichyaeNeul.

In: (Dy) (Bye

(4)

"Metal

Tons

in

Buolliogical

H.Sigel, Marcel Dekker, New York Taieelsis Median wWieiveleie, UaGrNc Brit.J. Pharmacol. 47: 586-594, Evans;, Ef.

Arch. Otolaryngol. 9105) Lauterbach, F. NeSeeArChinviesmOtPielam

(5)

Agar, W.T., Hird, F.J-R., Biochim.Biophys.Acta 14:

(6)

Krebs,

H.A.,

Hoppe-Seyl

Henseleit,

z 210:

33-36,

185—6, 2 Ouse

Systems’, (1982),

vol.

4

ed.

pp257-303.

(1973).

((19)7/9).

Olli 2 2 el OAT)ie

Sidhu, 80-84,

G.sS. (1954).

K.

(1932).

itt

ae ce

US j

eae

FT)

We

avotes

)

-

-

trp

==) Ge & & 2 .

-

-

»

Wy

iyi) § 9s Oae

ie a

ean .ae ohh

oabat :

7

=

5s

id

=

o

’ aS

Fe

Aiea

=) @

‘

099

2

7 wp

eae

Cle ar igee) 265 ad used th, iMae

i

»

ai

és

ao ai

'

-

ROG

sien

6

ae

aa 7

a

Mager

. ORs 2Curenit

or

:

eae

Tle

i o

GeeOAne

==

—s

P.Plenge

Serum

E.T.M

ini peak values, minimum

ellerup

lithium: the importance of

values and

values

mean

Psychochemistry Institute, Rigshospitalet, 2100 Copenhagen, Denmark Blegdams9, vej

ABSTRACT

is sthe

adjusted by mornang, | 2

Normally

12

hour

a

against

treatment

lithium

Prophylactic

mood-swings Exam on) vin

manic-depressive

measuring the serum lithium concenhours after aintake of the Past) dose.

lithium

concentration

between

0.5

and

1.0

mmol/L is effective. Two different treatment schedules are dominating: Either the serum lithium concentration is kept as constant as possible by administering the lithium in two daily doses in slow release lithium tablets, or the daily dose of lithium is given in one evening dose as lithium carbonate tablets, leading to larger diurnal serum lithium variations. Both treatment modalities are effective against mood-swings, but the side effects, particularly regarding kidney functions, seems more severe if lithium is given twice daily in smaller doses compared with lithium given once daily in a larger dose. The question may be asked whether therapeutic efficacy demands the lithium concentrations to be above a certainthreshold every day, or whether every second day would be enough. This question is at present being investigated in the clinic! RESULTS

AND

Lithium humans as decreased this

DISCUSSION

treatment induces an increased water excretion in well as in rats, an effect due to a lithium induced renal sensitivity to vasopressin. Up to the late 1970s

side

effect

although

annoying

appeared

(1)

resulted reports renewed in

showing

considered

many that

harmless

patients,

lithium

but

treatment

then in

and

reversible,

the some

first

report

patients

had

in irreversible kidney damage. This, and similar frightened both patients and psychiatrists and led to considerations regarding the optimal treatment schedule

long-term

especially following dingly

was

to

it

lithium-treated

the intake was

peak values of lithium advised

to

give

patients,

and

suggestions

that

in serum-lithium concentration probably were harmful (2). Accorlithium

in

slow-release

tablets,

divided into two or three doses a day. In a discussion of the importance of the lithium tion it should be remembered that this concentration

concentrais variable, as lithium is readily absorbed from the gastro-intestinal in the kidneys with a rapidly excreted fairly. also tract, . and life of about 24 hours in humans and 6 hours in rats. Three half

important questions are unanswered with regard to this. First: It is not known how high maximum plasma lithium has to rise to produce a psychotropic effect. Second: It is not known how long the lithium concentration has to remain above this critical

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric

© IRL Press Limited, Oxford, England.

Use

135

P.Plenge and E.T.Mellerup i

level.

upper

Third:

It

is

not

known

often

‘how

the

lithium

concentration should reach this upper level. is given twice lithium which in regimen, common most The is based on the dogma that preparation, a slow-release in daily are obtaiside effects effect and minimal psychotropic optimal ned the

the when selected

idea, kidney By

lithium 12-hour

remains concentration no However, value.

it may not be the best and, in fact, side effect. it was suggested the present authors

advantageous, side mizing

close to constantly this study supports

way

to

ameliorate

the

that it might be more and minieffects therapeutic for maximizing both if lithium were given in larger doses with effects,

e.g. every second or third day (3). If the thelarger intervals, many of the preserved with such a regimen, was effect rapeutic intoxication with and problems adjustment of the lithium dose disappear, as most of the previous dose of lithium would would be excreted before the next was given. The first study to show that varying lithium concentrations might be better than constant lithium concentrations regarding the kidney side effects came from an animal study (4). Rats received the same amount of lithium daily for 5 months, either administered in the food, or via an intraperitoneal injection The two different treatment schedules led to widely different

serum-lithium curves. Injection of lithium resulted each day in a serum-lithium peak of about 5 mmol/L but also a period lasting several hours where the serum-lithium concentration was below 0.5 mmol/L. serum-lithium the evening

The curve and

lithium fed rats in contrast, had a smooth with concentrations between 0.6 mmol/L in 0.9 mmol/L in the morning. The two different

ways of administering lithium affected the kidneys very different. The lithium fed rats had a large diuresis, and morphologically their kidneys were severely damaged, whereas the lithium injected rats had a smaller diuresis, and the morphological changes in the kidneys were moderate. From the study it was concluded that to avoid kidney damage during long term lithium treatment it may be more important regularly to have periods with low lithium concentrations than to avoid peak lithium concentrations. In patients given lithium prophylactically, two alternative treatment schedules have prevailed: either lithium is given as a Single dose at night or it is given in two or three doses morning, (noon) and evening. If lithium is given once daily at

night, serum lithium curves with higher peak values and lower Minimum values are obtained compared with the b.i.d or t.i.d. schedules where a more smooth serum lithium curve is obtained (Cac In a study of diurnal variations in different serum parameters in patients given their lithium once daily in the evening, serum-lithium was measured every hour. 24 hour diuresis was correlated to the maximum, 12 hour and minimum serum-lithium concentration (4). A positive and significant correlation was found between urinary volume and minimum serum-lithium concentration, indicating that in humans treated with lithium, it may be of importance to have regular periods with low lithium concentrations in order to reduce the unwanted renal effects of lithium. Due to the reports of structural changes in the kidneys of

136

Serum lithium —_—_—_——_—_____

nnnk._—nk—n— ee

values

ee

lithium-treated patients (e.g.(1)) many lithium clinics started a screening of their lithium-treated patients (for review (6)). In the Psychochemistry Outpatient clinic where many manic-depressive

did

patients

such

an

receive

their

investigation.

The

lithium

maintenance

investigation

therapy

consisted

of

we

too

diffe-

rent kidney function tests, measurement of 24 hour diuresis, and a renal biopsy. The patient population could be divided into two groups: one which had the lithium in one single dose at night, and another which had the lithium divided into two or three daily doses. In other respects such as mean age (50 years), mean 12 hour

serum-lithium

concentration

(0.9

mmol/L),

and

mean

length

of lithium treatment (8 years), the two groups were comparable. The patients thus offered the possibility of comparing the two different lithium treatment regiments regarding their effects on structural and functional kidney changes in long term lithium-treated patients (7). The results were essentially the same as those found in the animal study (4). In the patient group having their lithium divided into two or three doses, serum-lithium never decreased to levels lover than the 12 hour serum-lithium concentration of 0.7 to 1.0 mmol/L. These patients had rather large 24 hour urine volumes, and the mean amounts of sclerotic glomeruli, fibrosis and atrophic tubuli were in the order of 10% to 15% in the renal biopsies. In contrast to this were the patients who had their whole daily lithium dose in a single nightly dose. These patients had a period of about 12 hours’ each day where serum-lithium was lower than the the 12 hour concentration of 0.7 to 1.0 mmol/L. Their mean 24 hour urine volume was only 50% of the mean for the other patient group. With regard to kidney morphology, significantly fewer changes were observed. Two

other

studies

(8,9)

have

investigated

the

connection

between treatment regiment and urinary flow. In both studies, it was found that the patients given their lithium once daily had significantly smaller urine volumes than the patients given lithium in divided doses. In an attempt to reduce the kidney side effects associated with long term lithium treatment, most lithium clinics have in the recent years recommended a reduction in the 12 hour serum lithium concentration. This reduction in the lithium concentration decreases (as expected) the lithium induced polyuria, and if the 12 hour serum lithium concentration is reduced to about 0.5 mmol/L hardly any polyuria is seen (Vestergaard, personal communication). However a decrease in the serum lithium concenEnatlonmcarrilesmeantsmncreascdm ni sk ot secelapsenOts chesaiuiness (10,11), and as the relapse rate after discontinuing the lithium treatment follows the normal course of the illness (e.g.(12)), month may pass before it is realized that an inefficient several dose of lithium is given. lithium at present two alternative ways of administering Thus though the efficient, therapeutically seem Both use. in are In the one the lithium side effects probably differs. of amount in is above the 12 hour concentration, constantly concentration is above the 12 hour concen lithium concentraton the other the schedules howIn both treatment during the night. only tration to find the lowest daily dose of lithium difficult it is ever

TST

P.Plenge and E.T.Mellerup

which is therapeutically efficient due to the lag before a relapse may appear. It is evident that a certain concentration of lithium must’ be present to achieve the therapeutic response of the lithium treatment. The question is whether the lithium concentration needs to reach the therapeutic level every 24 hour or whether it is enough to reach a therapeutically efficient concentration of lithium at larger intervals. An alternative way of administering lithium could be to give lithium in larger doses every second or third day. Such an administration would led to a sharp increase in the concentration of lithium followed by a fairly long period with very low lithium concentrations. It is a known fact that maintenance electroconvulsive therapy given with monthly intervals (13) produces efficient prophylaxis against manic-depressive moodswings, thus indicating that a

continuous treatment is not necessary to obtain therapeutic effects. Whether the same is true for lithium treatment remains to be studied. Presently we investigate whether lithium prophylaxis may be obtained when lithium is given every second day in the evening in a dose leading to a 12 hour serum lithium concentration at about 0.8 mmol/L. A clinical study following these premises are now

in

progress!

References: 1: Hestbech J., Hansen H.E., Amdisen A., et al. (1977) Kidney Wane AAG AOssa71\ sk 2: Vestergard P., Amdisen A., Hansen H.E., et al. (1979) Acta psychiatr scand 60, 504-520. 3: Plenge P, (1978) Psychopharmacology 58, 317-322. 4: Plenge P., Melllerup "ESL. “and Norgaard) =f: CIISB1I) Acta psychiatr scand 63, 303-313. SeebauTeSene Bde, Mellerupr hale, ee lengerbe cerca lO Si mActa psychiatr scand 64, 314-319. 6; -Bendz H. (1983) Acta psychietr seand 66, 303=324. iP lenge Pe Me lilexup ash allan BOlwiage DaGe me taal mn Oe pymAcGia psychiatr scand 66, 121-128. Sse) oChou Misi, Amdisen TNS pF Thomsen Keer et ads (1982) Psychopharmacology 77, 387-390. 9: Lokkegaard H., Andersen N.F., Henriksen E., et al. (1985) scand 71, 347-355. Acta psychiatr VOR ty rer S.P., Shopsin B. and Aronson M. CUSRSVSE TY iebesics 8) PSC haraltetsyauta Oia ihe dit) Waters -B., Lapierre Y. and: Gagnon By 11982) Bic Psychiatry S2882or aa iZseBaastuupepp Ca Poulsen uMCay Schou Mo ,pece ale (lo 70Ne Lancet tah, I2G=330). 13: Stephenson G.H. and Geoghegan Jic. (1957) Am g Psychiatry 107, 743-748.

138

Janusz

Clinical significance of lithium

Rybakowski

pharmacokinetics and RBC lithium

i’

s

Wenecja Lehmann!

.

.

enn

transport

Kanarkowski!:2

‘Department of Psychiatry, Medical Academy, Bydgoszcz, and *Departmentof Biopharmaceutics, Medical Centre of Postgraduate Education, Bydgoszcz, Poland

ABSTRACT

The activities of erythrocyte lithium transport mechanisms: lithium-sodium countertransport (LSC) and passive lithium

diffusion

(PLD)

as

well

as

lithium

pharmacokinetics

were

studied in 11 patients with affective illness during depressive episode. The activity of erythrocyte LSC significantly correlated with the rate of lithium transport from intrato extra-

cellular

compartment

of

total

body.

INTRODUCTION It has been suggested that lithium ion may be handled differently by the cells of patients with affective illness, where lithium exerts its therapeutic effect, than by healthy subjects. The balance studies found that affective patients retained more lithium in the organism after test dose (1). Also, the greater accumulation of lithium in erythrocytes (higher lithium

ratio)

was

observed

in

affective

patients

(2).

Both

phenomena

were, however, documented only in subgroup of affective patients, and the attempts of linking them to specific clinical traits or response to lithium were not very successful. In erythrocytes, the principal mechanism of outward lithium transport is lithium-sodium countertransport - LSC, based on sodium exchange diffusion. The main mechanism of inward lithium

transport

is

passive

lithium

diffusion

-

PLD

(3).

Two-compartment model of lithium pharmacokinetics allows for the calculating of rate constant K21 for lithium transport from deep (intracellular) to central (extracellular) compartment as well as rate constant K12 for lithium transport from extracellular compartment of total body.

MATERIAL

AND

METHODS

Eleven depressive patients (5 male, 6 female) aged 29-61 years were studied. Eight were with unipolar and three with bipolar affective: vliness. For determination of lithium transport, erythrocytes were incubated with 150 mM of LiCl for 3 h. Lithium efflux was than measured into sodium and potassium medium. The difference between the rates of lithium efflux into these media was taken ase the maximal avelocitywot SG. PED was the rate ol lithium

efflux

into

potassium

medium

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

(4).

and Psychiatric Use

© IRL Press Limited, Oxford, England.

139

J.Rybakowski,

W.Lehmann

and R.Kanarkowski

Lithium pharmacokinetics was meagured after test dose 750 mg of lithium carbonate, given at 8 ~. Fourteen serial determinations of plasma lithium were done until 48 h. Pharmaco-

kinetic All

analysis

patients

RESULTS Table ee

AND

I.

was

studied

performed fitted

using

ESTRIP

two-compartment

program

(IBM

PC).

model.

DISCUSSION

CORRELATIONS BETWEEN ERYTHROCYTE LITHIUM TRANSPORT AND TOTAL BODY PHARMACOKINETIC PARAMETERS

K21/K12 0.070, 0.680 The main finding of our study is a significant correlation between the activity of LSC governing lithium transport out of the erythrocytes, measured in vitro and pharmacokinetic rate constant of lithium transport from intra- to extracellular compartment, measured in vivo. It may suggest a usefulness of erythrocyte LSC as a model of the intensity of lithium extrusion from the cells in whole organism. It may also explain the reports of both higher lithium ratio and greater lithium retention in subgroup of affective patients that may be related to decreased both LSC and K21. The rate of PLD correlated with K21/K12 ratio. This may be

due to the measurement of PLD as an efflux of lithium from the cells and its inward flux in physiological conditions. Our results also differ from the study of Mallinger et al. (5),who in 4 healthy persons found a correlation between LSC/PLD and K21/K12. Our study comprised affective patients and the assay of lithium transport was slightly different. ACKNOWLEDGEMENTS This

(CPBP

work

was

No 06-02.1.)

supported

by

the

Polish

Academy

of

Sciences

REFERENCES

l.

Serry

2.

Rybakowski

MPC1969)

3.

Commun.Psychopharmacol. ,2,105-112 Duhm J.(1982) in: Basic mechanisms

(ed.Emrich

Medica, Wa

140

Austin. Zeal. JJ Psychiat.

J.,Frazer

A.,Mendels

H.M.,Aldenhof

J.B.,Lux

53;5390=394

J.,Ramsey

in

the

H.D.),

T.A.(1978)

action

1-20,

of

lithium

Excerpta

Amsterdam Zaremba D.,Rybakowski J.(1986)Pharmacopsychiat. ,19,63-67 Mallinger A.G.,Poust R.I.,Mallinger J.,Himmelhoch J.M., Neil J.F.,Koo E,,Hanin I.(1985)) Clin. Psychopharm. ,5,78-82

The Course Therapy

of Lithium

M.T.Abou-Saleh

Predictors of response prophylactic lithium

to

University Department of Psychiatry, Royal Liverpool Hospital, PO Box 147, Liverpool L69 3BX, UK

ABSTRACT

Response to prophylactic lithium was studied in relation to clinical, personality, therapeutic and biological characteristics in a large series of patients with recurrent affective disorders. The therapeutic effects of lithium were also examined in relation to its adverse effects on thyroid and renal functions. The findings were that patients with bipolar illness, endogenous unipolar illness, unipolar illness with family history of depression of those with iess personality disturbance having more favourable outcome. There waS not association between response to lithium (24 renal

IV Alty, mach GOldu(T 4 pa hSH)mcrid ACE electrodermal DST, urinary osmolatity) volume, urine functions. An

and hour

initial response over the first six months and strongly associated with long-term response.

the

first

year

was

INTRODUCTION

We have recently studied the contribution of clinical and personality characteristics to response to prophylactic lithium Over two years follow-up in a large series of patients with recurrent affective disorders (Abou-Saleh and Coppen, 1986). Encouraged by these findings we examined the contribution of these clinical, personality factors and biological variables including DST, electrodermal activity, thyroid (T4, TSH) and renal

(24

hours

response

over

PATIENTS

AND

urinary

many

volume,

urine

osmolatity)

functions

to

years.

METHODS

Bipolar and unipolar patients attending the lithium clinic at the M.R.C. Neuropsychiatry Laboratory, were studied. There were 41 male and 75 female patients, whose age ranged between 22 and 83 (meanie51628,

«5S

Dili2ly

cars).

These

patients

have

received

prophylactic lithium for periods varying between 2 - 12 years (mean 6; SD 2.7 years). The clinical outcome was measured using the Affective Morbidity Index (AMI) (Coppen et al., 1973) for the patients whole time on lithium. Contribution of treatment variables including ECT and psychotropic medication was also studied. Methods for study of clinical, personality and initial response variables have been described elsewhere (Abou-Saleh and Coppen, 1986). The procedures for DST (Abou-Saleh et al. 1983) and electrodermal activity (Mirkin and Coppen, 1980) measurement have also been described. RESULTS

Bipolar

patients

illnesses

and

unipolar

(Newcastle

scores

patients of

pure familial depressive disease the whole time on lithium than

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

9

and

with

above)

highly and

endogenous

patients

with

had significantly lower AMI for patients with less endogenous

and Psychiatric Use

© IRL Press Limited, Oxford, England.

143

M.T.Abou-Saleh

illness and those with sporadic and depression spectrum diseases. Good responders to lithium showed significantly less neuroticism, significantly higher lie scales scores, significantly hijher validity (affective energy) and significantly lower Crown-Crisp Experiential Index total scores than poor to fair responders. Poor responders to lithium had 7 fold increase in AMI than good responders for the first six months and the first year on lithium. Good and poor responders had similar DST results (mean post-dexamethasone

cortisol

concentrations),

and

means

for

T4,

TSH, urinary volume and urine osmolatity. Patients who were hyper-responders, habituators and non-responders to electrodermal stimulation had similar AMI for the whole time on lithium. The relative

contribution

of

these

factors

to

outcome

(AMI

for

whole

time on lithium) were examined by multiple regression anaylses. There were Significant contributions from the aforementioned variables: more favourable outcome was associated with bipolar diagnosis, presence of family history of depression, lower neuroticism and lower validity scores, not having psychotrophic medication in addition to lithium the first six months and first year

and favourable response from starting lithium.

over

DISCUSSION

These findings confirm our previous findings and suggest few clinical and psychological predictors to response of long-term lithium therapy. Moreover, the administration of psychotropic medication was associated with poor outcome and patients continued to show morbidity dispite this extra medication. Poor outcome was not associated with DST, electrodermal activity or thyroid and renal functions. REFERENCES

Abou-Saleh prophylactic

M.T. and lithium?

Coppen Journal

A. of

(1986). Affective

Poor response to Disorders. 10, 115-

MAS) 6 Abou-Saleh

M.T.,

Suppression

Test

Coppen

open

A.,

Peet

prospective

diorders.

Milln

in M.,

P.

Bailey

studies

Psychiat.

and

Coppen

depression.

Neurol.

J.,

of

et

al.

(1983).

(1973).

lithium

Dexamethasone

22,

(Amst).

549-550.

Double-blind

prophylaxis

Neurochir.,

Mirkin A.M. and Coppen A. (1980). depression: clinical and biochemical of Psychiatry 137, 93-97.

144

A.

Neuropharmacology

76,

in

and

affective

501-510.

Bikecrrode cmadl) fac tailvast yam correlates. British Journal

B.Miillerec eed

Characteristics of recurrencies during ten years of lithium

Rae

prophylaxis?

H.Herrmann

Department

of Psychiatry,

FRG and Department Hannover, FRG

Free University of Berlin,

of Biometrics and Statistics,

The decrease in hospital admissions is a well documented result of lithium stabilization in affective disorders. Much less is known however about more refined benefits of long-term lithium treatment, such as remission functioning (2) and quantitative and qualitative episode characteristics. It also remains unresolved how the individual prophylactic response could be quantified. Data suitable for adequate quantification are lacking since mild and moderate recurrencies are not always properly documented. Furthermore, the data which are available pose problems for statistical analysis in retrospect, for instance in a routine lithium clinic patients are usually not seen in Strictly equidistant intervals. We have developed a procedure which quantifies the individual re-

sponse, in terms of recurrencies, without having to refer to the riod prior to lithium. Longitudinal observations on 86 patients

pewho had been admitted to our clinic (3) since 1967 were analyzed according to severity, (1=no change of medication; 2=significant change of medi3=hospitalization), polarity and duration of recurrencies, the cation; of end at the medication corresponding lithium level and additional this group are as follows: 37 remission. characterisics The each of males, 49 females; 21 unipolars, 55 bipolars, Pa10 schizoaffective. per year on the average. The data were 8 times assessed were tients analyzed with multivariate analyses and life table methods.

There were no statistically significant differences between the diagnostic group as to the Morbidity Index by Coppen (1) and the average recurrence frequency (table 1). Age and gender did not influence these findings.

Tab.1:

AVERAGE MORBIDITY INDEX SEVERITY 1-3) IN VARIOUS

AND FREQUENCY OF RELAPSES DIAGNOSTIC GROUPS (MEAN + SEM)

(F.R.)

847+. 156 1.2374. 281 8614. 162 However, more moderate and severe relapses occurred in the bipolar schizoaffective patients than in the unipolar ones. Over the span of ten years, the frequency, duration and polarity of recurrencies (severity 1-3) did not change. Significant changes of duration however, were seen when only moderate and severe recurrencies were considered. When divided by polarity, the average severity of manic relapses decreased significantly whereas severity of depressive setbacks remained unchanged (table 2). The mean intraindividual ratio of manic/depressive episodes and the polarity sequences in multiphasic and

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

© IRL Press Limited, Oxford, England.

145

B.Muller-Oerlinghausen

et al.

nn

SLE UEUUEEEEE IEEE EERE

or visa versa, were also unby depression followed (mania episodes for the that bipolar changed). Life-table calculations revealed pato stay without a recurrency existed probability a 50% group tient (severity 3) for at least 50 months after onset of treatment. Concernpatients, a corresponding expectancy value could not be ing unipolar calculated since only 5 out of 21 during were patients hospitalized observation period. the total Similar results were obtained when the

corrected

were

data

for age.

These

findings

did

not

differ

in

patients

with optimal and compliance those who temporarily discontinued their findings that lithium. These results appear remarkable in view of the and bipolar patients treated over 10 years, lithium plasma in unipolar

level

decreased

from

.77 to

.55 nmol/l

during

half of this second additional psychoreduced also be

the

period. During same time period, the number of the could of remissions) tropic medication (per number Significantly from .42+.07 to .2+.05.

Tab.2:

AVERAGE SEVERITY (GRADE 1-3) AND DURATION (MONTHS) OF RELAPSES IN PATIENTS WITH AT LEAST 10 YEARS OF LITHIUM MEDICATION DURING THE FIRST 5 AS COMPARED TO THE SUBSEQUENT 5 YEARS (MEAN + SEM)

Quality

Duration

Severity

manic (N=20) 1.-5. year 6.-10.year

4 .23+1.31 5.22+0.93

2.02+0.18 {.57+0.21

Ah ReSe CMON 60) 1.-5. year 6.-10.year

al & ume ent en P20 Wot 3.35+0.14 3.30+0 .26

oboe ees ae 1.89+0.13 1.8040 .29

REFERENCES 1.

Coppen A. et al. (1976) A double-blind comparison of lithium bonate and maprotiline in the prophylaxis of the affective orders. Lancet 2, 275-279

2.

Johnson,

3.

Press Ltd. London Mueller-Oerlinghausen, Nervenarzt 48, 483-493

146

F.N.

(1984)

The

psychopharmacology

B.

(1977)

10

of

Jahre

lithium.

cardis-

Macmillan

Lithiumkatamnese.

R.Wolf

Routine

pe eens Clcne

documentation of the lithium outpatient clinic

and course

A.Lovrek

Psychiatric University Clinic, Vienna

J.Wancata

Documentation),

(LOP-

Austria

A.Topitz E.Denk

In 1972 a lithium outpatient clinic was University Psychiatric Clinic. Owing to

patients

(800)

processing can

be

was

a documentation elaborated

performed

with

in

the

SAS

system 1985,

opened at the great

suitable

whereby

system

for

the Vienna number of

computer

statistical

(5th

version)

and

data

analysis other

available programs. The purpose was to collect the most important data of relevance for research in lithium and long term outcome of DErLOGNe Va hRectaverpSyiChOses his On all sbasie idacamon tne person (mame, address, age, sex, civil status) 6tes) “and date of initial lithium treatment are required. Then, each time the NEMS AS! roiaeiMOlIKeCl ila ie@ilownlioe iMebiniNe Cece, ics Keel lec wecis date, 12 hour serum lithium level, name of lithium preparation and its daily dosage (how much and when), any additional medication (serum carbamazepine levels are periodically monitored), body weight, type of recent psychopathology (syndrome code), and any SUdeTeLhecus. Waves ana hindings on haemavclkogy,, blood chemispny MIC LUG UN cOLdesuUnCtLOM kG. mand pSVCIOLOc1 Calas GesuIme mare BSOmreconded seAGmC Ve teV auins Vcr Gp OD ea Colles BO OCuUmMe Inia ERO as shown on the poster is compiled (age at illness onset; number of episodes, hospitalizations, and suicidal attempts while taking and not taking lithium; when lithium was begun and interrupted; affective illness in relatives; course symptomatology; intervals including degree of semission; Kind of medication during episodes and intervals; and concluding evaluation with ICD-9, DSM-III, and Vienna research criteria). If the patient remembers all his prior episodes well enough, the cycle documentation should be carried out for each episode and interval (cycle) and in addition to the

global documentation data covers duration, whether a relapse homlowed Mi thium discontanueatiton, anportant ite events, mypes episodes with ICD-9 and DSM-IIi numbers, intervals (characterization,

including

degree

of

taken. Codes are given and terms defined ones especially - in a small glossary.

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

remission),

-

some

and

of

medication

psychopathological

and Psychiatric Use

EE

© IRL Press Limited, Oxford, England.

147

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Gera

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W.Greil

Lithium

St.Schmidt

withdrawal

reactions

Psychiatric Hospital, University of Munich, Nussbaumstrasse 7, D-8000 Munich 2, FRG

ABSTRACT

Abrupt discontinuation of lithium long-term treatment may result in withdrawal reactions: transient symptoms of irritability and mood lability subsiding spontaneously and moderate to severe relapses. The relapses occur usually within two weeks and respond promptly to reinstitution of lithium. Gradual withdrawal of lithium under close supervision is therefore recommended, particularly for patients who continue to show mood swings, minor affective disturbances or relapses during lithium maintenance treatment.

INTRODUCTION

The efficacy of lithium long-term treatment in patients with affective psychoses is now well established. However, no definite criteria have been established, how long maintenance therapy with lithium should be continued and when and how it should be terminated. Furthermore, whether or not discontinuation of lithium long-term application can be associated with withdrawal syndromes is still a matter of debate. Up

to

the

early

80'

S

a

generally

accepted

view

was

that

lithium discontinuation was neither associated with abstinence phenomena nor with accumulation of relapses (rebound) immediately after discontinuation (l). However, in this paper we discuss recent evidence that the consequences of lithium withdrawal can range from no effect over transient symptoms of instability up to the rapid induction of moderate or even severe relapses of depression or

mania. RESULTS

We performed a single-blind lithium withdrawal study on 2l OWUEDat lenis vor Ou anitha UMmel an vCw (27.3) pe eDilicinG mater rst UG yast hie patients were abruptly switched to placebo for a period of 5 weeks. The purpose of this study - performed in 1980 - originally was to investigate various biological and psychological effects of long-term lithium application and their reversibility after withdrawal. Since we as other authors (1) at that time assumed that transient lithium interruption would bear no substantial risk for the patients, this study was considered to be ethically justified.

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

© IRL Press Limited, Oxford, England.

149

W.Greil

and St.Schmidt

i

the domiresulted in 11 relapses: The interruption of lithium nant clinical were manic features (n = 5), depressive (n = 5) were and depressive relapses and paranoid (n = 1). The manic in five patients. Thus, the combined with paranoid symptoms relapses

were

rather

severe.

Symptoms appeared in all cases between 5 days and 2 weeks after lithium withdrawal. The clinical features of the relapses were similar to those of the episodes the individual patients had experienced before lithium treatment. The majority of the patients recovered within 3 and 14 days after reinstitution of lithium. 10 patients did not relapse. In six of them, however, slight disturbances occured within a few days: restlessness, irritability, sleep disturbances, labile or elevated mood. These symptoms subsided spontaneously within about one week. A tendency was observed that patients with bipolar affective and with (bipolar) schizoaffective disorders may have a higher rate of relapses than the unipolar depressive patients. All relapsing patients with major depressions showed depressive relapses, whereas within the group of bipolar manic-depressive

patients

the

manic

relapses

prevailed.

Clear-cut differences between the relapsing and not-relapsing patients were obtained, when the concomitant medication during the previous lithium treatment was assessed. The majority of patients not relapsing during the withdrawal period had been treated with lithium alone. In contrast, most of the relapsing patients had been in need of additional psychotropic medication within the last 12 months before lithium discontinuation, because

of

mood

swings

or

moderate

the global assessment scale (GAS), lithium withdrawal were 90 for the

for

the

relapsing

patients

relapses.

Accordingly,

in

the mean values before non-relapsing group and

(p < 0.01,

Scheffe

73

test).

DISCUSSION

The results obtained might indicate putative risk factors for early relapses after lithium-withdrawal: additional medication (antidepressants, neuroleptics) within one year before lithium withdrawal; remaining disturbances, e.g. mood lability, more or less pronounced relapses while on lithium; previous manic episodes (bipolar I, schizoaffective disorder, manic type).

We are drawal

aware of six other studies on experimental lithium (table 1) that appear to corroborate our findings.

with-

In these studies the frequency of relapses varied between 0 (4) and 100 @ (5,6). As in our study, the patients relapsed usually several days after withdrawal (2 days to 6 weeks; mostly within 2 weeks). Including our study, 40 out of 107

patiens

150

(37

%)

relapsed

when

withdrawn

from

lithium.

%

rr

Table

1:

Experimental

Lithium

withdrawal

relapse

Lithium

withdrawal

reactions

studies

timing

of

relapses

after

withdrawal

Small et (LES 7a10)

al.

Lapierre

et

al.

5

days

5

5

20

4

2 days 6 weeks

5

(1980)

Our

4

study

(Klein

1981;

aul,

5 weeks

et

alk

ae

days

(n=3),

weeks

5-14

days

al.

Greil

et

iL)

Christodoulou Lykouras

Margo

&

&

15

days

18

3

2-4

4

2-11

days

4-18

days

days

(1982)

Mc

Mahon

et

al.

=

4

(1982) Svestka (1984) Goodnick (GES! 3159)

et

al.

14

days

3 weeks

total

Bi

13

LZ

0

107

40

=

Reevaluation of these other studies appears to indicate that similar risk factors as found by us may also apply for the relapses reported by others (6,7,8). Thus, in one study (7) two of the four relapsing patients had experienced hypomanic episodes while under lithium, the other two had shown signs of chronic disturbances (chronic hypomania; personality traits of aggressiveness and of liability to alcoholism).

The

four

patients

who

relapsed

in

another

study

(6)

had shown, respectively, relapses under lithium, only incomplete response to lithium (GAS value of 65 before withdrawal), early relapses after previous lithium withdrawal and very frequent relapses before lithium treatment. The patients of Svestka and coworkers (8) were treated with additional medication

(15x)

throughout

the

study.

of the cases in three studies no concerning possible risk factors

From

the

limited

description

information is available of the patients (4,5,9).

Our observation that patients recovered rapidly after reinstitution of lithium was verified in three studies (5,8,9). Furthermore, a questionnaire study (10) confirmed our findings that discontinuation of lithium may result in transient signs Of UEritabi ity sands anxiety.

151

W.Greil

and St.Schmidt ———

i

Conclusion: Discontinuation of long-term lithium treatment may result in importance: withdrawal reactions with varying degree of clinical - transient signs of irritability, mood lability and anxiety subsiding spontaneously, - moderate to severe relapses with symptoms similar to those of the

pre-lithium

recurrences

of

the

disease.

The withdrawal-induced relapses appear in the majority of cases within 2 - 14 days after discontinuation of lithium and remit mostly within the same time period after reinstitution of lithium treatment. A risk factor for early relapses after lithium withdrawal seems to be incomplete response to lithium prophylaxis, i.e. mood lability or relapses as well as the need of additional psychotropic medication during previous lithium long-term treatment. Furthermore, patients with bipolar affective / schizoaffective illness might run a higher risk for lithium withdrawal reactions than unipolar patients. The same might be true for patients who had previously experienced relapses immediately following lithium withdrawal. Although these conclusions are based on only few reports, it may be advisable to stop lithium treatment, if possible, only by gradual reduction of dose (over weeks or months) under close supervision of the patients. When withdrawal induced relapses occur, lithium treatment should be reinstituted as soon as possible - combined with antidepressants or neuroleptics, if necessary. Interruption of lithium treatment, e.g. for surgical intervention, should be as brief as possible, e.g. 2 - 4 days.

Interruption of lithium for scientific reasons might still be justified to evaluate the biological and psychological effects of long-term lithium treatment using an on-off design. For such studies, however, patients with clear-cut episodic disorders and symptom-free remissions should be chosen to minimize the risk. Further discontinuation studies are urgently required to clarify the actual risk of the lithium withdrawal reactions described.

REFERENCES

1. 2.

3.

4. a.)

152

Schou M. (1980) Lithium Treatment of Manic-Depressive Illness, 71 pages, S. Karger, Basel, Switzerland Klein, Hob. Brooucek, Barand Great wo Glos). Ba a Psychiatry, 1395. 2o5—25bo. Greil, W., Broucek, B., Klein, H.E. and Engel-Sittenfeld, P. (1982) in Basic Mechanisms in the Action of Lithium, (edse Emnich, HoMs, Alidenhonh,. vJ.B. and lux. Heb) pp Zeb 248. Excerpta Medica, Amsterdam, Oxford, Princeton Goodnick, P.J. (1985) Acta Psychiatr Scand 71, 608-614. Smalt w.G., Small. LoPewandsMoormen Debs a(lOi7el))evAnae ind) Psychwatey, 1027/7) 555d Soe.

Lithium

Mango,

sAswand

McMahon,

Pa

(1932)

410 hapierre, Y.D., Gagnon, A. and Biol Psychiaytry, 15, 859-864. Svestka,

DAO

J.,

Nahunek,

K.,

Br

oO Psychiatry,

Kokkinidis,

Rysanek,

withdrawal

R.,

L.

Ceskova,

1414

reactions

0i/—

(1980) E.

(1984)

Acta Nerv Super (Praha) 26,-. 237-238. Christodoulou, G.N. and Lykouras, E.P. (1982) Acta Psychietrrocand. "65495 .L0—34% Mabie), Odie. iil ialin. wie, (OES) tecalis wi IWShAolaaleeieyy 5 3:5ye

Si0K

153

Leonardo Tondo .

Lithium .

1

G anfranco

1

ee

Floris

withdrawal:

Raterots

©.

,

Clinica Psichiatrica,

Caterina Burrai Pier P.Pani

an outcome

:

:

Universita di Cagliari, and ‘Centro

‘Bini’, Cagliari, Italy

INTRODUCTION The

ed

issue

little

of

discontinuation

interest.

Since

subjects

who

do

compared

the

results

MATERIALS

We

AND

not

included

patients

responders

tmce

from

with

antidepressants

to

Lithium

sultation

due

or

is a

has

receiv-—

provided

study

on

about

them

and

relapse.

hospi

of

relapse

or

for

valisetaon,) We

reasons,

those

Affective

alone

neuroleptics.

whose

subjects

Disorders,

at

least

som

two

Spiecurt le

years,

-uherapy

selected

only

those

who

back

for

came

progress

Discontinuation

Ninety-five 19

diagnosis

different

personally.

included. and

treatment

out

did

treatment

nequirins for

to

contacted

females

carried who

with

Lithium

relapses

Suspended

not

we

those

Lithium

information

METHODS

good

were

relapse to

of

little

was

due

fulfilled

to

who con-

unknown

and was

hypomania

these

criteria:

76

males.

RESULTS Thie

results

groups: differ dupa

are

subjects in

wOn

(range

mean om

24

age

sia

—-

presented

with

and

at

or

the

table,

in

divided

relapses.

discontinuation,

Tekeatmenit

129);

in

without

40

The years

prior

The

dusicontinuatvon,

Li

levels,

two

groups

(range

plasma

0.55

into

two

42.3)

meq/l1

do

17

=

not

76);

months

(range

0.35-

OO ke DISCUSSION Our

TNE

methodology

Veco

Son

Or

habrust

anid

Other

COnm isan

oct

relapsies

in

evilo (i), SUL

Games

by

percentage

a

gradual

On

Ode

and The

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

a

wee anbinemm

other

Od ere of

decision

type

of

by our diSm

studies,

(Sy) 4 1ieehenuiilkos) cbs

therefore

timesmmade

Nonetheless

Lakh hime

to

prodedure,

SOne

patraenu.

suspension

Depression well-being.

Wass

similar

(2))5 Wicvavelleriattexs

with

of

naturalistic

the

COMta mich Om

a

iii,

Unipolar

period

a

Suelo rns HOM aGicl Ge asin

sociated

of

follows

UScontintauLOn

ig

en

the

eMle

treatment,

suspension

after

pisvien—

results aise.

mon

Baastrup

(AS

clpisieis ese cmS esGOn

made

thes

a

might

a

et

we Dc

sae

scsi

diagnosis

protracted support

the

and Psychiatric Use

© IRL Press Limited, Oxford, England.

155

L.Tondo et al.

hypothesis

occur thats

of

a

within the

lapses

minimum

is

occur.

might

However

than

the

the

of

interval

number

completely

OF

THE

NO

since

these

follow-up

the

therapy

RESULTS

syndrome",

Following

lower

exclude

from

aioe

months. length

longer

not

action

"withdrawal

six

of

the

that

for in

our

which

even

UP

Tor

the

must

most

relapses

lasts

of

it

in

after

noticed

without

relapses

Unipolar

patients

a

stabilising

its

suspension.

STUDY RELAPSES BPL

BPoiL

UP

N.

7(23%)

9(30%)

14(47%)

30

35(54%)

18(28%)

12(18%)

Males

2(29%)

4(57%)

1(14%)

7

7( 58%)

4(33%)

Females

5(22%)

5(22%)

13(56%)

23

28(53%)

14(26%)

BP

Treatment Duration:41.6 months (range 15 - 77) Reason:Side-effect 1(25%) 1(25%) 2(50%) 4

65

8%)

12

11(219)

53

43.0 months (range 16 —- 129) 10(62%) 3(19% 3(19%) 16

6(26%)

7(30%)

23

14(54%)

10(38%)

P's

0

0

0

O

6 (67%

2( 22%

1(11%)

9

O

1(33%)

2(67%)

3

5(36%)

3(21%)

6(42%)

14

Gradual

5(25%)

8(40%)

7(35%)

20

Rapid

2(20%)

1(10%)

7(70%)

10

decision

Interval: (months )

10(43%)

1

TOT

Well-being Other Type:

re—-

the

of

of

relapses

be

patients

possibility

RELAPSES

BEE

58%

data

6(40%)

1-6 6-12

More

Relapse:

than

5(33%

4(27%)

15

29(58%)

13(26%)

8(16%)

50

21(55%) SCBOR)

8(21%) S(SS3s)

9(24%) 38 a 750)) lS

5 (42%

2(16%)

12

O

O

30

12

5 (42%

M

30(100

D

2(

Mix

Follow-up

6%)

18(56%)

3(100)

(months)

42

ey

44

(10-69)

(12-68)

( 9-93)

2( 8%) 26

12(37%)

Oo

0

32 3

REFERENCES Ie

BEEING)

IIoCsy

Reblisam

wots

AMAgdisienizAv. «(lL O7O)

lance

tea

Zo

Viale IPs ih

iiealtes

G5

w

Mendlewicz,J.

(Cede

4.

(1984)

Comsa ma. Gauie)

pp.

Reginaldi,D.,

(1985)

PALC HOG

Plenum

L.

deans

Publishing

PS wWelasiere Trends

MiP

Rk). and

iG, in

G21

Lithium

Press

Ltd,

—

62a" anda

Rubidium

Lamcasterm .um.

Mist aaiokeVh aGag my WbreKsKoN INS 5 imil@geticy,ie4 -

Psychiatry:

CmmMer iPr

Thosen,

ceo —e3 Ol

IsS-l4is

and

Tondo,

SMeMow Ws

Current

Kukopulos,A., (ed.

156

(ISAO)

«

WO.

Corporation.

The

Rrra mG

State

of

ABIeNDLA Tee)

the Gove,

Art. “lnc y ea

Vol.3 VSS

Ch.Simhandl

Side effects (self rating and

eee

objective rating) in 265 patients

Ch.Spiel

E Denk

“aL: under lithium long term therapy

G.Lenz

Psychiatric University Clinic Vienna and ‘Institute of Psychology, Department for Methodology, University of Vienna, Austria

A.Lovrek

A.Topitz J.Wancata R.Wolf

In

this

paper

lithium

we

are

outpatient

going

to

clinic

present

(LOP)

at

the

the

Vienna. 265 patientswho came to the serum lithium level (SLL) were asked

results

of

psychiatric

a

study

at

university

IONE IMS Clogicieel to mark out of a

enh aleve: list of

the

of 12 22

Gal

possible side effects their subjective complaints. Then two doctors rated independently together with the patient, wether the complaints were related to lithium medication or other reasons like additional medication, symptomatology because of Cpasode,, scammed! distribution of lithium medication, duration, etc. We investigated

265

of

patients,

60

was

18,5

%

815,5

mg/d

(s we

=

(s

41.9

and

So

0,21).

% male,

above.

58,1

The

= 262,8 divided

% female

average

and

mg)

72,5

dosage

% under

of

age

average SLL was 0,61 mMol/1 groups of the SLL for further

The duration 0,65 - 1,6 mMol/1l. of 0,2-0,6and was separated groups: into the following 6-12

evaluation medication

the

lithiumcarbonat

the

two

into

with

daily

lithium months

(N=31, 11,7 %),1-3 years (N=94, 35,5 %), (N=76,28,7 %), 3-10 years 24,2 %). At time of investigation 73 patients over 10 years (N=64, (27,5 %) were in an episode, 192 patients (72,5 %) were free IMEeRVoaL Orel nhal Gas tol biG kon ot ithiuncarbonay medacanaon was divided our sample into a sample which had 1 dosage in the

tonmovers the erotic wanounern wa cial dasumibus eon Gu CVC (a = 67 day ia ="1985 57457 4). Additional medication was registemed for antidepressants (including long acting (38,5%), neuroleptics neuroleptics together with hypnotics tranquilizers (32,1%), (24,9%) and

no

additional

medication

9S

patients

(S5,1%).

172

(64),9%)

nad

medication. any add. Results: The frequencies of side effects are shown in the list below; it is) Sorted by the occurance in the self rating (SR):

MACHO

PANE INAS, ON

SDN

MINAS)

ALIN) SAkeiey DOGO

N MOnSuGememneetS

fatigue BMAiO Sie dry mouth GLemome poor memory polyuria muscle and headache

LOSS,

ue

joint

aches

J logieke

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

NeVNAT IE IN|IS) DOCTOR

%

N

2

%

TAO

SZ6

A

6 65 Sie Sy 5 39

Ze 24,4 ANS)2 ASS) e® 14,6

3 So) Psy Ze} 3 A5

3 iL

ils all 0,4

5

iS)

SELF

RATING

N

%

SisS

82

ab sa 2252 NO) G'S) 8,6 illo wll L659

82 80 76 63 54 46

2] O

Ore, O50)

Be 29

8

il pele

23}

and Psychiatric Use

© IRL Press Limited, Oxford, England.

157

Ch.Simhandl et al.

*

hairloss dizizane sis goitre muscular weakness sweating Smekmesis

5 O cli, 4 is) 2

others gastric dyscomfort diarrhea nausea Skin ver iecics oedema The calculations by chi-square Simelle racings: (doctor i= DIS

Cie Side et hecus SEX Grenor was

female

eS 0,0 Gre eS SAIS) OF

4 1 he, it 3 2

Dry

mouth

Al zeit 18 16 35 LS

We) os 67 60) i 5,6

4 iS) 4 de) 14 See 2 ORs aU 0,4 14 bee 6 DONe. 9 3,4 is Ag 1 0,4 1 0,4 3) 3,4 5 aS) 3) supa) 8 ria@) 2 Oy 6) ads 6 eas with the above mentioned groups Ss and "doctor 29= D2 endusel aeatane —) sh)

Showed hollow lier Sina Ga Sec nated by D2 (w= S763825 pi =

patients.

as 0,4 siete! 0,4 ileal Ord:

(v = 4,333,

p =

St oide One ea HOmm > O08) more GoLteal by,

0,037),

gastric

dyscomporit: (vy = 785260. p= 10),004)) occiimed more arequentr ia; cua self rating of females. AGE: The two groups of age showed no

SHEE alts ral @ell Way Salledolsind serenely |(elie sieievsigvellvers; 5 soiling pegardine (side eftecus and Sli was neu Star.

eens

invsneaeyen (en bk vevayel 0)2 Sloan. Diazzamess ye

Abed, Dp! = O),041)) wand muscular weakness (wa=— 4,875. p= 0027) i was higher in the SR when SLL was above 0,65 mMol/1. HPS ODEs imenor was raced mim Che eb gecta Vemmabaiie. by a wand pe stat. sign. more oftem when patients were rated as being in an episode: (it vie— eo 20OR pn = OnOOO KMD saya wh MoO) 104de mitra the

SR

less

isiideleitecers

patients were occured stat. weme

in)

am

mabed sign.

in (p

occurecdity

=

QSOs

=

0-002)

when

free interval. Nearly all side effects 0,05) more often in the SR when patients

episode.

ADDITIONAL

MEDICATION:

No

objective

rating

(D1,

D2)

was

stat.

sign.

regarding relationship antidepressant additional medication (AD) and occurence of side effects. SR showed regarding AD comedication

Stat. sagn. relation vo dry mouth (v=14,388; p=0),000)) and tremor (v=5,692, p=0,017). Neuroleptic comedication showed that the rating "no side effect" was statistically sign. for BDL (vsi3;226, p=0 000) and in SR (v=14,562, p=0,000) but not for D2. The side effects tremor (v=8,439, p=0,04) and thirst (v=10,799, p=0,001) occured Svat. Siem. More ohven ini che catine or Dl, fa taessR the esaide

effects dry mouth (v=7,560, p=0,006) thirst (v=12,975, p=0,000), tremor (v=4,331, p=0,037) and fatigue (v=6,319, p=0.012) occured more

often

when

tranquilizers

tremor SR dry

neuroleptics

and

OCGURECM

Stain

Sauce

"No

MOme

side

= 11,031, duration

p = 0,012)

was

with

tremor,

and D2

then

duration

following

under

long

fatigue).

occurence Of comedication

was

and D2 (v 10 years.

longer

long

rating

often

the

comedication.When

medication,

then

term

In

10

(v = 8,332, years.

rated

side

Side effects and the fact

less

by

the

p = 0,040)

Thirst D2

effects

treatment

sumary

statistically

rated

by

= 14,748, p = 0,002) when the "Polyuria" occured more often

(v

with

also

In

=

SVSaks

p

0,04

jel =

were

(thirst,

polyuria,

factors

main

stat.

Dl

OS OMENS

poor

=

when

sign.

rated

(v

duration in Dl (v

ratings,

was

two

more nigh

more

memory,

nyabael bt—elonip ayes

ame the psychopharmacological that the patient is in an epusode.

a 158

as

additional

orm Gene

effects"

10,222, p = 0,017) lasted longer then

self

administered

were

(v=4,154, p=0,042) occured stat. sign. more often in D1. mouth (v=5,332, p=0,021) and tremor (v=5,331, p=0,021)

DURATION:

often

were

hypnotics

ele

J.Wancata

Reliability of lithium related side

Ch.Simhandl

effects

E.Denk

Ne

el

G feng c

Psychiatric Clinic, University of Vienna and ‘Institute of Psychology, Department for Methodology, University

A.Lovrek

of Vienna, Austria

K.Thau A.Topitz R.Wolf Ch.Spiel'

Introduction: Mirthoush@the patients but

because

of

prophylactac also general

side

etficiacy of Lvuthilunm as well established. practitioners withdraw this medication

effects(SE).

How

difficult

the

evaluation

CHReCUSHIS Can be seen im the literature. where the frequencies show a great variety. In studies about

of

side

data about tremor e.g.

we find numbers between O and 78% of an occurance in lithium DALEeHino Ober eT wehnCime hAChORS On sue enrecous like =addusy moma medication, symptomatology of an affective episode, somatic diseases, nNeurotic Symptomatology, serum lithium level, age or sex are Often mot completely documented. iia SscuUCy abe the Miibhi uM OuULpDAbLenit Climnnce (EOP Wor. sae PVC eweLE Clwsts©, Wauyweresahiey jul Wikomine We alanelsipaleeureel, Ino frequent symptoms are due to side effects of lithium when other shige INGKEIA@ Laver IEA WOME GSS COmMiSCEMSCl, We aLiPiiNeI Wioneswieciesel 5 wae wel main i igye ee ‘cle Wehenlays One lee earreOws) lay elle we reac DSyVchiatrIsts Under= tnese (carcumsuances:.

Methods: COSpatuchtS, WwHOmcane sbOMLNecim Troutime onurol, of the 2 sn eserumn lithium level had been investigated because of their frequency of ParhlonecelaLedasvde cEneCuseNb Uae nui MemOn she tmnVvcoed oat Omani patients had been more than six month under a regular lithium medication. The patients had been asked to mark out on a list of 22 POSSmoleNsudenecrrcere TEMeInESUbyeceuly Ss COMPA mnbSR LNem tWOsbiccumned OSyyCskelioilsics shalcleyersraceicnely Teeveeie! ael fel qwellle yyiwlal ilaley joretiosten 5 whether the symptom is a SE of lithium, considering the following Ceiteria + temporal “connection beuween the besinnins of the symptom and tne Stamteen the lithium prophylaxis or a rise of tne serum lithium level, somatic or psychic disease, additional medication. The computation of the interraterreliability (IRREL): "total agreement" tests the agreement of the presence (Gi) Wand sone cine

Absence

GOO

statistic

MoOLea

technic,

SE

we

chink

because

in

thane rare

toveal

wagrecneno

symptoms

a

good

is

mol

agreement

exacr would

be simulated . "Signated konkordancerate"(SKR%) tests exclusively the agreement of the presence of a SE (SKR%=II/(II+I0+01); we considered

this

to

be

the

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

best

technic

to

get

exact

results.

and Psychiatric Use

em

© IRL Press Limited, Oxford, England.

159

J.Wancata

et al.

a

S

Results: The ecffects". "no side to have rated 30,8% of the patients as Sh of Jaemanany, items had been marked by the patients following

ranked

the

after

dry

(30,0%),

thirst

(30,8%),

fatigue

frequency:

polyuria (20,3%), poor memory (23,7%), tremor (28,5%), mouth (10% 9%"). “AE headache (12,0%), and joint aches muscle (17,3%), by tne pabvents. Ot than fewer had been marked symptoms other in the are presented the frequencies about informations (Detailed paper of Simhandl et al. in this volume.)

Table

1:

Frequency and

of

ratings

by

doctor

interraterreliability

selfrating

(SR)

by

the

1

(D1)

between

the

and

doctor

doctors

plaaere Sit, polyuria tremor

S58)

dry

VS

mouth

mo (In

side this

frequent

effectus table than

side 5%.

the SKR in this item GLher i venssoceuned performed. )

pi p2 Sera, Bye 6 ii

D1/D2/SR ailaa 45,8

Sg ©

PO

24,1

LORS,

Crs Sno Cre 526 effects

Diarrhea

are had

is 50%, rarely

TRREL

D2 NEN es ISS BS)

2

struma sweating diarrhea

(D2)

the

patient.

frequency (%) D1 24,4 14,6

2

and

36,9

22,4

Bio ial Bii4

54 25 On 50/70

Sivas OO 38:95

55.06

65,0

rarelyie

selected been

rated

,

which only

doctors in

3,4%,

rated

more

but

therefore it is listed here. and no correlations could be

Several

In the following SE the doctors is minimal 50%:

interraterreliability between the two thirst, struma, polyuria, diarrhea. The agreement of dry mouth, sweating, tremor was less than 50% .The AS EESMeMU Uate MOS LdemeRMeCDS MOCCUN md Sm Oom G7. mine mccdains Dosen between the 2 doctors and the patients selfrating is only in tremor

more

than

50%

correlation

(SKR),

(Pearson)

all

other

between

side the

effects

two

doctors

are

below.

agreement

The and

rank the

Peequency OL the sk mated by the doctors as O768%. Lheat Shows, that in SE, which are rated more often by the psychiatrists the IRREL between them is better. Only a weak correlation could be found between the frequency of selfrated SE and the IRREL between the two

dectors(Rank

corr.=0,40%)).

The low agreement between the patients and the doctors (only one item more than 50% SKR) suggests, that selfratings of patients alone gives no reliable information about the presence and the frequency of lithium related SE. The agreement between the two doctors Us cleanly better, bu Tt Shows. chateaerelaable AGL Omron SE by consideration of other influencing factors is Meiny: difficult.We have no informations about the reasons, why in some SE the reliability is good and in other worse. Preliminariliy we only can show, that SE, which are more often rated by doctors, show a better reliability. Other factors, which influence perhaps the agreement between the psychiatrists, like additional medicataon, diseases, etc. will have to be investigated in further studies.

160

G.Lenz

Lithium withdrawal study in

A.Lovrek

Les

: 7 . schizoaffectiv i e patients

A.Topitz

Psychiatric

Clinic, University of Vienna,

Austria

E.Denk Ch.Simhandl J.Wancata R.Wolf In a validation-study on therapy-response patients with RDCSchizoaffective Disorder (bipolar) of the Lithium-outpatientclinic,Psychiatric Clinic,University of Vienna, were withdrawn from lithium in a double-blind placebo-controlled study: in a cross-over-design patients received lithium for 4 months and placebo for 4 months.

Each 2 weeks placeboand

ratings (2 pre-study ratings,8 ratings during during lithium-period) were performed with BechRafaelsen scales for mania and melancholia, BPRS and GAS. It was intended to include 30 patients,but after 6 patients the study had to be stopped because of ethical reasons(high relapse-

rate

with

4 admissions

to

hospital).

5 of 6 patients had manic relapses during within 10 days to 6 weeks.Patient Nr.2, a

the placebo-period rapid cycler,entered

the study in a subdepressive state which improved and worsened throughout as well the lithium as the placebo-period (severe depression after 6 weeks on placebo) .In patient Nr.l,after 6 weeks on placebo a manic episode occurred, which switched into a depressive episode at the begin of the lithium-period; she stabilized again after 6 weeks on lithium. The evidence from the literature concerning the possible withdrawal symptoms or rebound phenomena after abrupt discontinuation of lithium is very conflicting.Several authors (SMALL et al.1971, ALEXANDER

1979,WILKINSON

1979,LAPIERRE

1980,KLEIN

et

al.

1981,

CHRISTOULOU and LYKOURAS 1982,MARGO and MCMAHON 1982) report an immediate onset of episodes after lithium-withdrawal mostly in bipolar patients,which is in contrast to SCHOU(1980),who is much more sceptic about abstinence phenomena or accumulation of re~lapses after withdrawal from lithium. We considered the relapses of our patients as real episodes not only

because

of

the

severity

,but

also

because

of

the

fact,that

it mostly took several weeks until the relapse occurred. Our results can be seen as a further step in the validation of RDC-criteria for schizoaffective disorder(bipolar):the high relapse-rate in our study suggests further evidence, that schizoaffective-bipolar patients are very similar to patients with bipolar disorder in respect to response to lithium salts.,which relationship about the close to other reports is in accordance (CLAYTON 1982). and bipolar patients schizoaffective between

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

© IRL Press Limited, Oxford, England.

161

iis

(82) 82

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162

et al. G.Lenz

J.L.Crammer

Lithium

in clinical use

—

the next

step Chinese University of Hong Hospital, London, UK

Kong;

and Maudsley

With Lithium treatment many manic patients in a few days lose their restless overactivity, talkativeness and irritable inappropriate good humour. Some depressed patients show a lessening of their pathological inactivity and gloom. People with regularly recurrent affective illnesses, especially bipolars, cease to show the illness if they continue to take lithium. The myth has grown up that lithium has a narrow specificity of action, confined to manic-depressive disorder, in striking contrast to its many biological actions in competition

with

sodium

and

calcium

and

in

enzyme

inhibition,

in interference with choline transport and endocrine secretions and so on. Clinicians have been content to accept basic science theories of lithium action without reference to the clinicial observations own their negate may which For example, theories. lithium in high dose usually produces dysarthria, clumsiness, slurred speech and mental confusion, parkinsonism, it quite making not but distinct from other therefore neurotransmitter of theories amine psychotropics: parkinsonism and affective disorder do not apply to it. The myth has been supported by a narrowing tendency to look at therapeutic utility rather than pharmacological action in man, and by a circular argument - that if lithium acts on a patient there must be an affective component in the illness. This is to misunderstand the nature of psychiatric diagnosis which is descriptive rather than pathological, and makeshift rather than ultimate. Clinical research has Concentrated jon icuoss—-sectional Study = State at a point an time - uSing procrustean rating scales scored by uninformed nurses and heterogenous groups of patients of unknown pathology, instead of observing in individuals the actual clinical changes longitudinally over time, which offers better chances of understanding lithium action. About 15 years ago I had a woman patient with early multiple Sclerosis and a recurrent manic-depressive illness difficult to control. I followed her in 22 episodes over 2 years. Every 30 days or so she would go into a depression lasting 2 to 3 weeks and suddenly switch into a manic phase lasting %-1 week. The depression began with 3 days of

irritability, then progressed to tiredness, weeping, not wanting to do anything: She became more depressed, incapable of action, anorexic, trembling. She slept more, from 9 hours up. imapranines ace oO mg perm day did little. Vtor shes: depression lasting 12-15 days, hypomania 3-5 days. Changed to lithium 800mg daily, she was depressed for only 10 days and the hypomanic phase was absent. The depression was not only shorter, it never reached the incapable anorexic phase, was lighter in the evening, there was no initial

Lithium: Edited

Inorganic Pharmacology by Nicholas

and Psychiatric Use

J.Birch

© IRL Press Limited, Oxford, England.

163

J.L.Crammer ee ——e—e—e———————eeE———EEEEEEEEEE ES

in 4 days for about of insomnia but a degree irritability, each attack. the lithium to the added 45mg daily was phenelzine When irritability days, to 14 again lengthened depression returned, and yet depression was milder still she could laugh and work. But the manic phase reappeared immediately at its worst, 7-10 days duration, with wild spending and aggression. This demonstrates the symptomatic complexity in time of a manic-depressive episode, and how lithium can modify certain aspects of it, even though therapeutically useless. It also demonstrates a very interesting drug interaction MAOI reversed some of the lithium effects. Recurrent illnesses provide good opportunity for study: so do drug withdrawals from patients on long term treatment. The sudden withdrawal of lithium may precipitate a manic attack in the following week or so (1) (2). Delva et al (3) found several schizophrenics already on lithium and neuroleptics. When lithium alone was withdrawn under individual double blind conditions, patients relapsed consistently about 12 days later, and recovered when lithium was resumed. But when thioridazine relapse again lithium has

alone was withdrawn, and lithium continued ensued. Here is incontrovertible evidence that a part to play in the treatment of some

schizophrenics

(see

also

be

there

may

a

also

Delva

drug

interaction

and

Letemendia

at

work:

(4)).

Here

Lithium

with

thioridazine. Reports (4a) of thioridazine inducing signs of lithium toxicity at low plasma levels of Li support this. A recent survey (5) makes it likely that there is no general risk in combining lithium with neuroleptics, in spite of a few early reports of brain damage, which must have other explanation. In drug therapy psychiatrists have proceeded on the assumption that soon as it is

each drug acts independently, and that as stopped its action disappears. This happy innocence must end. I have already instanced an MAOI imposed on lithium producing new results different from either alone. De Montigny and his colleagues (6) were the first to show that some patients whose depression did not respond to tricyclic antidepressant suddenly and quickly improved when lithium was added to the daily treatment. Has this anything to do with the pseudo parkinsonism seen as a side effect of imipramine plus lithium? Non-steroidal anti-inflammatory drugs (NSAID) given to patients on stabilised lithium dosage Hayvesproduceds svgns Or siithium, Coxitelty.. Cutcrentin 7 sthrcm ds explained as a renal effect, NSAID preventing lithium excretion and raising lithium plasma level. However the plasma concentrations at which toxic signs appear are so much lower than hitherto expected (e.g. piroxicam: Li 1.0-1.18 mm/l1

(7);

indomethacin

0.84,

unpublished)

as

to

suggest

a

lech auny ee NSALD Seimteraction, alco. me sehen bias ms The longitudinal study of individual cases with planned tests should allow us to elucidate the interactions between lithium and other medical treatments (psychotropic or not), and to call on this knowledge in explaining unusual treatment responses. Perhaps if NSAIDS lower the threshold at which lithium acts they might help in therapy of resistant cases. SS 164

ee

ee

ee

eee

ee

Lithium variety

which may the drug, manic

has

of

been

other

claimed

conditions,

of but

ee

Clinical lithium use

therapeutic

benefit

I

consider

will

only

in

a

two,

help to throw light on the fundamental actions of which cut across conventional diagnoses, whether

depressive,

schizophrenic,

or

other.

One

is

the

value

of lithium in suppressing aggressive behaviour. For example a report (8) from an American convict prison compared the behaviour of prisoners on lithium with those on placebo monthly over 4 months, as reported by the prison officers: those on lithium became markedly less aggressive. The Similar value of lithium in the aggressive handicapped was (9). recently confirmed Again from America, a group of confirmed alcoholics were put on lithium after drying-out, and in those who continued to take the drug in reasonable dose there was less tendency to

resume

less

drinking,

compulsion

to

less

satisfaction

continue

(10).

This

in

the

first

drink,

behavioural

change

sounds like that in the aggressive convicts: less impulsive action, more "time for thought". Of course we need more research, including more descriptions by those who take lithium of what the effects appear to be to them. We can link this with studies on normal volunteers. It is surprisingly hard to show any mental change when subjects take lithium in daily therapeutic dose for 2 weeks or so. Some report a slight dreamy feeling, an effort to keep fully alert. Karniol et al. (11) found a decline in measured short term

memory

(due

to

inattention?).

Kropf

and

Muller

-

Oerlinghausen describe experiments suggesting lithium induces a rise in the threshold of visual perception, and a reduction in recognising stimulus significance. A long time ago brain function was seen in terms of a central arousal system which raised or lowered cortical activity. It was suggested that chlorpromazine blocked some afferent stimuli coming into this system, lowering arousal, which in schizophrenia was seen as abnormaly raised and responsible for positive symptoms. We need some concept of this kind for lithium action, some central neural process which plays a part in normal function and even more so in some psychiatric manifestations. It will be defined by what lithium does not do as much as by what it usually does; and by the drugs and metabolic contexts which do, and which do NOtAmChaAange sehitise spec) sucibyO pei tecita, So far as we know lithium does not usually influence epilepsy in any way, neither frequency of attacks nor pattern of episodes (though lithium - phenytoin interaction has been reported (AS) There akewCase reports of 1lithium benefitting torsion dystonia (14) and torticollis (15) but being without effect on parkinsomism or L. Dopa dyskinesia (16).

There

is

need

for

a

full

critical

review

of

lithium

in

neurological conditions. Lithium actions cut across conventional psychiatric diagnostic boundaries, and must be studied by clinical pharmacology as well as practical therapeutics in many conditions. Manifest effects may be altered by other drugs Guvens beLore, with, Or satter lithium; sand by (presence or neurological lesions. More clinical observation and report of detailed responses in individuals, distinguishing rare

165

J.L.Crammer

Se

eee

eee

ee ee action

of

mode

The

needed.

are

effects,

common

from

ee

of

structure of the brain, lithium must depend on the functional clinical from created be must concepts new which for and interaction. of action explaining specificity knowledge, lack the themselves necessary Bio-molecular by events Spe Gated tyr. References Ine Margo, A] 407-410.

2

Mander

3.

Delva,

4. fae

J.

Asie N.,

N.

SeLlLers;,

McMahon)

Pz

(982))

(19816) |Britten Letemendia,

Psychiat.

Delva, Je

and

141,

F.

401-406.

and Letemendia

aa,

Psychiat.

Lyre,

1407

F.

Prowse,

(1982)

Psychaat.

A.W.

ibid,

Whiteley,

4ih,

Aj

(1982)

141,

et

ale

Brit.

387-400. Glos2))

Brat.

96235625).

Goldney, R.D. 143, 882-884.

6.

De Montigny, C., Cournoyer, G., bangloisy. ReviGal le sGeen (U9 35)

AOA USPIoussel. Vieilcrestclety, Wine

J)

PSyciia ata. leo aco eS o0 ue and

5.

fo

and

ba,

Brit.

Spence,

Glevel

D.

isveleguaeey

(1986)

Amer.

J.

Psychiat.

Morissette, R., meAtsCh michel mek Sic lacie.

ysis,

(MIs)

istebes

ape

PISViCiicltml Aui, a2 O02 Olas See

nonheard Je

O32

MoH

eMail

BSY Chi ace

.Craikty,

Mia

lo)

kO9

eSsmaty

eA

BE Lagesy

nC.ms

(ow6)

meAmcaae

Saas

Kast Slanamut cde

ele ne te cles

tt Osi)

Bicitt pd me PiSy Cha citeaeel5 0) mio S5— 090%. MO

reWMotee

Anche kis

wWhy,

gen.

“Uguaeyoil;

(Cllewal.a

6a

:

:

oe S664

>

Ge

Sag ro}

eA al i ee eo | i =e ee

20

Die

:

ee

>

=

2,

3/6

) pericellularly attached qr included in the membrane structure of the cell and its organelles, (c) free in intracellular fluid. The relative importance of these environments must now be assessed. Other studies Of the rate of flux across —Ehe erythrocyte membranes uSing ‘Li-NMR are in agreement with our interpretation (Espanol and Mota de Freitas 1988). A further study by Riddell et al (1988) on lithium transport, mediated by an ionophore, monensin, adds further weight to this argument. The implications of these findings are that be seeking an extracellular site of action

perhaps we should for lithium. We

have in this Congress papers describing immunological effects of lithium and effects on viruses. We also have papers on membrane receptors and receptor sensitivity. These are all extracellular in character. A broader implication may be the questron of (thes sole) of) extrace filiu lam sconcenitrativonsman therapeutic efficacy. Are the pharmacokinetic parameters for the steady state (or the fluctuating state depending on your point of view (Plenge and Mellerup 1988)) those which are most

226

Inorganic pharmacology

ee

ee

ee

appropriate or are we making assumptions of distribution intracellular compartment which now are not justified.

to

ee

an

On the other hand, perhaps we should consider that low intracellular lithium concentrations may indicate that the Locus Of action Us on a particular .system which is exceptionally sensitive to lithium. It is worthwhile pointing out, however, that the triphosphoinositide system, of which we have heard much, is aes particularly sensitive ‘to lithium at less than 0.1 m.mol.1°~ which is the maximum intracellular free lithium concentration in patients' cells inferred by our studies. A potential corollary to these considerations is that manic depressives might have a different cellular permeability to lithium, making some process more susceptible to lithium interference in these patients. Data of Rybakowski et al (1988) supports this view and echoes ideas current in the last decade. Riddell (1988) has reported that lithium transport is particularly sensitive to the phospholipid composition in model membranes. However, we must recognise that the apparent reluctance of lithium to cross cell membranes may be a key to its action. One of the characteristics of lithium is that it is not normally available in large quantities in the human body and homeostatic mechanisms presumably must react to the intruding ion as best they can. That the homeostatic response to lithium incursion should be beneficial to manic-depressive patients is to the great good fortune of those who find lithium

therapy The

beneficial.

results

outlined

above

were

carried

out

in

collaboration

with colleagues from a variety of disciplines and I wish to acknowledge their contributions both to the experimental evidence and to the ideas presented. Inorganic substances have been used in medicine from the earliest times. Only recently, however, has there been the possibility of applying powerful physical and chemical techniques to provide a basic understanding at the molecular level of inorganic pharmacology. REFERENCES

ite Die

3s

4.

Birch,N.J. (1976) Possible mechanism for the biological action Of sla thaume Nature, 264 681. Birch,N.J. (1982)\ Lithium in psychiatry, Ch. 11 in “Metall Tons in Biological Systems", Vol. 14, Sigel, H. (Ed), Marcel Dekker Inc., New York. jy) AS = Bulse Birch,N.J. (1987) Magnesium and psychiatry: Biochemistry and inorganic pharmacology related to lithium, in "Magnesium in Cellular Processes and Medicine', Altura, Bahia peDilalach 5 Jey OCC, |MoS. GhOS)ieKarndet,. sBasieds je BILA > Bal. Basch, Nevin fe hOSite Gr,|Ge,meNaT Gay beNe en (O61) iebinh eCie Sis Oi

lithium kinase. Die

and

calcium on manganese activated BiliteWJie phanmacon. TP MHOC.

Bitchy New apelin

ne sy MS.

nOMas, GMs

(1986) Lithium and magnesium: Magnesium Bulletin 8 145 - 147.

Hey

Inorganic

pyruvate

bak tie! gel or

pharmacology.

Dae

N.J.Birch

Crow,D.R.

(1988)

This

volume

pp

3095-307.

Davie, Ride, (COleman, lb shy eb reh, Neda Lithium ante xKodent small intestine. Ue rslelshe

ine

aeLhe msuptialkicr so: Biochem. Soc.

press.

Davie,R.J., Partridge,S. (1988) This volume pp 107-111. Espanol,M.C., Mota de Freitas,D. (1988) This volume 281-284. Espanol,M.C., Mota de Freitas,D. (1988) ‘Li NMR studies of lithium transport in human erythrocytes. Inorganic Chemistry. In press: Hughes,M.S. (1988) This volume pp 285-288. Hughes,M.S. (1988) This volume pp 285-288. Hughes Meise, —Partertdge,s., Thomas, GaMoHa,. Sa nem, News (1987) The use of dysprosium shift reagents in nuclear Magnetic resonance, Biochem. Soc. Trans. In press. Kagjidayp. ko, Bare h, Nei Wl QOlh)e hice na Un aim bicioa tearomn not phosphofructokinase. J. Inorgan. Biochem. 14 275 = 278.

Ws

Kagda,P.ks,) Burch, Nida, OUBTien, Meus, Hil in, Rat brain pyruvate kinase: Purification and Daten euins J. Inorgan. Biochem. l] 361 - 366. McCreadie,R.G. (1988) This volume pp11-13.

tars (1979) effects of

Parntrnavdge, Ss,

Burch,

(1987)

18. 20.

Lithium

Hughes;M.S.,

transport

in

Lhomas,GeMeH.,

erythrocytes.

Trans. In press. Plenge,P., Mellerup,E.T.

(1988)

Riddell,F.G.

volume

(1988)

This

This

News

Biochem.

volume

Soc.

pp 135-138.

pp 293-295.

Riddell,F.G., Arumugam,S., Cox,B.G. (1987) Ion transport through phospholipid bilayers studied by magnetisation transfer; membrane transport of lithium mediated by monensin. Chem. Comm. In press. Rybakowski,J.,

Lehmann,W.,

Kanarkowski,R.

(1988)

Thats

volume pp 139-140. Thomas,G.M.H., Hughes,M.S., Olufunwa,R., Partridge,S., Marr,G., Birch,N.J. (1987) Lithium transport into isolated hepatocytes. Biochem. Soc. Trans. In press.

Thomas,G.M.H., Thomas,G.M.H.,

Olufunwa,R. Olufunwa,R.

(1988) (1988)

This This

volume volume

289-291. 289-291.

The Kidney

Klaus Thomsen

The renal excretion

of lithium

The Psychopharmacology Research Unit, The Psychiatric Hospital, Risskov, Denmark INTRODUCTION

Interest in the renal excretion of lithium prospered in the mid-sixties due to the introduction of prophylactic lithium treatment of manic-depressive illness. It became evident that knowledge about the renal lithium clearance (CLi) was rather limited and that this shortcoming had to be remedied. The success of long-term prophylactic lithium treatment with constant doses depends on the maintenance of a constant serum lithium concentration, and since this concentration is inversely proportional to

the

lithium

constant.

In

clearance,

it

can

only

be

addition,

it

was

soon

found

kept

constant

desirable

if to

CLi be

is

able

to

increase the renal excretion if lithium poisoning should develop. This last point became our starting point. We examined the effect of various diuretic drugs on CLi and became surprised by the finding that diuretics acting mainly on the proximal tubules enhanced CLi, whereas diuretics acting mainly on the loop of Henle or the distal tubules and collecting ducts showed no effect at all on CLi (1). Our interpretation of these findings was that veniam iS! reabsorbed in the’ proximal tubulles but not in the loop of Henle, the distal tubules, or the collecting ducts. We also found that the fractional renal excretion of lithium amounts to 20-30%, which corresponds exactly to the fraction of sodium and water which is excreted from the proximal tubules. On the basis of these observations we hypothesized that CLi would be quantitatively equal to the proximal tubular fluid output (V-prox) and therefore might be used as a marker of the excretion of sodium and water from the proximal tubules (2). Since then a great number of animal and human investigations have been carried out which have established and confirmed our conclusion that Chi reflects V-prox and therefore can be used as a measure of this kidney parameter (3). We have found but one exception: Distal lithium reabsorption does take place in rats on a low sodium diet. Under such circumstances CLi can therefore not be used as a measure of V-prox. However, acute administration of amiloride can inhibit the distal reabsorption without affecting V-prox (4). In case of doubt amiloride can therefore be used to clarify whether distal reabsorption is present. According to our

present

knowledge

no

distal]

reabsorption

occurs

in

humans,

but further investigations on this important point are much needed (5). Measurement of the proximal output of water and sodium plays an important role for the understanding of the kidney physiology under normal and pathological conditions and for the understanding of the pharmacological and toxicological effects of various drugs on the kidneys. Until recently it was not possible to perform

such

lithium has

measurements

clearance

created

increasingly

an

eager

used

in

method

in

humans,

has

interest

many

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

but

the

introduction

improved

the

possibilities.

in

fields

the

method,

outside

the

and

it

is

psychiatric

of

the

This now

being

sphere.

and Psychiatric Use

© IRL Press Limited, Oxford, England.

231

K.Thomsen eee ee

The

eee

eee

eee

knowledge

thus

eee

acquiréd

from

eee

non-psychiatric

sources

does

not only serve the specific purposes for which investigations have been designed. It is as valuable for the long-term lithium treatment of manic-depressive patients. Similarly, the accunulating

knowledge

obtained

from

psychiatric

lithium

treatment

will

contribute to the general knowledge about the proximal excretion of sodium and water. Changes in the serum lithium concentration reflect changes in the lithium clearance and patients in longterm lithium treatment therefore constitute, so to speak, a large source of information obtained under much varying circumstances - just such circumstances as life in general implies. REVIEW

OF

RESULTS

The growing use of the lithium clearance method has already provided many results. Space does not allow mentioning every single investigation, but some main findings should be emphasized. Lithium clearance is correlated to the glomerular filtration rate (GFR) and hence to sex, age, and body surface (2,6). The dependence of CLi on GFR is also responsible for the increase of CLi seen during pregnancy (7). Lithium clearance is almost unaffected by the sodium and votassium content of the food (with the exception of extremely low and extremely high contents) and it is unaffected by the diuresis (1,8).

since

It

a

shows

little

constant

day-to-day

lithium

variation

clearance

is

a

-

a

fortunate

prerequisite

ful lithium treatment. On the other hand, hour variations with fluctuations between,

for

fact,

success-

it shows large hour-toe.g., 20 and 30 ml/min

in the same person. The sodium and potassium excretions are linearly related to these fluctuations which makes it likely that the oroximal excretion has a certain function in the rapid regulation of the excretion of these electrolytes (8). Lithium

clearance

decreases

through

volume

contraction,

for

example during dehydration (9). In experimental animals it may also decrease following laparotomy, a procedure which in many respects affects the kidneys in the same way as volume contraction. On the other hand, lithium clearance increases during volume expansion as, for example, during infusion of sodium chloride, during mineralocorticoid escape, during a recumbent position, and during

water

immersion

(10,11,12).

From the above it will be seen that CLi increases under several circumstances which also involve an increase of atrial natriuretic factor, and it has in fact been shown to increase after such infusion (13,14). On the other hand, it decreases after infusion of angiotensin, even though anelotensin induces an increase of the perfusion pressure, which in itself is known to increase CLi

(15,16).

As

a

general

rule,

an

increased

renin

concentration

is found under circumstances with a lowered CLi, erg. during low potassium or sodium intake. Lithium clearance is lowered

ter

adrenalectomy

bie

shows

that

in

it

spite

is

also

of

ample

affected

supplies

by

of

adrenal

sodium

gland

a af-

chloride

hormones

Lithium clearance may be changed during diseases which involve changes in renal function and during kidney diseases. It is lowered during glomerulonephritis and pyelonephritis and after uni-

nephrectomy

(2,18).

It

can

be

either

lowered,

ee 232

unchanged,

or

in-

ee

ee

ae

ee

ee

ae

eh

Renal excretion aces ee

creased during essential hypertension, depending on the experimental conditions (10,19). It is lowered or unchanged during hepatic cirrhosis, both with and without ascites (20). It is un> changed

in

diabetes

mellitus

in

spite

of

an

increased

GFR,

and

anereased dneBaresen s syndromer(21,22)\c TES CLi is affected by diuretic drugs which may present vroblens when patients are treated with a combination of lithium and diuretires. However, different diuretics affect Chi to different degrees. Chronic treatment with thiazide lowers CLi (23,24). Chro-

nic furosemide treatment does not affect CLi when measured over the 24-hour day; it increases shortly after intake of furosemide and then decreases to below normal levels for some hours before returning to its normal level (9,25). Chronic treatment with acetazolamide,

on

the

other

of these differences is targets in the nephron. these

hand,

increases

The

exvlanation

targets.

Lithium

clearance

is

also

affected

by

drugs. For example, chronic cyclosporin and there are some indications that CLi marker

CLi.

that different diuretics have different CLi can therefore be used to determine

of

toxic

influence

on

the

renal

various

nephrotoxic

A treatment can be used function,

lowers CLi as an early

because

the

de-

crease Of CLi becomes apparent before that of GFR (26). Acute cisplatin treatment causes CLi to increase (27). CLi remains unchanged by neuroleptics and antidepressants, which is convenient in psychiatric treatment (28). It is lowered or unaffected by non—-sterord antaintlammatory drugs (297,307,391). CONCLUDING

REMARKS

Finally it should be mentioned that the lithium clearance method is still young. Although many of the above mentioned findings look reasonable inasmuch as they show what would be pected,

there

may

be

circumstances

where

CLi

is

not

a

ex-

precise

Measure of the proximal tubular fluid output. What could be feared is that due to experimental difficulties in distinguishing between reabsorption in the straight proximal tubules and in the ascending limb of the loop of Henle, 5-10% of the filtered amount of lithium might be reabsorbed in the loop of Henle without being noticed. Changes in this reabsorption might occasionally occur separately from changes in the proximal tubular fluid output, thus giving rise to misinterpretations of changes in CLi. There is therefore good reason to be cautious in the interpretation of small chenges in Cli, while in case of larger changes one may take things more lightly. Lithium can also unexpectedly be reabsorbed distally. We have observed this phenomenon in rats ona sodium-poor diet, and the same may be seen under other circumOne may of This is another reason for being cautious. stances. course take up an attitude of hesitance until the method has If so, been thoroughly tested under all thinkable circumstances. its use may very well have to wait until we have passed however, because experience with the method then into the next century, - It is therefore better to use the method cannot be obtained. now but to preserve a certain scepticism and show great caution In this way we will be able to when results are interpreted. acquire knowledge about the circumstances under which the method can or cannot be used. ——_—_————————————————__$_$_$_$_$_$—

283

K.Thomsen

REFERENCES —> .

Thomsen;

Keeandeschot,

Ma

(196.0)

Anew

J.

Phystoles

215

o2o—

ee Thc TRONSen,y Thonseny; DHonseny

ROOS

h- Creal (1969) PEitigers Archos 08, 100-110 4s Ke (1984) Nephuons si 217s223. Wanandeleyssac; Pere (ISG Renal =Phys1Ol opel

Uae

Ctra

Schou

sete

(190 5)) Amn

alte

(1.956)

aur C.etmciles(iliO SG.)

Themsen,

Ko

ietbeall, 5S. Ce

Phy Sion

Clan geNephrol

Abherton,

WO PO OND OW Cheuscenseny

iO mle

249) eb 25m

=Gr

lio Aye

Om S2diie

bh vicious

(1987) Glin’ Nephrols” (te be pubsashed)): al (19 S8o)Mwe) Pharmacol shxp. Ther. 230),

22S Holstein-Rathliou,

Sd —5 16s Boece Wola Seyikehwyoia>

Brown,

N.-H.

chal. Tei,

J.

W195)

“Eke

and

et

Euls

al.

sama

(CMSKeKa))

Dollery,

(1985)

das

J.

Bypertension

Physiol a2 527

Wellaiiey = Syesle 7 / i

C.T.

(1986)

Clin.

57

roo! —BaBo.

esses) -

Res.

34,

729A.

Burnere J .Coamerral. |(iOS) mAh Ens. Olmert GS —haG.OKe Olsen, M.E. et al. (1985) Am. J. Physiol. 249, F299-F307. Halas;

Smith,

BU Aietaal on (9S6)

D.F.

sams

and Thomsen,

Wie

K.

baySlolem

(1973)

Am.

250m

erZ45—r2a0e

J. Physiol.

225,

159-161. Steele,

Weder, HatTon,

T.H.

et

al.

A.B.

(1986)

We

Cteal.

(1975)

New

(i986)

Brgchner-Mortensen, 2 Obl Dorhout

Mees,

E.J.

tLles , SOrrentor,. exeweipecyeials War ie

Am.

Engl.

J. et

Ely

et

J:

J.

Med.

Med.

Sci.

314,

269,

Hepatology

OpmdilioG

al.

Diabetologia

al.

(1984)

(1986)

(q\Se/CN)

ihe,

Abstr. WiteYol,

re

349-363.

198-201.

Int. ee

ite

27,

Meeting

189Diure-

ee

Shirley, D.G. et al. (1983) Pfltigers Arch. 399, 266-270. Satfer, D. and.Coppen, A, (1983) J. Affect. Dis. 5, 229-257 JDkeyerswerloNs

ely

Che

cule

“(UIMEIS))

inbwes

Gra

C@liskas

IneSSeC

MA.

GoS77 -

Daugaard, G. et al. (1986) Renal Physiol. 9, 308-316. Lassen, E. et al. (1986) Arch. Gen. Psychiatry 43, 481-482. Imbs, J.-L. et al. (1980) Int. Pharmacopsychiatry 15, 143149. pons ca Sule

E.

et

al.

Nie tremS ON mw Wiese

(1986) curate

Acta OCO)

Pharmacol. MAN

Mad

Toxicol. amd

melo

9: 59, ee

377-

Sten Christensen

Lithium

effects on renal function

and morphology Department

of Pharmacology,

Copenhagen,

University of

Juliane Maries Vej 20, DK-2100

Copenhagen @, Denmark

ABSTRACT The effects of Li on renal function and morphology with emphasis on experimental studies are reviewed. Li has marked influence on _ renal function, ranging from harmless reversible polyuria to chronic. renal failure, dependent on species, dose and mode of administration. Li also changes renal morphology and enzyme histochemistry. Initial changes occurring after a few days comprise hypertrophy of the collecting duct cells associated with increased mitotic and mitochondrial enzyme activity. These changes appear to be related to changes in renal concentrating ability, although the meaning of the histomorphological picture remains obscure. Li-induced polyuria is caused mainly be inhibition of vasopressin-stimulated adenylate cyclase in collecting duct cells; contributing factors may be polydipsia and dissipation of the cortico- medullary osmotic gradient. High K intake prevents the early functional, morphological and enzyme histochemical changes. Chronic renal failure asociated with cortical cysts, interstitial fibrosis and reduced proximal tubular mass is induced by administration of Li to newborn rats. Due to species difference this syndrome is not likely to occur in humans. However, the rat model with chronic uraemia illustrates the nephrotoxic potential of Li, which should

be kept in mind pregnancy.

in order

to

avoid

over-

dosing

and

administration

during

INTRODUCTION Li

ions

exert diverse and characteristic effects on renal function, enzyme histochemistry, and morphology. Current interests in renal effects of Li may be summarized in two basic questions: (i) Is Li treatment harmful to the kidney in patients receiving the drug for years? (ii) What is the mechanisms and probable relationship between the multiple effects on the kidney? This short review intends to give some answers to the second question , mainly on the basis of experimental studies. biochemistry,

FUNCTIONAL

RENAL

CHANGES

Changes in kidney function cover the range chronic renal failure (Table). With few exceptions, described

both

irreversible

controlled

in experimental

functional

animals

damage

renal

and

is

from mild polyuria to these effects have been

in humans.

probably

low

However,

in

risks

the

patients

on

of

well-

Li therapy.

Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

eet nee

© IRL Press Limited, Oxford, England.

SEE SSEEE

235

S.Christensen

RENAL

CHANGES

INDUCED

BY LITHIUM

IN HUMANS

Functional

-

- Collecting

acidosis

Natriuretic

effect.

Na excretion

duct

hypertrophy, and atrophy (cysts)

dilatation

Polyuria Nephrotic syndrome Acute renal failure Chronic renal failure

increases

ANIMALS

Structural/histochemical

- Natriuresis

- Tubular

OR EXPERIMENTAL

-

Increased DNA synthesis Increased mitochondrial activity - Interstitial fibrosis

Both

and

in

humans

induces

and

rats

a negative

Li

Na

enzyme

treatment

balance

(2).

initially

The

acute

natriuresis is probably due to inhibition of proximal tubular Na reabsorption combined with a direct or anti-aldosterone effect on the collecting ducts. Na reabsorption in the loop of Henle is not impaired. The natriuresis is modest and not clinically important. However, Na and volume depletion are undesired because it may lower the renal Li clearance with accompanying risk of Li intoxication. Thus, Li intoxication induced by otherwise toxic Li doses in rats can be prevented or cured by increased NaCl supply and saline infusion may be expected to increase Li excretion in patients with Li intoxication induced by Na deficiency (3).

Incomplete

animals

distal

tubular

acidosis.

Li treatment increases

baseline

Both

urine

in

patients

and

pH and impairs

experimental

the ability to

excrete and acid load, the socalled incomplete distal tubular acidosis (4). The clinical significance of this mild acidification defect is unknown. The mechanism seems to be inhibition of distal nephron H+ secretion through a reduction of the lumen-negative transepithelial potential difference, an effect mimicked by the diuretic amiloride ("short-circuit" renal tubular

acidosis)

(5).

Concentrating common side-effect

defect and polyuria. Polyuria was early recognized as a to Li therapy and has been studied extensively (cf. 6). Although animal studies have suggested that Li may stimulate thirst by a central mechanism, it is beyond doubt that the major cause of Li polyuria is impairment of the renal ability to concentrate the urine in response to antidiuretic hormone (ADH), the socalled nephrogenic diabetes insipidus. The polyuria is resistent to usual doses of exogenous ADH but can be

reversed

by high doses

of synthetic

most patients Li-polyuria is long-term Li therapy, although

defects

have been reported

(8).

ADH-analogue

fully reversible a few cases of

in rats

(7).

In rats

and

after discontinuation of irreversible concentration

The mechanism of inhibition of the antidiuretic response to ADH has recently been elucidated in experiments with isolated collecting ducts. Li added in vitro inhibits the hydroosmotic response to ADH in perfused rabbit

collecting ducts (9) and collecting ducts microdissected from Li-treated rats show a marked decrease of adenylate cyclase activity and cyclic AMP generation when stimulated with ADH and forskolin (10). There is thus strong evidence that the concentrating defect is due to inhibition of the generation of cyclic AMP, which acts as an intracellular mediator for the water permeability response of ADH in the collecting duct cells. However, possible additional effects of Li on ADH receptor binding and biochemical steps beyond cyclic AMP generation have not been excluded. Increased delivery of tubular fluid to the distal nephron, due to inhibition of proximal fluid reabsorption, and dissipation of the cortico-medullary osmotic gradient may contribute to enhance the polyuria caused by Li (6). ee 236

ee

Effects on renal function

SS

eS Se eee

and morphology

eee

Clinically, Li polyuria is considered a relatively harmless although disturbing side-effect. However, excessive polyuria may enhance the risks of volume depletion leading to Li intoxication (3). Urinary concentrating tests have been advocated in clinical praxis to evaluate possible kidney

damage (see later). However, because is functional and reversible, such

in most cases the concentration defect tests have no value unless performed

several weeks after withdrawal of Li. In rats treated with Li for 2-21] weeks we found no correlation between concentrating ability and light microscopical renal changes (8). Nephrotic

development

syndrome.

of nephrotic

Several

case

syndrome

reports

(11).

In

have

some

linked

reports

Li

with

proteinuria

the

dis-

appeared when Li was withdrawn and reappeared when Li was reinstituted. Glomerular changes and proteinuria are not regular findings in rats treated with Li. It is not known why Li causes glomerular injury in selected patients, but the incidence of this disturbance is very small. Acute

renal

failure.

morphological damage

has

Acute

been

nephrotoxicity

described

associated

occasionally

in

with

uraemia

patients

with

and

Li

intoxication (12). In the rat model acute renal failure develops when Na supplies become inadequate to replace Li-induced Na losses. A vicious cycle links Na deficiency, lowered Li clearance and increased plasma Li levels, and fatal Li intoxication is preceded by acute renal failure (3). Also in patients acute renal failure is associated with lowered Li clearance, but Na deficiency does not seem to be an important precipitating factor for the intoxication syndrome. Chronic renal failure. There is patients Li treatment may Tead to severe

no convincing evidence that in chronic renal failure or terminal indicate that the glomerular filtration

uraemia. However, several studies rate (GFR) declines slowly, but significantly, in the course of long-term Li treatment (13, 14). Although for many patients the GFR values pass the lower limit of the normal range, the GFR depression is only moderate and very few patients decline below 40 ml/min. Adult rats given high doses of Li do not develop chronic renal failure, but fatal intoxication is preceded by acute renal failure (15). However, administration of Li to the mothers of newborn lactating rats results in irreversible kidney damage, associated with lowering of the GFR, uraemia, tubular atrophy and interstitial fibrosis (16, 17, 18, 19). This condition is progressive after withdrawal of Li and accompanied by increased mortality. Since the plasma Li levels are below 1.0 mM in young rats when developing chronic renal failure, it seems that the rat kidney is particularly sensitive to damage by Li in the first weeks after birth.

MORPHOLOGICAL

AND ENZYME

HISTOCHEMICAL

CHANGES

A great variety of morphological renal changes have been observed by biopsy and autopsy in Li-treated patients. However, due to the lack of an appropriate reference material, it has often been questioned whether these changes were caused by Li. The rat model offers an opportunity to

investigate morphological, biochemical under controlled conditions.

and

enzyme

histochemical

changes

Adult rats. In adult rats given low doses of Li in the diet (S-Li 0.5-1 mM), a variety of changes occur within 1-3 weeks in the late distal tubules and the collecting tubules (8, 20, 21). Initially, the cortico-medullary collecting duct cells show swelling and bulging into the

S.Christensen

lumen, associated with increased mitotic activity, DNA synthesis and mitochondrial enzyme activity. The number of mitochondria increases and there is nuclear polymorphism and vacuolization of the cytoplasma. Both the outer diameter and the protein content per mm length is increased (10). After several weeks, the tubules become more dilated and most cells become flattened and atrophic. After prolonged treatment with higher doses (S-Li > 1 mM) focal cortical interstitial fibrosis is observed around the even more

dilated

tubules,

glomeruli,

the

now proximal

appearing

as

tubules

and

cortical the

microcysts

limb

of

Henle

(22, remain

23).

The

grossly

normal. The location of these histomorphological changes is well in accordance with the location of the predominant functional changes (see above) and it is obvious to suspect a causal structural-functional relationship. It has been suggested that the dilated tubules was a morphological manifestation of the increased urine flow, but similar changes were observed in Li-treated rats where the polyuria was prevented by water restriction or treatment with ADH-analogue (unpublished results). Also, there is no corre-

lation between the later morphological changes (being partly irrevesible) and the reversible defect in concentrating abililty (8). On the other hand, changes in mitochondrial enzyme activity correlate well with the changes in concentrating ability (24). It is probable, therefore, that the initial hypertrophic changes in the collecting duct cells have relation to the inhibition of ADH-mediated water flow, although the cellular mechanism remains obscure. The later irreversible morphological changes (tubular atrophy

and

concentrating

fibrosis)

seem

to

be

unrelated

to

the

functional

defect

in

ability.

Neonate rats. The morphological picture in rats given Li from birth resembles the changes observed in adult rats treated with high doses of Li for several weeks, but the changes are much more severe (16, 18, 19). The volume fraction of interstitial fibrosis is increased to 30% and the mass and total length of the proximal tubules is markedly decreased. Cortical cysts up to 3 mm, believed to be dilated distal/collecting tubules, are visible on the surface of the kidney. Both the volume and the size distribution of the glomeruli are changed (unpublished results). All these changes correlate with the decrease in renal function.

CONCLUSIONS

AND PERSPECTIVES

Animal studies have been useful in characterizing structural-functional renal changes induced by Li. Initial morphological/enzyme histochemical changes occur in the collecting ducts which is also the site of several functional disturbances (polyuria, acidosis, aldosterone blockade). Tnis is in addition the site where Li is highly concentrated in the tubular fluid (up to 30 mM), and there is evidence that amiloride, a Na channel blocking agent, can ameliorate Li-induced polyuria by inhibition of cellular Li uptake from the distal tubular fluid (25). An interesting observation is that high K intake in rats can prevent both morpholocial, enzyme histochemical and functional renal effects of Li (26). High K intake ("K-adaptation") leads to a reduction of the luminal (outside positive) membrane potential of the collecting duct cell (27) and it may be speculated that K protection against Li-induced renal damage is due to decreased intracellular accumulation of Li. The protective effect of K has not yet been shown in humans. The link between the early reversible changes in the collecting duct system and the more widespread chronic changes, which may eventually lead

238

Effects on renal function

a

ee

and morphology

ee

to uraemia, remains to be elucidated. It seems that the primary insult of the distal nephron in some way results in progressive interstitial fibrosis with a reduction in the amount of proximal tubules. REFERENCES [eeivenSenwmH

Eee

2. Singer,

I. (1981)

SSImDnugs

3. Thomsen, K., 4. Perez, G.0., 09, 455-462.

Kidney

225046467.

International

and Olesen, 0.V. Oster, J.R. and

19, 374-387.

(1978) Gen. Pharmacol. Vaamonde, C.A. (1977)

9: 85-89. J. Lab. Clin.

Med.

5. Kurtzman, N.A. (1980) J. Lab. Clin. Med. 95, 633-636. 6. Christensen, S. (1987) in Lithium Therapy Monographs. Vol. 2, Chapter 3. (ed. Johnson, FIN.): Tn press. 7. Christensen, S. (1980) Scand. J. clin. Lab. Invest. 40, 151-157. 8. Christensen, S., Hansen, B.B. and Faarup, P. (1982) Renal Physiol. 5, 95-104. ro 9. Cogan, E. and Abramow, M. (1986) J. Clin. Invest. 77, 1507-1514. 10.

Christensen, S., Kusano, E., Yusufi, A.N.K., T.P. (1985) J. Clin. Invest. 75, 1869-1879.

11.

Kalina,

12.

148-150. Lavender, S., Wy GLY Sa Se

13.

Smigan,

K.M.

L.,

and

Burnett,

Brown, Bucht,

J.N. G.,

G.B. and

von

(1984)

Berril, Knorring,

J.

W.T. L.,

Murayama,

Clin. (1973) Perris,

N.

and

Dousa,

Psychopharmacol. Postgraduate C.

and

Med.

Wahlin,

4, i J. A.

(1984) Neuropsychobiology 11, 33-38. 14. Lokkegaard, H., Andersen, N.F., Henriksen, E., Bartels, P.D., Brahm, M., Baastrup, P.C., J@rgensen, H.E., Larsen, M., Munck, 0., Rasmussen, K. and Schroder, H. (1985) Acta psychiatr. scand. 71, 347-355. 15. Thomsen, K. and Olesen, O.V. (1978) Toxicol. Appl. Pharmacol. 45, 16.

17. 18. 19. 20.

IBS=1Glls Christensen, S., Ottosen, P.D. and Olsen, S. (1982) Acta path. microbiol. immunol. scand. Sect. A. 90, 257-267. Christensen, S. and Ottosen, P.D. (1983) Pflugers Arch. 399, 208-212. Ottosen, P.D., Sigh, B., Kristensen, J., Olsen, S. and Christensen, S. (1984) Acta path. microbiol. immunol. scand. Sect. A. 92, 447-454. Christensen, S. and Ottosen, P.D. (1986) Acta pharmacol. et toxicol. Hoy SSIeeHy/ Jacobsen, N.O., Olesen, 0.V., Thomsen, K., Ottosen, P.D. and Olsen, S.

(1982)

Lab.

Invest.

46 298-305.

21. 22.

McAuliffe, W.G. and Olesen, 0.V. (1983) Nephron 34, 114-124. Hestbech, J., Olesen, 0.V. and Thomsen, K. (1978) Acta path. microbiol. SCalidls SSeu, Na BG, WGocilGi/c 23m SONGZeE Keen Ne COhmeAeeOnhtStenSennm San OLLOSeNa mr Dim cance Olsennemlin sr (1984) in Acute Renal Failure. Correlations Between Morphology and Function, (eds. Solez, K. and Whelton, A.) pp. 409-417. Marcel Dekker, Inc., New York. Zoe NOrgdard.aalles sncdabUp ups manSeih "BeBe NiISLeCNSeN> suAskmm cn Christensen, S. (1985) Renal Physiol. 8, 60-61. 25. Batlle, D.C., von Riotte, A.B., Gaviria, M. and Grupp, M. (1985) New Engl.

J. Med.

312,

408-414.

26. Olesen, O0.V. (1984) Dan. Med. Bull. 31, 270-282. 27. Hayslett, J.P. and Binder, H.J. (1982) Am. J. Physiol.

243, F103-112.

239

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Pgamma>Palpha in all three cases with the alpha phosphate being closest to the adenosine moiety and the gamma being furthest away. The degree of shift caused by the addition of the metals was observed to be Mg>Ca>Li (figure 1.). The vicinal coupling constant between the phosphorus atoms was also seen to change. The coupling constant value decreased on the addition of the metal ions until equimolar concentrations were reached, after which they reverted back to their previous levels. A change in coupling constant is indicative of an alteration in the conformational state of the triphosphate chain, and gives a measure of the degree of interaction between the phosphate atoms. However it is not possible to specify the nature of the change in conformational state by these values alone. This data leads us to conclude that all three metal ions form a 1:1 complex with Na ATP by binding to the beta and Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

© IRL Press Limited, Oxford, England.

285

M.S.Hughes

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(PE

Et et

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©

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Hannah Steinberg . Elizabeth A.Sykes

Lithium and animal models: . introduction to 4 ‘Round Table’

1

.

discussion Psychopharmacology Group, Department of Psychology, University College London, Gower Street, London WC1E 6BT, UK and ‘School of Psychology, Middlesex Polytechnic, UK

Although

‘animal

models’

can

be

broadly

defined

to

include

e.gisolated tissues, the focus here will be on models involving animal behaviour. The kind of animal behaviour model proposed for any psychoactive drug is naturally largely determined by the drug's clinical use. For lithium, the main use is still for mania, and many models have involved inducing, by drugs or other means, manialike behaviour in laboratory rodents typically forms of "spontaneous' hyperactivity - and modifying it by pretreatment of various lengths with lithium. Co-administration of a benzodiazepine, chlordiazepoxide (CDZP),

with

amphetamine

induces’

striking

locomotor

hyper-

activity - repetitive, compulsive and prolonged - in rats and mice placed in novel environments, which appears particularly reminiscent of human mania, and a single lithium pretreatment

can reduce or abolish effects on the more dexamphetamine

behaviour

ified The

et

due

after

it ((1), diffuse

alone

to

have

large

lithium

doses

though

(6) was

and by Vale therefore

been

model

equivocal,

seems

pretreatment

CDZP-dexamphetamine

al It

(2); see also hyperactivity

has

reviews

now

been

and Ratcliffe (7). surprising to read

‘reference-free'

and

unaffected

(see

publication

(8)

or

by

stereotyped

even

(4)

confirmed

in a

(3)). Lithium obtained with

an

intens-

and

(5)).

by Aylmer

authoritative

consensus

statement

to the effect that there existed more or less satisfactory animal behaviour models for e.g. psychoses, anxiety and panic, but NOT for mania. A second, related, clinical use of lithium is in the treatment of manic-depressive episodes, and here animal behaviour models seem to be sparse. Recently we have obtained unusual behaviour in mice by coadministering single moderate doses of CDZP with single moderate doses of conventional or putative (clenbuterol and salbutamol) antidepressant drugs ((9), (10)). A special effect of CDZP alone is that initial hyperactivity in an unfamiliar Y-shaped enclosure subsides after 2-3 minutes into immobility (11). If, during this immobile phase, the enclosure is gently lifted off the floor, the animal will ‘come cowas clenbuterol When if normal. as away walk and to' the enclosure inside behaviour mouse CDZP, with administered hyperactivity was reduced and though the initial was similar, the when However, intensified. immobility subsequent the the mouse again walked away, runway was lifted off the floor, If the backwards. conspicuously was locomotion its but now Lithium: Inorganic Pharmacology Edited by Nicholas J.Birch

and Psychiatric Use

a

© IRL Press Lirnited, Oxford, England.

313

H.Steinberg and E.A.Sykes

Steps of B/W No. Mean

Saline Pretreatment

Lithium Pretreatment

Figure 1. Clenbuterol 2.5 mg/kg co-administered with CDZP 7.5 mg/kg i.p. 30 mins. beforehand elicits increasing stressrelated backward walking in mice in two successive tests (cf

(10)).

Lithium

carbonate

pretreatment

(2

earlier; cf (2), (14)) reverses this trend 0.05, 1 tail), “suggesting ereatér stress second test.

3

hrs.

(n=6 per group. “adaptation at

meq/kg

i.p.

P< “the

mouse was briefly replaced in the enclosure and the repeated, backward walking during this second test intense and prolonged than during the first; the packward walking in these experiments is exacerbated stress such as changes in location (10), and is also greater the more intense the preceding immobility (9).

This

sequence

of

‘cyclic’

behaviour

-

procedure was more amount of by mild apt to be

hyperactivity,

immobility, backward walking - seemed a possible baseline for testing the ‘normalising’ effect of lithium. 24 mice were therefore divided into two groups of 12, pretreated once with either lithium or saline, and then further sub-grouped, according to whether they received the drug combination or

saline

before

being

tested

in the Y-maze

(Fig.

1).

Lithium pretreatment somewhat reduced locomotor activity in the enclosure, especially rearing, which was almost abolished in both sub-groups. Most remarkably of all, however, backward walking under the influence of the drug combination, which normally increased at the second trial, decreased sharply. If the amount of backward walking is indeed an indication of

"stress',

then

this

reduction

could

be

interpreted

as

reduced

stress and therefore improved stress adaptation with lithium. Further work is in progress and these results are preliminary. Their trends are, however, consistent with other research in our laboratory and elsewhere, and with reinterpret-

ations

of

cognitive

‘exploratory’

terms,

such

behaviour

as

in

information

novel

environments

processing,

7 SSS

314

in

selective

Lithium and animal

models

attention to stimulus change and protection from decline in vigilance, all of which are mentioned as differentially susceptible to lithium treatment in the papers that follow Cé.2.(12)) From a somewhat different viewpoint, the new results presented may also have implications for the triple combination of lithium with two antidepressant drugs in the clinical treatment of resistant endogenous depressions (13). The help of Drs. C. Davies gratefully acknowledged.

and R.A.

Webster

and Mr.

P. Terry

is

REFERENCES

1.

Steinberg,

2.

Davies,

3. 4. 5. 6. 7.

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Per Plenge

Animal

models and lithium

treatment Psychochemistry institute, Rigshospitalet, Denmark

Copenhagen,

Tithium treatment of rats are used in different animal models both where the focus is on biochemical, pharmacological and toxicological effects of lithium, and where the purpose is investigation of effects on behavior or modification of learned behavior. Lithium has been given to all species of experimental animals, but the absolute majority of experiments has been with rats. The suggestions and evidences put forward in this paper therefor relates to rats, as the experience with other animals is very limited. However most of the lithium effects desc~ibed with rats probably are reproducible in other mammals. Lithium is given as lithium salts, either as LiCl in solu-

EOS Oi as these

eis} iho salts “thé

wher. given in the food. When administered Li’ ion is readily absorbed and distributed

in the body. Further more lithium is rapidly excreted with a hale ees Ine isdcs Or Mabou MOmnouuss (ain many ches ta lit allies aks about 24 hours). The rapid absorption and short half life of lithium has importance for the pharmacokinetics of lithium, as it leads to rather varying lithium concentrations in the body when lithium is given in divided doses. When lithium is given in the food the lithium concentration is more constant as the rats are eating over a long period of time. This pattern of concentration changes is important to remember as some lithium effects are seen only in periods with increasing lithium concentration, whereas other effects are seen as long as the lithium concen-

tration is above a Investigation

certain level (1). of lithium effects in rats may be divided into acute and more chronic treatment with lithium. In acute experiments the effect of lithium is investigated after a single dose of lithium, often given as an intraperitoneal injection. It is important not to inject the lithium as a strong hypertonic solunem, S64 1 mel/ il, aS