Atlas of Psychiatric Pharmacotherapy, Second Edition

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Atlas of Psychiatric Pharmacotherapy

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Atlas of Psychiatric Pharmacotherapy Second Edition

Roni Shiloh, MD Geha Mental Health Center Sackler Faculty of Medicine Tel-Aviv University Israel

Rafael Stryjer, MD Beer-Yaakov Mental Health Center Sackler Faculty of Medicine Tel-Aviv University Israel

Abraham Weizman, MD Director of Research Geha Mental Health Center Sackler Faculty of Medicine Tel-Aviv University Israel

David Nutt, DM, FRCP, FRCPsych, FMedSci Professor of Psychopharmacology School of Medical Sciences University of Bristol UK

Graphics Roni Shiloh, MD Geha Mental Health Center Sackler Faculty of Medicine Tel-Aviv University Israel

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©2006 Taylor & Francis, an imprint of the Taylor & Francis Group Taylor & Francis Group is the Academic Division of Informa plc First published in the United Kingdom in 2006 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park, Abingdon, Oxon OX14 4RN Tel.: Fax.: E-mail: Website:

44 (0) 207 017 6000 44 (0) 207 017 6699 [email protected] http://www.tandf.co.uk/medicine

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN 1-84184-281-8 ISBN 978-1-84184-281-3 Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel: 800 272 7737; Fax: 800 374 3401 Outside Continental USA Tel: 561 994 0555; Fax: 561 361 6018 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: 44 (0)1264 332424 E-mail: [email protected] Composition by J&L Composition, Filey, North Yorkshire Printed and bound in Italy by Printer Trento

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Contents List of abbreviations

xii

Chapter 1 Basic principles of psychiatric pharmacotherapy 1.1

Principles of drug action – presynaptic nerve terminal Main reactions relevant for psychiatric pharmacotherapy

2

1.2

Principles of drug action – postsynaptic nerve Main reactions relevant for psychiatric pharmacotherapy

4

Signal transduction (I) G-protein complex and activation of second messengers

6

Signal transduction (II) Activation of cAMP-dependent protein kinase and subsequent protein phosphorylation

7

Signal transduction (III) Gene expression

8

1.6

Neurotransmitters (I) Monoamines – synthesis and degradation

9

1.7

Neurotransmitters (II) Glutamate (excitatory) – synthesis and degradation

10

1.8

Neurotransmitters (III) GABA (inhibitory) – synthesis and degradation

11

1.9

Vesicular monoamine transporter type 2 (VMAT2) Main mode of action

12

Intracellular modifications following activation of various receptors (I) Changes in intracellular compounds following activation of major receptors

14

1.3

1.4

1.5

1.10

1.11

Intracellular modifications following activation of various receptors (II) Changes in intracellular compounds following activation of major receptors

15

1.12

Receptor-mediated psychiatric symptoms/syndromes Assumed roles of specific receptors in major psychiatric syndromes

16

1.13

Receptor/transporter-mediated ‘non-psychiatric’ symptoms Assumed role of specific receptors in protecting from/inducing ‘non-psychiatric’ symptoms

17

1.14

Drug pharmacokinetics Main pathways of drug metabolism

18

1.15a Cytochrome P450 (CYP) hepatic enzymes (I) Major CYP enzymes responsible for metabolizing various drugs

20

1.15b Cytochrome P450 (CYP) hepatic enzymes (II) Major CYP enzymes responsible for metabolizing various drugs

21

1.16

Drug pharmacokinetics Major ‘psychiatric’ drugs blocking the hepatic cytochrome P450 (CYP) enzymes

22

References

23

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Contents

Chapter 2 Antidepressant drugs and mood stabilizers 2.1

Major depressive disorder Depressive state – no treatment

26

2.2

Antidepressant drugs Schematic classification according to main mode of therapeutic action

28

Major depressive disorder Cellular changes following antidepressant treatment

30

Antidepressant drugs Recently developed antidepressants (I) – SNRIs

32

2.5

Antidepressant drugs Recently developed antidepressants (II) – mirtazapine

34

2.6

Antidepressant drugs Recently developed antidepressants (III) – escitalopram

36

Pindolol – 5-HT1A and b-adrenergic antagonist Supposed mode of accelerating and augmenting the antidepressant effect of SSRIs

38

2.8

Antidepressant drugs Comparative affinities for various receptors/transporters

40

2.9

Antidepressant drugs The main cytochrome P450 (CYP) hepatic enzymes responsible for metabolizing antidepressant drugs

41

Antidepressant drugs Main adverse side-effects (I) – anticholinergic and central nervous system effects

42

2.3

2.4

2.7

2.10

2.11

Antidepressant drugs Main adverse side-effects (II) – gastrointestinal and cardiovascular effects

43

2.12

Antidepressant drugs Effects on sexual function

44

2.13

Antidepressant drugs Effects of antidepressant drugs on various sleep parameters

45

2.14

Antidepressant drugs Monoamine oxidase inhibitors

46

2.15

Antidepressant drugs Potential future developments

48

2.16

Antimanic drugs Supposed mechanism of action

50

2.17

Mood stabilizers Lithium

52

2.18

Mood stabilizers Carbamazepine

54

2.19

Mood stabilizers Valproate

56

2.20

Mood stabilizer-like drugs Topiramate

58

2.21

Mood stabilizer-like drugs Lamotrigine

60

2.22

Mood stabilizers Comparative profile

62

References

63

Chapter 3 Anxiolytic drugs 3.1

Anxiolytics (I) The ‘fear’ network and the role of serotonin in suppressing anxiety

68

3.3

Anxiolytics (III) New approaches for developing anxiolytic drugs

72

3.2

Anxiolytics (II) Mechanism of anxiolytic action of various drugs

70

3.4

c-Aminobutyric acid (GABA) macromolecular complex (I) Benzodiazepines and agents that enhance chloride channel/GABAA receptor activity

74

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Contents

Chapter 3 Anxiolytic drugs (cont.) 3.5

3.6

3.7

c-Aminobutyric acid (GABA) macromolecular complex (II) Agents that suppress chloride channel/GABAA receptor activity (cause anxiety)

76

Sedatives and hypnotics Comparative clinical and side-effect profile

77

Antihistaminergic drugs Comparative clinical and side-effect profile

78

3.8

Buspirone Supposed mechanism of action in anxiety disorders

80

3.9

Obsessive–compulsive disorder (OCD) Supposed mechanism of action of anti-OCD drugs

82

3.10

Benzodiazepines Hepatic metabolism

84

References

85

4.6

Antipsychotic drugs Specific characteristics: typical versus atypical antipsychotic drugs

99

4.7

Antipsychotic drugs Main adverse side-effects (I)

100

4.8

Antipsychotic drugs Main adverse side-effects (II)

101

4.9

Antipsychotic drugs Comparative affinity for different receptors

102

References

103

Chapter 4 Antipsychotic drugs 4.1

Schizophreniform disorder No treatment

90

4.2

Schizophreniform disorder The potential role of GABAergic hypofunction

92

Antipsychotic drugs Typical (first-generation) antipsychotic drugs – mechanism of action

94

Antipsychotic drugs Second-generation (atypical) antipsychotic drugs – mechanism of action

96

Antipsychotic drugs Schematic characteristics: typical versus atypical antipsychotic drugs

98

4.3

4.4

4.5

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Contents

Chapter 5 Drugs affecting sexual function 5.1

Neurobiology of sexual function Assumed modulators of sexual function

106

5.2

Male sexual function (I) Drugs that can maintain/induce erection

108

5.3

Male sexual function (II) Main drugs affecting ejaculation

110

5.4

Drugs affecting sexual function Sexual adverse side-effects associated with various psychotropics

112

References

113

Chapter 6 Drugs for the treatment of symptoms related to substance abuse 6.1

Abused substances – opiates Supposed mechanism of dependence, withdrawal symptoms, and treatment options

116

6.7

Abused substances – cannabis Supposed mechanism of dependence, withdrawal symptoms, and treatment options

128

6.2

Abused substances – amphetamines (I) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

118

6.8

Abused substances – lysergic acid diethylamide Supposed mechanism of dependence, withdrawal symptoms, and treatment options

130

6.2

Abused substances – amphetamines (II) Supposed mechanism of dependence, adverse effects, and treatment options

119

6.9

Abused substances – benzodiazepines Supposed mechanism of dependence, withdrawal symptoms, and treatment options

132

6.3

Abused substances – cocaine Supposed mechanism of dependence, withdrawal symptoms, and treatment options

120

6.10

Abused substances – nicotine Supposed mechanism of dependence, withdrawal symptoms, and treatment options

134

6.4

Abused sustances – MDMA (ecstasy) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

122

6.11

Abused substances – psilocybin Supposed mechanism of dependence, withdrawal symptoms, and treatment options

136

6.5

Abused substances – phencyclidine (PCP) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

124

6.12

Abused substances – inhalants (volatile solvents) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

138

6.6

Abused sustances – alcohol Supposed mechanism of dependence, withdrawal symptoms, and treatment options

126

6.13

Abused substances – acute intoxication (I) Frequently encountered ‘non-psychiatric’ symptoms

140

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Chapter 6 Drugs for the treatment of symptoms related to substance abuse (cont.) 6.14

Abused substances – acute intoxication (II) Frequently encountered ‘psychiatric’ symptoms

141

6.15

Abused substances – withdrawal symptoms Frequently encountered withdrawal symptoms

142

References

143

Chapter 7 Miscellaneous drugs/treatment modalities 7.1

Drugs for the treatment of dementia of Alzheimer’s type (DAT) Suggested mechanisms involved in DAT and potential drug treatments

148

7.2

Drugs effective for the treatment of extrapyramidal side-effects (EPS) Suggested mechanisms involved in EPS and relevant drug treatments

150

7.3

Drugs effective for the treatment of extrapyramidal side-effects (EPS) Comparative clinical and side-effect profile

152

7.4

Electroencephalogram (EEG) Findings associated with specific drugs

153

7.5

Drugs effective for the treatment of obesity Suggested mechanisms involved in obesity and potential drug treatments

154

7.6

Electroconvulsive therapy (ECT) Supposed mechanism of action

156

7.7

Major depressive disorder with seasonal pattern (MDDSP) Supposed mechanism of action of light therapy in major depressive disorder as part of SAD

158

References

159

Chapter 8 Drug interactions 162

8.2.3 Selective serotonin reuptake inhibitors (SSRIs) – fluvoxamine Drug interactions

168

8.2.1 Selective serotonin reuptake inhibitors (SSRIs) – citalopram/ escitalopram Drug interactions

164

8.2.4 Selective serotonin reuptake inhibitors (SSRIs) – paroxetine Drug interactions

170

166

8.2.5 Selective serotonin reuptake inhibitors (SSRIs) – sertraline Drug interactions

172

8.2.2 Selective serotonin reuptake inhibitors (SSRIs) – fluoxetine Drug interactions

8.1

Tricyclic and tetracyclic antidepressant drugs Drug interactions

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Chapter 8 Drug interactions (cont.) 8.3

Serotonin–norepinephrine reuptake inhibitors (SNRIs) Drug interactions

174

8.4

Norepinephrine reuptake inhibitors – bupropion and reboxetine Drug interactions

176

8.5.1 Mood stabilizers – lithium Drug interactions

178

8.5.2 Mood stabilizers – carbamazepine Drug interactions

180

8.5.3 Mood stabilizers – valproate Drug interactions

182

8.6

Lamotrigine and topiramate Drug interactions

184

Monoamine oxidase inhibitors (MAOIs) Drug interactions

186

Reversible inhibitors of monoamine oxidase type A (RIMAs) Drug interactions

188

8.7

8.8

8.9.1. First-generation (‘typical’) antipsychotic drugs – phenothiazines Drug interactions

8.9.2 First-generation (‘typical’) antipsychotic drugs – haloperidol and others Drug interactions

192

8.9.3 Second-generation (‘atypical’) antipsychotic drugs (SGAs) – amisulpiride, aripiprazole, clozapine, and olanzapine Drug interactions

194

8.9.4 Second-generation (‘atypical’) antipsychotic drugs (SGAs) – quetiapine, risperidone, sertindole, and ziprasidone Drug interactions

196

8.10

Benzodiazepines Drug interactions

198

8.11

Alcohol (ethanol) Drug interactions

200

8.12

Electroconvulsive therapy (ECT) Drug interactions

202

8.13

Acetylcholinesterase inhibitor – donepezil Drug interactions

204

References

205

190

Chapter 9 Treatment strategies (evidence-based)

9.1

Major depressive disorder (MDD) (non-resistant) Treatment strategies (evidence-based)

208

9.6

Premenstrual dysphoric disorder (PMDD) Treatment strategies (evidence-based)

216

9.2

Major depressive disorder (MDD) with psychotic features Treatment strategies (evidence-based)

209

9.7

Dysthymic disorder Treatment strategies (evidence-based)

218

9.8

Major depressive disorder (MDD) with atypical features Treatment strategies (evidence-based)

210

Major depressive disorder as part of bipolar I disorder Treatment strategies (evidence-based)

220

9.3

9.9

Major depressive disorder (MDD) (treatment-resistant) Treatment strategies (evidence-based)

212

Acute manic episode Treatment strategies (evidence-based)

222

9.4

9.10

Panic disorder (PD) Treatment strategies (evidence-based)

224

Major depressive disorder (MDD) in the geriatric population Treatment strategies (evidence-based)

214

9.11

General anxiety disorder (GAD) Treatment strategies (evidence-based)

226

9.5

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Contents

Chapter 9 Treatment strategies (evidence-based) 9.12

Obsessive–compulsive disorder (OCD) Treatment strategies (evidence-based)

228

9.13

Post-traumatic stress disorder (PTSD) Treatment strategies (evidence-based)

230

9.14

Specific phobia Treatment strategies (evidence-based)

232

9.15

Social anxiety disorder (SAD) Treatment strategies (evidence-based)

234

Acute psychotic exacerbation of schizophrenia Treatment strategies (evidence-based)

236

9.17

Schizoaffective disorder – depressed episode Treatment strategies (evidence-based)

238

9.18

Schizoaffective disorder – manic episode Treatment strategies (evidence-based)

240

9.19

Delusional disorder Treatment strategies (evidence-based)

242

9.20

Anorexia nervosa (AN) Treatment strategies (evidence-based)

244

9.16

Index

9.21

Bulimia nervosa (BN) Treatment strategies (evidence-based)

246

9.22

Attention deficit hyperactivity disorder (ADHD) Treatment strategies (evidence-based)

248

9.23

Neuroleptic malignant syndrome (NMS) Treatment strategies (evidence-based)

250

9.24

Tardive dyskinesia (TD) Treatment strategies (evidence-based)

252

9.25

Acute neuroleptic-induced akathisia Treatment strategies (evidence-based)

254

9.26

Delirium Treatment strategies (evidence-based)

256

9.27

Tobacco smoking Treatment strategies (evidence-based)

258

9.28

Borderline personality disorder Treatment strategies (evidence-based)

260

References

262

267

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Abbreviations list AC Acetyl-CoA ACh AChE AChM1,...

a-MSH AN AP4 APD ATP

Adenylate cyclase Acetyl coenzyme A Acetylcholine Acetylcholinesterase Acetylcholine muscarinic receptor subtypes Acetylcholine nicotinic receptor 1-Aminocyclopentyl-1,3-dicarboxylate Alzheimer’s disease Attention deficit hyperactivity disorder Adenosine diphosphate Adrenergic receptor Agouti-related gene product a-Ketoglutarate a-Amino-3-hydroxy-5-methylisoxazole4-propanoic acid Melanocortin-stimulating hormone Anorexia nervosa 2-Amino-4-phosphonobutyrate Antipsychotic drug Adenosine triphosphate

Bcl-2 BDNF BDZ BN BuChE

B-cell lymphoma protein 2 Brain-derived neurotrophic factor Benzodiazepine Bulimia nervosa Butylcholinesterase

cAMP CART

Cyclic adenosine monophosphate Cocaine- and amphetamine-related transcript Cognitive–behavioral therapy Cholecystokinin Cholecystokinin receptor, type A Cyclic guanosine monophosphate Central nervous system Ciliary neurotrophic factor Catechol-O-methyltransferase cAMP-response element cAMP-response element-binding protein Corticotrophin-releasing factor Cardiovascular system Cytochrome P450 enzyme isoforms

NK2

D1,... DAG DMT DNA DSM

Dopaminergic receptor subtypes Diacylglycerol N,N-Dimethyltryptamine Deoxyribonucleic acid Diagnostic and Statistical Manual (American Psychiatric Association)

ECT EKG

Electroconvulsive therapy Electrocardiogram

FDA FGA

Food and Drug Administration (USA) First-generation (‘typical’) antipsychotic drug

GABA GABAA,B GABA-T

c-Aminobutyric acid GABA receptor subtypes GABA ketoglutarate transaminase (aminotransferase) General anxiety disorder

AChN ACPD AD ADHD ADP ADR AgRP a-KG AMPA

CBT CCK CCKA cGMP CNS CNTF COMT CRE CREB CRF CVS CYP ...

GAD

GC GDP GHSR GIT GLP 5’-GMP GnRH GSK-3b GTP GU

Guanylate cyclase Guanosine diphosphate Growth hormone secretogogue receptor Gastrointestinal tract Glucagon-like peptide 1 Guanosine 5’-monophosphate Gonadotrophin-releasing hormone Glycogen synthase kinase 3b Guanosine triphosphate Genitourinary

H1,2 5-HIAA 5-HT 5-HT1,... HVA

Histaminergic receptor subtypes 5-Hydroxyindole acetic acid 5-Hydroxytryptamine (serotonin) Serotonergic receptor subtypes Homovanillic acid

INR

International Normalized Ratio (blood coagulation test) Inositol monophosphate Inositol trisphosphate

IP1 IP3 LAAM LC LSD

L-a-Acetylmethadol

MAO MAOI MCH mCPP MDD MDDSP mRNA

Monoamine oxidase MAO inhibitor Melanin-concentrating hormone m-Chlorophenylpiperazine Major depressive disorder MDD with seasonal pattern Messenger ribonucleic acid

NAc NARI

NMDA NMS NO NPY NRT NT-3/4/5

Nucleus accumbens Selective noradrenaline (norepinephrine) reuptake inhibitor Norepinephrine (noradrenaline) Nerve growth factor Neurokinin receptor, type 1 (receptor for substance P) Neurokinin receptor, type 2 (receptor for neurokinin A) N-Methyl-D-aspartate Neuroleptic malignant syndrome Nitric oxide Neuropeptide Y Nicotine replacement therapy Neurotropin-3/4/5

ObRb OCD OX-A/B

Functional long leptin receptor Obsessive–compulsive disorder Orexin A/B

PD PDE4/5 PK PKA PLC PMDD PMT POMC

Panic disorder Phosphodiesterase-4/5 Protein kinase Protein kinase A Phospholipase C Premenstrual dysphoric disorder Plasma membrane transporter Propiomelanocortin

NE NGF NK1

Locus ceruleus Lysergic acid diethylamide

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Abbreviations list PTSD RIMA RNA SAD SCN SGA SNRI SRI SSAD

Post-traumatic stress disorder Reversible inhibitor of monoamine oxidase type A Ribonucleic acid Social anxiety disorder Suprachiasmatic nucleus of hypothalamus Second-generation (‘atypical’) antipsychotic drug Serotonin–norepinephrine reuptake inhibitor Serotonin reuptake inhibitor Succinic semialdehyde dehydrogenase

SSRI

Selective serotonin reuptake inhibitor

T3 TCA TD TeCA trkB

tRNA

Triiodothyronine Tricyclic antidepressant Tardive dyskinesia Tetracyclic antidepressant Receptor for brain-derived neurotrophic factor (BDNF) Thyroid-stimulating hormone (TSH)-releasing hormone Transfer ribonucleic acid

VMAT2 VTA

Vesicular monoamine transporter type 2 Ventral tegmental area

TRH

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Chapter 1 Basic principles of psychiatric pharmacotherapy

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Basic Principles of Psychiatric Pharmacotherapy

1.1 Principles of drug action – presynaptic nerve terminal Main reactions relevant for psychiatric pharmacotherapy

Axon Metabolites Plasma membrane transporter

Plasma membrane

(reuptake site)

Mitochondria

PMT ~30% ~70%

MAO

VMAT2 From adjunct neuron

IAR

IHR

Nerve terminal First messengers

Available for postsynaptic interaction

Legend

MAO

Neurotransmitter

IAR

Inhibitory autoreceptor

Inhibits

IHR

Inhibitory heteroreceptor

Monoamine oxidase

PMT VMAT2

2

Plasma membrane transporter Vesicular monoamine transporter type 2

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Basic Principles of Psychiatric Pharmacotherapy A comprehensive understanding of neuronal functioning and the various mechanisms of drug action is a key factor for achieving proper mastery of psychiatric pharmacotherapy. Practically all of our ideas about the therapeutic effects of the major psychotropic drugs are based on their action at pre- and postsynaptic receptors/transporters.

●

Notes about the scheme

Furthermore, there are several main modulatory systems that together govern the rate of neurotransmitter release into the synaptic cleft:

In the central nervous system, information is transferred via electrical impulses (action potentials) originating in the cell bodies of neurons and progressing along their axons and up to their terminal regions, where it is transformed into chemical information in the form of neurotransmitters. Neurotransmitters are stored in intracellular vesicles, and, following the arrival of an action potential, they undergo exocytosis (a calcium-dependent process) into the synaptic cleft, where they are available for postsynaptic interaction. Those compounds (e.g. neurotransmitters) acting on postsynaptic receptors to induce consequent intracellular changes are termed first messengers. Following their interaction with receptors, they are either metabolized or taken for reuse. Research in recent years has focused on a better understanding of these receptor interactions and the intracellular changes attributable to drug administration. There are several hundreds of known neurotransmitters: those most known and relevant to psychiatric pharmacotherapy are listed in Table 1.1. The amount of a neurotransmitter available for exocytosis depends on several mechanisms: ●

●

●

●

proper reuptake of the neurotransmitter into the presynaptic nerve terminal by the plasma membrane transporter (PMT) and intact transport of the neurotransmitter from cytoplasm into storage vesicles by vesicular monoamine transporter type 2 (VMAT2); appropriate metabolism of the neurotransmitter by enzymes such as mitochondrial monoamine oxidase (MAO).

Autoreceptors (ARs) interact with neurotransmitters produced by the same nerve, and consequently suppress or stimulate neurotransmitter release into the synaptic cleft. They are located in the presynaptic nerve terminals or in the soma, dendrites, and axons of central nervous system neurons. Heteroreceptors (HRs), like autoreceptors, can either suppress (inhibitory autoreceptors such as the a2-adrenergic) or enhance the release of neurotransmitters. They are termed heteroreceptors since they are activated by neurotransmitters (e.g. norepinephrine) different from those produced by the nerve on which they are located (e.g. serotonergic). There might be numerous different heteroreceptors that bind various neurotransmitters on a single nerve. Table 1.2 summarizes some of the main modulating mechanisms relevant to intact functioning of the presynaptic nerve. Psychotropic medications can either enhance or suppress many of the major processes or modulatory events listed in this chapter.1–4

the availability of the neurotransmitter and the proper functioning of the sites of its reuptake into the presynaptic nerve;

Table 1.1 Biogenic amines

Amino acids

Peptides

Acetylcholine Dopamine Histamine Norepinephrine (noradrenaline) Serotonin

Aspartate Glutamate Glycine c-Aminobutyric acid (GABA) Homocysteate

Angiotensin Bombesin Bradykinin Cholecystokinin Endorphins Melatonin

Miscellaneous Oxcytocin Prolactin Somatostatin Tachykinins Vasoactive intestinal peptide

Adenosine Adenosine triphosphate (ATP) Nitric oxide Carbon monoxide

Table 1.2 Nerve type

Inhibitory AR

Inhibitory HR

Stimulatory AR

Stimulatory HR

Cholinergic

Muscarine type 2 (M2)

a2-adrenoreceptor; dopamine type D2/D3; serotonin type 5-HT3

Nicotinic

N-methyl-D-aspartate (NDMA)

Dopaminergic

Dopamine type D2/D3

Muscarinic type 2 (M2); serotonin type 5-H3?

Nicotinic: N-methyl-Daspartate (NMDA)

GABAergic (releases GABA type B (GABAB) c-aminobutric acid) Histaminergic

Histamine type 3 (H3)

Noradrenergic

a2-adrenoreceptor

Dopaminergic type D2; histamine type 3 (H3); muscarinic type 2 (M2); opiate

b2-adrenoreceptor

Serotonergic

Serotonin type 5-HT1B,D

a2-adrenoreceptor;

Serotonin type 5-HT3

Nicotinic

3

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1.2 Principles of drug action – postsynaptic nerve Main reactions relevant for psychiatric pharmacotherapy

Neurotransmitter

Membrane receptor linked to G-protein

Intracellular Ca2 storage vesicle

G-protein complex

IP3

PLC

AC

GC

DAG

cAMP

cGMP

Activation of specific protein kinases

Specific intracellular responses

Legend

Activates/stimulates

DAG

Second messengers

GC

Guanylate

IP3

Inositol trisphosphate

AC Adenylate cyclase cAMP Cyclic adenosine monophosphate cGMP Cyclic guanosine monophosphate

4

PLC

Diacylglycerol

Phospholipase C

Signal transduction

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Postsynaptic interactions are one of the major aspects of almost all drugs used in psychiatry. These interactions may account for a drug’s therapeutic effects and/or its adverse side-effects. Most drugs in use are non-selective, meaning that they have interactions with multiple pre- and postsynaptic receptors or transporters. Most current knowledge about the mechanism of drug action is based on direct pre- and postsynaptic drug interactions and the subsequent modulation of intracellular components such as second, third, and fourth messengers. Second messengers are specific intracellular components that are indirectly stimulated by the first messengers to activate intracellular components such as certain enzymes termed protein kinases (PKs). The most studied second messengers are calcium ion, inositol trisphosphate (IP3), diacylglycerol (DAG), cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP).

Notes about the scheme As previously noted, first messengers interact with plasma membrane components with consequent activation of intracellular molecules such as protein kinases. Hence, normal neuronal activity requires intact pre- and postsynaptic interactions between first messengers/ neurotransmitters and their target receptors/ transporters located on the extracellular membrane. Neurotransmitters bind with high affinity to postsynaptic receptors that are linked either to protein complexes termed G-proteins (see Section 1.3) or to ion channels. G-proteins are so-called because of their ability to bind the guanine nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). Three major types of G-proteins are involved in signal transduction: Gp, Gs, and Gj. These protein complexes differ from one another in their a subunits, which, in turn, gives rise to different and sometimes opposing effects on consequent

intracellular functioning. Many of the drugs used in psychiatry can either antagonize the receptors linked to specific G-proteins or stimulate them in a similar way to that of the endogenous first messenger. Synaptic responses mediated by receptorgated ion channels and G-protein-linked receptors have considerably different time courses. The direct effects of ligand-gated channels are rapid and transitory, usually ending in less than 1 ms, whereas those mediated by G-protein-linked receptors are slower in onset (requiring at least 100 ms to develop) and can be very long in duration (minutes). Some drugs also bind with high affinity to receptors whose transmitters have not been identified as yet (orphan receptors). Pharmacotherapy that alters first-messenger activities and interacts with various membrane receptors inevitably alters the functioning of second-messenger components. These are substances such as phospholipase C (PLC), adenylate cyclase (AC), guanylate cyclase (GC), phospholipids, and arachidonic acid. They can also modify cellular functioning by changing the intracellular concentrations of major ions, especially calcium, which is also considered a second messenger. The outcome of the altered second-messenger activities is a modification of PK functioning, which is followed by enduring intra- and intercellular responses. PKs activate cellular components by phosphorylating various proteins that are inactive/less active unless phosphorylated. Following PK activation, the phosphorylated proteins (also termed third messengers) cause numerous subsequent modifications in cellular functioning. Usually, PKs are activated by second messengers and they are often named after these second messengers (cAMP-dependent PK for example). However, there are also other types of PKs that are not second-messengerdependent. Among these are protein tyrosine kinases (which phosphorylate substrate proteins specifically on tyrosine residues), casein kinases, and numerous others.4–7

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1.3 Signal transduction (I) G-protein complex and activation of second messengers

Inactive membrane receptor

Activated receptor

linked to G-protein

(e.g. by neurotransmitter)

b c

S

b c

a

S a

GDP

G-protein GDP complex Inactive AC

ATP

Activated AC

S a GTP cAMP-dependent protein kinase

cAMP

GTP

Catalytic domain (inactive when covered by the regulatory domain)

Regulatory domain (covers the catalytic domain if cAMP is not attached to it)

Legend Activates/stimulates Dissociates Neurotransmitter

a,b,c,S Various subunits of the G-protein complex

6

AC cAMP

Adenylate Cyclic adenosine monophosphate

GDP

Guanosine diphosphate

GTP

Guanosine triphosphate

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1.4 Signal transduction (II) Activation of cAMP-dependent protein kinase and subsequent protein phosphorylation

Active protein kinase

Inactive protein kinase

(cAMP attached)

cAMP

cAMP-dependent protein kinase (inactive; without cAMP attached)

ADP

Inactive (not phosphorylated) protein or transcription factor

ATP

Activated (phosphorylated) protein or transcription factor (see Section 1.5)

Alters intracellular functioning (e.g. may affect lipid/protein/glucose metabolism, cell division/differentiation, permeability/excitability , of cell membrane, secretory processes, gene expression)

Legend Catalytic domain

ADP

Adenosine diphosphate

Phosphate residue

ATP

Adenosine triphosphate

Regulatory domain

cAMP

Cyclic adenosine monophosphate

Metabolic pathway

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1.5 Signal transduction (III) Gene expression

Cell nucleus

Double-stranded DNA

Active TF

RNA polymerase II

mRNA

tRNA Active TF

Protein

Legend Activates Regulatory element Transcribed region DNA mRNA

8

Deoxyribonucleic acid Messenger ribonucleic acid

RNA TF tRNA

Ribonucleic acid Transcription factor Transfer ribonucleic acid

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1.6 Neurotransmitters (I) Monoamines – synthesis and degradation

Noradrenergic nerve terminal

Serotonergic nerve terminal

Tyrosine Tyrosine hydroxylase

Tryptophan

5-HIAA

Mit.

L-dopa

2

NE-PMT

5-OH-tryptophan

DA DA-b-hydroxylase

NE

MHPG

Tryptophan hydroxylase

Dopa decarboxylase

1

Amino acid decarboxylase

a2-ADR

a2-ADR

5-HT1D

Mit.

5-HT

NE

Dopaminergic nerve terminal

Cholinergic nerve terminal

Tyrosine

HVA

Choline-PMT

Acetyl-CoA

3

Tyrosine hydroxylase

Mit.

Acetic acid Choline L-dopa

DA-PMT

Choline acetyltransferase Dopa decarboxylase

AChM2 D2,3 Dopamine

Acetylcholinesterase (on postsynaptic membrane)

Acetylcholine

Legend

Name

1–3

1 2 3

AChM2 D2,3

Enzymes

5-HIAA 5-HT Inhibits Acetyl-CoA MAO type A COMT ADR MAO type A aldehyde COMT dehydrogenase DA MAO type A/B COMT HVA Receptors MAO MHPG Stimulates Mit. Acetycholine muscarinic receptor subtype NE Dopaminergic receptor subtype PMT

5-Hydroxyindole acetic acid 5-Hydroxytryptamine (serotonin) Acetyl coenzyme A Adrenergic Catechol-O-methyltransferase Dopamine Homovanillic acid Monoamine oxidase 3-Methoxy-4-hydroxyphenylglycol Mitochondria Norepinephrine (noradrenaline) Plasma membrane transporter

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1.7 Neurotransmitters (II) Glutamate (excitatory) – synthesis and degradation

Presynaptic glutamatergic nerve terminal

Mit.

Pyruvate

Glutamate

Glutamate-PMT

AP4

Cations (mainly Ca2)

Glutamate

Postsynaptic nerve (any kind) NMDA receptor complex

Combination of glycine and 2 molecules of glutamate is needed to properly open the cation channel

Increased cation influx (causes excitatory response)

Legend Inhibits

AP4

Stimulates Glycine Ketamine, phencyclidine (PCP), 2 Mg

10

NMDA

2-Amino-4-phosphonobutyrate (inhibitory autoreceptor) N-methyl-D-aspartate

PMT

Plasma membrane transporter

Mit.

Mitochondria

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1.8 Neurotransmitters (III) GABA (inhibitory) – synthesis and degradation

Inside the mitochondria

Presynaptic GABAergic nerve terminal

Pyruvate

Pyruvate Mitochondria

Acetyl-CoA

GABA a-KG

SC

T

-PM

Glutamate

A AB

SSA

G

GABAB

GABA

Cl ions

GABA

Postsynaptic nerve (any kind)

Glutamic acid decarboxylase

GABA-T

SSAD

GABA

A macromolecular complex

Increased Cl influx (reduces cell excitability; see Section 3.4 for more details)

Legend Name

Enzymes

GABA-T

Inhibits Stimulates Acetyl-CoA Acetyl coenzyme A a-KG a-Ketoglutarate GABA c-Aminobutyric acid

PMT SC SSA SSAD

GABA ketoglutarate transaminase (aminotransferase) Plasma membrane transporter Succinate Succinic semialdehyde Succinic semialdehyde dehydrogenase

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1.9 Vesicular monoamine transporter type 2 (VMAT2) Main mode of action

Metabolites

Presynaptic nerve terminal

MAO

Mitochondria

PMT 30%

Storage vesicle

70%

VMAT2

Neurotransmitter (i.e. biogenic amine)

Legend

Inhibits

Tetrabenazine

Neurotransmitter Hydroxyl group

Serine residue of VMAT2

Attaches to hydroxyl group of neurotransmitter

Stimulates

MAO PMT

Reserpine

12

VMAT2

Monoamine oxidase Plasma membrane transporter Vesicular monoamine transporter type 2

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Notes about the scheme A neurotransmitter, once released from the presynaptic nerve into the synaptic cleft, can be involved in several processes. A fraction of the released neurotransmitter binds to the corresponding post- or presynaptic receptors, with a consequent secondary intracellular change. Following this, it dissociates from the specific receptor back into the synaptic cleft, ready for reuptake into the presynaptic nerve or for further receptor interaction. Some is retransported into the presynaptic nerve terminal by the plasma membrane transporter (PMT). Having entered the presynaptic nerve terminal, about 30% of the neurotransmitter is metabolized by a specific catabolic enzyme termed a monoamine oxidase (MAO): MAO type A is the main enzyme responsible for metabolizing serotonin, norepinephrine, and epinephrine, while MAO type B metabolizes dopamine. Acetylcholine undergoes an extracellular catabolic process catalyzed by acetylcholinesterase. About 70% of the neurotransmitters taken up by the PMT are re-stored in intracellular vesicles located in the presynaptic nerve terminal. Each of these vesicles contains only a specific biogenic amine: norepinephrine is accumulated and stored in specific vesicles in noradrenergic nerves, serotonin in specific vesicles in serotonergic nerves, etc. Vesicular monoamine transporter type 2 (VMAT2) is located on the membrane of the intracellular storage vesicle, and it transports all biogenic amines (e.g. serotonin, norepinephrine, dopamine, acetylcholine, histamine) with practically equivalent affinity. Regional localization of VMAT2 is consistent with the known monoamine nerve terminal density; it is highest in the striatum, lateral septum, substantia nigra pars compacta, raphe nucleus, and locus ceruleus. Lower density is evident in the cerebral cortex and in the cerebellum. VMAT2 is a protein with 12 membrane segments, and both of its extremities are located in the cytoplasmatic site. The mechanism of VMAT2 action is complex and only partially

understood. It is thought that transport of biogenic amines is dependent on the pH gradient between the cytoplasm and the intravesicular space. The cytoplasm is a relatively high-pH region compared with the intravesicular space (low-pH region; pH 4–5). This pH gradient provides an essential driving force for the transport of the biogenic amine from the cytoplasm into the vesicle in exchange for a proton, which is transported in the opposite direction. Some data suggest that a serine residue in the third transmembrane domain of VMAT2 is the most important factor for recognizing the transported biogenic amine, and that hydroxyl groups on the different biogenic amines serve as substrates that are recognized by the serine residues. Several substances are known to affect VMAT2. The most studied are reserpine and tetrabenazine. Both inhibit VMAT2 activity with a consequent decrease in biogenic amine transport into storage vesicles. This results in a reduced amount of biogenic amine available for release into the synaptic cleft. Reserpine and tetrabenazine have different binding sites on VMAT2 and are presumed to exert their inhibitory effects on biogenic amine transport via different mechanisms. There is some evidence for the existence of two conformations of VMAT2, binding either reserpine or tetrabenazine. This means that when reserpine (or tetrabenazine) binds VMAT2, it inhibits its capacity to uptake monoamines but at the same time prevents the binding of the other antagonist (tetrabenazine or reserpine, respectively). Chronic use of these drugs leads to a relative depletion of amine stores, which is why they can cause depression. Other possible inhibitors of VMAT2 activity are cytotoxic compounds such as ethidium, isometamidium, tetraphenylphosphonium, and rhodamine, as well as agents such as tacrine, verapamil, and the hormones estrogen and progesterone. The way in which estrogen and progesterone affect VMAT2 is unclear, and might be via an indirect action (e.g. reduced VMAT2 gene expression).8–16

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1.10 Intracellular modifications following activation of various receptors (I) Changes in intracellular components following activation of major receptors

Affected intracellular components Na

Ca2

K

Cl

cAMP cGMP

IP3

DAG

a1-ADR a2-ADR b1–3-ADR d, j, l opioid j opioid 5-HT1A 5-HT1D 5-HT2A Activated membrane 5-HT2C

receptors

5-HT3 5-HT4,6,7 A1 A2 AChM1,3 AChM2 AChM4 AChN

Legend Increased concentration of intracellular component Decreased concentration of intracellular component 5-HT1–7 A1,2 a1,2/b1–3-ADR AChM1–4 AChN

14

Serotonergic receptor subtypes Adenosine receptors

cAMP

Cyclic adenosine monophosphate

cGMP

Cyclic guanosine monophosphate

DAG IP3

Adrenergic receptor subtypes Acetylcholine muscarinic receptor subtypes Acetylchlorine nicotinic receptor

Diacylglycerol Inositol trisphosphate

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1.11 Intracellular modifications following activation of various receptors (II) Changes in intracellular components following activation of major receptors

Affected intracellular components Na

Ca2

K

Cl

cAMP cGMP

IP3

DAG

ACPD1 ACPD2 AMPA CCKA D1,5 D2

Activated membrane receptors

D3,4 GABAA GABAB H1 H2 Kainate NK1 NK2 NMDA

Legend Increased concentration/activity of intracellular component Decreased concentration/activity of intracellular component ACPD1,2 Glutamatergic receptor subtypes (1-aminocyclopentyl-1,3-dicarboxylate) AMPA Glutamatergic receptor subtype (a-amino-3-hydroxy-5-methylisoxazole4-propionic acid) cAMP CCKA cGMP

Cyclic adenosine monophosphate Cholecystokinin receptor Cyclic guanosine monophosphate

D1–5 DAG IP3

Dopaminergic receptor subtypes Diacylglycerol Inositol trisphosphate

GABAA,B c-Aminobutyric acid receptor subtypes H1,2

Histaminergic receptor subtypes

NK1

Neurokinin receptor, type 1 (receptor for substance P) Neurokinin receptor, type 2 (receptor for neurokinin A) N-Methyl-D-aspartate

NK2 NMDA

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1.12 Receptor-mediated psychiatric symptoms/syndromes Assumed roles of specific receptors in major psychiatric syndromes

Presynaptic

5-HT1A 5-HT1D

Postsynaptic

5-HT1A 5-HT2A/2C a1-ADR D2 GABAA

Psychosis

Depression

Bulimia

Phobia (social)

Panic attacks

Stimulated receptors

Obsessive– compulsive

Generalized anxiety

Anxiety spectrum

Sexual dysfunction

Psychiatric symptoms/syndromes

Legend Improved symptom (by activation of the correspondent receptor) Worsened symptom (by activation of the correspondent receptor) 5-HT1A,1D,2A,2C a1-ADR D2 GABAA

16

Serotonergic receptor subtypes Adrenergic receptor subtype Dopaminergic receptor subtype c-Aminobutyric acid receptor, type A

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1.13 Receptor/transporter-mediated non-psychiatric symptoms Assumed role of various receptors in protecting from/inducing various 'non-psychiatric' symptoms

Stimulated/inhibited receptors/transporters

DA-PMT

5-HT-PMT

NE-PMT

H1

GABAA

D2

Transporters

AChM1

a1-ADR

a1-ADR

5-HT3

5-HT3

5-HT2A/2C

Postsynaptic 5-HT2A/2C

a2-ADR

5-HT1D

5-HT1A

Presynaptic

Agitation Akathisia Dry mouth EPS (c) EPS (p) Headache (c) Headache (p) Hyperthermia Hypothermia Insomnia Memory impairment (c) Prolactinemia Sedation Seizures (c) Sweat (c) Sweat (p)

CNS

Hypertension Hypotension Tachycardia

CVS

GIT

GU

Appetite (c) Appetite (p) Constipation Diarrhea GIT discomfort Nausea/vomiting (c) Nausea/vomiting (p) Weight gain Anorgasmia Erectile dysfunction Libido (decreased) Priapism Retrograde ejaculation Sexual dysfunctions (c) Sexual dysfunctions (p) Urinary retention

Others

Blurred vision Photophobia Tremor

Legend Green-colored receptor/transporter Red-colored receptor/transporter

(c) (p) 5-HT1A,1D,2A,2C,3 5-HT-PMT a1,2-ADR AChM1

CNS Data fairly well established Data not well established CVS Stimulated receptor/transporter D2 Inhibited receptor/transporter DA-PMT Causes specific symptom EPS Protects from specific symptom GABA Serotonergic receptor subtypes A Plasma membrane transporter for serotonin Adrenergic receptor subtypes Acetylcholine muscarinic receptor, type 1

GIT GU H1 NE-PMT

Central nervous system Cardiovascular system Dopaminergic receptor subtype Plasma membrane transporter for dopamine Extrapyramidal side-effects c-Aminobutyric acid receptor, type A Gastrointestinal tract Genitourinary Histaminergic receptor subtype Plasma membrane transporter for norepinephrine

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1.14 Drug pharmacokinetics Main pathways of drug metabolism

Systemic circulation GIT

Free (active)

form

Liver CYP

CYP

A

Renal tubules

Biliary tract

Excreted in the urine

Excreted in the feces

Legend Drug

A

Drug (albumin-bound) Drug (conjugated; following phase II)

18

Metabolite/s (following phase I) CYP

Cytochrome P450

GIT

Gastrointestinal tract

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Notes about the scheme Pharmacokinetic interactions are subdivided into absorption, distribution, metabolism, and excretion.

Absorption Orally administered drugs can undergo processing while passing through the gastrointestinal trace. Such processes may interfere with absorption by affecting the rate and total amount of drug absorbed. The rate of absorption is important if a rapid response is needed. It has little importance if the drug is given chronically or in multiple daily doses. In the case of a drug given in a single dose, with a need for an immediate response, altered absorption might prevent the expected therapeutic response (due to inability to reach the appropriate serum level). There are several factors governing absorption: ●

●

●

Gastrointestinal pH. Absorption from the gastrointestinal tract (mostly from the proximal parts of the ileum) depends on the solubility of the agent (the more lipid-soluble, the better is the diffusion through the intestinal membrane) and on the electrical charge of the agent (the non-ionized form usually diffuses well through the mucous membrane). The gastrointestinal pH may alter these parameters. Absorption–precipitation. Many agents may form a larger complex – precipitates with other particles such as metallic ions (aluminum, bismuth, calcium, iron) – while passing via the gastrointestinal tract. These complexes are sometimes poorly absorbed. Gut motility. Some agents can alter gut motility, which can have opposite effects – decreased gut motility, or delayed emptying of the stomach, causes the drug to spend more time in the gastrointestinal tract, and can either enhance absorption (with drugs for which a prolonged time enables better dissolution) or impair it (with drugs that are metabolized by gut wall catabolic enzymes).

Distribution Once absorbed from the gastrointestinal tract, drugs pass through the liver via the portal circulation and are metabolized to various extents (the first-pass effect). Following passage through the liver, the drugs are distributed to the tissues by the systemic circulation.

Changes in distribution can be evident if perfusion to a target organ or tissue is altered. Initially, highly perfused tissues (central nervous system, heart, kidneys, liver) exhibit a rapid blood–tissue equilibration of drugs. Then, the drug may be redistributed to less-perfused tissues (muscle, adipose). This redistribution can mean that a drug with a long elimination half-life might exert a shorter therapeutic effect than a second drug with a shorter elimination half-life due to the former drug’s greater affinity for adipose tissue (or a larger volume of distribution). Distribution is also affected by a drug’s protein-binding properties. Most drugs are bound to plasma proteins, particularly to albumin. The bound fraction is pharmacologically inactive. Once some of the free drug has been metabolized, a portion of the bound drug becomes unbound and can exert its pharmacological activities and, at the same time, is subjected to metabolic processing and excretion. Significant drug–drug interactions are associated with drugs that are more than 90% bound to plasma proteins.

Metabolism Metabolism is the biotransformation of a drug to another chemical and a less lipid-soluble form that is more easily excreted. The vast majority of metabolic processing is done by a group of enzymes (i.e. cytochrome P450 (CYP)) located in microsomes of the endoplasmic reticulum of hepatic cells. There are four main types of metabolic reactions: oxidation, reduction, and hydrolysis (termed phase I), and conjugation (termed phase II). Phase I reactions change the parent compound into a more polar form, which may be still pharmacologically active, partially active, or inactive. When a drug has been metabolized by phase I reactions, it can be metabolized further by phase II, or it can be hydrophilic enough to be eliminated without further metabolism. Phase II reactions involve the conjugation (coupling) of a drug with a polar substrate such as glucuronic, acetic, sulfuric or an amino acid, which generally leads to total inactivation of the parent compound. Many drugs alter the activities of these metabolic processes by either stimulating catabolic enzymes or inhibiting them, and many drug–drug interactions are due to this.

Excretion Most drugs are excreted via the bile/kidneys to be finally eliminated in the feces or the urine.9,17–43

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1.15a Cytochrome P450 (CYP) hepatic enzymes (I) Major CYP enzymes responsible for metabolizing various drugs

CYP enzymes Substrates

1A2

2B6 2C19 2C9 2D6 2E1

3A4

Acetaminophen Alprazolam Astemizole Betaxolol Caffeine Carbamazepine Celecoxib Chlorpheniramine Cisapride Codeine Cyclosporine Dexamethasone Dexfenfluramine Dextromethorphan DHEA Diazepam Diclofenac Diltiazem Donepezil Doxycycline Erythromycin Estradiol Ethanol Felodipine Flecainide Ibuprofen Lidocaine Loratadine Lovastatin Mefenamic acid Methadone

Legend

Major enzyme/s responsible for the hepatic metabolism of the specific substrate (e.g. drug) DHEA

20

Dehydroepiandrosterone

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1.15b Cytochrome P450 (CYP) hepatic enzymes (II) Major CYP enzymes responsible for metabolizing various drugs

CYP enzymes Substrates

1A2 2B6 2C19 2C9 2D6

2E1

3A4

Metoprolol Midazolam Naproxen Nifedipine Omeprazole Ondansetron Orphenadrine Phenytoin Piroxicam Progesterone Propafenone Propranolol Quinidine Rifampin Sibutramine Sildenafil Simvastatin Tacrine Tamoxifen Terfenadine Testosterone Theophylline Timolol Tolbutamide Tramadol Triazolam Verapamil Warfarin (R) Warfarin (S) Zolmitriptan Zolpidem

Legend Warfarin (R/S)

Major enzyme/s responsible for the hepatic metabolism of the specific substrate (e.g. drug) Specific isomers of warfarin

Note: For psychiatric drugs and CYP enzynes, see the relevant drug sections

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1.16 Drug pharmacokinetics Major 'psychiatric' drugs blocking the hepatic cytochrome P450 (CYP) enzymes

Affected CYP enzymes

Various inhibitors of CYP enzymes

1A2

2C

2D6 3A4

Amitriptyline Clomipramine Desipramine Fluoxetine Fluvoxamine Antidepressant Nefazodone drugs Paroxetine Reboxetine* Sertraline Venlafaxine Fluphenazine Antipsychotic Haloperidol drugs Perphenazine Thioridazine RIMA

Moclobemide

Various stimulators of CYP enzymes Carbamazepine Phenobarbital Smoking**

Legend Strongest effect

*

Medium effect Little effect RIMA

22

Reversible inhibitor of monoamine oxidase type A

**

Reboxetine appears to be devoid of any inducing/inhibiting effects on major hepatic metabolizing enzymes Cigarette smoking; through the action of polyaromatic hydrocarbons

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References 1. Baron BM, Ogden AM, Siegel BW et al. Rapid down regulation of beta adrenoreceptors by coadministration of desipramine and fluoxetine. Eur J Clin Pharmacol 1988; 154: 125–134. 2. Liu G. Presynaptic control of quantal size: kinetic mechanism and implications for synaptic transmission and plasticity. Curr Opin Neurobiol 2003; 13: 324–331. 3. Greengard P. The neurobiology of slow synaptic transmission. Science 2001; 294: 1024–1030. 4. Baron BM, Ogden AM, Siegel BW et al. Rapid down regulation of beta adrenoreceptors by coadministration of desipramine and fluoxetine. Eur J Clin Pharmacol 1988; 154: 125–134. 5. Blitzer RD, Iyengar R, Landau EM. Postsynaptic signaling networks: cellular cogwheels underlying long term plasticity. Biol Psychiatry 2005; 57: 113–119. 6. Gonzalez MI, Robinson MB. Neurotransmitter transporters: Why dance with so many partners? Curr Opin Pharmacol 2004; 4: 30–35. 7. Amara SG, Kuhar MJ. Neurotransmitter transporters: recent progress. Annu Rev Neurosci 1993; 16: 73–93. 8. Darchen P, Scherman D, Henry JP. Reserpine binding to chromaffin granules suggests the existence of two conformations of the monoamine transporter. Biochemistry 1989; 28: 1692–1697. 9. DeVane CL. Pharmacogenetics and drug metabolism of new antidepressant agents. J Clin Psychiatry 1994; 55(12 Suppl): 38–45. 10. Peter D, Jimenez J, Liu Y et al. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J Biol Chem 1994; 269: 7231–7237. 11. Scherman D, Gasnier B, Jaudon P et al. Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter. Mol Pharmacol 1988; 33: 72–77. 12. Scherman D, Henry JP. Reserpine binding to bovine chromaffin granule membranes with dihydrotetrabenazine binding. Mol Pharmacol 1984; 25: 113–122. 13. You dim MBH, Finberg JPM. New directions in monoamine oxidase A and B: selective inhibitors and substrates. Biochem Pharmacol 1990; 41: 155–162.

14. Greenshaw AJ. Neurotransmitter interactions in psychotropic drug action; beyond dopamine and serotonin. J Psychiatry Neurosci 2003; 28: 247–250. 15. Frey KA, Koeppe RA, Kilbourn MR. Imaging the vesicular monoamine transporter. Adv Neurol 2001; 86: 237–247. 16. Fleckenstein AE, Hanson GR. Impact of psychostimulants on vesicular monoamine transporter function. Eur J Pharmacol 2003; 479: 283–289. 17. Ereshefsky L, Riesenman C, Lam YWP. Antidepressant drug interactions and the cytochrome P450 system: the role of CYP2D6. Clin Pharmacokinet 1995; 29(Suppl 1): 10–19. 18. Ereshefsky L, Riesenman C, Lam YWF. Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. J Clin Psychiatry 1996; 57(Suppl 8): 17–25. 19. Erickson JD, Eiden LE. Functional identification and molecular cloning of a human brain vesicle monoamine transporter. J Neurochem 1993; 61: 2314–2317. 20. Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35–39. 21. Goff DC, Midha KK, Brotman AW et al. Elevation of plasma concentrations of haloperidol after addition of fluoxetine. Am J Psychiatry 1991; 148: 790–792. 22. Goldstein JA, de Morais SMF. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994; 4: 285–299. 23. Goodnick PJ. Pharmacokinetic optimisation of therapy with newer antidepressants. Clin Pharmacokinet 1994; 27: 307–330. 24. Gram LF, Hansen MGJ, Sindrup SH et al. Citalopram: interaction studies with levomepromazine, imipramine and lithium. Therap Drug Monitor 1993; 15: 18–24. 25. Greene DS, Salazar DE, Dockens RC et al. Coadministration of nefazodone and benzodiazepines: a pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 1995; 15: 399–408. 26. Guentert TW, Mayersohn M. Clinicalpharmacokinetic profile of moclobemide and its comparison with other MAOinhibitors. Rev Contemp Pharmacother 1994; 5: 19–34.

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27. Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin re-uptake inhibitors: Part 1. J Clin Psychopharmacol 1996; 16: 273–278. 28. Henry JP, Botton D, Sagne C et al. Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffine granules. J Exp Biol. 1994; 196: 251–262. 29. Kerr BM, Thummel KE, Wurden Q et al. Human liver carbamazepine metabolism: role of CYP3A4 and CYP2C8 in 10,11epoxide formation. Biochem Pharmacol 1994; 47: 1969–1979. 30. Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinetics 1994; 26: 144–160. 31. Kronbach T, Mathys D, Umeno M et al. Oxidation of midazolam and triazolam by human liver cytochrome P4503A4. Mol Pharmacol 1989; 36: 89–96. 32. Langer SZ. 25 years since the discovery of presynaptic receptors: present knowledge and future perspectives. Trends Pharmacol Sci 1997; 18: 95–99. 33. Leinonen E, Lillsunde P, Laukkanen V et al. Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients. J Clin Psychopharmacol 1991; 11: 313–318. 34. Lemoine A, Gauthier JC, Azoulay D et al. Major pathway of imipramine metabolism is catalyzed by cytochromes P450 1A2 and P450 3A4 in human liver. Mol Pharmacol 1993; 43: 827–832.

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35. Levy RH. Cytochrome P450 isoenzymes and anti-epileptic drug interactions. Epilepsia 1995; 36(Suppl 5): S8–S13. 36. Lydiard RB, Anton RF, Cunningham T. Interactions between sertraline and tricyclic antidepressants. Am J Psychiatry 1993; 150: 1125–1126. 37. Maguire KP, Norman TR, Burrows GD et al. A pharmacokinetic study of mianserin. Eur J Clin Pharmacol 1982; 21: 517–520. 38. Mayersohn M, Guentert TW. Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide. Clin Pharmacokinet 1995; 29: 292–332. 39. Nelson DR, Kamataki T, Waxman DJ et al. The P450 super-family: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993; 12: 1–51. 40. Otton SV, Ball SE, Cheung SW et al. Comparative inhibition of the polymorphic enzyme BYP2D6 by venlafazine and other 5–HT reuptake inhibitors. Clin Pharmacol Ther 1994; 55: 141 (abst). 41. Shami M, Elliot HL, Kelman AW et al. The pharmacokinetics of mianserin. Br J Clin Pharmacol 1983; 15: 313S–322S. 42. Roberts SA. Drug metabolism and pharmacokinetics in drug discovery. Curr Opin Drug Discov Devel 2003; 6: 66–80. 43. Alavijeh MS, Palmer AM. The pivotal role of drug metabolism and pharmacokinetics in the discovery and development of new medicines. Drugs 2004; 7: 755–763.

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Chapter 2 Antidepressant drugs and mood stabilizers

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Antidepressant drugs and mood stabilizers

2.1 Major depressive disorder Depressive state – no treatment

Upregulated inhibitory autoreceptors (e.g. a2-adrenergic)


IAR

Low synaptic NE and/or 5-HT

Rec. Soma

SM

Postsynaptic nerve

Nucleus CREB BDNF

trkB

Loss of dendrites/ changes in morphology Nerve terminal

Low synaptic neurotrophic factor (e.g. BDNF)

Legend

5-HT Feedback inhibition (enhanced) Loss of dendrites and/or change in morphology

Brain-derived neurotrophic factor

CREB

Cyclic adenosine monophosphate (cAMP)-response element-binding protein

IAR NE

Low concentration

26

Serotonin

BDNF

Inhibitory autoreceptor Norepinephrine

Rec. SM

Receptor Second messenger (e.g. cAMP)

trkB

Receptor for BDNF

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Present knowledge about the biological mechanism of normal mood has made much progress in recent years, although it is not yet fully understood. Decades ago, it was assumed that decreased norepinephrine or serotonin in the synaptic cleft is the major, and possibly the only, factor involved in inducing major depressive disorder (MDD). However, recent evidence demonstrates that in mood disorders, and especially in MDD, there is regional reduction in central nervous system (CNS) volume, probably secondary to reductions in number and/or size of glia and neurons (especially in number and morphology of dendrites) in discrete brain areas (e.g. the hippocampus). Although the precise cellular mechanism underlying these morphometric changes remain to be fully elucidated, data suggest a predominant role of altered neuronal plasticity and cellular resilience. The concept of neuroplasticity refers to the capacity of the CNS to adapt itself to changing external stimuli through appropriate signal transduction, consequent gene expression, and the production of various neurotrophic factors responsible for normal cell connectivity.

Notes about the scheme MDD, which has traditionally been conceptualized as a ‘pure’ neurochemical disorder, is currently thought to derive from changes in neuronal plasticity and cellular resilience (e.g. alterations in morphology and number of dendritic spines, direction of axonal/dendritic outgrowth, synaptic connectivity, and the capacity of neurons to survive toxic and non-toxic abuses). Hence, various neurochemical modifications (e.g. decreased synaptic concentration of norepinephrine and/or serotonin) and consequent changes in intracellular signal transduction and gene expression are currently conceptualized as merely representing a cascade of events associated with the development of such alterations in neuronal adaptability that may eventually lead to MDD. Thus, normal regulation of mood is currently conceived as proper modulation of the adrenergic and/or serotonergic systems via:

● ● ●

correct functioning of various pre- and postsynaptic receptors/transporters; appropriate secretion of norepinephrine and/or serotonin from presynaptic neurons; intact signal transduction involving appropriate production/stimulation of intracellular messengers (e.g. cyclic adenosine monophosphate, cAMP) and production of various neurotrophic brain factors, especially cAMP-response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and B-cell lymphoma protein 2 (Bcl-2), as well as neurotrophin-3,4,5 (NT-3,4,5), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF).

Correct signal transduction culminates in intact neuroplasticity and resilience in specific brain areas and results in maintenance of euthymic mood. Postsynaptic b1-adrenergic and 5-HT4,6,7 serotonergic receptors activate the adenylate cyclase–cAMP cascade, which eventually leads, among other things, to the production of CREB and BDNF. CREB is also modulated by Ca2-dependent protein kinases stimulated by other postsynaptic receptors such as the a1-adrenergic and the 5-HT2A,2C serotonergic. Other mechanisms, as yet less understood, are supposed to be involved in the maintenance of euthymic mood. Among them are proper regulation of postsynaptic 5-HT1A serotonergic receptors and concentration of intracellular Bcl-2. It is presumed that most antidepressant drugs that exert their antidepressant activity by antagonizing the postsynaptic 5-HT2A serotonergic receptors (e.g. mianserin, mirtazapine, nefazodone, and trazodone; as opposed to the ‘classic’ antidepressants that stimulate noradrenergic/serotonergic transmission via blockade of the reuptake of these neurotransmitters to the presynaptic nerve terminals) exert at least some of their therapeutic action by enhancing the 5-HT1A receptors (5-HT2A,2C receptors suppress 5-HT1A receptor functions). All of the above mentioned reactions are supposed to play a role in maintaining proper neuroplasticity.1–13

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2.2 Antidepressant drugs Schematic classification according to main mode of therapeutic action

Presynaptic nerve terminal Reuptake inhibitors

Inhibitors of MAO AD

of NE: NARI (reboxetine) SNRIs (duloxetine, milnacipran

RIMA: Moclobemide

MAOIs:

venlafaxine)

TCAs (e.g. amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, desipramine) TeCAs (e.g. amoxapine, maprotiline)

PMT

Isocarboxazid, phenelzine, tranylcypromine

MAO

AD

of 5-HT: Inhibitors of presynaptic IAR

SSRIs (e.g. citalopram, fluoxetine, fluvoxamine, paroxetine, setraline)

(e.g. a2-adrenergic receptors)

SNRIs TCAs

IAR

of both NE and 5-HT: SNRIs Others (nefazodone)

Mianserin, mirtazapine, trazodone

AD Inhibitors of postsynaptic 5-HT receptors Mianserin, mirtazapine, nefazodone, trazodone

Postsynaptic nerve

AD

NE/5-HT receptors

Inhibition

Legend

Inhibits Enhanced secretion

5-HT

28

Serotonin

AD

Antidepressant drug

IAR

Inhibitory autoreceptor

5-HT2 receptors

MAO MAOI NARI NE PMT RIMA SNRI SSRI T/TeCA

Monamine oxidase MAO inhibitor Seletive noradrenaline (norepinephrine) inhibitor Norepinephrine Plasma membrane transporter Reversible inhibitor of MAO type A Serotonin–norepinephrine reuptake inhibitor Selective serotonin reuptake inhibitor Tri/tetracyclic antidepressant

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As a rule of thumb, all antidepressant drugs have comparable efficacy but different adverse effects profiles, although there are a few exceptions to this (e.g. selective serotonin reuptake inhibitors (SSRIs) are less efficacious in severe major depressive disorder). The antidepressants can be classified according to their mechanism of action, specifically: ●

●

●

Inhibiting the transporters responsible for the uptake of monoamines (e.g. reuptake inhibition of noradrenaline and/or serotonin), leading to excessive concentration of monoamines in the synaptic cleft. Blockade of monoamine receptors (pre- and postsynaptic, or both). Some of these are presynaptic inhibitory auto/heteroreceptors (e.g. a2-adrenergic), which, when blocked, cause the presynaptic neurons to release more neurotransmitter to the synaptic cleft. Postsynaptic blockade of various receptors modulates cellular activities and is presumably responsible for the antidepressive effects. Inhibition of the metabolism of the mitochondrial monoamine oxidase (MAO) responsible for the degradation of approximately 30% of cytoplasmic serotonin, norepinephrine, and dopamine. By blocking MAO, the excess neurotransmitters are stored and released again upon need.1

Notes about the scheme Antidepressants are classified as: ●

●

Reuptake inhibitors, which include the tricyclic and tetracyclic antidepressants (TCAs and TeCAs),the SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), the serotonin and norepinephrine reuptake inhibitors (SNRIs; duloxetine, milnacipran, and venlafaxine), and the norepinephrine and dopamine reuptake inhibitor (bupropion). Receptor (both pre- and postsynaptic) blockers, which include mianserin, mirtazapine, nefazodone, and trazodone. These are dual-acting

●

antidepressants since (1) they block the a2 auto- and heteroreceptors with consequent enhancement of serotonin and norepinephrine neurotransmission and (2) they also block the postsynaptic 5-HT2A,2C and 5-HT3 (only mirtazapine) receptors. Trazodone also inhibits the a1 postsynaptic receptor, and this effect probably accounts for some of its side-effects such as postural hypotension, priapism and sedation. MAO inhibitors (MAOIs), which include irreversible MAOIs (isocarboxazid, phenelzine, and tranylcypromine) and reversible inhibitors of MAO type A (RIMAs: befloxatone, moclobemide, and toloxatone).1,13

The MAOIs (isocarboxazid, phenelzine, and tranylcypromine) are irreversible inhibitors of MAO types A and B. MAO type A is the main metabolizing enzyme of serotonin and norepinephrine, while type B metabolizes dopamine. Under normal conditions, MAOs metabolize about 30% of serotonin, norepinephrine, and dopamine taken up by the plasma transporters into the cytoplasm, while the other 70% are stored in vesicles to be released again when needed. When the MAOs are inhibited, some of the 30% of the neurotransmitters that were supposed to be metabolized are stored and are available for future release. Therefore, the concentrations of serotonin, norepinephrine, and dopamine in the synaptic cleft increase following MAOI administration.1 The role of enhanced dopaminergic transmission in the treatment of major depressive disorder is controversial and current research suggest that it is relatively minor compared with the role of norepinephrine and/or serotonin. Most of the data about dopamine and depression come from clinical experience with various pharmacological agents that enhance dopaminergic transmission (e.g. the inhibition of MAO type B by selegiline increases the availability of dopamine in the synaptic cleft; however, its main use is in parkinsonism, although there are some anecdotal reports of its efficacy in major depressive disorder6) or with some of the abused substances (e.g. amphetamines) that cause, among other things, euphoria.

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2.3 Major depressive disorder Cellular changes following antidepressant treatment

Downregulated inhibitory autoreceptors

Presynaptic nerve terminal IAR

(e.g. a2-adrenergic)

High synaptic NE/5-HT

Soma Rec. trkB trkB

SM Nucleus CREB

Postsynaptic nerve

trkB trkB BDNF

Nerve terminal

High synaptic neurotrophic factor (e.g. BDNF)

'Original' part of dendrite

Newly formed part of dendrite

Growth of new dendrites and/or change in morphology Downregulated receptor High concentration

30

Promotes cellular resilience (see text)

Feedback inhibition (decreased)

Legend

BDNF CREB

IAR NE/5-HT Rec. SM trkB

Brain-derived neurotrophic factor Cyclic adenosine monophosphate (cAMP)-response element-binding protein Inhibitory autoreceptor Norepinephrine/serotonin Receptor Second messenger (e.g. cAMP) Receptor for BDNF

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Although antidepressant drugs are considered very effective (about 75% of treated patients respond favorably), only one-third of depressed patients who begin treatment achieve full remission (defined as virtually complete relief of symptoms and return to full functioning in all areas of life) within the first 8 weeks of therapy. The achievement of a proper response is essential because residual symptoms are often associated with a myriad of risks, including a higher rate of relapse and suicidality. As previously described, practically all antidepressants increase the monoamine concentration in the synaptic cleft. This effect is acute and it is probably not associated with direct antidepressive action. The chain of intra- and intercellular events following chronic antidepressant administration corresponds chronologically to the resolution of depression, which takes between 4 and 8 weeks to develop.7

Notes about the scheme Chronic antidepressant administration causes a chain of events, which begins with receptor targeting, intracellular second-messenger activation, gene expression, and the production of neurotrophic brain factors. These events modulate the neuroplasticity vital for the maintenance of normal mood and the resolution of the depressive mood. This chain of events corresponds chronologically to the resolution of depression, which usually takes at least 4 weeks.2 Studies conducted decades ago demonstrated various alterations in pre- and postsynaptic receptors that were thought to be associated with the development of major depressive disorder. Among these were upregulation of presynaptic inhibitory auto/heteroreceptors such as the a2-adrenergic, decreased synaptic concentrations of both norepinephrine and serotonin (see Section 1.1), and upregulation of postsynaptic receptors, especially the b1-adrenergic. Moreover, it was even demonstrated that antidepressant treatment was associated with further alterations in these abnormal parameters (e.g. increases in

synaptic norepinephrine and serotinin and downregulation of postsynaptic b1-adrenergic receptors). However, these antidepressant drug-related changes could not fully explain the clinical resolution of depression, since (a) increased synaptic concentrations of serotonin and norepinephrine are observed immediately following drug administration (within a few minutes; after the drug has been absorbed from the gastrointestinal tract, has entered the systemic circulation, and has crossed the blood–brain barrier), while (b) postsynaptic downregulation of the b1-adrenergic receptors occurs up to weeks before the clinical resolution of depression is observed. Recent studies demonstrate that chronic antidepressant treatment targets pathways involved in the production of factors associated with cell survival and plasticity such as cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). These components are upregulated by antidepressant treatment, at least in animal models of depression (e.g. in mouse limbic regions), and reach proper intracellular concentrations following 4–6 weeks of treatment (chronologically comparable to the clinical resolution of depression). Chronologically, following the normalization of intracellular CREB and BDNF, changes in brain morphology (e.g. growth of dendrites and their correct topographic position) as well as increased cell survival are evident. These effects on proliferation and survival of neurons (observed mainly in hippocampal regions) support the notion that alterations in hippocampal neurogenesis are fundamental to the resolution of the clinical syndrome of depression. All of the above-mentioned morphological changes, which correspond (at least chronologically) to the resolution of depression, are not merely normalization of previous morphology but rather a distinct new morphological setting. For example, the chronically ‘treated’ neurons have many more dendrites than the ‘depressed’ neurons and also more neurons than the premorbid ‘euthymic’ neurons.2

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2.4 Antidepressant drugs Recently developed antidepressants (I) – SNRIs



SNRI

SNRI NE-PMT 5-HT-PMT

5-HT NE

Increased synaptic NE

Increased synaptic 5-HT ADR

5-HT rec.

Consequent intra- and intercellular alterations (see Section 2.3 for details)

Legend

5-HT

5-HT

Serotonin

Induces

ADR

Adrenergic receptor

NE NE SNRI

PMT rec. SNRI

32

Postsynaptic nerve

Norepinephrine Plasma membrane transporter Receptor Serotonin–norepinephrine reuptake inhibitor

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The earliest antidepressant drugs (e.g. tricyclics, TCAs) were aimed mainly at inhibiting the reuptake of norepinephrine, while the later selective serotonin reuptake inhibitors (SSRIs) specifically block the reuptake of serotonin. Recently, newly developed dual-acting antidepressants have been introduced, and accumulating data may suggest that they might be more effective and have a shorter lag response in severe depression when compared with older drugs, especially the SSRIs. These dual-acting antidepressants are serotonin and norepinephrine reuptake inhibitors (SNRIs: duloxetine, milnacipran, and venlafaxine) and mirtazapine (see the following pages for the relevant schemes). Even so, although they exhibit a somewhat different mechanism of action compared with the older drugs, the SNRIs still enhance noradrenergic and serotonergic transmission by using the ‘old’ technique (i.e. blockade of the plasma membrane transporter responsible for the reuptake of serotonin and/or norepinephrine).14

Notes about the scheme Several findings support the view that antidepressants that enhance both serotonin and norepinephrine (dual-acting antidepressants) have greater therapeutic efficacy compared with antidepressants that enhance either neurotransmitter alone (e.g. SSRIs enhance mainly serotonin, while reboxetine and desipramine enhance predominantly norepinephrine). It is specifically proposed that the dual-acting SNRIs may display faster onset of action and can be more efficacious in cases of severe depression. There are four newgeneration dual-acting antidepressants: duloxetine, milnacipran, mirtazapine, and venlafaxine.14 Duloxetine is the most potent inhibitor of the reuptake of serotonin and norepinephrine (among the SNRIs). It is a little more potent at blocking the reuptake of serotonin, although at higher doses (within the therapeutic range) it is

a relatively balanced reuptake inhibitor of both serotonin and norepinephrine, with weak effect on dopamine reuptake. It lacks affinity for other neurotransmitter receptors, and its most frequent adverse side-effects include nausea, insomnia, headache, somnolence, and sweating, which usually dissipate with continued treatment. Unlike venlafaxine, there is no increased incidence of hypertension with duloxetine compared with placebo. Milnacipran is a reuptake inhibitor of norepinephrine and serotonin with little effect on dopamine reuptake or other neurotransmitter receptors. Compared with the SSRIs, milnacipran has a higher incidence of headache, dry mouth, and dysuria. Unlike duloxetine and venlafaxine, it is more potent at blocking the noradrenergic transporter (norepinephrine reuptake inhibition); thus, at low therapeutic doses, it is more of a ‘noradrenergic’ drug. Venlafaxine is a potent reuptake inhibitor of serotonin, with a less potent effect on norepinephrine and dopamine, and does not interact with other neurotransmitter receptors. The lower affinity for norepinephrine transport requires dose elevation in order to achieve both serotonin and norepinephrine inhibition. Emerging evidence indicates that higher doses of venlafaxine (200–375 mg/day) may have a faster onset of action, observed as early as 4 days to 1 week following treatment initiation. The most frequent reported adverse events are nausea, dizziness, somnolence, insomnia, sweating, and dry mouth. It is associated with sustained hypertension in up to 13% of patients on higher doses. Mirtazapine is a potent antagonist of central a2-adrenergic auto- and heteroreceptors (see Section 2.5). Hence, like the SNRIs (although via a different mechanism), it enhances the release of both norepinephrine and serotonin to the synaptic cleft. Mirtazapine also antagonizes post-synaptic 5-HT2A and 5-HT3 serotonergic receptors and it indirectly activates the postsynaptic 5-HT1A receptor.14–18

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2.5 Antidepressant drugs Recently developed antidepressants (II) – mirtazapine



NE-PMT

5-HT-PMT

a2-ADR

a2-ADR

Mrtz

Mrtz

NE

5-HT Increased synaptic 5-HT

Increased synaptic NE Mrtz ADR Postsynaptic nerve

Consequent intra- and intercellular alterations (see Section 2.3 for details)

Inhibition

Legend

5-HT Enhanced secretion of neurotransmitter

Mrtz

Mirtazapine NE

5-HT 5-HT2,3 ADR a2-ADR NE PMT rec.

34

5-HT2,3

5-HT rec.

See text for details

Serotonin Serotonergic receptor subtypes Adrenergic receptor a2-adrenergic inhibitory receptor Norepinephrine Plasma membrane transporter Receptor

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Notes about the scheme Mirtazapine is a tetracyclic antidepressant that is marketed as a racemic mixture of its optical isomers. Pharmacologically, the drug is an antagonist at the a2-adrenergic receptor, with the S-() enantiomer exhibiting an approximately 50-fold more potent effect than the R-() enantiomer at these receptors. As a consequence of its a2-antagonistic action, the drug has been shown to increase both noradrenergic and serotonergic neurotransmission (the latter by blockade of a2-adrenergic heteroreceptors located on serotonergic neurons). It also blocks the postsynaptic 5-HT2 and 5-HT3 receptors, leading to indirect enhancement of 5-HT1A-mediated neurotransmission. The efficacy of orally administered mirtazapine has been well established in controlled clinical trials in patients with moderate to severe depression in both in- and outpatient clinical settings. Mirtazapine has a non-specific affinity for plasma proteins and is approximately 85% bound to them, although it is not expected to have an effect on the protein binding of coadministered drugs. Food has minimal effects on the rate and extent of absorption of the drug. It is essentially completely absorbed orally and its bioavailability after oral administration is about 50%, due to first-pass effects. The half-life is 37 hours in women compared with 26 hours in men, and the drug reaches a steady state after 4–6 days of once-daily administration. The drug is metabolized through hydroxylation and demethylation, followed by glucuronidation. The predominant active metabolite, N-desmethylmirtazapine, is 5–10 times less active than the parent compound. Mirtazapine is primarily metabolized by CYP450 2D6, 1A2, and 3A4. Mirtazapine is at least as effective as the tricyclic antidepressants and trazodone in a wide range of patient subgroups, including in- and outpatients with moderate to severe depression. It also appears to be at least as effective as the serotonin and norepinephrine reuptake inhibitor venlafaxine in the treatment of severely depressed melancholic patients.

When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine may show an earlier onset of action (although data are currently not well established). Mirtazapine has also been found to be efficacious in the treatment of elderly patients with depression. Mirtazapine has been shown to be effective in the treatment of panic disorder, social phobia, and posttraumatic stress disorder. In one study, mirtazapine combined with citalopram in obsessive–compulsive patients induced an earlier response when compared with citalopram plus placebo. It was suggested that antagonism of presynaptic a2-adrenergic receptors does not enhance serotonin neurotransmission directly, but rather disinhibits the norepinephrine activation of serotonergic neurons and thereby increases serotonergic neurotransmission by a mechanism that may not require a time-dependent desensitization of receptors. An orally disintegrating tablet formulation of mirtazapine has been developed (mirtazapine SolTab), with the drug ingredients being microencapsulated into a quickly dissolving tablet. The bitter taste of the drug is disguised with an orange flavor in the case of mirtazapine SolTab. The formulation is designed to increase compliance in patients who have difficulty in swallowing conventional capsules or tablets. A comparative study of mirtazapine SolTab versus the SSRI sertraline was conducted in a large study of patients with a DSM-IV diagnosis of major depressive disorder. Statistically, there were no differences between mirtazapine SolTab and sertraline. Mirtazapine can be administered intravenously. In a recent study, mirtazapine i.v. was administered to patients with a DSM-IV diagnosis of major depression. After a washout of 3 days, mirtazapine 15 mg was given as an intravenous infusion over 1 hour once a day for 14 days. At the end of the intravenous period, depression improved significantly, and there was some evidence for an early onset of action of mirtazapine. Adverse effects of mirtazapine administered intravenously did not differ from those reported in other trials of mirtazapine administered orally.14–18

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2.6 Antidepressant drugs Recently developed antidepressants (III) – escitalopram

R enantiomer of citalopram: the molecule is (1) completeley inactive (does not block reputake) and (2) interferes with the binding of the S enantiomer (escitalopram) to its binding site in the plasma membrane transporter

Presynaptic serotonergic nerve terminal 5-HT-PMT

Serotonin is not blocked from entering into the nerve terminal

Serotonin freely enters the nerve terminal

S enantiomer: the molecule cannot bind to the allosteric site

5-HT 5-HT-PMT

Escitalopram (S enantiomer): Serotonin is blocked from entering into the nerve terminal (apparently better than with other SSRIs)

Storage vesicle

Serotonin is available in greater concentrations for postsynaptic interactions

Legend

R-citalopram Escitalopram (S-citalopram) 5-HT Transporter (primary binding site) Transporter (allosteric binding site)

36

5-HT 5-HT-PMT SSRI

Serotonin Plasma membrane transporter for serotonin Selective serotonin reuptake inhibitor

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Escitalopram is the therapeutically active S enantiomer of RS-citalopram, a commonly prescribed selective serotonin reuptake inhibitor (SSRI). There is some evidence of greater efficacy than citalopram and probably other SSRIs due, presumably, to its unique mode of action. The antidepressant mechanism of escitalopram is presumed to be the result of stimulation of serotonergic neurotransmission in the central nervous system (CNS) as a consequence of higher serotonin levels resulting from inhibition of the serotonin transporter. The S enantiomer (escitalopram) binds to a primary binding site of the serotonin plasma membrane transporter and blocks the reuptake of serotonin. At the same time, escitalopram also binds to a different (i.e. allosteric) site on the serotonin transporter, and by doing so it more effectively blocks the reuptake of serotonin into the presynaptic nerve terminal. Citalopram has an equal amount of the R and S enantiomers. The R enantiomer binds to the primary binding site (like the S enantiomer), but by doing so, and due to its unique conformational state, it interferes with the binding of the S enantiomer to the allosteric site. Moreover, the R enantiomer by itself is not sufficiently efficacious in blocking the reuptake of serotonin. Hence, the capacity of citalopram to block the reuptake of serotonin is relatively weak compared with that of escitalopram. Escitalopram has no or very low affinity for a variety of other serotonin, dopamine, a- and b-adrenergic, histamine, muscarinic, and benzodiazepine receptors. Also, it does not bind to or has low affinity for a range of ion channels, including those for Na, K, Cl, and Ca2. Escitalopram is transformed into two metabolites, S-desmethylcitalopram and S-didesmethylcitalopram, both of which are less potent than the parent drug. Escitalopram is the predominant plasma compound. The primary isoenzymes involved in the metabolism of escitalopram are cytochrome P450 (CYP) 2C19, CYP3A4, and CYP2D6. Elimination of escitalopram is principally via hepatic and renal routes as metabolites. The oral clearance is 36 l/h (600 ml/min) and the elimination half-life is between 27 and 32 hours. The oral clearance of RS-citalopram was reduced by 37% and its half-life doubled in patients with hepatic

impairment. Antidepressant efficacy of escitalopram was observed in patients with major depression receiving 10–20 mg/day versus those receiving placebo – noted as early as 1–2 weeks after starting therapy. Escitalopram has shown superior efficacy compared with placebo in patients with generalized anxiety disorder, social anxiety disorder, and panic disorder, while recent reports hold promise for escitalopram in the treatment of obsessive–compulsive disorder. The adverse events profile for escitalopram is similar to that observed with RS-citalopram in both major depression and anxiety disorders. Discontinuation rates due to adverse events were similar in patients receiving escitalopram or placebo in several trials. Nausea and ejaculatory problems were reported in both fully published trials in patients with major depression. In addition, diarrhea, insomnia, dry mouth, headache, and upper respiratory tract infections were experienced by patients receiving escitalopram, although the incidence of these events was not significantly higher than in patients receiving placebo. The recommended dose of escitalopram for the treatment of major depression is 10 mg/day, which, depending on the individual patient response, may be titrated up to 20 mg/day. No dosage adjustment is required in patients with mild to moderate renal impairment; however, escitalopram should be used with caution in patients with severe renal impairment. Escitalopram is contraindicated in combination with irreversible monoamine oxidase inhibitors (MAOIs), and a period of at least 2 weeks should be allowed between discontinuation of escitalopram and commencement of an irreversible MAOI and vice versa. Escitalopram appears to be a well-tolerated and effective antidepressant. With a favorable side-effect profile, it appears to be well tolerated even in patients who are intolerant of other SSRIs. Escitalopram may possess safety advantages, in that it appears to have potential for fewer drug–drug interactions due to little effect on the CYP system, and is less highly protein-bound than other SSRIs. At 20 mg/day of escitalopram (twice the recommended daily starting dose), there is some elevation in levels of coadministered desipramine and metoprolol, which appear comparable to the effect of RS-citalopram.14,19,20

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2.7 Pindolol – 5-HT1A and b-adrenergic antagonist Supposed mode of accelerating and augmenting the antidepressant effect of SSRIs

Pindolol

Soma of presynaptic nerve

5-HT1A

5-HT-PMT

SSRI

Pindolol

5-HT1A

Increased synaptic serotonin

Postsynaptic nerve

Legend

due to (1) 5-HT1A blockade by pindolol and subsequent increased excitability of the serotonergic nerve and decreased inhibition of secretion of 5-HT from nerve terminal and (2) reuptake inhibition by the SSRI

5-HT-R

Action potential

5-HT 5-HT1A

Inhibition

Serotonin Inhibitory somatodendritic serotonergic autoreceptor

5-HT-PMT

Plasma membrane transporter for serotonin

5-HT-R

Serotonergic receptors (any kind)

5-HT SSRI

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Notes about the scheme Some of the b-adrenergic receptor antagonists have a potential use in psychiatric pharmacotherapy. There are several distinct badrenergic receptors (b1, b2, b3). The b1 receptor is located mainly in the central nervous system and the heart, while b2 is located predominantly in peripheral tissues such as the liver, pancreas, pulmonary tree, blood vessels, and gastrointestinal tract. Pindolol is a lipophilic (quite easily crossing the blood–brain barrier) and selective b1-adrenergic and 5-HT1A serotonergic antagonist with some intrinsic sympathomimetic activity. The use of pindolol in alleviating depressive symptoms is based predominantly on its capacity to antagonize 5-HT1A receptors. The 5-HT1A autoreceptor is inhibitory in nature; thus, it responds to synaptic serotonin and inhibits, through a cascade of intracellular signal transduction, the depolarization of the cell, and, finally, it inhibits the release of serotonin from nerve terminals. Hence, when pindolol is administered, it inhibits the autoinhibition caused by 5-HT1A receptors and thereby causes a net increase in synaptic 5-HT concentration. There is good evidence that facilitation of serotonergic neurotransmission may act either directly or indirectly as a unifying mechanism of antidepressant treatment. One of the major drawbacks in the pharmacotherapy of depression has been the delay in response of 2–4 weeks between administering an antidepressive drug and the resolution of depression, despite immediate uptake blockade/reduced metabolism of monoamines at a synaptic level. The 5-HT1A receptors are a subgroup of G-protein-coupled serotonergic receptors that are present postsynaptically on the soma and dendrites of serotonergic neurons. These receptors are found mainly in the mid and dorsal raphe nuclei of the midbrain and their main effect is inhibitory in nature. It has been demonstrated (mainly in rats) that repeated administration of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants leads to functional desensitization of the somatodendritic 5-HT1A

receptors, the timing of which correlates with the delay in onset of action of SSRIs. In effect, the initial rise in extracellular serotonin following SSRI administration feeds back onto 5-HT1A somatodendritic receptors in raphe nuclei, resulting in inhibition of the neuron, reduced firing and reduced serotonin synthesis. With repeated administration of SSRIs, there is downregulation of somatodendritic 5-HT1A receptors, reduced negative-feedback autoinhibition, and increased firing and serotonin synthesis. When this occurs, and in the presence of ongoing serotonin reuptake inhibition at the synapse by SSRIs, there is a facilitation of serotonergic neurotransmission and only then an antidepressant response. The action of pindolol speeds up the inhibition of the 5-HT1A receptors and thereby, presumably, facilitates and perhaps even enhances antidepressant action. Preclinical studies provide a plausible pharmacodynamic rationale for the addition of 5-HT1A antagonists to drug regimens for the treatment of depression. The current data regarding the clinical efficacy of pindolol in speeding/augmenting the response to SSRIs is contradictory and not well established. The few controlled studies have revealed no beneficial results with such combinations, while other studies have demonstrated some efficacy of pindolol as augmentation treatment to SSRIs as well as to milnacipran (a serotonin and norepinephrine reuptake inhibitor, SNRI) in patients with major depression. Moreover, pindolol might be useful as an augmentator in patients with obsessive–compulsive disorder and panic disorder, both of which are believed to respond to serotonergic enhancement therapies. While a number of selective 5-HT1A antagonists may become available for future clinical use, the current absence of selective compounds, the conflicting results of 5-HT1A augmentation in the treatment of major depression, and the potentially fatal consequences of pindolol overdose mean that pindolol augmentation of antidepressant therapy should be considered a third- or fourth-line augmentation strategy for the treatment of major depression.21–24

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2.8 Antidepressant drugs Comparative affinities for various receptors/transporters

Amitriptyline

5-HT/NE blockade ratio

NE/5-HT blockade ratio

5-HT2A blockade

a2-ADR blockade

a1-ADR blockade

AChM blockade

H1 blockade

5-HT-RI

Antidepressants

NE-RI

Receptor/transporter interaction

2

Clomipramine

TCAs

TeCAs

SSRIs

5

Desipramine

85

Doxepin

15

Imipramine

2

Nortriptyline

35

Amoxapine

25

Maprotiline

450

Citalopram

400

Escitalopram

400

Fluoxetine

15

Fluvoxamine

150

Paroxetine

200

Sertraline

150

NARI

Reboxetine

150

SNRIs

Duloxetine Milnacipran Venlafaxine

3

Bupropion

7

Others

9

5

Mianserin Mirtazapine Trazodone

High affinity for the specific receptor/transporter

Legend

Moderate affinity for the specific receptor/transporter Minior affinity for the specific receptor/transporter Negligible affinity for the specific receptor/transporter No affinity for the specific receptor/transporter (in therapeutic doses) 5-HT AChM ADR

40

25

H1 NARI

Acetylcholine muscarinic receptor

Selective noradrenaline (norepinephrine) reuptake inhibitor

NE

Norepinephrine

RI

Reuptake inhibition

SNRI

Serotonin–norepinephrine reuptake inhibitor

SSRI


Serotonin Adrenergic receptor

Histaminergic receptor, type 1

TCA TeCA

Tricyclic antidepressant Tetracyclic antidepressant

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2.9 Antidepressant drugs The main cytochrome P450 (CYP) hepatic enzymes responsible for metabolizing antidepressant drugs

Specific CYP enzyme Substrate

1A2

2B6

2C19

2C9

2D6

2E1

3A4

Amitriptyline Clomipramine Desipramine

TCAs

Doxepin Imipramine Nortriptyline

TeCAs

Amoxapine Maprotiline Citalopram Escitalopram Fluoxetine

SSRIs

Fluvoxamine Paroxetine Sertraline

NARI

Reboxetine

SNRIs

Milnacipran

Duloxetine Venlafaxine Bupropion Mianserin

Atypical

Mirtazapine Nefazodone Trazodone

Legend

Major capacity for metabolizing the specific drug Moderate capacity for metabolizing the specific drug

NARI Selective noradrenaline (norepinephrine) reuptake inhibitor

Minor capacity for metabolizing the specific drug Negligible capacity for metabolizing the specific drug No capacity for metabolizing the specific drug or data are not well established

SNRI Serotonin–norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitor TCA Tricyclic antidepressant TeCA Tetracyclic antidepressant

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2.10 Antidepressant drugs Main adverse side-effects (I) – anticholinergic and central nervous system effects

Pregnancy risk factor (PRF)

Weight gain

Tremor

Toxicity in overdose

Seizure induction

Sedation

Agitation

Akathisia-like

Antidepressant

Anticholingeric

Main adverse effects

Amitriptyline Clomipramine

TCAs

Desipramine Doxepin Imipramine Nortriptyline

TeCAs

Amoxapine Maprotiline Citalopram Escitalopram

SSRIs

Fluoxetine Fluvoxamine Paroxetine Sertraline

NARI

Reboxetine

SNRIs

Milnacipran

Duloxetine Venlafaxine Bupropion Mianserin

Atypical


Legend

Major capacity for inducing side-effect PRF: 'D': Positive evidence of human fetal risk but the benefits from use in pregnant women may be acceptable Moderate capacity for inducing side-effect NARI PRF: 'C': Positive evidence of animal fetal risk but there are no controlled studies in women, or there are no studies in animals/women SNRI Minor capacity for inducing side-effect PRF 'B'. Studies show no evidence of animal fetal risk but there are no controlled studies in women, or SSRI adverse effects were evident in animal studies but studies in women did not confirm such findings TCA Negligible capacity for inducing side-effect Rarely causes side-effect or data are not well-established

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TeCA

May induce weight loss Selective noradrenaline (norepinephrine) reuptake inhibitor Serotonin–norepinephrine reuptake inhibitor Selective serotonin reuptake inhibitor Tricyclic antidepressant Tetracyclic antidepressant

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2.11 Antidepressant drugs

Tachycardia

QR, QTc, QRS

Orthostatism

Arrhythmogenic

Liver function

Nausea/vomiting


Diarrhea

Antidepressant

Abdominal discomfort

Main adverse side-effects (II) – gastrointestinal and cardiovascular effects

Amitriptyline Clomipramine

TCAs

Desipramine Doxepin Imipramine Nortriptyline

TeCAs

Amoxapine Maprotiline Citalopram Escitalopram

SSRIs

Fluoxetine Fluvoxamine Paroxetine Sertraline

NARI

Reboxetine

SNRIs

Milnacipran

Duloxetine

Venlafaxine Bupropion Mianserin

Atypical


Legend

Major capacity for inducing side-effect

NARI

Moderate capacity for inducing side-effect Minor capacity for inducing side-effect

QR/S, QTc

Selective noradrenaline (norepinephrine) reuptake inhibitor Specific EKG intervals

Negligible capacity for inducing side-effect

SNRI


Rarely causes side-effect or data are not well established

SSRI


Prolonged/impaired, respectively

TCA

Tricyclic antidepressant

TeCA

Tetracyclic antidepressant

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2.12 Antidepressant drugs Effects on sexual function

TCAs

Decreased orgasm capacity

Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline Amoxapine

TeCAs

Maprotiline

SSRIs

Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

NARI

Reboxetine

SNRIs

Duloxetine Milnacipran Venlafaxine

Others

Bupropion Mianserin Mirtazapine Trazodone

NARI

Legend High capacity to cause the specific adverse effect Moderate capacity to cause the specific adverse effect Minor capacity to cause the specific adverse effect

NE

The adverse effect has not been reported with this drug

Selective noradrenaline (norepinephrine) reuptake inhibitor Norepinephrine

SNRI


SSRI


TCA


Negligible capacity to cause the specific adverse effect TeCA *

44

Decreased libido

Increased libido

Painful ejaculation

Inhibited ejaculation*

Priapism

Erectyle dysfunction

Decreased libido

Antidepressants

Increased libido

Sexual adverse side-effects Men Women

Tetracyclic antidepressant Might also cause inhibited orgasm capacity

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2.13 Antidepressant drugs Effects of antidepressant drugs on various sleep parameters

Potentially affected sleep parameters Antidepressant drug

REM latency

REM sleep

Sleep continuity

SW sleep

Amitriptyline Clomipramine Desipramine Maprotiline Mianserin Mirtazapine Nefazodone SSRIs Trazodone Trimipramine

Legend

Substantial increase (improvement) Minor increase (improvement) Major decrease Moderate decrease Minor decrease

REM

Rapid eye movement

SSRI


SW

Slow-wave (most probably influenced by central 5-HT2 serotonergic blockade)

No effect

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2.14 Antidepressant drugs Monoamine oxidase inhibitors

Presynaptic nerve terminal Metabolites RIMA

MAOI

If MAO is active

PMT

MAO

30%

Mitochondria 70%

If MAO is inhibited

Storage vesicle (full with neurotransmitter that was not metabolized by MAO)

MAOI (T) RIMA (B)

More neurotransmitter (e.g. norepinephrine, serotonin) is availble for excretion and, consequently, postsynaptic interactions

Legend

MAOI MAOI (T)

Neurotransmitter

PMT

MAO inhibitor Tranylcypromine Plasma membrane transporter

Inhibits RIMA MAO

46

Monoamine oxidase

RIMA (B)

Reversible inhibitor of MAO type A Brofaromine

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Notes about the scheme Monoamine oxidase (MAO) is an enzyme present in the outer mitochondrial membrane of neuronal and non-neuronal cells. Two isoforms of MAO exist: MAO-A and MAO-B. The MAO enzymes are responsible for the oxidative deamination of endogenous and xenobiotic amines, and have different substrate preferences, inhibitor specificities, and tissue distributions. MAO inhibition allows endogenous and exogenous substrates to accumulate, and may thereby alter the dynamics of regular monoamine transmitters, such as norepinephrine, serotonin, and dopamine. Specifically, MAO-A deaminates serotonin, norepinephrine, and dopamine, and MAO-B deaminates dopamine, b-phenylethylamine, and benzylamine. In the human brain, about 75% of MAO is of the B subtype. Hence, the primary effect of MAO inhibitors (MAOIs) is to increase the availability of these neurotransmitters at the nerve terminal. Monoamine oxidases (both MAO-A and MAO-B) also exist in peripheral tissue, specifically the gastrointestinal tract (GIT). In the GIT, they inhibit the first-pass metabolism of exogenous tyramine. Because of this property, treatment with non-selective irreversible MAOIs can result in the accumulation of tyramine and have the potential to precipitate a dangerous hypertensive crisis, the so-called ‘cheese effect’. This effect may occur more frequently in elderly than in younger patients, because the cardiovascular systems of the elderly are already compromised by age. Selective MAO-B inhibitors and reversible MAO-A inhibitors are free from this potentially fatal interaction. MAOIs are classified as selective and non-selective and as reversible and irreversible. The main non-selective MAOIs include isocarboxazid, nialamide, tranylcypromine, and phenelzine (all irreversible). The selective MAOIs are classified as MAO-A and MAO-B inhibitors. The MAO-A selective inhibitors include befloxatone, cimoxatone, moclobemide, and toloxatone (all reversible). The MAO-B selective inhibitors include pargyline and selegiline (deprenyl) (all irreversible). Presently, MAOIs are used for the treatment of

depressive disorders, anxiety disorders, Parkinson’s disease (selegiline), and Alzheimer’s disease (selegiline). The non-selective and irreversible MAOIs have serious side-effects, including hepatoxicity, orthostatic hypotension, and, most importantly, hypertensive crisis following the ingestion of foods containing tyramine. When these compounds are used, a strict tyramine-reduced diet must be observed. The use of sympathomimetic drugs in combination with MAOIs, particularly the irreversible non-selective MAOIs, may substantially elevate blood pressure. The pressor sensitivity towards tyramine is normalized 4 weeks after cessation of tranylcypromine therapy and more than 11 weeks after cessation of phenelzine therapy. Selegiline, especially when used in combination with levadopa, can cause anorexia/nausea, dry mouth, dyskinesia, and orthostatic hypotension. The most frequently reported adverse effects of the reversible selective MAO-A inhibitor moclobemide are sleep disturbances, increased anxiety, restlessness, and headaches. Regarding tolerability, moclobemide showed good results, including among the elderly. Fewer adverse effects were reported among moclobemide-treated patients compared with selective serotonin reuptake inhibitor (SSRI)-treated patients. Since moclobemide does not induce orthostatic hypotension, does not possess anticholinergic properties, and is not cardiotoxic, it is very well suited among the MAOIs for the treatment of depression. Moclobemide has limited potential to elicit a hypertensive crisis, because the pressor effect of tyramine from food is only marginally potentiated compared with tranylcypromine. The pressor effect of tyramine is normalized within 3 days of cessation of treatment with moclobemide. The combination of SSRIs and moclobemide has good efficacy in cases of refractory depression, but there is controversy as to whether toxic side-effects such as serotonin syndrome can result from this combination. Currently, more studies are needed before this combination can be recommended. Acute overdose with MAOIs causes agitation, hallucinations, hyperpyrexia, hyperreflexia, convulsions, and death. The most dangerous MAOIs in overdose are the irreversible non-selective MAOIs.13,25–27

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2.15 Antidepressant drugs Potential future developments

All 'conventional' antidepressants work by increasing the concentration (by different mechanisms) of synaptic serotonin and/or norepinephrine (i.e. they do not directly alter intracellular components)

Synaptic 5-HT or NE

Amantadine Felbamate Memantine Riluzide

Ca2 ions Dopaminergic agents Rolipram

Pramipexole

Glutamate NMDA rec. PDE4 Decreased 2 intracellular Ca

Bcl-2

CREB

Dopamine

Antidepressive effects Enhanced 5-HT neurotransmission (see also Sections 2.1 and 2.2) (mainly in limbic regions) Stimulate dopamine Enhanced striatal dopamine release release in limbic regions Induces long-term potentiation along with increased dendritic density/volume

Legend CREB Stimulates Inhibits 5-HT

Serotonin

Bcl-2 B-cell lymphoma protein 2

NE

Norepinephrine

NMDA rec. N-Methyl-D-aspartate recepto r (subtype of glutamatergic receptor) PDE4

48

Cyclic adenosine monophosphate (cAMP)-response element-binding protein

Phosphodiesterase-4 (metabolizes CREB)

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A significant percentage of patients (40–50%) do not fully respond to standard treatment with antidepressant drugs, and up to one-third do not respond at all.8 Therefore, new treatment strategies for the management of major depression are being evaluated in order to shorten the lag response and to improve remission rates. The mechanism of action of practically all antidepressant agents currently in use is based on extracellular manipulation of the monoamine system (e.g. all increase the synaptic concentration of norepinephrine and/or serotonin). Furthermore, accumulating data suggest that the antidepressant effects of drugs is associated with altering intracellular components (cyclic adenosine monophosphate (cAMP), cAMP-response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF)). Hence, most of the new potential treatment modalities are based on the assumption that direct manipulation of those intracellular components might result in greater/faster efficacy. It is important to stress that all new treatment strategies for major depression described below are still being evaluated in clinical trials and the monoamine-based strategies of the current antidepressants remain the mainstream of treatment.

Notes about the scheme There is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used in the treatment of mood disorders, including current ‘conventional’ antidepressants, mood stabilizers, atypical antipsychotic drugs, and electroconvulsive therapy, have direct and indirect inhibitory effects on the glutamatergic system.3,4 The monoamine-based therapies (i.e. the currently available antidepressants) ultimately inhibit the N-methyl-D-aspartate (NMDA) receptor for glutamate (although it is not classically conceived as their main therapeutic action). The mechanism behind the NMDA antagonisminduced antidepressant effect is not fully

understood. However, accumulating data suggest that modulation of intracellular calcium influx (via antagonism of the NMDA receptor) leads to enhanced serotonergic neurotransmission in limbic regions, increased dopamine secretion in the striatum, and increases in dendrite density and volume in limbic areas. The latter effects on dendritic morphology (and presumably functioning) are associated with improved neuroplasticity, a probable component of any modality with antidepressant capacity. Hence, some current research for new treatment of major depressive disorder (MDD) is focused on developing antiglutamatergic agents43 and studying their potential antidepressant capacity. Among the currently available antiglutamatergic agents (most are non-selective) are amantadine, felbamate, memantine, and riluzole. A different strategy to address the intracellular components relevant for the treatment of MDD is to enhance the activities of CREB, which is associated with cAMP-mediated gene transcription, and may be part of the mechanism underlying antidepressant activity. The current approach to potentiating the CREB cascade is based on inhibition of phosphodiesterase-4 (PDE4). PDE4 metabolizes CREB under normal physiologic conditions. Hence, its inhibition by agents such as rolipram increases intracellular concentrations of CREB and stimulates antidepressant effects. Another strategy is to directly enhance dopamine function as well as the activities of B-cell lymphoma protein 2 (Bcl-2), which is another important component that may play a role, eventually, in the resolution of depression. Examples of various non-selective enhancers of dopamine that also stimulate Bcl-2 are pergolide, ropinirole, and selegiline, while pramipexole may directly enhance Bcl-2. The antidepressant effect exhibited by enhanced dopaminergic transmission is thought to be at least partially related to increased dopaminergic transmission in limbic structures (e.g. the nucleus accumbens).1,2,9–12

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2.16 Antimanic treatments Supposed mechanisms of action

Orbitofrontal cortex (?) Exerts tonic inhibitory control of limbic activity

Lithium

BDZs

Unknown

APDs

DA-R

IP3; DAG

Clonidine

NE-R

ECT

VLP; CBZ

Limbic neurons

Hyperactivity of limbic neurons may induce manic symptoms via various connections to other brain regions (e.g. hypothalmus, basal ganglia)

Legend

Action potential

APD

Antipsychotic drug

Tonic inhibition

BDZ

Benzodiazepine

CBZ

Carbamazepine

DAG

Diacylglycerol

DA-R

Dopaminergic receptor

Inhibition Stimulation

50

Hyperdopaminergic state

ECT

Hypernoradrenergic state

NE-R

IP3 VLP

Electroconvulsive therapy Inositol trisphosphate Norepinephrine (noradrenergic) receptor Valproate

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Acute mania as part of bipolar I disorder is supposed to result from overexcitation of limbic neurons. This can arise either from loss of inhibitory tonic orbitofrontal control of limbic neurons or from various intra- and intercellular alterations (the full mechanism is unknown as yet). Manic episodes are often classified into euphoric (classical), dysphoric, mixed (along with clinical manifestations of major depressive disorder), mania with psychotic/catatonic features, and mania with a rapid cycling course of the disease. Clinical experience with various pharmacological regimens (mainly mood stabilizers) has suggested that a drug that is efficacious in one manifestation of mania is not necessarily the treatment of choice for the overall spectrum of manic states.28 Much progress have been made in the treatment of acute manic states, especially since the demonstrated efficacy of the secondgeneration antipsychotics (e.g. olanzapine, quetiapine, and risperidone) for the treatment of acute mania. However, treatment of acute manic states remains incomplete, and new treatment strategies are in continuous development.28

Notes about the scheme Treatment of acute manic states can be broadly classified according to the different types of mania.

Euphoric (classical) mania Until recently, most studies on antimanic agents were exclusively conducted in patients with bipolar I disorder and euphoric mania, resulting in firm evidence that lithium is especially effective in this type of mania. Valproate shows equal overall efficacy in mania; however, fewer studies support its efficacy in euphoric mania compared with lithium. Valproate usually has a more rapid onset of action than lithium as its wide therapeutic window allows loading treatment strategies.28 Valproate may be the preferred choice in patients with numerous (more than eight) previous manic episodes29 or more than four depressive episodes,30 and who

have failed on lithium prophylaxis.28 Both the high-potency typical antipsychotics and the second-generation antipsychotics olanzapine and risperidone have demonstrated efficacy in the treatment of euphoric mania.30–42

Dysphoric mania and mixed states So far there is limited evidence for the superiority of one drug over the other. However, lithium may not be as effective as valproate, carbamazepine, olanzapine, and risperidone in these patients.30,34–37 The use of first-generation antipsychotics, especially in higher doses, may exacerbate dysphoric or depressive experiences and should probably be avoided.38

Psychotic mania As for mixed states, evidence for superiority of one treatment over another is as yet limited.55 Anticonvulsants such as valproate and carbamazepine seem to be as efficacious as lithium, while other possibilities include the combination of either valproate or lithium with an antipsychotic agent.

Refractory mania Clozapine has been shown to be efficacious in both euphoric and dysphoric mania.28

Mania with a rapid cycling course The failure rate of lithium treatment appears to be high in rapid cycling patients and there is a large bulk of data favoring valproate over lithium in such cases. Carbamazepine has also been reported to be effective in rapid cycling, while a combination of valproate and lithium or clozapine (as sole agent) may be beneficial in refractory cases. Since a rapid cycling course appears more common in patients with hypothyroidism, high-dose thyroid hormone augmentation should be considered in such cases.28 Small open studies and case reports exist on numerous alternatives, which include calcium channel blockers, clonidine, topiramate, phenytoin, oxcarbazepine, zonisamide, clonazepam, and omega-3 fatty acids.28 Electroconvulsive therapy (ECT) is a treatment modality frequently chosen and anecdotally found effective when other approaches have failed.28

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2.17 Mood stabilizers Lithium

Stimulated neurons (manic state?) Increased (?) glutamatergic neurotransmission

Suppressed neurons (depression?) Serotonin

Glutamate

NMDA rec.

5-HT1A

p53

Inositol Ca2

Bcl-2

Lithium IP1

Tau b-Catenin

Decrease in action potential frequency (and firing rate)

Increase in action potential frequency (and firing rate)

Increased secretion of neurotransmitter (e.g. NE, 5-HT)

Legend

Decreased secretion of neurotransmitter (e.g. NE, 5-HT)

Increased action potential frequency

5-HT

Decreased action potential frequency Increased/decreased concentration, respectively Stimulates Inhibits

52

5-HT1A Bcl-2

Serotonin Serotonergic receptor subtype (inhibitory) B-cell lymphoma protein 2 (cytoprotective)

IP1

Inositol monophosphate

NE

Norepinephrine

NMDA rec. N-Methyl-D-aspartate receptor (subtype of glutamatergic receptor)

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Lithium is one of the group IA alkali metals (like potassium and sodium) and is not normally present in the body. It acts predominantly through the phosphatidylinositol (PI) second messenger system, causing alterations in calcium- and protein kinase C (PKC)-mediated processes. Lithium can also alter the adenylate cyclase (AC) system, but this action is probably related to its toxic effects. Many calciumdependent systems may be affected by lithium, among them regulation of receptor sensitivity, parathyroid hormone release, and proper functioning of intracellular microtubule structures.39–41 Lithium is the first-line drug for the treatment of bipolar disorder, since it is efficacious in acute euphoric mania without psychotic features (beneficial in up to 80% of cases), and for maintenance treatment of bipolar I disorder (mood stabilizer). It has some antidepressant capacity, although this is not well established. In addition, it exerts beneficial effects in many disorders as an adjuvant to other treatment modalities. Such effects are apparent only if it is administered to an already pharmacologically treated patient. For example, in unresponsive major depressive disorder, the co-administration of lithium to an ongoing antidepressant treatment increases the response rate by up to 50%. In most cases, the response to lithium augmentation is either considerable or not at all (‘all-or-none’ phenomenon). Some (currently not convincing) results have also been reported in unipolar depression, bulimia nervosa, and attention deficit hyperactivity disorder (ADHD). Lithium also exerts antiaggressive effects in conduct disorder, independent of any mood disorder, and can reduce behavioral dyscontrol and self-mutilation in mentally retarded patients. One of the most striking effects of lithium is its antisuicidal effect in patients who suffer from bipolar and unipolar depressive disorder irrespective of comorbid axis I disorder.41

Notes about the scheme The specific mode of action of lithium is not fully established. It has been found to alter

intracellular building stages essential for the proper production of inositol and consequently phosphatidylinositol bisphosphate (PIP2). Lithium is a non-competitive inhibitor of inositol monophosphatase and results in accumulation of inositol 1-monophosphate as well as a reduction in free inositol. These effects initiate a cascade of secondary changes at different levels of the signal transduction process and gene expression in the central nervous system – effects that are ultimately responsible for the therapeutic efficacy of lithium.39 Considerable data have shown that lithium can also affect neurotrophic signaling cascades (e.g. enhancing the activity of B-cell lymphoma protein 2 (Bcl-2)), and it is suggested that these effects may underline its efficacy in potentiating diverse classes of antidepressants.39 Long-term treatment of rats with lithium produces a doubling of Bcl-2 levels in the frontal cortex. Lithium may also reduce levels of the pro-apoptotic protein p53, which further supports the role of lithium as a neuroprotective agent.39 Lithium also inhibits glycogen synthase kinase (GSK)-3b, which regulates various cytoskeletal processes. GSK-3b is also involved in regulating the phosphorylation of tau and b-catenin, both of which have been implicated in certain types of disease-related neuronal death.39 In addition, lithium may increase gray-matter volume in bipolar patients, increase the levels of N-acetylaspartate (a putative marker of neuronal viability) in bipolar patients and healthy volunteers,39–43 and enhance neurogenesis in the hippocampus.44 Long-term treatment with lithium increases basal and stimulation-induced serotonin release; moreover, it produces a subsensitivity of inhibitory 5-HT1A receptors, which can result in a net increase in serotonin release from presynaptic nerve terminals. These findings provide the neurochemical basis for the clinical observation of the efficacy of lithium (50% of cases) as an adjuvant to antidepressants in the treatment of resistant depression and as anti-impulsive agent. The most commonly observed adverse side-effects of lithium are gastrointestinal (weight gain, nausea, and diarrhea), polyuria and polydipsia, fine tremor, and hypothyroidism.39

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2.18 Mood stabilizers Carbamazepine

Stimulated neurons (manic state?) Ca2

Suppressed neurons (depression?)

Glutamate

NE

NMDA rec.

b2-ADR

Cl

? GABAA

CBZ

Na Cl

Ca2

Na

In mania: increase in action potential frequency (and firing rate)

In depression: decrease in action potential frequency (and firing rate)

a2-ADR

b2-ADR

Net effect in mania (?): increased secretion of neurotransmitter (e.g. NE, 5-HT, glutamate, aspartate)

Legend

Increased action potential frequency Decreased action potential frequency Increased concentration Stimulates Inhibits

Net effect in depression: decreased secretion of neurotransmitter (e.g. NE and 5-HT)

a2/b2-ADR 5-HT CBZ GABAA NE

Serotonin Carbamazepine c-Aminobutyric acid receptor, type A Norepinephrine

NMDA rec. N-Methyl-D-aspartate receptor (subtype of glutamatergic receptor) ?

54

Noradrenergic receptor subtypes (inhibitory)

Questionable pathway/effect

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Carbamazepine is an anticonvulsant beneficial in the treatment of bipolar I disorder, and, as in the case of valproate, it may be more advantageous than lithium in non-classical bipolar conditions such as mixed mood states and rapid cycling conditions. It appears to have a teratogenic effect and, like valproate, has been associated with an increased risk of neural tube defects.45 Clinically, there are various possible good predictor signs (for beneficial effects of carbamazepine). The main ones are: ● ● ● ● ● ●

secondary mania (due to pharmacotherapy, brain disorder, or trauma); dysphoric mania; mixed episode; rapid cycling disorder; comorbid substance abuse disorder; good previous response to carbamazepine; absence of psychotic features; acute manic episode as part of schizoaffective disorder.

Notes about the scheme The main targets of carbamazepine are voltage-dependent sodium channels. Carbamazepineand carbamazepine-epoxide reduce the frequency of sustained repetitive firing action potentials in cultured mammalian central neurons. Moreover, evidence is accumulating that carbamazepine also has calcium-antagonist properties (perhaps by inhibiting N-methyl-D-aspartate (NMDA) receptors and enhanced c-aminobutyric acid type A receptor (GABAA) effects. These activities are presumed to play a role in its mood stabilizing effects (especially its antimanic capacity). It has also been proposed that the therapeutic and prophylactic effects of carbamazepine in bipolar I disorder (but not its anticonvulsant effect) may, at least in part, be related to the potent interaction of carbamazepine with adenosine-binding sites in the brain. Carbamazepine acts as an antagonist at adenosine A1 receptors and as an agonist at adenosine A2 receptors. Chronic treatment with carbamazepine induces

upregulation of adenosine A1 receptors in astrocytes and rats. Carbamazepine also induces the release of serotonin by a mechanism that does not involve the serotonin transporter (e.g. by inhibiting the inhibitory presynaptic a2- and b2-adrenergic auto- and heteroreceptors). It appears that enhanced serotonin release may play a role in the efficacy of carbamazepine in the treatment of bipolar disorder, both as an antidepressant effect (in major depressive disorder as part of bipolar I disorder) and as a suppressing neurotransmitter (in manic states). Carbamazepine blocks NMDA-activated membrane currents in cultured neurons in a dose-dependent fashion, and at therapeutic concentrations it markedly reduces the depolarization produced by NMDA. Carbamazepine may have weak GABAergic effects, which appear to be confined to certain types of neurons. Unlike lithium and valproate, however, carbamazepine inhibits the DNA-binding activity of the cyclic adenosine monophosphate (cAMP)-response elementbinding protein (CREB) transcription factor, and, unlike some other mood stabilizers (e.g. lithium and valproate), carbamazepine does not have direct or indirect effect on the action of glycogen synthase kinase (GSK)-3b (which regulates the phosphorylation of tau and b-catenin; see Section 2.17 on lithium), and thus it does not protect the cell from the apoptotic reactions associated with abnormal function of cellular tau and b-catenin. Carbamazepine appears to have teratogenic effects and, like valproate, has been associated with an increased risk of neural tube defects. Even so, carbamazepine can, and should, under certain instances, be given to pregnant women. The clinician’s decision whether to administer carbamazepine to a pregnant woman should take carefully into account the woman’s own preference, as well as the potential advantages (previous response to carbamazepine or to other drugs, if good prognostic signs exist, and the patient’s clinical status) versus the disadvantages (teratogenicity and other sideeffects) of giving the drug. Hence, the overall decision is not a simple ‘yes’ or ‘no’.44–46

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2.19 Mood stabilizers Valproate

Presynaptic nerve terminal (especially those originating from the substantia nigra)

Valproic acid

Mitochondria Pyruvate Acetyl-CoA

Valproic acid

Bcl-2 SC

a-KG

SSA

Glutamate

GABA-T

Storage vesicle for GABA

(in mitochondria)

GABA

GABA-PMT

(only small amount reaches the cell due to its uptake blockade by valproic acid)

Valproic acid

GABA

Net effect: increased GABA concentration in synaptic cleft

Acetyl-CoA Acetyl coenzyme A

Legend Inhibits

a-KG

a-Ketoglutarate

Bcl-2

B-cell lymphoma protein 2 (cytoprotective factor)

GABA Stimulates

GABA-T SC SSA

56

c-Aminobutyric acid

GABA-PMT Plasma membrane transporter for GABA GABA ketoglutarate transaminase (aminotransferase) Succinate Succinic semialdehyde

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Valproate is currently the most widely prescribed antiepileptic/mood-stabilizing drug and is being used increasingly in the treatment of bipolar I disorder, especially in the USA.47 It is effective as a mood stabilizer and appears to be more efficacious than lithium in rapid cycling mania and dysphoric mania.48 The mechanism of action of valproate as a mood stabilizer is not fully understood. It is proposed that it exerts its antimanic effects by suppressing the overexcitability of limbic neurons via enhancing c-aminobutyric acid (GABA) neurotransmission. Valproate enhances GABA activity by various mechanisms, especially by blocking the reuptake of GABA into the presynaptic nerve terminal and by inhibiting GABA ketoglutarate transaminase (aminotransferase) (GABA-T), the enzyme responsible for metabolizing the re-uptaken GABA. Its antidepressive effects are less well understood. It is possible that its stimulation of various neuroprotective factors such as B-cell lymphoma protein 2 (Bcl-2; see Sections 2.1 and 2.15) is relevant.

Notes about the scheme There has been increasing interest in the potential of anticonvulsants and mood stabilizers to provide neuroprotective effects. It was demonstrated that valproate increases the expression of the cytoprotective protein Bcl-2 in the central nervous system in vivo and in cells of human and rodent neuronal origin.49 Cross-sectional neuroimaging studies suggest that patients undergoing long-term valproate treatment do not show subgenual prefrontal cortex atrophy, in comparison with those treated with selective serotonin reuptake inhibitors (SSRIs), who show prefrontal atrophy.50 These clinical data support the hypothesis that some of the therapeutic actions of valproate may involve neurotrophic/ neuroprotective effects. Such effects may be consistent with recent morphometric studies reporting localized atrophy and neuronal and glial cell loss in bipolar disorders.51

Even so, the main established mechanism of action of valproate is GABAergic. It has been demonstrated that valproate increases brain concentration of GABA by three major mechanisms: inhibition of GABA degradation, increased GABA synthesis, and decreased GABA turnover. While the GABA-elevating effects of valproate were initially proposed to result from inhibition of GABA-T, more recent evidence suggests that valproate also inhibits the reuptake of GABA. The neural GABA membrane transporter, compared with the glial GABA transporter, is more sensitive to valproate inhibition and probably plays a role in elevating synaptic GABA concentration. Increased GABA synthesis appears to be regionally selective, being observed mainly in the substantia nigra, a region with one of the brain’s highest rates of GABA synthesis, and in limbic regions. These are assumed to be related to its antimanic and mood-stabilizing effects, although this is yet not completely clarified. Unlike benzodiazepines and barbiturates, valproate does not have any affinity for the GABAA receptor complex. A direct effect on sodium channels has not been consistently shown; while some reports suggest that valproate can slow sodium conductance, this is still a matter of debate. Valproate does not appear to have significant direct effects on calcium channels.52 The main adverse side-effects of valproate are headaches, tremor, weight gain, sedation, decreased liver function tests, decreased platelet count, and mild leukocytosis. Valproate can be used in various psychiatric diagnoses. However, it is found to be more efficacious in specific entities/settings, especially (with possible good prognosis) in: ● ● ● ● ● ● ●

rapid cycling mania absence of psychotic features dysphoric mania stable or decreasing frequency of manic episodes mixed episode no response to lithium or carbamazepine less severe forms of manic episode.47,52

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2.20 Mood stabilizer-like drugs Topiramate

Postsynaptic neuron (adjunct to presynaptic GABAergic and non-GABAergic nerves)

GABA

Cl ions

Topiramate

Na ions Glutamate

Topiramate

Chloride channel (opened by GABAA receptor)

GABAA receptor

AMPA rec.

Decreased intracellular Na concentration

Decrease cell excitability Increased intracellular Cl concentration

Mood-stabilizing effect (?) Action potential

( antimanic effect?)

Legend Action potential

AMPA rec.

Inhibits GABA Stimulates Stimulates

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GABAA

a-Amino-3-hydroxy-5-methylisoxazole4-propanoic acid receptor (subtype of glutamatergic receptor) c-Aminobutyric acid Postsynaptic GABA receptor, type A

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Topiramate is a structurally novel antiepileptic agent currently approved by the US Food and Drug Administration (FDA) for adjunctive therapy in patients with partial-onset seizures or primary generalized tonic clonic seizures. Results of preliminary studies show a trend toward improvement, and in some instances significant improvement, in patients with bipolar I disorder. However, its role as a mood stabilizer is still under investigation and its mood-stabilizing capacity is not yet fully accepted. Topiramate has been shown to exert beneficial effects in patients with acute mania,53–59 with a dose-dependent response, as well as in patients with bipolar depression.60,61 Anecdotal data suggest that topiramate can also exert a beneficial effect in rapid cycling bipolar disorder when added either to lithium or to valproate as adjunctive therapy.62 Furthermore, based on current data, topiramate seems to have some efficacy as add-on therapy to an ongoing mood stabilizer for patients with treatment-refractory mood disorders.61 Topiramate has also anecdotally demonstrated efficacy in eating disorders, such as improving multiple behavioral dimensions of bulimia nervosa.62 The most common side-effects of topiramate are paresthesia (27%), headache (21%), fatigue (20%), dizziness (14%), somnolence (13%), anorexia (11%), and weight loss (11%). Less common side-effects, but with important clinical implications, are depression (7%), difficulty with concentration (7%), and confusion (5%).63,64 As with other anhydrase inhibitors, topiramate has been associated with kidney-stone formation, and the incidence of nephrolithiasis is estimated to be 2–4 times higher than that expected in a similar untreated population.65 Many of the central nervous system effects of topiramate, including cognitive complaints, can be managed by gradual introduction and dose escalation.66

Notes about the scheme The mechanism of action of topiramate has not been fully elucidated, although three potential mechanisms are thought to be involved in its ‘mood-stabilizing’-like activity. First, topiramate is known to enhance c-aminobutyric acid (GABA) activity through interaction with the postsynaptic GABAA receptor. The GABAA receptor is located adjunct to a chloride channel and, upon activation it opens up the channel, causing increased ion influx. Consequently, topiramate indirectly increases intracellular chloride ion concentration, leading to neuronal hyperpolarization (similar to the effects of benzodiazepines). Second, there is some evidence, as yet anecdotal, that topiramate limits repetitive cell firing by blocking voltage-dependent sodium channels. Third, topiramate appears to antagonize the ability of kainite to activate the kainite/a-amino3-hydroxy-5-methylisoxazole-4-propanoic acid (AMPA) subtype of glutamatergic receptor, a known mechanism by which neuronal excitability can be decreased. Topiramate also antagonizes the effects of glutamate at non-N-methyl-D-aspartate (non-NMDA) receptors, and it also inhibits certain isoenzymes of carbonic anhydrase, although this effect may not be a major feature of its antiepileptic/mood-stabilizing activity. Hence, most of the knowledge about the mode of action of topiramate concerns its potential antimanic activities (e.g. by decreasing neuronal excitability), and very little is currently known about the mechanisms underlying its antidepressive effects.54 All in all, compared with the well-established group of ‘mood stabilizers’ (lithium, carbamazepine, and valproate), topiramate is currently considered the least potent/efficacious in ameliorating both manic and/or depressive symptoms (see Section 2.22).

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2.21 Mood stabilizer-like drugs Lamotrigine

Stimulated neurons (manic state ?)

Suppressed neurons (depression ?)

Glutamate

Ca2

Serotonin

NMDA rec.

5-HT3

? ?

?

LTG Ca2

Na

Ca2 2

Ca

Causing cell death

Na

In depression: decrease in action potential frequency (and firing rate)

In mania: increase in action potential frequency (and firing rate)

5-HT-PMT 5-HT3

Net effect in mania (?):

Net effect in depression:

increased secretion of neurotransmitter (e.g. NE, 5-HT, glutamate, aspartate)

Legend

decreased sescretion of neurotransmitter (e.g., 5-HT)

5-HT 5-HT3

Decreased action potential frequency

Serotonergic receptor subtype (inhibitory as presynaptic)

5-HT-PMT

Plasma membrane transporter for serotonin Lamotrigine

Increased concentration Stimulates Inhibits

LTG NE

Norepinephrine

NMDA rec. N-Methyl-D-aspartate receptor (subtype of glutamatergic receptor) ?

60

Serotonin

Increased action potential frequency

Questionable pathway / effect

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Lamotrigine is the second drug after lithium to be approved in the USA for the maintenance treatment of bipolar I disorder (in 2001). It has a broad spectrum of antiseizure activity, and is indicated in both partial and generalized seizures, including absence seizures.67 Double-blind, placebo-controlled studies found lamotrigine to be most effective in bipolar depression (and much less so in manic episodes),68 rapid cycling bipolar disorder,69 and treatment-resistant (primary rapid cycling) mood disorders.70 Lamotrigine has not shown antimanic activity and has not been associated with the induction of mania or of rapid cycling bipolar disorder. Hence, lamotrigine may ‘stabilize mood from below’. In contrast, the older mood stabilizers (lithium, carbamazepine, and valproate) appear to ‘stabilize mood from above’ in that they maximally impact manic or hypomanic symptoms in bipolar disorder.67–72

Notes about the scheme Present data suggest that the main cellular mechanism of action of lamotrigine is through voltage-dependent blockade of neuronal voltage-activated sodium channels,67 which some investigators hypothesize as being relevant to the mood-stabilizing effects of various drugs.73 In addition, lamotrigine attenuates calcium influx, which may also contribute to its neuroprotective and antidepressant action67 (overloading of calcium in the intracellular space can cause significant cellular damage and might be related to the induction/maintenance of depressive episodes). The effects of lamotrigine on calcium channels compared with sodium channels are less prominent, but are of potential interest in view of the beneficial use of calcium channel blockers (anecdotal data) in bipolar disorder.67 Many anticonvulsants enhance c-aminobutyric acid (GABA)ergic inhibitory neurotransmission (barbiturates, benzodiazepines, gabapentin, tiagabine, valproate, and

vigabatrin) and thereby induce calming or ‘sedating’ psychotropic profiles. In contrast, lamotrigine may enhance glutamatergic excitatory neurotransmission and thus possess an ‘activating’ profile, tending to yield alertness, activation, weight loss, and possibly antidepressant and anxiogenic effects. Thus, at least hypothetically, lamotrigine might be specifically beneficial in a subpopulation of bipolar I depressed patients with predominant symptoms such as apathy, psychomotor retardation, and hypersomnia. Taken together, it is hypothesized that the mood-stabilizing effect of lamotrigine is consistent with its glutamatergic action.67 There are some anecdotal data suggesting that lamotrigine can also inhibit the presynaptic inhibitory 5-HT3 serotonergic autoreceptors as well as the serotonergic plasma membrane transporter. These effects can result in a new increase in serotonin secretion and/or an increased concentration of serotonin in the synaptic cleft, respectively. They might also explain the predominant efficacy of lamotrigine in treating major depressive episodes as part of bipolar I (‘stabilizes mood from below’), as opposed to manic states. In that respect, lamotrigine is unique among the mood stabilizers, since the most widely used of these (i.e. carbamazepine, lithium, and valproate) are considered better antimanic agents than antidepressants. Lamotrigine is reported to be generally well tolerated in maintenance studies, with the most common adverse events being headache, nausea, insomnia, and, to a lesser extent, tremor. Incidences of diarrhea and tremor are lower with lamotrigine than with lithium. The incidence of serious rash with lamotrigine treatment is 0.1% (including rare cases of Stevens–Johnson syndrome). Lamotrigine does not appear to cause body weight gain. In that respect, it is also unique compared with the other mood stabilizers (i.e. carbamazepine, lithium, and valproate), all of which may cause, at least in some predisposed populations, significant weight gain.74

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2.22 Mood stabilizers

During acute exacerbation

Side-effects

During remission phase

Legend

Topiramate

Lamotrigine

Valproate

Antimanic Anti-dysphoric mania Anti-MDD Antimanic Anti-MDD Anti-rapid cycling

Leukocytosis Aplastic anemia; agranulocytosis Thrombocytopenia Thyroid hormones (decreased) Ca2 Hyponatremia Diabetes insipidus Psoriasis Migraine-like/headache Tremor Memory impairment Alopecia Hepatitis; decreased liver functions Ataxia; diplopia Pruritis rash (benign) SLE-like; Stevens–Johnson syndrome Teratogenic Nystagmus Sedation GIT disturbances; diarrhea Pancreatitis Weight gain

W

W

Most effacious in / major capacity for inducing side-effect Moderate efficacy / moderate capacity for inducing side-effect Minor efficacy / minor capacity for inducing side-effect Questionable efficacy / negligible capacity for inducing side-effect Data insufficient / not well-established Increased / decreased

62

Carbamazepine

Clinical efficacy

Lithium

Comparative profile

GIT MDD SLE W

Gastrointestinal tract Major depressive disorder Systemic lupus erythematosus Might worsen existing phenomena

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References 1. Nemeroff CB. Recent advances in the neurobiology of depression. Psychopharmacol Bull 2002 (Summer); 13: 6. 2. Manji HK, Quiroz JA, Sporn J et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult to treat depression. Biol Psychiatry 2003; 53: 707–742. 3. Zarate CA, Quiroz JA, Payne K et al. Modulators of the glutamatergic system: implications for the development of improvement of improved therapeutics in mood disorders. Psychopharmacol Bull 2002 (Autumn); 4: 35–83. 4. Skolnick P. Antidepressants for the new millennium. Eur J Pharmacol 1999; 375: 31–40. 5. Tran PV, Bymaster FP, McNamara RK et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacol 2003; 23: 78–86. 6. Bodkin JA. Transdermal selegiline in major depression: a double-blind placebocontrolled, parallel study in outpatients. Am J Psychiatry 2002; 159: 1869–1875. 7. Thase ME. Achieving remission and managing relapse in depression. J Clin Psychiatry 2003; 64: 3–7. 8. Thase ME, Ninan PT. New goals in the treatment of depression: moving towards recovery. Psychopharmacol Bull 2002; 36: 24–35. 9. Lattanzi L, Dell’Osso L, Cassano P et al. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord 2002; 4: 305–314. 10. Izumi T, Inoue T, Kitagawa N et al. Open pergolide treatemtn of tricyclic and heterocyclic antidepressant-resistant depression. J Affect Disord 2000; 61: 127–132. 11. Perugi G, Toni C, Ruffolo G et al. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry. 2001; 34: 137–141. 12. Kitamura Y, Taniguchi T, Shimohama S et al. Neuroprotective mechanisms of antiparkinsonian dopamine D2-receptor subfamily agonists. Neurochem Res 2003; 28: 1035–1040. 13. Robinson DS. Monoamine oxidase inhibitors: a new generation. Psychopharmacol Bull 2002 (Summer); 3: 124–138. 14. Trevor R, Olver N, Olver J. New formulations of existing antidepressants. CNS Drugs 2004; 18: 505–520. 15. Cees J, Timmer JM, Sitsen AD, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38: 461–474.

16. Ostacher MJ, Eisner L, Nierenberg AA. Mirtazapine in the treatment of mood and anxiety disorders. Expert Rev Neurotherap 2003; 3: 425–433. 17. Benkert O, Muller M, Szegedi A. An overview of the clinical efficacy of mirtazapine. Hum Psychopharmacol 2002; 17: S23–S26. 18. Pallanti S, Quercioli L, Bruscoli M. Response acceleration with mirtazapine augmentation of citalopram in obsessive compulsive disorder patients without comorbid depression; a pilot study. J Clin Psychiatry 2004; 65: 1394–1399. 19. Waugh J, Goa KL. Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 2003; 17: 343–362. 20. Wengel SP, Burke WJ. Escitalopram: What does it have to offer? Primary Psychiatry 2003; 10: 67–70. 21. Olver JS, Cryan JF, Burrows GD et al. Pindolol augmentation of antidepressants: a review and rationale. Aust NZ J Psychiatry 2000; 34: 71–79. 22. Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 435–451. 23. Dannon PN, Sasson Y, Hirschmann S et al. Pindolol augmentation in treatment resistant obsessive compulsive disorder: a double blind placebo controlled trial. Eur Neuropsychopharmacol 2000; 10: 165–169. 24. Sokolski KN, Conney JC, Brown BJ et al. Once daily high dose pindolol for SSRIrefractory depression. Psychiatry Res 2004; 15: 125: 81–86. 25. Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004; 25: 215–221. 26. Knoll J. ()Deprenyl (selegiline): past, present and future. Neurobiology 2000; 8: 179–199. 27. Wilcock GK, Birks J, Whitehead A et al. The effect of selegiline in the treatment of people with Alzheimer’s disease: a metaanalysis of published trials. Int J Geriatr Psych 2002; 17: 175–183. 28. Grunze H, Kasper S, Goodwin G et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorder, Part II: Treatment of Mania. World J Biol Psychiatry 2003; 4: 5–13. 29. Swann AC, Bowdem CL, Calabrese JR et al. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry 2000; 156: 1264–1266. 30. Swann AC, Bowden CL, Calabrese JR et al. Differential effects of previous depressive 63

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45. Harwood AJ, Agam G. Search for common mechanism of mood stabilizers. Biochem Pharmacol 2003; 66: 179–189. 46. Ambrosio AF, Soares-da-Silva P, Carvalho CM et al. Mechanism of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024*. Neurochem Res 2002; 27: 121–130. 47. Harwood AJ, Agam G. Search for a common mechanism of mood stabilizers. Biochem Pharmacol 2003; 66: 179–189. 48. Li X, Ketter TA, Frye MA. Synaptic, intracellular and neuroprotective mechanisms of anticonvulsants: Are they relevant for the treatment of bipolar disorder? J Affect Disord 2002; 69: 1–14. 49. Manji HK, Moore GJ, Rajkowska G et al. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 2000; 5: 578–593. 50. Gray NA, Zhou R, Du J et al. The use of mood stabilizers as plasticity enhancers in the treatment of neuropsychiatric disorders. J Clin Psychiatry 2003; 64(Suppl): 3–17. 51. Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 2001; 11: 240–249. 52. Owens MJ, Nemeroff CB. Pharmacology of valproate. Psychopharmacol Bull 2003; 37(Suppl 2): 17–24. 53. Topamax package insert. Raritan, NJ: Ortho-McNeill Pharmaceutical, 2000. 54. Suppes T. Review of the use of topiramate for treatment of bipolar disorder. J Clin Psychopharmacol 2002; 22: 599–609. 55. McElroy SL, Suppes T, Keck PE et al. Openlabel adjunctive Topiramate in the treatment of bipolar disorder. Biol Psychiatry. 2000; 47: 1025–1033. 56. Marcotte D. Use of topiramate, a new antiepileptic, as a mood stabilizer. J Affect Disord 1998; 50: 245–251. 57. Calabrese JR, Keck PE Jr, McElroy SL et al. A pilot study of topiramate as monotherapy in the treatment of acute mania. J Clin Psychopharmacol 2001; 21: 340–342. 58. Grunze HC, Norman C, Langosch J et al. Antimanic efficacy of topiramate in 11 patients in open trial with an on–off–on design. J Clin Psychiatry 2001; 62: 464–468. 59. Gupta S, Masand PS, Frank B et al. Topiramate in bipolar and schizoaffective disorder: mood stabilizing properties in treatment refractory patients. XXII Collegium Internationale Neuropsychopharmacologicum Conference, Brussels, Belgium, July 2000. 60. Spitzer RL, Gibbon M, Endicott J. Global Assessment Scale. New York: State Department of Mental Hygiene, 1973.

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61. Suppes T. Review of the use of topiramate for treatment of bipolar disorder. J Clin Psychopharmacol 2002; 22: 599–609. 62. Kusumakar V, Yatham L, O’Donovan C et al. Topiramate in rapid cycling bipolar woman. 152nd Annual Meeting of the American Psychiatric Association, Washington, DC, May 1999. 63. Gilliam FG, Veloso F. Tolerability of topiramate as monotherapy in patients with recently diagnosed partial epilepsy. Epilepsia 1998; 39(Suppl 6): 56. 64. Privitera MD, Brodie MJ, Neto W et al. Topiramate vs. investigator choice of carbamazepine or valproate as monotherapy in newly diagnosed epilepsy. Epilepsia 2000; 41: 93–94. 65. Wasserstein AG, Rak I, Reife RA. Nephrolithiasis during treatment with topiramate. Epilepsia 1995; 36(Suppl 3): S153. 66. Aldenkamp AP, Baker G, Mulder OG et al. A multicenter randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as addon therapy to carbamazepine in patients with partial-onset seizures. Epilepsia 2000; 41: 1167–1178. 67. Ketter TA, Manji HK and Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorder. J Clin Psychopharmacol 2003; 23: 484–495.

68. Calabrese JR, Bowden CL, Sachs GS et al. Lamictal 602 Study Group. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 1999; 60: 79–88. 69. Calabrese JR, Suppes T, Bowden CL et al. Lamictal 614 Study Group. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 2000; 61: 841–850. 70. Frey MA, Ketter TA, Kimbrell TA et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2002; 22: 607–614. 71. Ketter TA, Calabrese JR. Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature. J Clin Psychiatry 2002; 63: 146–151. 72. Bowden CL. Acute and maintenance treatment with mood stabilizers. Int J Neuropsychopharmacol 2003; 6: 269–275. 73. Xie X, Hagan RM. Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998; 38: 119–130. 74. Goldsmith DR, Wagstaff AJ, Ibbotson et al. Spotlight on lamotrigine in bipolar disorder. Int J Neuropsychopharmacol 2003; 6: 239–275.

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Chapter 3 Anxiolytic drugs

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Anxiolytic drugs

3.1 Anxiolytics (I) The 'fear' network and the role of serotonin in surpressing anxiety

Sensory input

Anterior thalamus

Cortex

Raphe nuclei

CNA

LNA

5-HT Amygdala

5-HT 5-HT 5-HT

PAG

Defensive behavior

HT

Activation of pituitary–adrenal axis

Sympathetic stimulation

Legend

Modulating respiration

BP Neuronal pathway

Nerve terminal

Serotonergic neurons Soma

5-HT

68

LC

Serotonin

CNA

Increased BP and HR; behavioral response to fear

Blood pressure Central nucleus of amygdala

HR

Heart rate

HT

Hypothalamus

LC

Locus ceruleus

LNA

Lateral nucleus of amygdala

PAG

Periaqueductal gray

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Notes about the scheme The ‘fear network’ is an interconnection of different anatomical brain structures thought to play a major role in the pathogenesis of anxiety disorders. Anxious behavior/disorders arise, at least in part, following pathological processing of sensory data and inadequate response of target organs to such stimuli. Specifically, viscerosensory information is conveyed to the amygdala by two major pathways: downstream, from the thalamus, and upstream, from the primary viscerosensory cortices and via corticothalamic relays allowing for higher-level neurocognitive processing and modulation of sensory information. Contextual information is stored in the hippocampus and conveyed directly to the amygdala. Major efferent pathways of the amygdala relevant to anxiety include: ●

● ●

to the locus ceruleus (LC), increasing norepinephrine release, and thereby contributing to physiological and behavioral arousal; to the periaqueductal gray regions (resulting in defensive behavior and postural freezing); to the hypothalamic paraventricular nucleus (activating the hypothalamic pituitary– adrenal axis, releasing adrenocorticoids), the hypothalamic lateral nucleus (activating the sympathetic nervous system), and the parabrachial nucleus (influencing respiratory rate and timing).1

These projections from the amygdala can be conceptualized as the ‘fear network’, which is abnormal in anxiety disorders – specifically in panic disorder. Accumulating data, based mainly on pharmacological interventions both in human and in animal models, support this hypothesis by demonstrating that the entire ‘fear network’ is activated following administration of agents that cause panic attacks (e.g. sodium lactate,2 CO2,3 yohimbine,4 fenfluramine,5 m-chlorophenylpiperazine (m-CPP),6 norepinephrine,7 epinephrine,8 hypertonic sodium chloride,9 and cholecystokinin analogs10). Most anxiolytic drugs have in common the capacity to enhance serotonergic transmission in the central nervous system (CNS). Hence, the therapeutic effects of the selective serotonin reuptake inhibitors

(SSRIs) can be discussed in this context, since SSRIs are the first-line treatment for many anxiety disorders, including the ‘prototype’ – panic disorder. SSRIs have in common the property of inhibiting the protein responsible for transporting serotonin back into the presynaptic neuron. This blockade of serotonin reuptake effectively increases the amount of serotonin available in the synapse, allowing it to bind both pre- and postsynaptic receptors while increasing overall serotonergic transmission in the CNS. Serotonergic neurons originate in the brainstem raphe nucleus and project widely throughout the entire CNS. Some of these projections are of particular relevance to an understanding of the antipanic effects of the SSRIs:11 ●

●

●

●

The projection of serotonergic neurons to the locus ceruleus is generally inhibitory.12 This suggests that SSRIs, by increasing serotonergic activity in the brain, have a secondary effect of decreasing noradrenergic activity, and thus inhibiting the cardiovascular manifestations of panic attacks. The projection from the raphe neurons to the periaqueductal gray region appears to modify/inhibit escape/defense behavior.13 Projections to the hypothalamus suppress hypothalamic release of corticotrophin-releasing factor (CRF),14 which is known to increase the firing rate of the locus ceruleus as well as the sensation of fear,15,16 a phenomenon found in long-term treatment with SSRIs. The serotonergic neurons originating in the dorsal and medial raphe nuclei project directly to the amygdala via the medial forebrain bundle.17 At the level of the amygdala, serotonin modulates sensory input at the lateral nucleus of the amygdala, inhibiting excitatory inputs from the glutamatergic thalamic and cortical pathways. Because the amygdala is known to receive dense serotonergic input from the raphe, it may be a prime site for the anxiolytic effect of the SSRIs, whereby an increase in serotonin inhibits excitatory cortical and thalamic inputs from activating the amygdala.1

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3.2 Anxiolytics (II) Mechanism of anxiolytic action of various drugs

Increased synaptic serotonin concentration Downregulated 5-HT1A and 5-HT2 receptors

5-HT1A,2

Less inhibition on cell excitability

(following chronic administration of MAOIs/TCAs/SSRIs)

(compared with physiological conditions; due to downregulated 5-HT1A, 2 receptors)

GABAergic nerve terminal

5-HT1D

Benzodiazepines

GABAA

Soma of noradrenergic nerve in locus ceruleus

Downregulation of hypersensitive inhibitory 5-HT1D receptors

Tyrosine

MAOIs / TCAs

Tyr.Hyd


Postsynaptic nerve (any kind)

SSRIs

a2-ADR

NE b-blockers

b-ADR

a2-ADR

Legend

Downregulate/inhibit, respectively

b-ADR

Adrenergic receptor subtype

Stimulate

5-HT1A

Serotonergic receptor subtype

Serotonin

5-HT1D

Serotonergic receptor subtype (inhibitory)

GABA (c-aminobutyric acid) Norepinephrine Downregulated receptor Upregulated receptor Increased firing rate

70

Adrenergic receptor subtype (inhibitory)

5-HT2


GABAA

GABAergic receptor subtype

MAOI

Monoamine oxidase inhibitor

SSRI


TCA


Tyr.Hyd

Tyrosine hydroxylase

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Notes about the scheme

●

The pathophysiology of anxiety differs between the various anxiety disorders. Therefore, pharmacological interventions that suppress one sort of anxiety do not necessarily exert the same anxiolytic effects in other anxiety disorders. Even so, there are some common pathological mechanisms/findings that are evident in many anxiety disorders, and they are discussed in this section. One of these findings is the increased firing rate from noradrenergic neurons arising from the locus ceruleus. It is assumed that increased norepinephrine in major brain regions plays a major role in modulating anxiety. Therefore, the end result of most clinically efficacious anxiolytic agents is believed to be associated with decreasing noradrenergic neurotransmission. The schematic mechanisms of action of the main classes of anxiolytic drugs are described below.

●

Benzodiazepines These exert their anxiolytic effects by enhancing the activities of the c-aminobutyric acid (GABA) type A receptor. Stimulation of the GABAA receptor results in increased chloride influx into neurons (including noradrenergic), which leads to hyperpolarization and decreased excitability (see Section 3.4). Furthermore, evidence from animal studies shows that benzodiazepines, as might be expected, decrease the firing rate of noradrenergic neurons, a phenomenon that explains their anxiolytic capacity.

Furthermore, evidence from animal studies shows that MAOIs/TCAs, like benzodiazepines, decrease the firing rate of noradrenergic neurons – a phenomenon that may explain their anxiolytic capacity.

Selective serotonin reuptake inhibitors (SSRIs) These have two main mechanisms in common with the MAOIs/TCAs: ●

Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) The anxiolytic effects of MAOIs/TCAs are believed to be mediated by three main mechanisms: ●

They increase the concentration of serotonin in the synaptic cleft (see Sections 2.2 and 2.14), which is followed (in the case of long-term MAOI/TCA administration) by downregulation of postsynaptic 5-HT1A,2 serotonergic receptors located on GABAergic cells. It is assumed that the downregulated receptors cause less inhibition of cell excitability, resulting in increased secretion of GABA into the synaptic cleft. The increased GABA stimulates postsynaptic GABAA receptors located on noradrenegic neurons arising from the locus seruleus, with consequent suppression of their neurons.

Both MAOIs and TCAs downregulate presynaptic 5-HT1D heteroreceptors located on GABAergic neurons. The 5-HT1D receptors are inhibitory in nature and, once stimulated, decrease the release of GABA from presynaptic nerve terminals into the synaptic cleft. The downregulation of these receptors following long-term administration of MAOIs/TCAs decreases their inhibitory capacity, resulting in increased GABA secretion and suppression of noradrenegic neurons arising from the locus ceruleus Both MAOIs and TCAs have the capacity to inhibit tyrosine hydroxylase, one of the main enzymes modulating the synthesis of norepinephrine from tyrosine. Inhibition of tyrosine hydroxylase may result in a decreased concentration of norepinephrine in presynaptic storage vesicles, which will eventually lead to decreased secretion into the synaptic cleft. However, it is not yet clear if this effect is clinically significant.

●

They increase the synaptic concentration of serotonin, and cause, following long-term use, downregulation of postsynaptic 5-HT1A,2 receptors, increased GABAergic neuron excitability, and consequent suppression of noradrenergic neurons. They downregulate presynaptic 5-HT1D receptors located on GABAergic neurons, which results in increased secretion of GABA into the synaptic cleft and consequent suppression of postsynaptic noradrenergic neurons.

b-adrenergic blockers The mechanism of action of these drugs is somewhat different from that of the other anxiolytics, because they do not decrease the firing rate of noradrenergic neurons or the concentration of norepinephrine in the synaptic cleft. The b-adrenergic blockers simply block excess norepinephrine from interacting with postsynaptic adrenergic receptors, leading to a net decrease in noradrenergic neurotransmission.17

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3.3 Anxiolytics (III) New approaches for developing anxiolytic drugs

GABAergic nerve terminal GABA-PMT Tiagabine

Substance P (increases during stress)

Ca2 Pagoclone Substance P antagonists

GABA

Pregabalin

NK1 receptor

Benzodiazepine receptor

GABAA Decreased Ca2 influx

Pagoclone is a partial agonist to the benzodiazepine receptor. Hence, it exerts a milder effect on GABAA (leading, presumably, to anxiolysis but not sedation/ addictive behavior)

Increased Cl influx

During stress, NK1 receptors are overstimulated by substance P. Hence, when NK1 receptors are blocked (e.g. by substance P antagonists such as L-760735), they exert a net anxiolytic effect

Decreased cell excitability and consequence anxiolytic effect

Legend Inhibits Stimulates 2

Ca

Cl GABA Pagoclone Pregabalin

72

GABA

c-Aminobutyric acid

GABAA

GABAergic receptor subtype

NK1

Neurokinin receptor, type 1

PMT


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Recent advances in neuroscience and understanding of the etiology of anxiety have led to new concepts for the treatment of anxiety. Accumulating data suggest that such treatments might be at least as effective as benzodiazepines (BDZs), which have been the traditional treatment of anxiety for the past 40 years. The c-aminobutyric acid (GABA) system has long been targeted in anxiety interventions via benzodiazepines, but better understanding of its role in anxiety disorders has led to the development of partial BDZ–GABA receptor antagonists and agents that target specific subunits of the GABA receptor and that manipulate GABA brain levels. The recognition that ‘antidepressants’ are also effective in anxiety disorders (even in non-depressed patients) has led researchers to develop antianxiety agents that affect the serotonin and norepinephrine systems. Other neurotransmitters, such as corticotrophin-releasing factor and substance P, appear also to be abnormally regulated in patients with anxiety disorders, so antagonists of these neurotransmitters may prove to be beneficial anxiolytics.18

Notes about the scheme Benzodiazepines potentiate the effect of the inhibitory neurotransmitter GABA. Benzodiazepines and GABA also enhance the binding of one another to the BDZ–GABA receptor complex. Since BDZ–GABA receptors are ubiquitous throughout the central nervous system, benzodiazepines are effective anxiolytics due to their rapid suppression of excitatory neurotransmission everywhere in the brain. The need for antianxiety treatments with the effectiveness, but not the side-effects, of benzodiazepines has led researchers to develop agents that partially stimulate BDZ–GABA receptors. Pagoclone is a partial BDZ–GABA receptor agonist that is under development for the treatment of panic and other anxiety disorders. The GABAA receptor is composed of several different subunits. The a1 subunit mediates the sedative but not the anxiolytic properties of benzodiazepines, while the a2 subunit mediates their anxiolytic effect.

Hence, agents (e.g. pagoclone) that activate specific subunits (e.g. the a2 subunit) may be effective for the treatment of anxiety disorders, and with a more favorable side-effect profile. Manipulation of GABA levels may be another effective antianxiety treatment. The anticonvulsant tiagabine is a selective GABA reuptake inhibitor. Preclinical and clinical trials with tiagabine suggest that this agent may be useful as an anxiolytic. Pregabalin has been shown to be effective for anxiety disorders in several controlled trials.19–30 Although its mechanism of action in treating anxiety is not yet clear, it may work by modulation of a subtype of calcium ion channel. Substance P belongs to a group of neurotransmitters named neurokinins that are released in excess during times of emotional stress. Substance P is localized in the brain, sensory afferents, lungs, and intestines, and binds preferentially to the type 1 neurokinin receptor (NK1), which is widely distributed in the brain and limbic system. Several substance P antagonists (e.g. L-760735, [2-cyclopropoxy-5(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2phenylpiperidin-3-yl)amine (CTBA)) appear to have anxiolytic effects. The discovery that the adult mammalian brain, including the human brain, is capable of neurogenesis has led to more specific targets for anxiety interventions. New neurons are generated from dividing progenitor cells in the dentate gyrus. Neurogenesis in the human hippocampus appears to be possible throughout life; however, it can be impeded by stress. Therefore, stress-related substances such as corticotrophin-releasing factor (CRF), glucocorticoids, and glutamate are associated with anxious feeling and behavior. Anecdotal evidence suggests that blocking glutamate/CRF and/or stimulation of neurotrophic factors may restore normal neurogenesis and reverse stress.32,33 Moreover, the amygdala appears to oversecrete stress-related factors such as CRF in anxiety disorders. Subsequently, a number of CRF antagonists (e.g. R278995/CRA0450 and DMP904) have been developed to block the effects of CRF in the central nervous system and are showing preliminary beneficial effects in anxious and depressed patients.31

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3.4 c-Aminobutyric acid (GABA) macromolecular complex (I) Benzodiazepines and agents that enhance chloride channel/GABAA receptor activity

From adjunct presynaptic GABAergic neuron

Postsynaptic neuron (adjunct to presynaptic GABAergic nerve) GABA

Cl ions Neurosteroids

BDZs, Zolpi.

Barb.

Zopic.

Chloride channel (opened by GABAA receptor)

GABAA receptor

BDZ receptor

Decreases cell excitability (inhibits action potential)

Inceased intracellular Cl concentration Action potential

Legend

Action potential Barb. Inhibits

BDZ GABA

Stimulates

GABAA

Benzodiazepine c-Aminobutyric acid GABAergic receptor subtype

Zolpi.

Zolpidem

Zopic.

Zopiclone

Neurosteroids [5a,3a-pregnanolone, tetrahydrodeoxycorticosterone (THDOC), alphaxalone]

74

Barbiturates

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Notes about the scheme Alterations in benzodiazepine binding as well as in the c-aminobutyric acid (GABA) system have been linked to the pathophysiology of most of the anxiety disorders.18–32 It is widely accepted that patients with anxiety disorders (e.g. panic disorder, post-traumatic stress disorder, and generalized anxiety disorder) have reduced benzodiazepine binding in various brain regions, and downregulated GABAergic systems20 in comparison with normal subjects.18–22 Specifically, the neurotransmitter GABA, which is inhibitory in nature, is known to act on two main GABA receptor subtypes: GABAA and GABAB.23 The GABAA receptor is a pentameric transmembrane glycoprotein composed of five subunits that are arranged around a central chloride channel.24 Upon activation of the receptors, the configuration of the chloride channel changes (it opens up) and it becomes more permeable to chloride ions, resulting in an augmentation of chloride influx into the cell. The excess intracellular chloride concentration causes the membrane to hyperpolarize and results in neuronal inhibition. Among the five subunits of the GABAA receptor, the a1 subunit preferentially binds zolpidem and other similar agonists with high affinity and has been linked to the sedative/hypnotic effects associated with benzodiazepine treatment.25 Receptors with the a2 or a3 subunits are thought to mediate the anxiolytic effects of the benzodiazepines.27 Receptor subunit distribution is heterogeneous within regions of the brain, but does show some brain region specificity. Receptors containing the a1 subunit constitute the majority of GABAA receptors and are expressed predominantly in the cerebellum and thalamus. Receptors with a2, a3, or a5 subunits appear mainly in the hippocampus. Receptors containing a1, a2, a3, or a5 are all found also in the cortex. The GABAA receptor is a known target of benzodiazepines and neurosteroids. The importance of the

GABAergic system in anxiety disorders has been firmly established by the proven efficacy of benzodiazepines in the treatment of anxiety disorders,24 and their therapeutic effects are related mainly to their capacity to target the a2 and a3 subunits with consequent enhancement of the GABA-mediated inhibition of neuronal overexcitability that is thought to be present in many of the anxiety disorders. The barbiturates as well as various neurosteroids also suppress brain excitability by enhancing chloride influx in most brain regions. However, they exert their action via different pathways than the benzodiazepines. The latter activate the GABAA receptor, which in turn opens up the chloride channel, allowing enhanced chloride influx. On the other hand, the various neurosteroids and barbiturates directly stimulate chloride channel opening and consequent chloride influx without the mediation of the GABAA receptor. Hence, such differences might be clinically relevant in the case of patients consuming overdoses of such substances. In the case of benzodiazepines, the administration of receptor antagonists such as flumazenil is effective in alleviating many benzodiazepine-induced symptoms, while, in the case of an overdose or extreme adverse side-effects of neurosteroids, flumazenil is not effective in restoring the brain suppression and/or other side-effects.33 GABAB receptors comprise two seventransmembrane-spanning proteins that are coupled to either calcium or potassium channels via G-proteins.26 When activated, either calcium currents are suppressed or membrane potassium conductance is increased, leading to neuronal hyperpolarization. Hence, activation of GABAA receptors causes the opposite effect to GABAB stimulation. Pathologies associated with the GABAA receptor play a major role in anxiety disorders, epilepsy, alcoholism, and other psychiatric and neurological disorders,24 while the involvement of the GABAB receptors in psychiatric disorders (especially in anxiety disorders) has yet to be determined.

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3.5 c-Aminobutyric acid (GABA) macromolecular complex (II) Agents that suppress chloride channel/GABAA receptor activity (cause anxiety)

Postsynaptic neuron (adjunct to presynaptic GABAergic nerve)

Neurosteroid

Cl ions GABA antagonists Convulsant

BDZ receptor antagonists (or partial inverse agonists)

Neurosteroid receptor blockers

BDZ receptor Convulsant receptor

GABAA receptor

Chloride channel (closed due to lack of GABAA receptor stimulation)

Increases cell excitability (stimulates action potential)

Decreased intracellular Cl concentration

Action potential

Legend

Action potential

Picrotoxin, pentylenetetrazole

Stimulates BDZ Inhibits Pregnenolone sulfate Bicuculine, SR 95531, R 5135 Flumazenil (antagonist); b-CCE, FG-7412, Ro 15-4513 (partial inverse agonists)

76

GABA GABAA

Benzodiazepine c-Aminobutyric acid GABAergic receptor subtype

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3.6 Sedatives and hypnotics Comparative clinical and side-effects profile

Chlordiazepoxide

96

100

Diazepam

98

75

Flurazepam

97

75

Halazepam

97

65

Prazepam

97

65

Lorazepam

85

15

Temazepam

96

12

Oxazepam

97

10

Alprazolam

80

12

Triazolam

89

3

Brotizolam Clonazepam

90

5

85

45

Flunitrazepam

98

20

Nitrazepam

87

30

2-Keto

3-Hydroxy

Triazolo

Others

Sleep architecture impairment

Memory impairment4

Hyperexcitability phenomena3

Sedation

T1/2 (average; hours)

Rate of absorption2

Protein binding (%)

Benzodiazepines

Hypnotic

Anxiolytic

1

Hepatic insufficiency (affected by)

Main characteristics

Non-benzodiazepines The ‘Z’ drugs

Legend

Zaleplon

??

1.5

Zolpidem

92

3

Zopiclone

60

5

More characteristic

1

High protein-bound capacity makes the drug more affected by pharmacokinetic (e.g. drug–drug) interactions

2

Faster rates usually cause more immediate anxiolytic effects (especially if drug is given acutely/on short-term basis)

Rarely causes side-effect or data is not well-established

3

Includes daytime anxiety, early insomnia, tension, and induction of tolerance

Most effective as

4

Mostly anterograde amnesia

Less characteristic

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3.7 Antihistaminergic drugs Comparative clinical and side-effect profile

Promethazine

Hydroxyzine

Antagonized receptors

Diphenhydramine

Cyproheptadine

Antihistamines

Histamine type 1 Acetylcholine muscarinic Serotonergic (5-HT2A, 2C)

Anorgasmia (reverses)

1

Therapeutic/ adverse effects

Anxiolytic

2

Appetite (stimulator) Cough (improves)

3

Dystonia (induces) Dystonia (improves)

4

Glucose (alters serum levels) Hepatotoxic (potentially) Motion sickness (improves) Pregnancy test results (alters) Sleep induction/daytime sedation Vascular headache (improves)

Legend 1

Cyproheptadine has been shown to reverse anorgasmia caused by selective serotonin reuptake inhibitors (SSRIs)

2

The exact mechanism is unknown

3

Not in children

4

Its antidystonic capacity is associated, probably, with its strong anticholinergic properties

Most efficacious in / major capacity for inducing side-effect Moderate efficacy / moderate capacity for inducing side-effect Minor efficacy / minor capacity for inducing side-effect Questionable efficacy / negligible capacity for inducing side-effect Data are insufficient / not well-established

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Neuroanatomical, neurochemical, and neuropharmacological studies support a role for histamine and especially the histamine H1 receptor in the control of the sleep/wake cycle. Acute administration of first-generation H1 receptor antagonists such as chlorpheniramine, diphenhydramine, mepyramine, and triprolidine produces somnolence, and increased likelihoods of falling asleep and reduced concentration. The limited number of studies directed at disclosing the effects of first-generation antihistamines on sleep in patients with insomnia tend to discount these compounds for the treatment of chronic insomnia. Moreover, the development of acute tolerance to the sedative effects of firstgeneration H1 antagonists calls into question their effectiveness as sleep aids, especially in long-term sleep disturbances. Their sedative effects led to the use of these drugs as over-thecounter medication to promote sleep and sedation/calmness. For this reason, psychiatrists should be familiar with their pharmacological profile, including their adverse effects.34

Notes about the scheme Histamine immunoreactive neurons have been identified in the tuberal region of the posterior hypothalamus (tuberomammilary nucleus), projecting to nearly all parts of the brain. Three histamine receptors are known: histaminerelated functions in the central nervous system (CNS) are regulated at postsynaptic sites by the HI and H2 receptors, while the H3 receptor exhibits the features of a presynaptic autoreceptor, mediating the synthesis and release of histamine. The H1 receptor is widely distributed in the CNS. It is present in all areas and layers of the cerebral cortex, limbic system, caudate putamen, nucleus accumbens, thalamus, hypothalamus, mesencephalon, and lower brainstem and spinal cord.35 The H2 and H3 receptors are also distributed extensively and in a heterogeneous fashion in the CNS. Regarding the role of histamine in the CNS, there is substantial evidence that it plays a role in control of the sleep/wake cycle. Whether the

histaminergic system promotes the waking state directly, via hypothalamocortical projections, or indirectly, via other ascending pathways to the thalamus and preoptic area, is still a matter of debate.36 The first-generation antihistaminergic drugs include brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine (a phenothiazine), mepyramine, and triprolidine. They are well absorbed following oral administration, and readily cross the blood–brain barrier. Peak plasma concentrations are achieved in 2–3 hours. The plasma half-life values range from a few hours for diphenhydramine and triprolidine to approximately 24 hours for hydroxyzine and chlorpheniramine.34 Although these compounds were originally developed for the treatment of symptoms related to allergies and colds, the tendency to produce somnolence, an increased likelihood of falling asleep, loss of alertness, and reduced concentration led to their use as sleep aids. Diphenhydramine, hydroxyzine, and promethazine have the most marked sedative activity among these agents. Diphenhydramine is the primary active ingredient in various proprietary preparations for insomnia that are sold over the counter in many countries. Currently, the concept is that in spite of their widespread use as over-the-counter medications, the available evidence does not support the use of these agents for the treatment of transient (lasting several days), short-term (lasting 1–3 weeks), or long-term (lasting more than 3 weeks) insomnia, due to the development of acute tolerance to their sedative effects. However, hydroxyzine seems to be an exception to these agents, and, to date, tolerance has not been reported to develop following its long-term use. Hence, hydroxyzine may be useful in the treatment of generalized anxiety disorder.37 Since promethazine is a phenothiazine, one always should bear in mind the possible (though rare) emergence of extrapyramidal side-effects, including tardive dyskinesia, secondary to the use of this drug.38

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3.8 Buspirone Supposed mechanism of action in anxiety disorders

Buspirone is a partial agonist at postsynaptic 5-HT1A receptors. Hence, it binds to the receptors but agonizes them less than serotonin itself – leading to a net inhibition (vs. physiological conditions) of the receptor. Furthermore, long-term use of buspirone causes downregulation of the 5-HT1A receptors. Since the 5-HT1A receptors are inhibitory in nature, the 'net' effect (following buspirone administration) on serotonergic neurons is excitatory (i.e. more serotonin is secreted from these neurons)

Postsynaptic neurons in hippocampus

5-HT1A

1PP also inhibits a2-ADR receptors located on serotonergic/noradrenergic nerve terminals. Hence, it also causes a net increase of serotonin (and norepinephrine in specific regions) secretion from the nerve terminals a2-ADR

1PP Serotonin Consequent anxiolytic effect (due to enhanced serotonin inhibitory effects)

Improves sexual dysfunction (?) (due to enhanced secretion of norepinephrine from noradrenergic nerve terminal) 5-HT2A

Consequent antidepressant effect (?)

Legend Stimulates Inhibits Action potential Serotonin Buspirone

80

1PP

5-HT1A,2A a2-ADR

1-Pyrimidinylpiperazine. Weak active metabolite of buspirone. Antagonizes the inhibitory a2-ADR receptor Serotonergic receptor subtypes Presynaptic inhibitory auto/heteroreceptor

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Buspirone (and tandospirone in Japan) are the only non-selective serotonergic medications presently approved for the treatment of generalized anxiety disorder (GAD) in many countries, including the USA. They have a relatively unique mechanism of action (i.e. being 5-HT1A partial agonists), very different from those of the selective serotonin reuptake inhibitors (SSRIs) and the other ‘antidepressants’ used to treat anxiety disorders. Buspirone does not cause sedation and has minimal or no potential for abuse or dependence, in contrast to most benzodiazepines.

Notes about the scheme Buspirone acts as a partial 5-HT1A agonist at the postsynaptic population of serotonergic receptors located in the hippocampus, and at the 5-HT1A serotonergic autoreceptors located in the dorsal raphe nucleu.39–42 Binding to these receptors enables the drug to influence the activity of serotonergic neurons through modulating receptor activities. Activation of the postsynaptic 5-HT1A receptors (with subsequent downregulation following long-term use) causes inhibition of the inhibitory effects of the 5-HT1A receptor on cellular excitability, resulting in enhanced serotonin secretion from these neurons. The excessive serotonergic transmission is probably associated with the anxiolytic effect of buspirone (see Section 3.1). In addition, buspirone has a moderate affinity for presynaptic D2 dopaminergic receptors. However, it is not yet clear whether this affinity for dopaminergic receptors contributes to its anxiolytic effect. Buspirone has also been shown to downregulate postsynaptic 5-HT2 serotonergic receptors. This effect may explain its moderate antidepressant properties. However, the antidepressant capacity of buspirone has not been well established and the drug is not proven as an antidepressant agent. Buspirone also has a weakly active metabolite, 1-(pyrimidinyl)piperazine (1PP), with

a2-adrenergic antagonistic properties that have been related to improved sexual dysfunction in anxious patients.42 Buspirone has little or no potential for abuse or dependence, and is relatively safe in overdose.43 It does not cause respiratory depression,44,45 which is a therapeutic advantage in patients who suffer from chronic obstructive pulmonary disease. There is practically no withdrawal syndrome as seen with benzodiazepines, and it does not cause psychomotor or memory impairment. The most frequent adverse effects of buspirone are dizziness, drowsiness, nausea, and headaches.43 To date, buspirone has shown no drug–drug interactions with benzodiazepines or alcohol.46–53 One of the most salient clinical features of buspirone, compared with the benzodiazepines, is its gradual, relatively slow onset of action, with many patients taking 4–6 weeks to respond.54–59 This slow onset of action makes buspirone usually ineffective for the treatment of acute and incapacitating anxiety such as in certain patients with panic disorder. Even so, benzodiazepines can be given for a short period of time (to avoid, as much as possible, addiction to the drug) as adjuvants to buspirone if a patient suffers from incapacitating anxiety. The clinician should remember to taper-off the benzodiazepines as soon as possible. Considering all of the above-mentioned, buspirone could be considered as a first-line drug and it is often quite suitable for the treatment of GAD. One of the main limitations in using buspirone relates to the observed relative ineffectiveness of the drug in anxious patients formerly/currently on benzodiazepines. This is a significant limitation, since most of the anxious population are given benzodiazepines first, either from their general practitioners or from treating psychiatrists. Psychic symptoms of anxiety such as worry, anger, and irritability respond better to buspirone than to benzodiazepines, which have more robust effects on the somatic symptoms of anxiety such as muscle tension and insomnia.58

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3.9 Obsessive–compulsive disorder (OCD) Supposed mechanism of action of anti-OCD drugs

Compulsions Obsessions (due to overactivation by thalamocortical pathways)

Fear

(presumed to be due to increased activities in corticostriatal pathways and enhanced dopaminergic neurotransmission from the substantia nigra)

Cortex

(presumed to be due to decreased 5-HT activities and/or overactivation by striatal neurons)

Striatum

Amygdala

Substantia nigra

Thalamus Impaired thalamic gating (presumed to be due to decreased neurotransmission in striatalthalamic pathways)

Low (?) serotonergic neurotransmission from raphe nuclei

Serotonin reuptake inhibitors (SRIs) SSRIs/clomipramine/SNRIs; suppress the overactive neurons (colored in green) by increasing serotonergic neurotransmission and activating 5-HT inhibitory receptors on the green-colored pathways

Raphe

Legend Stimulated neuronal pathway Inhibited neuronal pathway 5-HT (serotonin) Dopamine Unknown neurotransmitter systems

82

5-HT

Serotonin

SNRI


SSRI


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Obsessive–compulsive disorder (OCD) is a complex psychiatric disorder characterized by recurring obsessions and compulsions that cause significant distress to the patient or significantly interfere with the patient’s normal home, work, or social activities. Epidemiological studies demonstrate that 1–2% of the population has OCD. Thus, OCD is among the most common of mental disorders and its overall impact on society is tremendous. There is a strong evidence that neurobiological as well as psychologic factors play an important role in the pathogenesis of OCD. The selective response of OCD to serotonin reuptake inhibitors (SRIs) focused the interest of researchers on the serotonergic system. In contrast to the various neurocircuitry models relevant for the other anxiety disorders, the leading theories of OCD do not emphasize a central role for the amygdala. Rather, considerable evidence implicates corticostriatal circuitry in the pathophysiology of OCD.60,61

Notes about the scheme Overactivity of corticostriatal circuitry is implicated in the pathophysiology of OCD. In addition to mediating motor activities, the striatum has been implicated in a variety of cognitive and affective functions. Specifically, it is believed to mediate repetitive, stereotyped cognitive processes on an implicit level. The striatum, through its influence at the level of the thalamus, is believed to influence reciprocal thalamocortical interactions. Obsessions may be mediated by overactivity within the frontal cortex while stemming from impaired thalamic gating fundamentally attributable to deficient striatal function. In addition, the repetitive ritualized behaviors or compulsions might be the expression of aberrant or compensatory striatal activity. Given the intimate connections between the amygdala and the striatum, their anatomical proximity, and their respective roles, it has been suggested that activation of the amygdala during a state of fear or anxiety could readily

induce stereotyped behaviors observed during striatal activation. Functional brain imaging studies in OCD patients are also strongly suggestive of an abnormality in basal ganglia–thalamic–orbitofrontal–cortical circuitry, which may normalize to some extent during treatment.62 Although it is unlikely that one neurotransmitter system can explain all the complexities of OCD, the leading hypothesis is centered largely around the role of serotonin. Clomipramine (a potent SRI) and the selective serotonin reuptake inhibitors (SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) all have beneficial effects in OCD, while other antidepressants with less potent inhibitory effects on serotonin reuptake (amitriptyline, desipramine, and imipramine) are not effective in OCD, supporting the hypothesis that the antiobsessional effects of these various pharmacological agents result from their potent serotonergic reuptake blocking activity.60 The hypothesis that SSRIs work in OCD by a serotonergic mechanism is also supported by studies showing a strong positive correlation between improvement in obsessive–compulsive symptoms during clomipramine treatment and drug-induced decreases in cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) and platelet serotonin concentration. Moreover, it has been demonstrated that obsessive–compulsive symptoms can be transiently exacerbated in some patients with OCD by orally administering m-chlorophenylpiperazine (mCPP) which is known to inhibit serotonergic neurotransmission).62 In conclusion, the role of enhanced serotonergic transmission in alleviating OCD symptoms is fairly well established. However, the relatively moderate response to serotonergic enhancement therapies and the fact that as many as 20–60% of OCD patients remain with at least some residual symptoms following pharmacotherapy suggest that other, more complex, interactions are involved in OCD.

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3.10 Benzodiazepines Hepatic metabolism

Liver

Clonazepam

Flurazepam

R

A

H Triazolam

H Diazepam

Alprazolam

Chlordiazepoxide

Chlorazepate

O

Halazepam

C

Oxazepam

Glucuronide form

Lorazepam

(the final pathway for excretion, by the kidney)

C Prazepam

50–100 50 hours hours

Legend

Temazepam

15 10 hours hours

2-Keto 3-Hydroxy Triazolo

Enzymatic reaction: Subgroup of benzodiazepines

Others

Average half-time (T1/2) for the compound/s listed directly above the red arrow

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0 hours

A

Acetylation

C

Conjugation

H

Hydroxylation

O

Oxidation

R

Reduction

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References 1. Gorman JM, Kent JM, Sullivan GM et al. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000; 157: 4; 493–505. 2. Liebowitz MR, Gorman JM, Fyer AJ et al. Lactate provocation of panic attacks, II: biochemical and physiological findings. Arch Gen Psychiatry 1985; 42: 709–712. 3. Gorman JM, Fyer MR, Goetz R et al. Ventilatory physiology of patients with panic disorder. Arch Gen Psychiatry 1988; 45: 31–39. 4. Charney DS, Heninger GR, Breier A. Noradrenergic function in panic anxiety: effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1984; 41: 751–763. 5. Targum SD, Marshall LE. Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Res 1989; 28: 295–306. 6. Klein E, Zohar J, Geraci MF et al. Anxiogenic effect of m-CPP in patients with panic disorder: comparison to caffeine’s anxiogenic effect. Biol Psychiatry 1991; 30: 973–984. 7. Pyke RE, Greenberg HS. Norepinephrine challenges in panic patients. J Clin Psychopharmacol 1986; 6: 279–285. 8. Veltman DJ, van Zijderverld GA, van Dyck R. Epinephrine infusion in panic disorder: a double-blind placebo-controlled study. J Affect Disord 1996; 39: 139–140. 9. Jensen CF, Peskind ER, Veith CR et al. Hypertonic saline infusion induces panic in patients with panic disorder. Biol Psychiatry 1991; 30: 628–630. 10. Bradwejn J, Koszycki D. The cholecystokinin hypothesis of anxiety and panic disorder. Ann NY Acad Sci 1994; 713: 273–282. 11. Tork I, Hornung J-P. Raphe nuclei and the serotonergic system. In: The Human Nervous System (Paxinos G, ed). San Diego: Academic Press, 1990: 1001–1022. 12. Aston-Jones G, Akaoka H, Charlety P et al. Serotonin selectively attenuates glutamateevoked activation of noradrenergic locus ceruleus neurons. J Neurosci 1991; 11: 760–769. 13. Deakin JFW, Graeff F. 5-HT and mechanism of defense. J Psychopharmacol 1991; 5: 305–315. 14. Brady LS, Gold PW, Herkenham M et al. The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res 1992; 572: 117–225. 15. Elkabir DR, Wyatt ME, Velluci SV et al. The effects of separate or combined infusion of

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26. 27. 28.

corticotropin-releasing factor and vasopressin either intraventricularly or into the amygdala on aggressive and investigate behaviour in the rat. Regul Pept 1990; 28: 199–214. Butler PD, Weiss JM, Stout JC et al. Corticotropin-releasing factor produces fear-enhancing and behavioural activating effects following infusion into the locus ceruleus. J Neurosci 1990; 10: 176–183. Cannistraro PA, Rauch SL. Neural circuitry of anxiety: evidence from structural and functional neuroimaging studies. Psychopharmacol Bull 2003; 37: 8–25. Tiihonen J, Kuikka J, Rasanen P et al. Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol Psychiatry 1997; 2: 463–471. Gorman JM. New molecular targets for antianxiety interventions. J Clin Psychiatry 2003; 64 (Suppl 3). Rickels K, Bielski RJ, Feltner DE et al. Efficacy and safety of pregabalin and alprazolam in generalized anxiety disorder. In: New Research Abstracts of the 155th Annual Meeting of the American Psychiatric Association, May 21, 2002, Philadelphia, PA: Abst NR162: 44. Kasper S, Blagden M, Seghers S et al. A placebo-controlled study of pregabalin and venlafaxine treatment of GAD. In: New Research Abstracts of the 155th Annual Meeting of the American Psychiatric Association, May 21, 2002, Philadelphia, PA: Abst NR202: 55. Malizia AL, Cunningham VJ, Bell CJ et al. Decreased brain GABAA–benzodiazepine receptor in binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998; 55: 715–720. Goddard AW, Mason GF, Almai A et al. Reductions in occipital cortex GABA levels in panic disorder detected with H-magnetic resonance spectroscopy. Arch Gen Psychiatry 2001; 58: 556–561. Bremmer JD, Innis RB, Southwick SM et al. Decreased benzodiazepine receptor bonding in prefrontal cortex in combatrelated posttraumatic stress disorder. Am J Psychiatry 2000; 157: 1120–1126. Bremmer JD, Innis RB, White T et al. SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000; 47: 96–106. Borman J. The ‘ABC’ of GABA receptors. Trends Pharmacol Sci 2000; 21: 16–19. Kerr DIB, Ong J. GABAB receptors. Pharmacol Ther 1995; 67: 187–246. Smith TA. Type A c-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to 85

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29.

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31.

32.

33.

34.

35.

36.

37.

38. 39. 40.

41.

42.

43.

clinical syndromes and their treatment. Br J Biomed Sci 2001; 58: 111–121. Rudolph U, Crestani F, Benke D et al. Benzodiazepine actions mediated by specific c-aminobutyric acid-A receptor subtypes. Nature 1999; 401: 796–800. Low K, Crestani F, Keist R et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000; 290: 131–134. Zorilla EP, Koob GH. The therapeutic potential of CRF1 antagonists for anxiety. Expert Opin Investig Drugs 2004; 13: 799–828. Homes A, Heilig M, Rupniak NM et al. Neuropeptides systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 2003; 24: 580–588. Dubrovsky BO. Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 169–192. Monti JM, Monti D. Histamine H1 receptor antagonists in the treatment of insomnia. Is there a rational basis for use? CNS Drugs 2000; 13; 87–96. Pollard H, Bouthenet ML. Autoradiographic visualization of the three histamine receptor subtypes in the brain. In: The Histamine Receptor (Schwartz JC, Haas HL, eds). New York: Wiley-Liss, 1992: 179–192. Dringenberg HC, Vanderwolf CH. Involvement of direct and indirect pathways in electrocorticographic activation. Neurosci Biobehav Rev 1998; 22: 243–257. Lader M, Scotto JC. A multicentre double blind comparison of hydroxyzine, buspirone and placebo in patients with generalized and anxiety disorder. PsychopharmacologyBerl 1998; 139: 402–406. Schwinghammer TL, Kroboth FJ, Juhl RP. Extrapyramidal reaction secondary to oral promethazine. Clin Pharm 1984; 3: 83–85. Eison MS. Azapirones: mechanism of action in anxiety and depression. Drug Ther 1990; 20(Suppl): 3–8. De Montigny C, Blier P. Potentiation of 5-HT neurotransmission by short-term lithium: in vivo electrotransmission studies. Clin Neuropharmacol 1992; 15: 610A–611A. Eison AS, Temple DL. Buspirone: review of its pharmacology and current perspectives on its mechanism of action. Am J Med 1986; 80: 1–9. Norden MJ. Buspirone treatment of sexual dysfunction in patients with generalized anxiety disorder. J Clin Psychiatry 1987; 48: 201–203. Newton RW, Marunycz JD, Alderdice MT et al. Review of the side effect profile of

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46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

buspirone. Am J Med 1986; 80(Suppl 3B): 17–21. Craven J, Sutherland A. Buspirone for anxiety disorders in patients with severe lung disease. Lancet 1991; 338: 249. Rapaport DM, Greenberg HE, Goldring RM. Differing effects of the anxiolytic agents buspirone and diazepam on control of breathing. Clin Pharmacol Ther 1991; 49–401. Boulenger J, Squillance K, Simon P et al. Buspirone and diazepam: comparison of subjective, psychomotor, and biological effects. Neuropsychology 1989; 22: 83–89. Schaffler K, Klauznitzer W. Placebocontrolled study on acute and subacute effects of buspirone versus bromazepam utilizing psychomotor and cognitive assessments in healthy volunteers. Pharmacopsychiatry 1989; 22: 26–33. Moskowitz H, Smiley A. Effects of chronically administered buspirone and diazepam on driving related skills performance. J Clin Psychiatry 1982; 43: 45–55. Van Laar MW, Volkerts ER, van Willgenburg AP. Therapeutic effects and effects on actual driving performance of chronically administered buspirone and diazepam in anxious outpatients. J Clin Psychopharmacol 1992; 12: 86–95. Lucki I, Rickels K, Giesecke A et al. Differential effects of the anxiolytic drugs, diazepam and buspirone on memory function. Br J Clin Pharmacol 1987; 23: 207–211. Boulenger J-P, Gram LF, Jolicoeur FB et al. Repeated administration of buspirone: absence of pharmacodynamic or pharmacokinetic interaction with triazolam. Hum Psychopharmacol 1993; 8: 117. Buch AB, Van Harker DR, Seidehamel RJ et al. A study of pharmacokinetic interaction between buspirone and alprazolam at steady state. J Clin Pharmacol 1993; 33: 1104–1109. Erwin CW, Linnoila M, Hartwell J et al. Effects of buspirone and diazepam, alone and in combination with alcohol, on skilled performance and evoked potentials. J Clin Psychopharmacol 1986; 6: 199–209. Rickels K, Schweizer E, Csanalosi I et al. Long term treatment of anxiety and risk of withdrawal: prospective comparison of clorazepate and buspirone. Arch Gen Psychiatry 1988; 45: 444–450. Pollack MH, Worthington JJ, Manfro GG et al. Abecarnil for the treatment of generalized anxiety disorder: a placebo controlled comparison of two dosage ranges of abecarnil and buspirone. J Clin Psychiatry 1997; 58: 19–23.

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56. Davidson JR, Dupont RL, Hedges D et al. Efficacy, safety and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry 1999; 60: 528–529. 57. Enkelmann R. Alprazolam vs. buspirone in the treatment of outpatients with generalized anxiety disorder. Psychopharmacology 1991; 105: 428–432. 58. Pecknold JC, Matas M, Howarth BG et al. Evaluation of buspirone as an antianxiety agent: buspirone and diazepam vs. placebo. Am J Psychiatry 1989; 34: 766–771. 59. Nutt D, Rickels K, Stein DJ. Generalized

Anxiety Disorder. Symptomatology, Pathogenesis and Management. London: Martin Dunitz, 2002. 60. Micallef J, Blin O. Neurobiology and clinical pharmacology of obsessive compulsive disorder. Clin Neuropharmacol 2001; 24: 191–207. 61. Cannistraro PA, Rauch SL. Neural circuitry of anxiety: evidence from structural and functional neuroimaging studies. Psychopharmacol Bull 2003; 37(4): 8–25. 62. Zohar J, Mueller EA, Insel TR et al. Serotonergic responsivity in OCD: comparison of patients and healthy controls. Arch Gen Psychiatry 1987; 44: 946–951.

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4.1 Schizophreniform disorder No treatment

Intact extrapyramidal system 'Negative' signs

Decreased dopaminergic transmission in mesocortical pathway

D2

Limbic system

D2

VTA

2

Normal dopaminergic transmission in nigrostriatal pathway

5-HT

Frontal cortex

D1,2

Striatum

S.nigra

'Positive' signs

Increased dopaminergic transmission in mesolimbic pathway

Legend

Dopamine

Nerve Soma terminal

Dopaminergic neurons 'Negative' and 'positive' signs Serotonin Serotonergic neurons

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Raphe nuclei

Serotonin secreted by neurons causes 5-HT2 receptor stimulation and subsequent inhibition of mesocortical dopaminergic neurons

Inhibit? Receptor 5-HT2 D1,2 S.nigra VTA

Serotonergic receptor subtypes Dopaminergic receptor subtypes Substantia nigra Ventral tegmental area (midbrain)

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The term ’schizophreniform psychosis’ refers to the clinical symptoms observed during the course of schizophrenia, during either the acute psychotic exacerbation or the remission periods. There are many possible associated abnormalities in schizophrenia, among them genetic, infectious, autoimmune, seasonal, and neurotransmitter. Among these, neurotransmitter abnormalities are the best studied and best understood. However, it is accepted by most researchers that the neurotransmitter abnormalities are only a part, maybe even only a small one, of the biological pathology of schizophrenia. All in all, to date, no specific abnormality, or combination, has proved satisfactory in explaining the complex phenomena observed in schizophrenia.

Notes about the scheme Among the above-listed abnormalities in schizophrenia, neurotransmitter abnormalities (especially the dopamine/serotonin hypothesis of schizophrenia) are widely accepted as directly inducing or at least mediating certain symptoms of the disorder. The major empirical observations concerning the role of abnormal neurotransmitter functioning in schizophrenia are as follows.

Evidence of dopaminergic overactivity in the mesolimbic dopaminergic pathway (from the ventral tegmental area (VTA) to limbic regions) This is believed to be associated with the induction of ‘positive’ psychotic symptoms (delusions, hallucinations, bizarre behavior, and thought disorder) and it is a widely accepted/consistent abnormality, which relies mainly on the following findings: ●

●

Psychotic symptoms, indistinguishable from the characteristic symptoms found in schizophrenia, can be induced by the use of dopaminergic agents such as amphetamines, bromocriptine, cocaine, L-dopa, and phencyclidine (PCP). The efficacy of almost all antipsychotic drugs (APDs) has been found to be correlated with their ability to antagonize dopamine receptors, specifically the D2 receptors.

●

Plasma levels of homovanillic acid (HVA), a metabolite of dopamine, often correlate with the severity of the psychotic symptoms in schizophrenia patients, and with their consequent response to APD treatment.

Decreased dopaminergic transmission is the mesocortical pathway (from the VTA to the prefrontal cortex) This phenomenon is believed to modulate the ‘negative’ symptoms of schizophrenia (affective flattening, anhedonia, avolition, alogia, and asociality). Along with the decreased dopaminergic transmission in the mesocortical pathway, there is, possibly, excessive serotonergic transmission from the raphe nuclei to this pathway. At the same time, the dopaminergic transmission in the nigrostriatal pathway (from the substantia nigra to the basal ganglia) is believed to be intact in schizophrenia (untreated). Extrapyramidal side-effects (EPS) are a consequence of inhibited dopaminergic transmission in these regions. Hence, EPS are not evident in schizophrenia per se, but rather are the result of APD treatment.

Possible serotonergic overactivity in various brain regions Serotonergic involvement in schizophrenia is based on two main findings: (a) psychotic symptoms (mainly hallucinations) can be induced by the administration of the partial serotonin agonist lysergic acid diethylamide (LSD); (b) the beneficial role of atypical APDs (drugs with enhanced capacity to block postsynaptic serotonergic receptors; see Section 4.4) in ameliorating psychotic symptoms. It is believed that enhanced serotonergic neurotransmission in the mesocortical pathway suppresses the dopaminergic neurons originating in the VTA and projecting to cortical regions, causing ‘negative’ symptoms. Atypical (second-generation) APDs block this excess serotonin, with consequent potential reduction of ‘negative’ symptoms.

c-Aminobutyric acid (GABA) hypoactivity GABAergic neurons are inhibitory, and a loss of these inhibitory effects can produce, at least in part, the overactivity seen with other neurotransmitter systems (dopaminergic, serotonergic, and possibly adrenergic). 1 For a complete overview, see Section 4.2.

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4.2 Schizophreniform disorder

D1,2

The potential role of GABAergic hypofunction

Decreased dopaminergic transmission in mesocortical pathway

Increased serotonergic transmission in raphe–VTA pathway (affecting mostly the mesocortical dopaminergic pathway)

VTA

D2

5-HT2

GABA B

GABAB

Raphe nuclei Increased dopaminergic transmission in mesolimbic pathway

Hypoactive GABAergic neurons (due to NMDA receptor hypoactivity?)

Decreased stimulation

Glycine

NMDA rec.

Glutamate

Legend

The hypoactive GABAergic neurons activate GABAB receptors (inhibitory heteroreceptors on dopaminergic and serotonergic nerve terminals) and/or GABAA receptors (on the cell body) much less than in physiological conditions, leading to increased dopamine secretion in the mesolimbic pathway and increased serotonin secretion from serotonergic neurons at the VTA (causing inhibitory effects on dopaminergic neurons of the mesocortical pathway)

Receptor Inhibitor

Dopaminergic neurons GABAergic neurons Serotonergic neurons Dopamine Serotonin GABA Glutamate Glycine

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5-HT2 D1,2 GABA GABAA,B NMDA VTA

Decreased stimulation Serotonergic receptor subtype Dopaminergic receptor subtypes c-Aminobutyric acid GABAergic receptor subtypes N-Methyl-D-aspartate Ventral tegmental area (midbrain)

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Notes about the scheme The dopamine hypothesis of schizophrenia posits diminished dopaminergic activity in the prefrontal cortex and reciprocal dopaminergic hyperactivity in the mesolimbic pathways, associated presumably with the induction of ‘negative’ and ‘positive’ symptoms, respectively. The exact mechanisms responsible for such changes in dopaminergic transmissions are not yet fully understood. However, accumulated data suggest that altered (i.e. hypoactive) glutamatergic receptor expression/function may contribute to the observed abnormalities. It is postulated that c-aminobutyric acid (GABA)ergic neurons innervating limbic regions and serotonergic projections from the raphe nuclei to the ventral tegmental area (VTA) are suppressed (due to dysfunction of glutamatergic receptors on these neurons). The suppressed GABAergic neurons do not secrete as much GABA as they should, leading to decreased activation of GABAB receptors located on presynaptic nerve terminals of dopaminergic neurons (in limbic regions) and serotonergic neurons (in the VTA). The GABAB receptors are inhibitory in nature; hence, their suppression leads to increased dopamine secretion in the mesolimbic pathway and increased serotonergic transmission in the VTA. The enhanced serotonergic transmission inhibits mesocortical dopaminergic pathway by acting at postsynaptic 5-HT2A serotonergic receptors located on their dopaminergic neurons. This hypothesis is further supported by the similarities between the behavioral effects caused by the administration of N-methyl-Daspartate (NMDA) receptor antagonists to human subjects and the clinical symptoms of schizophrenia. Moreover, clinical trials in which NMDA receptor activity was enhanced by agents acting at the glycine modulatory site have demonstrated decreases in negative symptoms and variable improvements in cognitive function. There are also data from postmortem studies suggesting alterations in

pre- and postsynaptic markers for glutamatergic neurons in schizophrenia patients. The NMDA receptor for glutamate has a number of modulatory sites that affect its activity (i.e. regulating the influx of cations (mainly Ca2) via a cation channel located adjunct to the receptor). Within the channel, there is a binding site for dissociative anesthetics such as phencyclidine (PCP) and ketamine, which serve as non-competitive antagonists. There is also a strychnine-insensitive binding site for the co-agonist glycine. PCP binds to a site within the ion channel of the NMDA receptor that blocks the influx of cations, thereby acting as a non-competitive antagonist. PCP produces a syndrome in normal individuals that closely resembles schizophrenia and exacerbates symptoms in patients with chronic schizophrenia. Ketamine is an anesthetic that has approximately a 10- to 15fold lower affinity for the NMDA receptor, and it produces the characteristic cognitive deficits of schizophrenia. When ketamine is administered to patients with schizophrenia stabilized with antipsychotic medication, it produces delusions, hallucinations, and thought disorder, consistent with the patient’s typical pattern of psychotic relapse. Consistent with this model, chronic PCP administration also increases subcortical dopamine release, particularly in the nucleus accumbens, emphasizing the reciprocal modulation of the glutamate and dopamine neuronal systems in schizophrenia. Evidence for hypoactivity of NMDA receptors in schizophrenia has led to therapeutic trials with agents (e.g. glycine, D-serine, and D-cycloserine) that indirectly or directly activate the NMDA receptor, with some beneficial results. When these agents were added to ongoing antipsychotic treatment, there seemed to be improvements in negative symptoms, cognitive function, and psychosis. However, the addition of glycine site agonists to clozapine produced no changes in negative symptoms or cognitive function, possibly due to the action of clozapine in increasing the occupancy of the glycine modulatory site at the NMDA receptor.2,3

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4.3 Antipsychotic drugs Typical (first-generation) antipsychotic drugs – mechanism of action

Potential worsening of 'negative' signs

EPS

(due to blockade of the alreadydecreased dopaminergic transmission in the mesolimbic pathway)

Striatum Frontal cortex

Typical APD

Typi c APD al

D1,2

D2

Limbic system

Typi c APD al

D2

5-HT

2

VTA

Substantia nigra

Serotonin excreted by sseroic neurons serotonergic neurons causes 5-HT2 receptor stimulation and subsequent inhibiton of mesocortical dopaminergic neurons

Improved 'positive' signs (due to blockade of excessive dopaminergic transmission in the mesolimbic pathway)

Legend Soma

Dopaminergic neurons

5-HT2 D1,2

'Negative' and 'positive' signs Serotonin Serotonergic neurons

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Receptor

Dopamine

Nerve terminal

Raphe nuclei

Serotonergic receptor subtype Dopaminergic receptor subtypes

EPS Extrapyramidal side-effects Typical APD VTA

Typical (first generation) antipsychotic drug Ventral tegmental area (midbrain)

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The common pathway of all typical/ first-generation as well as ‘atypical’/ second-generation antipsychotic drugs (APDs) is their capacity for antagonizing dopamine receptors. Moreover, their clinical potency is closely related to their specific affinity for D2 dopamine receptors, with a therapeutic effect being evident if more than 70% of D2 receptors are occupied by APDs. Although the antagonism of the D2 receptors takes place almost immediately, it takes a few weeks for amelioration of psychotic symptoms to occur, implying a secondary mechanism (presently unknown). Virtually all APDs are non-selective. They possess a wide range of antagonizing capacities, particularly dopaminergic, adrenergic, serotoninergic, cholinergic, and histaminergic. Most of the neurological and endocrinological adverse effects associated with APDs are related to their antagonistic effects on those receptors. As mentioned, all typical APDs have a high affinity for D2 receptors. Practically all APDs (both first- and second-generation) are equally efficacious, although they exert their maximal antipsychotic effects in various doses (different potency).1,4

Notes about the scheme All typical APDs block (at least to some extent) D2 dopaminergic receptors and are not selective, meaning that they do not target specific brain regions. Sulpiride is a relative exception, since it is quite selective as a D2 blocker (although non-selective in its brain distribution). In that respect, sulpiride is often considered by clinicians as ‘atypical’ in nature. The major dopaminergic pathways that are most relevant to schizophrenia are: ●

Mesolimbic and mesocortical. These are dopaminergic neurons that project from the ventral tegmental area (VTA) to frontal and other cortical areas (mesocortical pathway) and to limbic structures such as the nucleus accumbens, the amygdala, and the olfactory tubercle (mesolimbic pathway). It is assumed that in schizophrenia, there is increased dopaminergic neurotransmission in the mesolimbic pathway and decreased transmission in the mesocortical region (see Section 4.1 for details).

●

●

Nigrostriatal. These are dopaminergic neurons that project from the substantia nigra to the basal ganglia (caudate nucleus, putamen, and globus pallidus). Extrapyramidal side-effects are mostly related to the antagonistic effect of APDs on these dopaminergic pathways. Tuberoinfundibular. These are dopaminergic projections from the posterior hypothalamus to the medial eminence and the posterior and intermediate lobes of the pituitary. Prolactin secretion is enhanced following this blockade, since dopamine inhibits prolactin secretion.

At the mesolimbic pathway, typical APDs block mainly the D2 component, whereas atypical APDs block, more dominantly, other receptors (e.g. 5-HT and D4). The D2 blockade induces a subsequent improvement of ‘positive’ psychotic symptoms (delusions, hallucinations, disorganized behavior, disorganized speech, and catatonia). Decreased dopaminergic transmission in the mesocortical pathway might induce negative symptoms (e.g. affective flattening, avolition, and alogia). Typical APDs, by blocking D2 receptors, might further decrease these suppressed dopaminergic activities and worsen these ‘negative’ symptoms. Furthermore, typical APDs decrease dopaminergic transmission in the nigrostriatal pathway. Hence, typical APDs often cause extrapyramidal side-effects, especially the following:1,4,5 ●

●

●

Dystonia. This occurs usually during the first few hours/days of treatment in about 10% of patients. Risk factors are male sex, age less than 40 years, high-potency antipsychotic agents, and intramuscular administration. Parkinsonism. This usually occurs during the first 3 months of treatment, and affects up to 10% of treated patients. It is characterized by rigidity, tremor, bradykinesia, and postural instability. Risk factors are age over 40 years, and high-potency antipsychotic agents. Akathisia. This is a subjective feeling of muscular discomfort, which leads to restless pacing, agitation, and dysphoria. It occurs in up to 90% of patients during the first 10 weeks of treatment.

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4.4 Antipsychotic drugs Second-generation (atypical) antipsychotic drugs – mechanism of action

Infrequent extrapyramidal side-effects

Potential improvement in 'negative' signs (due to the much-increased dopaminergic transmission in mesocortical pathway)

Striatum

Frontal cortex

D2 SGA

SGA

D1,2

Increased dopaminergic firing rate in mesocortical and nigrostriatal pathways overrides the blockade by atypical APDs

Limbic system

SGA

SGA

D2

5-HT2

VTA

Substantia nigra

5HT2

Raphe nuclei

SGA

5-HT2 receptor blockade (by SGAs) stops the inhibitory effect of the serotonergic neurons on mesocortical and nigrostriatal dopaminergic neurons (i.e. with subsequent increase in their firing rate)

Improved 'positive' signs (due to blockade of excessive dopaminergic transmission in the mesolimbic pathway)

Legend Nerve terminal

Soma

Dopaminergic neurons

5-HT2 D1,2

Serotonergic receptor subtype Dopaminergic receptor subtypes

'Negative' and 'positive' signs

SGA Second-generation ('atypical') antipsychotic drug

Serotonin

VTA

Serotonergic neurons

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Receptor

Dopamine

Ventral tegmental area (midbrain)

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Second-generation (‘atypical’) antipsychotic drugs (SGAs, ‘atypical’ APDs) are a class of new APDs that share a diminished capacity to cause extrapyramidal side-effects (including tardive dyskinesia) while having a minimal effect on serum prolactin levels. Some researchers believe that alleviating, at least to some extent, some of the ‘negative’ symptoms of schizophrenia should also be a necessary criterion for defining a drug as an ‘atypical’ APD. However, this criterion is controversial because only clozapine has shown a consistent and significant capacity to improve negative symptoms in large and well-established studies of schizophrenia patients. Other SGAs (amisulpiride, olanzapine, quetiapine, risperidone, and ziprasidone) have also shown some capacity to improve ‘negative’ symptoms, although such results are usually inconsistent .4,6,7

Notes about the scheme Amisulpiride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are termed second-generation APDs (SGAs; often designated as ‘atypical’). There is no one specific receptor interaction responsible for a drug’s atypical propensities, although a few have been postulated (see also Sections 4.5 and 4.6). Schematically, SGAs are potent inhibitors of postsynaptic 5-HT2A serotonergic receptors, while most exert a mild–moderate capacity to antagonize D2 dopaminergic receptors. 5-HT2A receptors are located on dopaminergic neurons of the mesocortical pathway (see Section 4.1) (as well as in other regions that are less relevant to schizophrenia), and stimulation of these receptors decreases, physiologically, dopaminergic transmission in these neurons. In schizophrenia, it could be that there is a basal overstimulation of 5-HT2A receptors, resulting, presumably, in suppression of the dopaminergic neurons of the mesocortical pathway, with consequent induction of the ‘negative’ symptoms of the disorder. Hence, chronic blockade (by SGAs) of 5-HT2A postsynaptic serotonergic receptors located on dopaminergic neurons of the mesocortical pathway may cause:

●

●

Decreased inhibition of the mesocortical dopaminergic pathway and a consequent increase in dopamine secretion in cortical regions. This could explain the potential beneficial effects of SGAs in alleviating ‘negative’ symptoms. Upregulation of 5-HT2A receptors in other brain regions (i.e. besides the mesocortical dopaminergic pathway). Especially relevant for schizophrenia might be upregulation of 5-HT2A receptors located on dopaminergic neurons of the mesolimbic pathway. This may result in a decreased firing rate of these neurons, and enhancement of the potential antipsychotic effects of a drug (which is usually attributed to the drug’s capacity to block postsynaptic D2 dopaminergic receptors). Hence, although the efficacy of SGAs in alleviating ‘positive’ symptoms of schizophrenia is usually considered to be as good as that of typical APDs (because of their similar capacity to block D2 receptors), the increased serotonergic transmission (caused by the upregulated receptors) in the mesolimbic region may explain their potential superior efficacy in improving some aspects of schizophrenia, and especially the ‘positive’ symptoms in specific subjects (e.g. treatment-resistant patients). However, at present, this latter concept is quite hypothetical and further research is needed to establish its role in schizophrenia.7,8

SGAs, except risperidone in relatively high doses, do not usually cause marked extrapyramidal side-effects. The reason for this is not fully established, although several main mechanisms have been suggested: (a) SGAs bind less to D2 receptors in the striatum (i.e. they are more selective for other brain regions). (b) They have comparable affinity for these striatal D2 receptors but they bind much more loosely (‘loose binding’), allowing nearly normal dopaminergic transmission. (c) SGAs block 5-HT2A receptors located on nigrostriatal dopaminergic neurons, with a consequent increase in dopaminergic transmission; this phenomenon may ‘over-ride’ the decrease in dopaminergic transmission due to the blockade of D2 receptors (by the SGAs).1,4–12

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4.5 Antipsychotic drugs Schematic characteristics: 'typical' versus 'atypical' antipsychotic drugs

At brain level Cortex

Striatum Cortex

Striatum

LS LS

Selective and differential effects

Non-selective and no differential effects 'Atypical' APD

'Typical' APD

At neuronal level a2-ADR

5-HT1A,6,7

5-HT2

Postsynaptic nerve

Legend

D1,3

Decreased Inhibition (due to enhanced 5-HT2 sertonergic blockade)

Name

98

Receptor

D2

Except in limbic regions, where the D2 blockade is enhanced

Enhanced inhibition

Activation

D2

5-HT1A,2,6,7 a2-ADR

Serotonergic receptor subtypes Adrenergic receptor subtype

APD

Antipsychotic drug

D1,2,3

Dopaminergic receptor subtypes

LS

Limbic system

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4.6 Antipsychotic drugs Specific characteristics: 'typical' versus 'atypical' antipsychotic drugs

Presynaptic nerve

NE-PMT

a2-ADR

D2

Aripiprazole

Clozapine

Risperidone

Zotepine

Olanzapine

Quetiapine

Amisulpiride

Ziprasidone

Typical APDs

5-HT2 D2

5-HT2 D2

D2 5-HT2

5-HT6 D3 5-HT1A,1D

Legend

Stimulates Inhibits

Postsynaptic nerve

Main mode of therapeutic 5-HT1A,1D,2,6 action (ratio of antagonizing a2-ADR the receptors) APD Secondary mode of D2,3 therapeutic action 5-HT D2 Receptor

NE-PMT

Serotonergic receptor subtypes Adrenergic receptor subtype Antipsychotic drug Dopaminergic receptor subtypes Ratio of the affinity for the respective receptors Plasma membrane transporter (reuptake site) for norepinephrine

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4.7 Antipsychotic drugs

Phenothiazines

Pregnancy risk factor (PRF)

Weight gain

Parkinsonism

Dystonia

Akathisia

Seizure induction

Sedation

Antipsychotic


Agitation

Anticholinergic (via AChM1)*

Main adverse side-effects (I)

Chlorpromazine Fluphenazine Levomepromazine Perphenazine Thioridazine Trifluopenthixol Chlorprothixene

Thioxanthenes

Thiothixene Zuclopenthixol Clothiapine Haloperidol

Miscellaneous

Loxapine Molindone Pimozide

Second-generation ('atypical') antipsychotics

Amisulpiride Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Sulpiride** Ziprasidone Zotepine

Legend

Major capacity for inducing side-effect PRF:'D'. Positive evidence of human fetal risk but the benefits for use in pregnent women may be acceptable Major capacity for inducing side-effect PRF:'C'. Positive evidence of animal fetal risk but there are no controlled studies in women, or there are no studies in animals/women Major capacity for inducing side-effect PRF:'B'. Studies show no evidence of animal fetal risk but there are no controlled studies in women, or adverse effects were evident in animal studies but studies in women did not confirm such findings Negligible capacity for inducing side-effect Rarely causes side-effect or data are not well established

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* Via blockade of postsynaptic M1 cholinergic receptors ** Sulpiride is actually a firstgeneration drug but is classified with the secondgeneration antipsychotics due to its 'atypical'-like properties

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Phenothiazines

Chlorpromazine

Miscellaneous

Liver dysfunction

Sexual dysfunction

Hyperglycemia

Tachycardia

QTc

Main adverse effects Postural hypotension

Antipsychotic drug

Cholinergic (via AChM2)*

Main adverse side-effects (II)

1

Fluphenazine Levomepromazine Perphenazine Thioridazine

2

Trifluopenthixol Chlorprothixene

Thioxanthenes

Thiothixene Zuclopenthixol Clothiapine Haloperidol Loxapine

Miscellaneous

Molindone Pimozide Amisulpiride Second-generation ('atypical') antipsychotics

Aripiprazole

Quetiapine

3 4,5 6 7

Risperidone

8

Clozapine Olanzapine

Sulpiride** Ziprasidone Zotepine

AChM2

Legend QTc

Acetylcholine muscarinic receptor subtype Prolongation of the specific EKG interval

Major capacity for inducing side-effect Moderate capacity for inducing side-effect

1 Benign and reversible pigmentation of anterior lens following chronic consumption 1 kg 2 Irreversible retinal damage (including blindness) can occur in chronic use of doses 800 mg/day 3 May cause nausea 4 Agranulocytosis in 0.8%; benign eosinophilia in 3–60% 5 May cause cardiomyopathy 6 Benign eosinophilia in about 0.3% 7 May cause cataract 8 May elevate prolactin

Minor capacity for inducing side-effect Negligible capacity for inducing side-effect Data are not well established

* Via blockade of presynaptic inhibitory M2 cholinergic receptors ** Sulpiride is actually a first-generation drug but is classified with the second-generation antipsychotics due to its 'atypical'-like properties

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Phenothiazines

Chlorpromazine

D2/5-HT2A blockade ratio

H1 blockade

5-HT2A blockade

a1-ADR blockade

AChM blockade

D4 blockade

D3 blockade

D2 blockade

Antipsychotic drug

D1 blockade

Affinity for various receptors

5-HT2A/D2 blockade ratio

Comparative affinity for different receptors

10

Fluphenazine

2

Levomepromazine

Trifluopenthixol

5 2 5 2

Chlorprothixene

30

Perphenazine Thioridazine

Thioxanthenes

Thiothixene

40

Zuclopenthixol

3

Clothiapine

15

Haloperidol Miscellaneous

25

Loxapine

7

Molindone

8 5

Pimozide

1 10

Second-generation ('atypical') antipsychotics

Amisulpiride Aripiprazole Clozapine Quetiapine

30 50 1

Risperidone

8

Olanzapine

Sulpiride*

50

Ziprasidone

8 1

Zotepine

Legend


High affinity for the specific receptor

5-HT2a

Moderate affinity for the specific receptor

AChM Acetylcholine muscarinic receptor

Minor affinity for the specific receptor Negligble affinity for the specific receptor No affinity for the specific receptor (in therapeutic doses)

a1-ADR Adrenergic receptor subtype D1–4 Dopaminergic receptor subtypes H1 Histaminergic receptor subtype

* Sulpiride is actually a first-generation drug but is classified with the second-generation antipsychotics due to its 'atypical'-like properties

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References 1. Marchese G, Pani L. The role of limbic cortical regions in schizophrenia: focus on dopamine. Eur Psychiatry 2002; 17(Suppl 4): 349–354. 2. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001; 158–1377. 3. Freedman R. Schizophrenia. N Engl J Med 2003; 349: 1738–1749. 4. Lieberman JA. Dopamine partial agonists, a new class of antipsychotics. CNS Drugs 2004; 18: 251–267. 5. Bandelow B, Meier A. Aripiprazole, a ‘dopaminergic–serotonin system stabilizer’ in the treatment of psychosis. German J Psychiatry 2003; 6: 9–16. 6. Kapur S, Seeman P. Does fast dissociation from dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001; 158: 360–369.

7. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; 47: 27–38. 8. Mortimer AM. Antipsychotic treatment in schizophrenia: atypical options and NICE guidance. Eur Psychiatry 2003; 18: 209–219. 9. Kapur S, Seeman P. Atypical antipsychotics, cortical D2 receptors and sensitivity to endogenous dopamine. Br J Psychiatry 2002; 180: 465–466. 10. Scatton B, Claustre Y, Cuddenec A et al. Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol. 1997; 12(Suppl 2): S29–S36. 11. Adams C. The Cochrane Schizophrenia Group. Drug Treatments for Schizophrenia, 5. NHS Center for Reviews and Disseminations. 1999 Effective Health Care. 12. Davis JM, Schaffer CB, Killian GA. Important issues in the drug treatment of schizophrenia. Schizophrenia Bull 1980; 6: 70–87.

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Chapter 5 Drugs affecting sexual function

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Drugs affecting sexual function

5.1 Neurobiology of sexual function Assumed modulators of sexual function

Receptors/hormones/neurotransmitters involved in mediating sexual function

D2/D1 ratio a1-ADR

Penile reflexes

5-HT1A a1-ADR Acetylcholine Dopamine Testosterone

5-HT2A,2C Progesterone Prolactin

Arousal

Centrally mediated

(centrally mediated)

Penile reflexes (peripherally mediated; see Sections 5.2 and 5.3 for details)

Sexual function Legend Stimulates parameters of sexual function

5-HT1A,2A,2C Serotonergic receptor subtypes a1-ADR Adrenergic receptor subtype

Suppresses parameters of sexual function

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D1,2 Dopaminergic receptor subtypes

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Increasing research attention has been paid to the neurobiology of sexual function. This has been fostered by growing awareness of the potentially deleterious effects of psychopharmacological agents on sexual function and behavior, and by the increasing number of new treatment regimens for sexual dysfunction, of which the best known are the phosphodiesterase-5 (PDE5) inhibitors for the treatment of male erectile dysfunction. Understanding human sexual function and behavior and the various neurotransmitters and endocrine factors involved in the human sexual cycle is of paramount importance for proper diagnosis, understanding, and treatment of sexual dysfunction.1 Moreover, it is estimated that 20–85% of non-adherence to psychopharmacology is due to adverse sexual side-effects of the drugs.

Notes about the scheme Cholinergic system The clinical evidence pointing towards involvement of the cholinergic system in sexual function and dysfunction is based largely on the side-effects of psychotropic drugs possessing potent anticholinergic activity, notably tricyclic antidepressants (TCAs). Erectile difficulties and orgasmic inhibition are the main side-effects attributable to antagonism of the cholinergic system. These clinical observations are supported by physiological findings indicating cholinergic innervation of the human corpora cavernosa and the presence of cholinergic receptors in penile tissue. However, central cholinergic transmission may also play a role in modulating sexual function, and it is suspected that central muscarinic receptors may mediate arousal.2

Adrenergic system Stimulation of a1-adrenoreceptors will likely lead to detumescense, whereas blockade of these receptors, centrally and peripherally, including penile tissue, may produce erection. Female sexual arousal has been associated with an active sympathetic nervous system, but the overall data concerning the role of various neurotransmitters in female sexual function are still scanty.

Dopaminergic system There is strong evidence from animal and human data that dopamine plays a major role in human sexual response. Intact dopaminergic function is necessary for both female and male sexual arousal and orgasm/ejaculation. Hence, antipsychotic drugs, presumably by their dopaminergic blockade, cause delayed or inhibited orgasm/ejaculation. The dopaminergic system is diffusely distributed in the central and peripheral nervous system, including the sex organs. Dopaminergic stimulation of the ventral portion of the striatum enhances desire, whereas the dorsal portion of the striatum controls intromission and ejaculation. However, these may not be the only brain regions involved in the complex regulation of desire, arousal, and orgasmic phases of the sexual response cycle. Increased sexual desire and arousal were noted among patients receiving L-dopa (levodopa), apomorphine, and bromocriptine (dopamine agonists). Two dopamine reuptake blocking agents, nomifensine (withdrawn from the market) and bupropion, exert sexual facilitatory effects in the desire and arousal phases. Cocaine potently enhances dopaminergic activity and may produce intense sexual pleasure.2

Serotonergic system Most prominent among the psychotropics that enhance serotonergic transmission are the selective serotonin reuptake inhibitors (SSRIs), which may induce sexual dysfunction in as many as 50–75% of patients, in part by activation of central 5-HT2 receptors. Antidepressants that antagonize the 5-HT2 receptor, such as mirtazapine and trazodone, cause fewer sexual side-effects compared with the SSRIs. Stimulation of the 5-HT1A receptor facilitates sexual functioning, while activation of the 5-HT1B,1D and 5-HT1C receptors inhibits it.1,2

Other compounds Other neurotransmitter systems, as well as various hormones, have been shown to modulate sexual function; among these are progesterone and prolactin (which inhibit centrally mediated arousal) and testosterone (which stimulates centrally mediated arousal).

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5.2 Male sexual function (I) Drugs that can maintain/induce erection

PDE5 inhibitors (sildenafil, tadalafil, vardenafil) Decrease in PDE5 activity causes accumulation of cGMP

NO

Sexual arousal

PDE5

GC

GTP

5ⴕ-GMP

cGMP

Vasodilated vessels (allowing more blood to enter the corpus cavernosum and to induce erection)

Urinary bladder

Urogenital diaphragm (sphincter is constricted, thus preventing urine from entering the urethra and semen from passing retrogradely to the urinary bladder)

Corpus cavernosum (filled with arterial blood)

Erect penis

Testis

Legend

5ⴕ-GMP Stimulates

Inhibits

Vasodilates

cGMP GTP

Guanosine 5ⴕ-monophosphate Cyclic guanosine monophosphate Guanosine triphosphate

GC

Guanylate cyclase

NO

Nitric oxide

PDE5

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Urethra

Phophodiesterase-5

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Understanding the treatment options for sexual disorders is of importance to most psychiatrists as well as other professionals in clinical practice. Both primary and secondary sexual dysfunction are common in clinical practice and are frequent side-effects of psychopharmacological treatment. For example, it is estimated that as many as 15–60% of neuroleptic-medicated subjects (especially with first-generation drugs such as thioridazine) suffer from sexual adverse effects, including erectile dysfunction. Effective treatments for sexual dysfunction, and especially for erectile dysfunction, have progressed enormously. Hence, it is important to be acquainted with psychotropic-induced sexual dysfunction and with the rapid evolving treatments available for such adverse effects (e.g. phosphodiesterase-5 (PDE5) inhibitors). Such treatments may increase patients’ adherence to psychiatric pharmacotherapy, as well as their quality of life.

Notes about the scheme Erectile dysfunction Most of the currently utilized treatments for erectile dysfunction involve agents that are presumed to have their major activity at the target organ. At the cellular level, smooth muscle is mediated by the cyclic adenosine monophosphate (cAMP) or the cyclic guanosine monophosphate (cGMP) pathway. During sexual excitement, nitric oxide (NO) activates guanylate cyclase (GC), which produces cGMP. The latter acts as a second messenger of NO and provides a signal for smooth muscle relaxation by a decrease in intracellular calcium. The relaxed musculature causes vasodilatation, allowing more blood to enter the corpus cavernosa and induce erection. The enzyme PDE5, which is present in the tissue of the corpora cavernosa, breaks down cGMP, causing the smooth muscle to contract, allowing the penis to return to a flaccid state. Sildenafil works by inhibiting PDE5, with consequent accumulation of cGMP. The resultant reduction in intracellular calcium leads to vasodilatation and penile erection. The efficacy of sildenafil has been demonstrated in

erectile dysfunction associated with numerous conditions, including hypertension, major depression, diabetes, spinal cord injury, and after prostatectomy. Two other marketed PDE5 inhibitors are tadalafil and vardenafil.3 Other agents used to treat erectile dysfunction include intracavernosal and transurethral alprostadil (prostaglandin E1), which increase intracellular cAMP in the smooth muscle of the corpora cavernosa and induce subsequent erection. Other intracorporal agents used to induce penile erections include papaverine, a drug with a relaxant effect on smooth muscle, and phentolamine, an a-adrenergic receptor blocker. Yohimbine, an a2-adrenoreceptor antagonist, enhances noradrenergic neurotransmission and may improve erectile dysfunction via adrenergic system activation. Another approach to the treatment of erectile dysfunction has been the use of dopaminergic agents. Apomorphine is a non-selective dopaminergic agonist that presumably works at the level of the spinal cord and centrally at the paraventricular nucleus of the hypothalamus. It is assumed that dopaminergic neurons impinge on oxytocinergic cell bodies in the paraventricular nucleus, with consequent activation of these oxytocinergic neurons. Some data suggest that these neurons mediate apomorphine-induced penile erections.3

Premature ejaculation Controlled double-blind studies have consistently demonstrated that a number of serotonin enhancers (confirmed with clomipramine, fluoxetine, paroxetine, and sertraline) can delay ejaculation. Current data suggest that among the selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and citalopram appear to have the least effect on ejaculation [3]. The serotonergic drugs have been hypothesized to delay ejaculation by increasing serotonergic (i.e. inhibitory) activity in the nucleus paragigantocellularis of the medulla. This nucleus sends inhibitory serotonergic fibers to sexual centers in the spinal cord.3 Hence, treatment with SSRIs can be considered for patients with premature ejaculation.

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5.3 Male sexual function (II) Main drugs affecting ejaculation

e 1-adrenergic antagonism e 1-adrenergic activity constricts the urogenital diaphragm and stimulates synchronized rhythmic contractions of the vas deferens. Hence, agents that enhance e1-adrenergic transmission (*) have the capacity to restore/maintain anterograde ejaculation

dilates the urogenital diaphragm and inhibits the contractility of the vas deferens. Hence, agents that antagonize e1-adrenergic transmission (**) have the capacity to induce retrograde ejaculation

Vasodilated vessels (allowing more blood to enter the corpus cavernosum and to induce erection)

Urinary bladder

Corpus cavernosum (filled with arterial blood)

Urogenital diaphragm (sphincter is constricted, thus preventing urine from entering the urethra and semen from passing retrogradely to the urinary bladder)

Ejaculate Vas deferens

Testis

Urethra

Erect penis

Legend Stimulates urogenital * Ephedrine, imipramine sphincter constriction ** Chlorpromazine, clomipramine, and contractility of the perphenazine, phenoxybenzamine, vas deferens risperidone, thioridazine Inhibits

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Notes about the scheme Initial stimulation of the sympathetic nerves from sympathetic motor neurons emerging in segments T12(11)–L3, produces emission of semen from the ampulla of the vas deferens into the posterior urethra. Following the initial emission of semen into the posterior urethra, sympathetic contraction of the posterior urethra and closure of the bladder neck, together with parasympathetically (originating from S2–S4) induced contraction of the bulbocavernosus and ischiocavernosus muscles and pelvic floor activity, leads to antegrade ejaculation through the urethral meatus. Failures in the initial step can lead to anejaculation, which is defined as total failure of seminal emission into the posterior urethra. Failures in the latter two steps lead to retrograde ejaculation, which is defined as substantial propulsion of seminal fluid from the posterior urethra into the bladder. Retrograde ejaculation can appear as complete (no antegrade fraction) or incomplete (only minimal antegrade emission). Diagnostic clues to anejaculation are complete absence of antegrade ejaculation combined with non-viscous, fructose-negative, and sperm-negative postorgasmic urinalysis. Diagnostic evidence of retrograde ejaculation includes absent or intermittent emission of ejaculate, orgasm without ejaculation, ability to empty the bladder during erection, and the absence of spermatozoa and fructose in postcoital specimens of urine. In the absence of antegrade ejaculation, retrograde ejaculation is the most common cause of ejaculatory dysfunction and accounts for 0.3–2% of cases of male infertility. The most common reasons for retrograde ejaculation in patients attending infertility clinics are a history of retroperitoneal lymph node dissection, diabetes mellitus, bladder neck surgery, transurethral resection of the prostate, and idiopathic retrograde ejaculation (no identifiable cause for ejaculatory dysfunction), which together account for more than 80% of patients with retrograde ejaculation. Spinal cord injury is the most common diagnosis in patients with anejaculation.

Various medical treatments have been proposed for the treatment of anejaculation or retrograde ejaculation. Drugs used in the medical treatment of retrograde ejaculation include a-adrenergic agonists or anticholinergic and antihistaminic drugs, which either increase the sympathetic or decrease the parasympathetic tone of the bladder. Drugs frequently used are imipramine, midodrine, chlorpheniramine plus phenylpropylamine, and brompheniramine. Frequent side-effects at the doses given are various degrees of dizziness, sleep disturbances, weakness, restlessness, dry mouth, nausea, and sweating. The most effective pharmacological treatments of retrograde ejaculation include chlorpheniramine plus phenylpropylamine, imipramine, and midodrine (with 50–80% success rates). Premature ejaculation is defined as persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it. Behavioral therapies include the stop–start technique, the squeeze technique, and other psychotherapeutic interventions. However, it has been shown that the initial positive effects of behavioral techniques disappear after 3 years. Pharmacotherapy is also used to delay ejaculation. Initially, local anesthetic ointments were recommended, but later case reports and open trials described the beneficial effects of monoamine oxidase inhibitors (MAOIs), clomipramine, benzodiazepines, and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, and sertraline. The involvement of central serotonergic neurotransmission in human ejaculation has been investigated mainly in animal studies. To date, it seems that the beneficial effect of SSRI treatment in premature ejaculation results from 5-HT2C receptor stimulation. Among the SSRIs, paroxetine has been demonstrated to be more effective than clomipramine and the other SSRIs. Moreover, it has been suggested that long-term SSRI administration is much more efficient than short-term treatment.4–6

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5.4 Drugs affecting sexual function Sexual adverse side-effects associated with various psychotropics

Sexual adverse side-effects

Decreased orgasm capacity

Decreased libido

Increased libido

Painful ejaculation

Inhibited ejaculation*

Women

Priapsim

Erectile dysfunction

Psychotropics

Decreased libido

Increased libido

Men

Chlorpromazine Haloperidol Fluphenazine Antipsychotic drugs

Perphenazine Pimozide Thioridazine Trifluoperazine

Carbamazepine Isocarboxazid Others

Lithium Phenelzine Tranylcypromine

Legend

* Might also cause inhibited orgasm capacity High capacity to cause the specific adverse effect Moderate capacity to cause the specific adverse effect Minor capacity to cause the specific adverse effect Negligible capacity to cause the specific adverse effect The adverse effect has not been reported with this drug

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References 1. Meston CM, Frohlich PF. The neurobiology of sexual function. Arch Gen Psychiatry 2000; 57: 1012–1030. 2. Halaris A. Neurochemical aspects of the sexual response cycle. CNS Spectr 2003; 8: 211–216. 3. Segraves, RT. Pharmacologic management of sexual dysfunction: benefits and limitations. CNS Spectr 2003; 8: 225–229.

4. Kamischke A, Nieschlag E. Update on medical treatment of ejaculatory disorders. Int J Androl 2002; 25: 333–344. 5. Waldinger MD, Berendsen HHG, Blok BFM et al. Premature ejaculation and serotonergic antidepressants induced delayed ejaculation: the involvement of the serotonergic system. Behavioural Brain Res 1998; 92: 111–118. 6. Waldinger MD, Olivier B. Utility of selective serotonin reuptake inhibitors in premature ejaculation. Curr Opin Invest Drugs 2004; 5: 743–747.

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Chapter 6 Drugs for the treatment of symptoms related to substance abuse

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Treatment of symptoms related to substance abuse

6.1 Abused substances – opiates Supposed mechanisms of dependence, withdrawal symptoms and treatment options

During abstinence (withdrawal phenomema) Chronic use causes upregulation of intracellular 'excitatory' substances (e.g. AC, cAMP). If opiates are not consumed, then the upregulated substances cause net excitation of the noradrenergic neurons – causing the characteristic withdrawal symptoms

Opioid receptors (mainly l)

GABAergic neurons

Less GABA is available for postsynaptic interaction

Mesolimbic pathway (dopaminergic projections from VTA to NAc)

Noradrenergic neurons from LC Hyperdopaminergic neurotransmission

Opiates 'Reward' phenomena Self-stimulation, ignoring food, compulsive behaviour/self-administration, euphoria (?), reinforcement to various stimuli (other than for 'classic' stimuli such as food/sex)

Treatment options

Legend

During acute intoxication The activated receptors (mainly l) cause downregulation of intracellular 'excitatory' substances (e.g. AC, cAMP), causing inhibition of noradrenergic neurons (i.e. decrease in state activation of essentially the entire central nervous system)

Drugs that antagonize the opioid receptor

Drugs that stimulate the opioid receptor

Drugs that decrease noradrenergic transmission

naloxone, naltrexone

methadone, LAAM

clonidine, lofexidine

Inhibit Dopaminergic neurons/ dopamine Noradrenergic neurons/ norepinephrine GABAergic neurons/GABA

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AC cAMP

Adenylate cyclase Cyclic adenosine monophosphate

GABA

c-Aminobutyric acid

LAAM

L-a-Acetylmethadol

LC

Locus ceruleus

NAc

Nucleus accumbens

VTA

Ventral tegmental area

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The opiates and their synthetic analogs are the most effective analgesics known, but at the same time can produce tolerance, dependence, and addiction. Opiate drugs bind to three subtypes of opioid receptors, denoted l, j, and d, which are members of the G-protein-coupled receptor family. This coupling results in inhibition of adenylate cyclase (AC), activation of inwardly rectifying potassium (K) channels, and inhibition of the sodium current. Opioid receptors thus typically mediate inhibitor responses that reduce membrane excitability and reduce the likelihood of cell firing. Morphinelike opiates, including heroin (diamorphine), a widely abused substance, are both analgesic and addictive, and interact with greatest affinity with the l receptor. These drugs appear to produce both reward and reinforcement by means of activation by disinhibition – i.e. they inhibit inhibitory neurons affecting dopaminergic transmission of the ventral tegmental area, releasing dopamine in the nucleus accumbens – and by direct binding to opioid receptors in the nucleus accumbens, independent of dopamine.

Notes about the scheme Opiates acutely inhibit the functional activity of cyclic adenosine monophosphate (cAMP)dependent protein phosyphorylation. This causes acute ‘down regulation’ of intracellular components such as cAMP and AC, with consequent decreased firing rate of various neurons. However, with continued and chronic opiate exposure, functional activity of the cAMP pathway gradually recovers and increases far above control levels upon removal of the opiate (e.g. by administration of the opioid receptor antagonist, naloxone). These changes in the functional state of the cAMP pathway are mediated via induction of AC and protein kinase A (PKA) in response to chronic opiate administration. Induction of these enzymes accounts for the gradual recovery in functional activity of the cAMP pathway seen during chronic opiate exposure (tolerance and dependence) and for the full activation of the

cAMP pathway seen upon removal of the opiate (which causes typical withdrawal symptoms). The locus ceruleus (LC), the major noradrenergic nucleus in the brain, has served as a useful model system for understanding the molecular details that underlie upregulation of the cAMP pathway. This brain region provides most of the noradrenergic innervation of the cerebrum and is thought to be important for regulation of alertness, vigilance, and attention state. Opiates acutely inhibit LC neurons, probably via opening of inwardly rectifying K channels (mediated by direct G-protein gating) and via closing of a sodium (Na) current (mediated via inhibition of the cAMP pathway). Repeated administration of opiates increases the level of expression of AC and PKA, with a consequent increases in the excitability of LC neurons by activating a Na current. Some of the adaptation to chronic opiate administration is mediated by the transcription factor cAMP-response element-binding protein (CREB). CREB binds specific DNA sequences, termed cAMP-response elements (CREs), that are present within the regulatory regions of certain genes to regulate transcription. Chronic opiate use increases the expression of CREB in the LC. Upregulation of the cAMP pathway in LC neurons contributes to the dramatic activation of these neurons upon induction of opiate withdrawal, which in turn leads to many of the signs and symptoms of physical opiate withdrawal (mostly diarrhea, nausea, cramps, aches, headache, and agitation), which may explain in part the beneficial attenuating effect of the a2 presynaptic agonists clonidine and lofexidine in the treatment of opiate withdrawal, as they inhibit the noradrenergic firing rate. Treatment options for acute opiate intoxication are based mainly on drugs that antagonize the opioid receptors (naloxone and naltrexone), while chronic treatment aims at reducing the craving for opiates by replacing the prohibited drug with legal substitutes such as opioid receptor agonists (e.g. methadone and L-a-acetylmethadol (LAAM)) and the partial agonist buprenorphine1–5.

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6.2 Abused substances – amphetamines (I) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Axon

DA-PMT (reuptake site)

Small amount of dopamine enters the neuron ~30% ~70%

MAOB

Nerve terminal

VMAT2 Mitochondria

(the cell body originates in the ventral tegmental area while the terminal is in limbic regions, mainly the nucleus accumbens)

DAR

Most of the dopamine is blocked from being reuptaken into the neuron and is available for postsynaptic interaction

Excessive secretion of dopamine in the mesolimbic ('reward') pathway

Postsynaptic neurons

Treatment options

Legend

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Dopaminergic receptors

Drugs that antagonize the postsynaptic dopaminergic receptor

Drugs that modulate the serotonergic system and decrease self-administration behavior

Antipsychotic drugs

Selective serotonin reuptake inhibitors (SSRIs)

Inhibits

5-HT 5-HT1,2 Stimulates a1,b1,2ADR DA Upregulates/upregulated receptor DAR MAOA,B Inhibited pathway/ reaction NE Dopamine PMT VMAT2 Amphetamines

Serotonin Serotonergic receptor subtypes Adrenergic receptor subtypes Dopamine Dopaminergic inhibitory autoreceptor Monoamine oxidase inhibitor, types A and B Norepinephrine Plasma membrane transporter Vesicular monamine transporter type 2

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6.2 Abused substances – amphetamines (II) Supposed mechanisms of dependence, adverse effects, and treatment options


5-HT-PMT

(originating from raphe nuclei)

5-HT

5-HT1,2 MAOA

Excessive 5-HT in synapse Postsynaptic neurons


Excessive NE in synapse

(originating from locus ceruleus)

NE MAOA

a1,b1,2ADR

NE-PMT

Notes about the schemes Amphetamines are among the most widely used illicit drugs, and they may also cause dependence, abuse, and psychosis. Various drugs may produce subjective effects similar to those of amphetamines, among them methylphenidate, phenmetrazine, diethylproprion, benzphetamine, and phentermine. Amphetamines cause the release of dopamine, norepinephrine, and serotonin from storage sites, increasing monoamine concentrations in the synaptic cleft. Some of those actions are relevant to the toxic actions of amphetamines, especially cardiovascular toxicity. The release of dopamine in the nucleus accumbens and related structures is thought to account for their reinforcing and mood-elevating effects. Methylphenidate, widely used for the treatment of attention deficit hyperactivity disorder (ADHD), has a mechanism different from that of amphetamine-related drugs, since it blocks the reuptake of dopamine.

Amphetamine psychosis is a toxic reaction closely resembling schizophrenia that may occur after long-term or short-term use or a single large dose of amphetamine. The treatment of acute amphetamine psychosis centers on the management of agitation and the reversal of psychotic symptoms with antipsychotic medication. Treatment recommendations for acute amphetamine intoxication include dopamine antagonists such as droperidol, haloperidol, and chlorpromazine or benzodiazepines such as lorazepam. Acceleration of the renal elimination of amphetamines may be accomplished by acidification of the urine with ammonium chloride or ascorbic acid. Complete clearing of amphetamine psychosis may require up to a week. Amphetamine withdrawal is often associated with dysphoria and sometimes suicidal ideation, so patients should remain hospitalized until completely free of signs and symptoms of intoxication.6–10

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6.3 Abused substance – cocaine Supposed mechanism of dependence, adverse effects, and treatment options

Dopaminergic nerve terminal originating at the ventral tegmental area

Serotonergic neurons from the raphe nuclei

Noradrenetgic neurons from the locus ceruleus

DA-PMT 5-HT-PMT

NE-PMT

Excess DA Excess 5-HT and NE 5-HT receptor

Postsynaptic neurons at limbic regions

NE receptor

Various side-effects (see text)

D2 and D1 (less)

(mainly nucleus accumbens)

Activated 'reward' pathway

Treatment options

Drugs that increase withdrawal symptoms (all increase dopaminergic transmission)

Dopamine precursors (L-tyrosine, L-dopa) Dopamine reuptake inhibitors (amantadine) Dopamine releasers (amantadine) Dopamine agonists (bromocriptine) Inhibitors of monoamine oxidase type B (selegiline, phenelzine) Stimulants (methamphetamine, methylphenidate, pemoline)

Legend

Antipsychotic drugs

Drugs that decrease withdrawal (mechanism is unclear) Norepinephrine reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs)

Upregulates (stimulates) Dopamine Norepinephrine Serotonin Upregulated postsynaptic dopaminergic receptors Cocaine

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Drugs that increase dependence (all decrease dopaminergic transmission)

5-HT

Serotonin

DA

Dopamine

D1,2

Dopaminergic receptor subtypes

NE PMT

Norepinephrine Plasma membrane transporter

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Cocaine is an alkaloid derived from the shrub Erythroxylon coca, which is indigenous to South America, where leaves of the shrub are chewed by the population to obtain antifatigue effects. The main mechanism of action of cocaine is related to blockade of dopamine reuptake by the dopamine transporter, resulting in stimulation of the D1 and D2 dopaminergic receptors. However, it also has some capacity to stimulate the postsynaptic dopaminergic receptors. Moreover, cocaine also blocks the reuptake of norepinephrine and serotonin into the presynaptic nerves. However, these effects are relatively minor compared with the capacity to block dopamine reuptake. Cocaine has powerful addictive qualities, related, presumably, to its activities at the mesolimbic dopaminergic pathway. Current research strategies that involve blocking cocaine euphoria or reversing cocaine-induced neuroadaptations may actually have fundamental limitations. Blocking reward is unlikely to address craving and the low hedonic function reported by many cocaine-addicted patients. Complex brain reward circuitry, currently a barrier to cocaine research, should ultimately provide new insights in the search for abstinence-promoting agents.

Notes about the scheme Dopamine transporter blockade by cocaine affects reward regions that have complicated connections to the nucleus accumbens (NAc) and extended amygdala sites, where extracellular dopamine is acutely increased by most addictive drugs. Midbrain dopaminergic neurons in the ventral tegmentum that project to the NAc form a ‘reward circuit’ that is activated by cocaine. During novel rewarding activity, the baseline pacemaker firing of these dopaminergic neurons transforms to burst firing. After a period of time, dopaminergic neuron burst firing habituates to predictable rewards and occurs instead when the organism perceives environmental cues that are associated with the rewarding activity. This capacity of dopaminergic neurons to fire upon exposure to conditioned cues involves learning and is an essential feature of the addictive process. When anticipated

reward does not materialize (in animal models of craving), dopaminergic neuron firing plunges below basal level, with resulting reductions in dopaminergic neurotransmission within the prefrontal cortex and extended amygdala. Pharmacological attempts to reverse dopamine dysregulation may be relatively ineffective because constant receptor occupancy is unlikely to replace the interactive and modulatory role of a functional dopaminergic system. The restoration of normal hedonic function after protracted cocaine exposure might instead require the passage of time and innovative biological approaches. Although a medication with robust efficacy for cocaine dependence has yet to be identified, several trials have yielded some success. Agents that increase dopaminergic activity have the theoretical capacity to decrease withdrawal symptoms, and current data suggest that such dopaminergic agents (e.g. amantadine, bromocriptine, bupropion, dextroamphetamine, pemoline, modafinil, and selegiline) can be beneficial in some cocaine abusers. Among the non-dopaminergic enhancers, uncontrolled trials of divalproex (semisodium valproate), gabapentin, and venlafaxine have shown good tolerability and a reduction in cocaine use. However, the exact mechanism underlying their beneficial effects is unclear and their potential to alleviate cocaine-induced symptoms is currently quite questionable. Cocaine toxicity has both somatic and psychiatric manifestations. Somatic effects include myocardial depression, malignant dysrhythmias, stroke, and sudden death, partially due to cocaine-related myocardial sodium channel blockade and coronary and cerebral vasoconstriction. Such life-threatening conditions occur mainly when cocaine is combined with other abused drugs. Psychiatric effects can mimic the positive and negative symptoms of schizophrenia. Pharmacological treatment of cocaine intoxication is non-specific and includes general medical support and administration of psychotropics for specific symptoms.11–16

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6.4 Abused substances – MDMA (ecstacy) Supposed mechanism of dependence, withdrawal symptoms and treatment options

Axon 5-HIAA


Serotonin plasma membrane transporter

(the cell body originates in the raphe nuclei)

(reuptake site) Small amount of serotonin enters the neuron ~30% ~70%

MAOA

Excessive secretion of dopamine and norepinephrine from dopaminergic neurons of the mesolimbic ('reward') pathway and noradrenergic neurons originating in the locus ceruleus, respectively (by similar mechanisms?)

VMAT2

Excessive serotonin

Most of the serotonin is blocked from being reuptaken into the neuron and is available for postsynaptic interaction

Legend

Mitochondria

in the synaptic cleft (due to enhanced secretion and reuptake inhibition)

Stimulates release of neurotransmitter from presynaptic nerve terminal Serotonin

5-HIAA

5-Hydroxyindole acetic acid (metabolite of serotonin)

MAOA

Monoamine oxidase type A

MDMA

3,4-Methylenedioxymethamphetamine

VMAT2

Vesicular monoamine transporter type 2

MDMA

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Notes about the scheme The illicit drug used most commonly by young people at parties and ‘raves’ is 3,4methylenedioxymethamphetamine (MDMA) or ‘ecstasy’. The mechanism of action of MDMA is not completely understood, but it is believed to inhibit the reuptake of serotonin, to facilitate serotonin release, and to a lesser extent enhance dopamine and norepinephrine release from presynaptic nerve terminals. The serotonin boost can produce a sense of emotional closeness, elation, and sensory delight, and, along with the potential of MDMA to increase dopamine transmission in the ‘reward’ pathway, it might be associated with the addictive properties of the drug. The acute adverse effects of MDMA may include increased heart rate and blood pressure, tremor, sweating, bruxism, and life-threatening hyperthermia that may be further complicated by rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. The cytochrome P450 enzyme CYP2D6 is the primary metabolizer of MDMA. Hence, potent CYP2D6 inhibitors (bupropion, cocaine, fluoxetine, haloperidol, methadone, paroxetine, pimozide, quinidine, and ritonavir) potentially slow the metabolism of MDMA and may further stimulate its toxic effects. The proserotonergic effects of MDMA can be augmented by the ingestion of other proserotonergic drugs. These drugs (e.g. various amphetamines) may be ingested inadvertently as contaminants of MDMA. Proserotonergic drugs such as amphetamines, clomipramine, fluoxetine, lithium, St John’s wort, tramadol, and venlafaxine prescribed for medical disorders may increase the likelihood and severity of the serotonergic effect of MDMA. A florid central serotonin syndrome involving autonomic, cognitive, neuromuscular symptoms may develop. Moderate symptoms manifest as sweating, shivering, hyperreflexia, and agitation; severe symptoms include myoclonus, diarrhea, and fever. The most serious cases of central serotonin syndrome can develop with the irreversible monoamine oxidase inhibitors (MAOIs).

Cases of death have been reported from MDMA interactions with the irreversible MAOI phenelzine and the reversible MAOI moclobemide. Linezolid, a new antibacterial with mild MAOI properties, may also interact dangerously with MDMA. The plasma concentration of MDMA increases 9–15% when the drug is taken with alcohol. More importantly, this combination leads to a longerlasting feeling of euphoria and the false impression that one’s performance of a task has improved when it has actually been impaired. The most troublesome, potential outcome adverse effects of MDMA ingestion result from sympathetic overload, and include tachycardia, mydriasis, diaphoresis, tremor, hypertension, arrhythmias, parkinsonism, esophoria (a tendency for the eyes to turn inward), and urinary retention. The most dangerous effects of MDMA ingestion is hyperthermia and the associated serotonin syndrome, resulting in rigidity, myoclonus, autonomic instability, rhabdomyolysis, and acute renal failure. Psychiatric and neurological manifestations include confusion, delirium, paranoia, depression, irritability, and nystagmus. Treatment includes primary supportive measures such as cardiorespiratory maintenance, cardiac monitoring, pulse oximetry, urinanalysis, chemical panel, toxicology screen, and seizure precautions. Hyperthermia should be treated by rapid cooling. Serotonin syndrome should be treated with primary supportive measures, and cyproheptadine (an antihistaminergic and 5-HT2A blocker) or chlorpromazine should be considered. Anxiety can be treated with benzodiazepines. Severe hypertension may be treated with labetalol (an a1- and b2-adrenergic receptor antagonist), phentolamine (a potent a1-antagonist, or nitroprusside. Rhabdomyolysis should be treated with alkaline intravenous fluids (D5W with sodium bicarbonate). Gastrointestinal decontamination with activated charcoal and a cathartic may be useful in acute exposure if the drug was taken orally within the previous 60 minutes. Induction of emesis is not recommended.17–27

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6.5 Abused substances – phencyclidine (PCP) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Dopaminergic neurons from the ventral tegmental area

Serotonergic neurons from the raphe nuclei

DA-PMT

'Net' effect of PCP on serotonergic system is unknown

5-HT-PMT

(e.g. PCP stimulates and inhibits serotonergic transmission at the same time) ?

?

Glutamate Cations (mainly Ca2)

Excess dopamine

DA receptor

5-HT1,2

NMDA rec. Decreased 2ⴙ Ca in flux

Activates the 'reward' pathway

Central nervous system depression

'LSD-like' effects (?) (see text)

(e.g. ‘negative’- like symptoms of schizophrenia)

Treatment options

Legend

Drugs that alleviate psychosis and possibly 'reward' (all antagonize the postsynaptic dopaminergic receptor)

Drugs that decrease some of the excitatory effects of PCP

Antipsychotic drugs

Benzodiazepines

Stimulates Inhibits Dopamine Serotonin

5-HT 5-HT1,2 DA LSD

Serotonin Serotonergic receptor subtypes Dopamine Lysergic acid diethylamide

NMDA rec. N-Methyl-D-aspartate receptor PCP

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PCP

Phencyclidine

PMT


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Phencyclidine (PCP) is a synthetic drug that is often abused; in the USA, it is probably second to marijuana in frequency of use among drugs of abuse. The substance was originally developed as a general anesthetic. However, the medical use of PCP is presently contraindicated due to its potential severe adverse side-effects – mainly delirium (in about 33% of abusers), agitation, hallucinations, and rhabdomyolysis (in about 2%). It alters sensory perception and may produce peculiar experiences and even psychotic behavior. Clinical studies have consistently shown that a single exposure to PCP may produce behavioral disruption in healthy individuals that mimic schizophrenic symptoms. PCP seems to be unique among psychostimulants because of its ability to cause not only ‘positive’ psychotic symptoms such as delusions and hallucinations but also ‘negative’ or deficit state symptoms of schizophrenia. Hence, PCP stands as the current best model of schizophrenia in humans and animals, which may lead to new medications that could be helpful to people who do not respond to the antipsychotic drugs (APDs) that are currently available.

Notes about the scheme Scientists have recently begun to focus on the potential of PCP as a probe for a new model for understanding and treating schizophrenia. Although amphetamines may also produce symptoms that closely mimic those of schizophrenia, PCP-induced symptoms in humans (especially its capacity to induce ‘positive’- and ‘negative’-like symptoms) appear to offer a more complete model of schizophrenia than that offered by amphetamine-induced symptoms. The ability of PCP to produce schizophrenia-like symptoms in healthy people is related to its ability to block the N-methyl-Daspartate (NMDA) receptor (see Section 4.2), which is one of the various receptors in the brain though which the neurotransmitter glutamate exerts its effect. PCP intoxication may be viewed as occurring in three stages. Mild intoxication, the first and most common stage, is manifested

primarily by psychiatric signs and symptoms. Acute exposure to PCP may cause intense psychosis; visual hallucinations; delusions and euphoric or flattened affect; impaired cognition; and increased frontal blood flow. Repeated exposure to PCP may cause intense psychosis; auditory hallucinations; delusions with religious content; thought disorder; anxious, labile, or paranoid affect; persistent impaired cognition; overt impulsiveness; social incompetence; poor social judgment; poor attention span and concentration; poor interpersonal relationships; and decreased frontal blood flow. Thus, long-term, but not acute, PCP exposure models the behavioral and metabolic dysfunction of schizophrenia. In the second stage, patients can often become stuporous and comatose, but they still have intact deep pain responses. In the third stage, patients tend not to respond to deep pain stimuli, and death can follow. No antidote has been found beneficial, to date, for PCP intoxication. Treatment is symptomatic, and includes careful monitoring of the patient’s level of consciousness and their cardiovascular and respiratory functioning. Activated charcoal is indicated if the patient reaches the hospital soon enough. Treatment of PCP intoxication includes APDs and benzodiazepines; for more severe intoxication, treatment in an intensive care unit is mandatory. However, the use of APDs should be limited to severe psychotic/agitated patients, since these agents can lower the seizure threshold and induce convulsions, or they may cause averse side-effects that can aggravate patients’ problems (e.g. akathisia and dystonia). If APDs are employed, it is preferred to use high-potency drugs (e.g. haloperidol), since these have a relatively reduced capacity to induce seizures compared with the low-potency phenothiazines (e.g. chlorpromazine, levomepromazine, and thioridazine) or some of the relative newly introduced second-generation APDs (SGAs: clozapine, olanzapine, and quetiapine). Benzodiazepines are usually used to treat autonomic instability, muscle spasms, and PCPinduced seizures, and may also aid in controlling some of the aggressive/agitated behavior.28–30

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6.6 Abused substances – alcohol Supposed mechanism of dependence, withdrawal symptoms and treatment option

Acute alcohol intoxication

Acute alcohol withdrawal (following chronic abuse)

Ca2

NMDA rec.

Cl

Ca2

Cl

NMDA rec.

GABAA

High intracellular Cl

GABAA

High intra2 cellular Ca

Low intracellular Cl

Low intra2 cellular Ca

Net inhibitory effect on central nervous system

Treatment options

Legend

Net excitatory effect on central nervous system

Drugs that treat acute intoxication

Drugs that treat acute withdrawal

Drugs that minimize alcohol intake

Benzodiazepine partial-inverse agonist (?)

Bezodiazepines Carbamazepine Clonidine Propranolol

Acamprostate Bromocriptine Calcium carbamide/disulfiram* Naltrexone Ondansetron

GABAA

Toxic when accumulated !!

c-Aminobutyric acid receptor, type A

NMDA rec. N-Methyl-D-aspartate receptor

Acetic acid

Acetaldehyde

Liver

Alcohol

Up-/downregulated receptors, respectively * Induces typical 'disulfiram reaction':

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Calcium carbamide/ disulfiram

Aldehyde dehydrogenase

Alcohol dehydrogenase

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Notes about the scheme The brain maintains neurochemical balance through inhibitory and excitatory neurotransmitters. The brain’s main inhibitory neurotransmitter is c-aminobutyric acid (GABA), which usually acts through GABAA receptors, while the major excitatory neurotransmitter is glutamate, which acts through the N-methyl-Daspartate (NMDA) receptor. Acute alcohol (ethanol) intoxication enhances the effect of GABA, resulting in decreased overall excitability. Acute alcohol intoxication also downregulates NMDA receptors, while chronic alcohol exposure results in upregulation of these receptors. Hence, abrupt cessation of alcohol exposure results in brain hyperexcitability, because receptors inhibited by alcohol are no longer inhibited and excitatory receptors (i.e. NMDA) are upregulated. Brain excitability manifests clinically as anxiety, irritability, agitation, seizures, and delirium tremens. From a neurochemical perspective, alcohol also interacts with several other brain neurotransmitter systems, including the dopaminergic, serotonergic, and opioid systems. Treatment options for alcohol abuse have focused on all of the above-mentioned neurotransmitter systems. The following are among the best studied treatments, which have shown at least some established efficacy. Disulfiram is the first-line therapy for alcohol abuse. Disulfiram (and calcium carbamide) prevent the metabolism of alcohol by inhibiting the enzyme aldehyde dehydrogenase, leading to accumulation of acetaldehyde and subsequent unpleasant intoxication. The objective of disulfiram treatment is to create an aversion to alcohol, rather than modulating its neurochemical effects. However, controlled clinical trials have yielded inconsistent results. Naltrexone is an opioid antagonist that is thought to reduce the positive reinforcing pleasurable effects of alcohol and to reduce craving. However, the largest study performed to date produced negative findings. Nalmefene is also an opioid antagonist, and its use has demonstrated a reduction in frequency of heavy drinking. As with

naltrexone, the treatment effects seemed to wane after discontinuation of treatment. Acamprosate has effects on drinking behavior that are related to modulation of glutamatergic transmission. In particular, acamprosate depresses the elevated glutamatergic transmission and NMDA receptor activation that occur in alcohol dependence and withdrawal. The effect of acamprosate appears to be most effective in decreasing alcohol consumption and prolonging abstinence. This drug remains the most widely validated treatment medication for the treatment of alcoholism. Topiramate is an antiepileptic drug that attenuates the rewarding effect of alcohol associated with abuse by inhibiting mesocorticolimbic dopamine release via facilitation of GABA activity and inhibition of glutamate function. It has been demonstrated to reduce both alcohol consumption and craving. Ondansetron, a 5-HT3 serotonergic receptor antagonist, has demonstrated some efficacy with regard to measures of drinking frequency and intake. Carbamazepine has shown some efficacy with regard to alcohol consumption, while lithium has no effect on drinking behavior. Pharmacological treatment of alcohol withdrawal involves the use of medication that is cross-tolerant with alcohol. Benzodiazepines have been shown to be safe and effective, particularly for preventing or treating seizures and delirium, and are the preferred agents for treating the symptoms of alcohol withdrawal syndrome. Carbamazepine is an effective alternative to benzodiazepines in the treatment of alcohol withdrawal syndrome in patients with mild to moderate symptoms. It is not sedating and has little potential for abuse; however, there is not sufficient evidence that carbamazepine prevents seizure and delirium due to alcohol withdrawal. Haloperidol or medium- to high-potency antipsychotics can be used to treat agitation and hallucinations. Treatment with b-blockers should be considered in patients with coronary artery disease. Dopamine antagonists (tiapride, flupenthixol, and amisulpiride) have been tried in alcohol-dependent patients, with negative results.31–45

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6.7 Abused substances – cannabis Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Postsynaptic neurons in basal ganglia, cerebellum, hippocampus (where CB1 receptors are abundant)

11-OH-THC

Cation channel 2

(mainly K , Ca )

CB1 Gi

Increased intra 2 cellular K , Ca

Decreased intracellular AC activities

Decreased intracellular cAMP activities

Inhibits cholinergic and glutamatergic neurotransmission (possible mechanism for cannabis-induced adverse effects)

Treatment options

Enhances dopaminergic neurotransmission (possible mechanism for 'rewarding' effects)

Only symptomatic treatments are well established For psychosis For depression For agitation/tension/anxiety

Legend

11-OH-THC Stimulates

AC cAMP CB1

Inhibits

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Via inhibiting central nervous system GABAergic (e.g. inhibitory) neurons

Antipsychotic drugs Antidepressants Benzodiazepines

11-Hydroxy-D9-tetrahydrocannabinol Adenylate cyclase Cyclic adenosine monophosphate Central cannabinoid receptor

GABA

c-Aminobutyric acid

Gi

G-protein, inhibitory

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The active compound in herbal cannabis, 9-tetrahydrocannabinol (THC), is contained in marijuana at a concentration of over 5%. Despite being illegal, cannabis is one of the most widely used intoxicants; almost half of all 18-years-olds in the USA and most European countries admit to having tried it at least once, and about 10% of that age group are regular users. The experience of cannabis use is highly variable, depending on the dose of the drug. Smoking remains the most efficient means of delivering the drug; experienced users can titrate the dose by adjusting the frequency and depth of inhalation. Cannabis can also be taken orally in fat-containing foods or dissolved in a suitable pharmaceutical oil, but absorption is delayed. Apart from being an abused substance, interesting and important cannabis-induced effects are emerging as potential future treatments for psychiatric and neurological conditions.

Notes about the scheme Cannabis acts as an agonist at the CB1 cannabinoid receptor, which is the only one known to date to be expressed in the brain. It is particularly distributed in the frontal regions, the basal ganglia, the cerebellum, and the limbic forebrain (particularly in the hypothalamus and in the anterior cingulated cortex). The relative scarcity of cannabinoid receptors in the brainstem nuclei may account for the low toxicity of cannabis when given in overdose. A second cannabinoid receptor, CB2, is expressed only in the peripheral immune system. Both cannabinoid receptors are members of the G-protein-coupled class, and their activation is linked to inhibition of adenylate cyclase activity. There are a series of arachidonic acid derivatives (endogenous cannabinoids) with potent action at cannabinoid receptors. These are anandamide (N-arachidonylethanolamine) and 2-arachidonylglyceryl ether. The endogenous cannabinoids known as endocannabinoids are present in only small amounts in the brain or other tissues, and appear to be synthesized and released locally on

demand. Anandamide and other endogenous cannabinoids are rapidly inactivated by a combination of a transporter mechanism and by the enzyme fatty acid amide hydrolase. To date, there are no well-established data regarding the physiological role of the endocannabinoids, although they are assumed to play a role in the regulation of food intake and body weight. The discovery of agents that could interfere with the activation of endogenous cannabinoids may provide a novel means of pharmacologically modifying cannabinoid function in the brain. Among the well-established effects of acute intoxication with cannabis is an impairment of short-term memory. Some users often report a subjective enhancement of visual and auditory perception, sometimes with synesthesia (where sounds take on visual qualities). One subjective effect that has been confirmed is the sensation that cannabis users experience time as passing more quickly relative to real time. Many subjective reports suggest that cannabis intoxication is associated with increased appetite, particularly for sweet foods. Cannabis has been demonstrated to have significant beneficial effects in counteracting the loss of appetite and reduction in body weight in patients suffering from AIDS-related wasting syndrome. This suggests that cannabinoids may play a role in the regulation of food intake and body weight, and this is one of the medical indications for which the drug has official approval in the USA. Moreover, the CB1 antagonist rimonabant has been demonstrated to suppress appetite and to induce weight loss. The second medical indication for THC use is associated with the ability of the synthetic cannabinoid nabilone to control the nausea and vomiting associated with cancer chemotherapy. A temporary form of drug-induced psychosis can occur in some cannabis users as a result of taking large doses. Cannabis has some addictive properties, but these are much less than amphetamines, for example. The addictive properties, of cannabis are due, probably, to its indirect capacity to enhance dopaminergic transmission in the ‘reward’ pathway (i.e. by suppressing GABAergic neurons that modulate the dopaminergic pathway).46–48

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6.8 Abused substances – lysergic acid diethylamide (LSD) Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Serotonergic projections from the raphe nuclei

Serotonin LSD 5-HT2A LSD

Presynaptic neurons (chronic LSD abuse; no typical perceptual distortions)

Causes degeneration of presynaptic serotonergic nerve terminals

Decreased secretion of serotonin from presynaptic neurons Serotonin Postsynaptic neurons (acute LSD abuse)

LSD 5-HT2A

Enhanced serotonergic transmission (causing characteristic perceptual distortions)

Legend Enhances, stimulates Inhibits Action potential Downregulated receptor

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5-HT2A LSD

Serotonergic receptor subtype Lysergic acid diethylamide

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Notes about the scheme Hallucinogens are generally considered to be physiologically safe molecules whose principal effects are on consciousness. That is, hallucinogens are powerful in producing altered states of consciousness as their primary effect, perceptual distortions (depersonalization, derealization, and synesthesias), hallucinations (usually visual), and heightening of consciousness. They usually do so at doses that are not toxic to mammalian organ systems. Among the adverse consequences of hallucinogen use are so-called ‘flashbacks’. A flashback essentially consists of the reexperiencing of one or more of the perceptual effects that were induced by hallucinogens but occurring after the effect of the drug has worn off or at some later time, in the complete absence of the drug. Flashbacks most often appear as visual symptoms and can persist for months or, in some cases, years, and there appears to be no relationship between frequency of hallucinogen use and rate of occurrence.49 There is no evidence that any of the hallucinogens cause damage to any human body organ. Many natural and synthetic hallucinogens are abused by humans. The natural substances most commonly abused are N,N-dimethyltryptamine (DMT), mescaline, and psilocybin (see Section 6.11). The most studied and the ‘first’ abused (prototypic) synthetic hallucinogen is lysergic acid diethylamide (LSD). It is relatively well established that LSD acts at two main sites. It enhances the activities of postsynaptic 5-HT2 serotonergic receptors and it causes a decrease in the firing rate of serotonergic neurons. LSD binds with high affinity either to the serotonin binding site itself or to an adjacent site on the serotonergic receptor. Serotonergic antagonists prevent animals from identifying LSD in drug discrimination tests. It can also stimulate (probably indirectly) dopaminergic transmission, including the mesolimbic and mesocortical pathways, which have been termed the ‘reward’ system. These are dopaminergic neurons, originating from the ventral tegmental area

(VTA) and projecting to major limbic structures (the nucleus accumbens and olfactory tubercle) and to the frontal cortex. In contrast to other abused drugs (heroin and cocaine), the stimulation of these reward mechanisms is relatively slight, and LSD does not produce the classic reinforcing effects, or dependence. There are some animal data implying that chronic LSD abuse causes depletion of serotonin from presynaptic nerve terminals, due possibly to degenerative processes at these neuron endings. Repeated administration of LSD to rats was also found to downregulate the 5-HT2 receptors. The net effect of these changes is tolerance to the drug effects and decreased serotonergic transmission in the affected regions.50 The mental effects of LSD occur within an hour after ingestion and last for about 12 hours (with a peak effect in 2–4 hours). Hallucinogen abuse can lead to death, usually as a consequence of fatal accidents such as during LSD intoxication. Tolerance to the psychological and behavioral effects of LSD develops quite rapidly (2–4 days of repeated use), and it reverses in about a week following complete abstinence, probably due to the decreased serotonergic transmission mentioned above. Hallucinogens or LSD do not induce physical dependence and no clinically significant withdrawal syndrome is apparent. Reassurance, reduction of sensory input, and supportive care are the hallmarks in the treatment of hallucinogen intoxication. To date, no antidote has been found to be beneficial in reducing or eliminating hallucinogen-induced clinical symptoms. The use of antipsychotics is usually not indicated, but if the patient is severely agitated, psychotic, or possibly aggressive, low doses of high-potency antipsychotic drugs (APDs) might be administered. Low-potency APDs such as chlorpromazine have been shown to induce seizures and to cause cardiovascular collapse when co-administered with hallucinogens. Anxiety states can be treated with benzodiazepines. Controlled studies of the use of 5-HT2 antagonists as possible antidotes for hallucinogens have not been performed, although animal studies have demonstrated that such compounds can antagonize some of the effects of LSD.49,50

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6.9 Abused substances – benzodiazepines Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Postsynaptic neuron

Cl ions

(during chronic abuse of BDZs)

GABA BDZs GABAA Convulsant receptor

BDZ receptor

a1 subunit

Cell nucleus

Chloride channel

Abnormal transcription factor (?)

(relatively closed due to diminished GABAA stimulation)

Decreased intracellular chloride concentration

Tolerance

Abnormal mRNA for the a1 subunit

(larger doses of BDZs are needed to exert similar response)

Withdrawal symptoms (If BDZs are withdrawn, then the downregulated GABAA receptors will not be able to normalize Cl ion influx – causing a net excitatory effect)

Legend

Stimulates Induces

BDZ GABA

Intracellular events following chronic stimulation of the BDZ receptor Downregulated receptor

132

Benzodiazepine c-Aminobutyric acid

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Notes about the scheme Benzodiazepines exert their therapeutic effects by increasing the affinity of c-aminobutyric acid (GABA) to the GABAA receptor and thus increasing chloride influx into the intracellular space. The increased influx hyperpolarizes the neuron and further enhances the inhibitory effects of the GABAergic neuron. Therefore, benzodiazepines act as neuromodulators that enhance the inhibitory effects of GABA. Benzodiazepine abuse is different from other substance abuse disorders (opiates, amphetamines, and nicotine) because benzodiazepines cause much less euphoria and do not activate the ‘classic’ reward systems that are activated with other substances (mainly the mesolimbic and mesocortical dopaminergic projections). In fact, most people do not find the subjective effects of benzodiazepines pleasant beyond their therapeutic anxiolytic or sleep-inducing effects. Therefore, abuse of benzodiazepines is usually secondary to other substance-abuse disorders, with the benzodiazepine being taken for relief from symptoms induced by the use of another drug. As potential drugs of abuse, short-acting benzodiazepines seem to be preferred among addicts because of the rapidity of their onset of action (alprazolam, flunitrazepam, and lorazepam). Benzodiazepines enhance the activities of GABA at its receptor site, and at the same time, and when they are chronically abused, they suppress the expression of the specific messenger ribonucleic acid (mRNA) coding for the production of the a1 subunit of the GABAA receptor. This subunit is one of the major components responsible for the effective coupling between the GABAA receptor and the adjacent chloride channel. Thus, chronic benzodiazepine abuse impairs the effectiveness of the GABAA receptors, leading eventually to their downregulation and to a decrease in chloride influx. Because of the decreased chloride influx into the intracellular GABAergic nerves that follows chronic benzodiazepine abuse, larger doses of benzodiazepines are needed to exert the same clinical effects. This is the physiological basis for the development of tolerance. When

benzodiazepines are withdrawn, the GABAA receptors are still downregulated and their activities are relatively suppressed compared with their baseline status. Since GABAergic nerves exert inhibitory effects on major brain regions, when they are suppressed, the affected brain regions are in a relatively hyperexcitable state. This excitability causes increased noradrenergic neurotransmission and it might play a major role in the induction of characteristic withdrawal symptoms (agitation, insomnia, anxiety, and tremor). Several treatment options are relevant in the case of benzodiazepine abuse. Gradual tapering of benzodiazepines is probably the hallmark and the most effective approach. The tapering schedule should include a reduction of about 20–25% of the consumed dosage per week. Detoxification can be accomplished within 7–21 days. For short-acting benzodiazepines (e.g. alprazolam), a more conservative detoxification plan should be taken (e.g. alprazolam should be tapered at a maximum rate of 0.5 mg every 3 days). Alternatively, a short-acting benzodiazepine can be replaced by a longer-acting one, with tapering-off starting only afterwards. The gradual tapering enables the downregulated GABAA receptors to recover in parallel with the decrease in benzodiazepine dose.51–53 Buspirone (a 5-HT1A partial agonist) or ‘antidepressants’ (especially selective serotonin reuptake inhibitors (SSRIs)) should be considered if tapering is not fully successful and there is still a need for an anxiolytic agent. Both are used primarily as anxiolytic agents, and their main advantages are diminished abuse potential, the absence of withdrawal syndromes during acute abstinence, non-impaired psychomotor performance, and no anterograde amnesia. Buspirone has been found to be beneficial in reducing the craving for benzodiazepines, probably due to its anxiolytic effects. The main drawback in using buspirone or SSRIs is the relatively long time needed before the anxiolytic effects are achieved (at least 1–2 weeks). Another drawback is related to accumulating data suggesting that buspirone is not as effective in ongoing/formerly benzodiazepine-treated patients as in benzodiazepine-naive/free patients.51–53

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6.10 Abused substances – nicotine Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Neuronal mechanism of 'reward'

Neuronal mechanism leading to withdrawal symptoms

Acetylcholine

Na

Na

Nicotine AChN

AChN

Na

Na

Downregulated (?) opioid receptors (following enhanced secretion of endorphins/enkephalins)

Net effect during acute intoxication Increased secretion of dopamine in the mesolimbic pathway (the 'reward' pathway)

Postsynaptic noradrenergic neurons originating from the locus ceruleus

Dopamine

Legend

Opioid receptors

Net effect during withdrawal from nicotine Decreased inhibition of the postsynaptic neurons (due to the downregulated opioid receptors), leading to excessive stimulation of noradrenergic neurotransmission

Increased action potential frequency Increased concentration Stimulates Inhibits Downregulated receptor

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Enhanced secretion of endorphins/enkephalins

AChN

Acetylcholine nicotinic receptor

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In developed countries, smoking is presently estimated to cause 20% of all deaths, making it the largest single cause of preventable death. Nicotine is the primary psychoactive component of tobacco. It motivates smoking by about 1.1 billion people all over the world, representing approximately one-third of the global population aged 15 and over. The addictive power of tobacco is exemplified by the difficulty in quitting. Most attempts to quit smoking fail, and success is achieved only after repeated attempts in the minority of smokers.54

Notes about the scheme For nicotine and other psychostimulant drugs of abuse, the accumulation of evidence supports the hypothesis that mesocorticolimbic dopaminergic systems mediate the reinforcement for continued drug use despite the harmful consequences. The mesocorticolimbic pathway originates in the ventral tegmental area, innervating the striatum, the amygdala, and the prefrontal cortex. An oversimplification of the standard hypothesis of addiction, and for nicotine in particular, may be summarized as follows: nicotine elevates dopamine in the nucleus accumbens, and that elevation reinforces tobacco use. Blocking dopamine release in the nucleus accumbens with antagonists or lesions attenuates the rewarding effects of nicotine, as indicated by reduced self-administration in animals.55 The strongest evidence for the reinforcing influence of nicotine is that it supports self-administration, which is attenuated by preventing dopaminergic signaling in the nucleus accumbens. Cigarette smoke provides an ideal vehicle for the administration of nicotine, since it delivers the drug directly to the lungs, from which it reaches the brain very rapidly as series of boli each time the smoker takes a puff of cigarette smoke. This

administration route serves to maximize the addictive potential of nicotine because it provides a means of frequent and repetitive exposure to the drug in the context of cues that can rapidly develop conditioned or secondary reinforcing properties. Thus, dependence on cigarette smoke represents a particularly potent form of nicotine addiction, which perhaps explains the difficulty many smokers experience when they try to quit the habit.56 Treatment of tobacco dependence involves a combination of behavioral therapies and pharmacological treatment. Pharmacological treatments include nicotine-replacement therapy and non-nicotine medications, including ‘antidepressants’. To date, the most efficacious ‘antidepressant’ for the treatment of tobacco dependence is bupropion, the efficacy of which is attributed to blockade of dopamine reuptake in the mesolimbic dopaminergic system. This area of the brain is believed to mediate reward for nicotine use and for other drugs of dependence. Nortriptyline, a tricyclic antidepressant, is a non-selective norepinephrine reuptake inhibitor. Some anecdotal data suggest that it may have similar beneficial effects as bupropion, at least in long-term abstinence outcomes. However, to date, only nicotine-replacement therapy and bupropion are approved by the US FDA for the treatment of tobacco dependence.57 Nortriptyline carries the risk of postural hypotension, cardiac arrhythmia, and serious toxicity with overdose.58 Clonidine, a central a2-agonist that enhances the inhibitory effects of a2-adrenergic auto- and heteroreceptors (with consequent decreased secretion of norepinephrine and serotonin from presynaptic nerve terminals), may also be effective in prevention of smoking relapse. However, data concerning its efficacy are limited and not well-established.59

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6.11 Abused substances – psilocybin Supposed mechanism of dependence, withdrawal symptoms, and treatment options

Presynaptic neurons originating at the raphe nuclei

Psilocybin

5-HT1A

Postsynaptic neurons at various brain regions

Decreased secretion of 5-HT from presynaptic neurons

Low synaptic 5-HT 5-HT

Psilocybin 5-HT2A

Eventually leading to inhibitory effects on various neurons, including serotonergic neurons that physiologically inhibit noradrenergic neurons of the locus ceruleus, with consequent:

Alterations in sensory interpretation

Legend

Excitation of the noradrenergic system

Action potential

5-HT

Suppresses

136

Serotonin

5-HT1A

Serotonergic receptor, somatodendritic, inhibitory

5-HT2A

Serotonergic receptor, postsynaptic. Its enhanced activation (by psilocybin; in serotonergic neurons) leads, eventually, to enhanced inhibition of serotonergic neurons that physiologically inhibit the noradrenergic neurons at the adjacent locus ceruleus

Stimulates/mediates Stimulates

Alterations in affective regulation

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Psilocybin (4-phosphoryloxy-N, Ndimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms with a worldwide distribution. These mushrooms represent a growing problem regarding hallucinogenic drug abuse throughout the world, and it is assumed that psilocybin-containing mushrooms are among the major hallucinogenic drugs of abuse today. Their abuse potential produces partially harmful effects in a growing population of psychedelic drug users. To date, no physical damage has been well documented, but many psychiatric complications have been reported. Therefore, it is essential to understand basic pharmacological data about psilocybin and to know what kind of symptoms to anticipate.60

Notes about the scheme Psilocybin is a substituted indolealkylamine that belongs to the group of hallucinogenic tryptamines. Psilocybin was isolated from Central American mushrooms (Psilocybe mexicana), although it has been found in many species of mushrooms worldwide. Its main psychic effects produce a well-controlled altered state of consciousness manifested by marked stimulation of affect, enhanced ability for introspection, altered psychological functioning, perceptual changes such as illusions and synesthesias, affective activation, and alteration of thought and time sense. The effects usually last from 3 to 6 hours.60 Psilocybin interacts mainly with serotonergic neurotransmission (5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C serotonergic receptor subtypes), where it binds with higher affinity to the 5-HT2A and to a lesser extent the 5-HT1A receptors.61 Psilocybin interaction with serotonergic receptors has inhibiting effects on the dorsal raphe nuclei. The serotonergic neurons arising from the raphe physiologically inhibit the adjacent locus ceruleus. Hence, psilocybin-induced inhibition of these raphe neurons causes a net activation of the nearby

locus ceruleus. The latter, besides its role as a major site for noradrenergic projections to various brain regions, represents a major center for the integration of sensory input. This may explain some forms of perceptual alterations such as synesthesias.60 Another hypothesis generated by recent human studies with psilocybin assumes that alterations of different feedback loops between cortex and thalamus are responsible for an ‘opening of the thalamus filter for sensory output’,60 with consequent perceptual alterations. It should be noted that psilocybin and its active metabolite psilocin have, in contrast to the indoleamine lysergic acid diethylamide (LSD), no affinity for dopaminergic D2 receptors.62 The evidence reviewed suggests that psilocybin exhibits low toxicity and may be physiologically well tolerated. It does not cause alteration in electrolyte levels, or liver toxicity, or alterations in blood sugar.63–65 However, it should be stressed that its psychotomimetic effects in vulnerable individuals may lead to unexpected dangerous behavior. Since it seems that psilocybin has agonistic activity at 5-HT2A receptors, hallucinations produced by psilocybin intake may be treated with 5-HT2A antagonists such as ritanserin and ketanserin. Concerning the use of antipsychotic drugs (APDs) in cases of psilocybin-induced hallucinations, risperidone, a second-generation antipsychotic (SGA) with 5-HT2A/D2 antagonistic properties, has been demonstrated to be superior to haloperidol (a firstgeneration APD with practically no 5-HT antagonistic capacity) in the treatment of visual illusions or hallucinations caused by psilocybin (probably due to the 5-HT2A antagonistic properties of risperidone). Based on the capacity of SGAs to antagonize the 5-HT2A receptor compared with the first-generation APDs, it is possible that the SGAs (especially those with a higher 5-HT/D2 blockade ratio) may be a better alternative for the treatment of psychosis induced by psilocybin.66,67

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6.12 Abused substances – inhalants (volatile solvents) Supposed mechanisms of dependence, withdrawal symptoms, and treatment options

Subcortical-like dementia, depression, euphoria, altered consciousness, psychosis, drowsiness

In extreme cases Common possible mechanisms involved in toxic effects of inhalants

Intoxication

Slowing of axonal ion channel transport Hypersensitization of GABAergic receptors

Cerebellar atrophy

Inhalants

Cardiac complications

Legend

Type of complication

Inhalants (e.g. benzene, trichloroethylene, chlorohydrocarbons, chloroform, glue, lead, manganese, spray paints, toluene) GABA

138

c-Aminobutyric acid

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Despite its prevalence and serious sequelae, inhalant abuse remains one of the least discussed areas in substance abuse treatment. In contrast to other classes of substances in which one basic compound is abused by different routes, inhalants are defined solely by their route of administration and are classified into three types: volatile solvents, nitrous oxide, and nitrites. Inhalants are further subdivided into whether the substance is volatile at room temperature, and whether it is used by sniffing, snorting, bagging (inhaling from a bag containing the substance), huffing (saturating a rag with the substance, placing the rag in the mouth, and inhaling), or spraying into the mouth. Abuse of such substances is most often associated with alteration of the level of consciousness, which is the predominant effect sought by the user.68

Notes about the scheme Volatile solvents form the largest and most diverse group of abused inhalants. This group consists of both industrial and household products containing such constituents as toluene, n-hexane, chlorohydrocarbons, benzene, and others. Volatile solvents quickly gain access to the brain because of rapid absorption via the pulmonary circulation and high lipid solubility. For most abused solvents, 15–20 inhalations produce euphoria and subsequent drowsiness within seconds to minutes. Rebreathing of exhaled air (as is done in bagging) leads to hypercapnia and hypoxia, which potentiates the intoxicating effect of the solvent.69 The intoxication is similar to that with alcohols, with accompanying diplopia, slurred speech, ataxia, and disorientation. At high exposures, visual hallucinations may also occur, as may coma, seizures, and death. The mechanism of action by which inhalants induce intoxication is unclear. One hypothesis involves ‘fluidization’ of neuronal membranes, leading to

slowing of axonal ion channel transport. Another theory proposes that volatile solvents potentiate hyperpolarization of c-aminobutyric acid (GABA)ergic receptors. Both tolerance and withdrawal may develop to volatile solvents. In chronic abusers, the liver and heart are commonly affected. Hepatotoxicity is associated with carbon tetrachloride, chloroform, trichlorethylene, and possibly toluene abuse; fortunately, even in chronic abusers, the elevated liver functions often improve within 2 weeks of abstinence.70 Rapid cooling of the larynx, as frequently occurs when abusing aerosol inhalants such as spray paints or lighter fuels, causes reflex vagal inhibition, which can precipitate a cardiac arrhythmia and sudden death.71 These compounds can also have direct effects on the heart by inducing sinus bradycardia, myocarditis, or fibrosis, and an indirect effect by causing hypoxia-induced heart block.72,73 Hence, cardiac complications are probably the most serious medical problem in volatile solvent abusers and may have lethal consequences. Another lethal consequence occurs in glue sniffers, who are at increased risk of losing consciousness with subsequent suffocation due to adherence of the glue-filled bag to their face and mouth.68 Inhalant abuse can also precipitate a broad variety of neurological sequelae that tend to develop when the person is using inhalants for at least 2–3 times a week for at least 6 months; these may be due to cerebellar atrophy, particularly along the corpus callosum and the hippocampus, and white matter degeneration.68,74,75 The neurological sequelae include optic neuropathy (toluene), peripheral neuropathy (n-hexane), trigeminal neuralgia (trichloroethylene), parkinsonism (inorganic manganese), subcortical-like dementia, memory loss, poor attention, psychosis (lead), depression, apathy, and decreased IQ. To date, there are no established data about any beneficial pharmacotherapy for abusers of volatile solvents.68,76–80

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6.13 Abused substances – acute intoxication (I)

Nicotine

LSD

Cannabis

Alcohol

PCP

Cocaine

Amphetamines

Opiates

Abused substances

Benzodiazopines

Frequently encountered 'non-psychiatric' symptoms

Amnesia (anterograde) Drowsiness, stupor, coma Dykinesia, dystonia Incoordination Transient ischemic attacks (TIAs)

CNS

Seizures

Slurred speech, decreased attention Triad: ataxia/dysarthria, hyperacusis Wericke's syndrome Bradycardia Tachycardia

CVS

Hypertension Hypotension Arrythmias Appetite (decreased) Appetite (increased) Diarrhea

GIT

Nasal congestion Nausea/vomiting Weight loss Blurred vision Distorted color vision Conjunctival infusion ('red eyes') Nystagmus

Ophthalmic

Ptosis (bilateral) Pupillary constriction Pupillary dilatation Wernicke's syndrome – ocular manifestations Hyperthermia

Miscellaneous

Hypoglycemia Rhabdomyolysis

Legend More frequently observed symptom Less frequently observed symptom Practically not observed

140

CNS

Central nervous system

CVS

Cardiovascular system

GIT

Gastrointestinal tract

LSD

Lysergic acid diethylamide

PCP

Phencyclidine

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6.14 Abused substances – acute intoxication (II) Frequently encountered 'psychiatric' symptoms

Nicotine

Benzodiazopines

LSD

Cannabis

Alcohol

PCP

Cocaine

Amphetamines

Opiates

Abused substances

Affective blunting Dysphoria

Affective

Euphoria Manic-like Mood liability

Depersonalization/derealization Formication Hallucinations (non-specific) Ideas of reference Impulsiveness Inappropriate sexual behavior

Psychotic

Impaired judgment Paranoid delusions Paranoid ideation

Distorted space/time perception Stereotyped behavior Synesthesias Non-specific anxiety

Anxious

Panic-like attacks Phobias

Assaultiveness, belligerence

Miscellaneous

Flashbacks Hypervigilance

Impaired social/occupational skills Interpersonal sensitivity Psychomotor agitation/retardation Tension, anger

Legend More frequently observed symptom

LSD


Less frequently observed symptom

PCP

Phencyclidine

Practically not observed Can decrease

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6.15 Abused substances – withdrawal symptoms Frequently encountered withdrawal symptoms

Nicotine

Benzodiazopines

LSD

Cannabis

Alcohol

PCP

Cocaine

Symptoms

Amphetamines

Opiates

Abused substances

Anxiety Appetite (decreased) Appetite (increased) Autonomic hyperactivity Autonomic hypoactivity Impaired concentration Delirium Dysphoria Diarrhea Dreams (unpleasant) Fatigue Fever Hallucinations (non-specific) Hypersomnia Insomnia Irritability, frustration Lacrimation, rhinorrhea Muscle/bone aches Nausea/vomiting Photophobia Psychomotor agitation Psychomotor retardation Pupillary dilatation Seizures Tremor Tremulousness Yawning

Legend More frequently observed symptom

LSD


Less frequently observed symptom

PCP

Phencyclidine

Practically not observed

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dependence. Alcohol Clin Exp Res 1994; 18: 879–885. Johnson BA, Roace JD, Javors MA et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized clinical trial. JAMA 2000; 284: 1016–1017. Baya M, McIntyre J, Hill K et al. Alcohol withdrawal syndrome. Am Fam Physician 2004; 69: 1443–1450. Schwartz RH. Marijuana: A decade and a half later, still a crude drug with underappreciated toxicity. Pediatrics 2002; 109: 284–289. Iversen L. Cannabis and the brain. Brain 2003; 126: 1252–1270. Rodriguez De Fonseca F, Gorriti MA et al. Role of the endogenous cannabinoid system as a modulator of dopamine transmission: implication for Parkinson’s disease and schizophrenia. Neurotox Res 2001; 3: 23–35. Nichols DE. Hallucinogens. Pharmacol Therap 2004; 101: 131. Marona-Lewicka D, Nichols DE. Behavioral alterations in rats following long term treatment with low doses of LSD. 2002 5th IUPHAR Satellite Meeting on Serotonin: 114. Longo LP, Johnson B. Addiction: Paper I. Benzodiazepines side-effects, abuse risk and alternatives. Am Fam Physician 2000; 61: 212–218. Roache JD, Meisch RA. Findings from self administration research on the addiction potential of benzodiazepines. Psychiatric Ann 1995; 25: 153–157. Parram TV. Prescription drug abuse. A question of balance. Med Clin North Am 1997; 81: 967–78. Dani JA. Role of dopamine signaling in nicotine addiction. Mol Psychiatry 2003; 8: 255–256. Corrigall WA. Nicotine self administration in animals as a dependence model. Nicotine Tob Res 1999; 1: 11–20. Balfour DJK. The psychopharmacology of tobacco dependence. J Clin Psychiatry Monogr 2003; 18: 12–21. Fagerstrom K. Smoking cessation treatment with sustained released bupropion: optimizing approaches to management. Drugs Suppl 2002; 62: 1–70. Baldessarini RJ. Drugs and the treatment of psychiatric disorders: depression and mania. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th edn. (Hardman JG, Limbird LE, Molinoff PB et al, eds.) New York: McGraw-Hill, 2001: 447–485. Ahmadi J, Ashkani H, Ahmade M et al. Twenty four week maintenance treatment of

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cigarette smoking with nicotine gum, clonidine and naltrexone. J Subst Abuse Treat 2003; 24: 252–255. Passie T, Seifert J, Schneider U et al. The pharmacology of psilocybin. Addiction Biol 2002; 7: 357–364. McKenna DJ, Repke DB, Peroutka SJ. Differential interactions of indolealkylamines with 5-hydroxytryptamines receptor subtypes. Neuropsychopharmacology 1990; 29: 193–198. Creese I, Burt DR, Snyder SH. The dopamine receptors: differential binding of d-LSD and related agents to agonist and antagonists states. Life Sci 1975; 17: 15–20. Hidalgo W. Estudio comparative psicofisiologico de la mescaline, dietilamina del acido D-lysergico y psilocibina. Acta Med Venezolana 1960; 8: 56–62. Delay J, Pichot P, Lemperiere T, NicholasCharles PJ. Etude psychophysiologique et clinique de la psilocybine. In: Les champignons hallucinogens due mexique. (Hein R, Wasson RG, eds). Paris: Museum de Histoire Naturelle; 1958: 287–310. Hollister LE. Clinical, biochemical and psychologic effects of psilocybin. Arch Int Pharmacodyn Ther 1961; 130: 42–52. Nichols DE. Hallucinogens. Pharmacol Therap 2004; 101: 131–181. Vollenwider FX. Advances and pathophysiological models of hallucinogenic drug actions in humans: a preamble to schizophrenia research. Pharmacopsychiatry 1998; 31(Suppl 2), 92–103. Brouette T, Anton R. Clinical review of inhalants. Am J Addict 2001; 10: 79–94. Watson JM. Solvents abuse: presentation and clinical diagnosis. Hum Toxicol 1982; 1: 249–256.

70. Fornazzari L. Clinical recognition and management of solvent abusers. Intern Med Specialist 1988; 9: 2–7. 71. Shepherd RT. Mechanism of sudden death associated with volatile substance abuse. Hum Toxicol 1989; 8: 287–291. 72. Wiseman MN, Banim S. ‘Glue sniffer’s’ heart? BMJ 1987; 294: 739. 73. Taylor GJ, Harris WS. Glue sniffing causes heart block in mice. Science 1970; 170: 866–868. 74. Yamanouchi N, Okada S, Kodam K et al. White matter changes by chronic solvent abuse. AJNR Am J Neuroradiol 1995; 168: 1643–1649. 75. Ron MA. Volatile substance abuse: a review of possible long-term neurological, intellectual, and psychiatric sequela. Br J Psychiatry 1986; 148: 235–246. 76. Daynes G, Gillman MA. Psychotropic analgesic nitrous oxide prevents craving after withdrawal for alcohol, cannabis and tobacco. Int J Neurosci 1994; 76: 13–16. 77. Gillman MA. Nitrous oxide abuse in perspective. Clin Neuropharmacol 1992; 15: 297–306. 78. Atkinson RM, Green JD. Personality, prior drug use, and introspective experience during nitrous oxide intoxication. Int J Addict 1983; 18: 717–738. 79. Gyulai FE, Firestone LL, Mintun MA et al. In vivo imaging of human limbic responses to nitrous oxide inhalation. Int J Addict 1983; 18: 717–738. 80. Newell GR, Spitz MR, Wilson MB. Nitrites inhalants: historical perspectives. Natl Inst Drug Abuse Res Monogr Ser 1988; 83: 1–14.

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Chapter 7 Miscellaneous drugs/treatment modalities

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Miscellaneous drugs/treatment modalities

7.1 Drugs for the treatment of dementia of Alzheimer's type (DAT) Suggested mechanisms involved in DAT and potential drug treatments

Late stages of AD

Memantine

Early stages of AD

Glutamate

2⫹

Ca

NMDA rec. Lecithin Choline

Acetyl-CoA

Ca2⫹ Choline–PMT

Cell death

Acetic acid

Decreased secretion of ACh (mechanism unknown)

Choline

No secretion of ACh from affected cells

AChE

Donepezil, tacrine

ACh–R

Galantamine

Acetyl-CoA Acetyl coenzyme A

Legend Stimulates Inhibits

Increased intracelluler concentration

ACh AChE ACh-R AD

Acetylcholine Acetylcholinesterase Acetylcholine receptor Alzheimer's disease

NMDA rec. N-Methyl-D-aspartate receptor PMT

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Much of the current and approved pharmacotherapy of mild to moderate Alzheimer’s disease (AD) is directed at reversing the known deficient cholinergic transmission in AD. In the early stages of AD, there are functional changes in synaptic neurotransmission mediated by acetylcholine while anatomical degeneration of cholinergic projection pathways can be demonstrated in later stages of the disease.1 Hence, most currently approved treatments for AD are based on acetylcholinesterase (AChE) inhibitors (agents that increase cholinergic neurotransmission, e.g. donepezil, galantamine, and rivastigmine). Even so, memantine is an uncompetitive N-methyl-Daspartate (NMDA) antagonist that has demonstrated beneficial effects in moderate to severe AD. Its presumed mechanism of action is based on the assumption that excessive glutamate-mediated activation of NMDA receptors may contribute to the neuronal death that characterizes AD.2

Notes about the scheme Donepezil is an AChE inhibitor that is beneficial in the treatment of mild to moderate AD, and that improves cognitive function and activities of daily living and behavior in AD patients.3 Rivastigmine is an AChE inhibitor that may offer some unique advantages because of its ability to inhibit also butyrylcholinesterase (BuChE). BuChE activity increases in the brains of patients with AD and lowers acetylcholine activity. Thus, it may be an important additional therapeutic target in addition to AChE inhibition.4 Galantamine is an AChE inhibitor that may increase the lifetime of acetylcholine within the synaptic cleft, secondary to its ability to reversibly and competitively inhibit AChE. In addition, it may improve the transduction of the acetylcholine signal by the acetylcholine nicotinic receptor. This latter effect results from the action of galantamine as a positive allosteric modulator of nicotinic receptors in the

brain, improving the efficiency of the coupling between the binding of acetylcholine and the opening of the receptor-associated ion channel. Furthermore, galantamine may be able to preserve the receptor in a state that is responsive to stimulation by acetylcholine, which is a desirable property in view of the rapid agonistinduced desensitization of nicotinic receptors.5 Hence, the actions of galantamine at the receptor site do not proceed to the relatively ‘normal’ desensitization process undergone by most stimulated receptors. Increasing evidence suggests that, besides the already-described deficient cholinergic transmission in AD, disturbances in glutamatergic activity may also play an important role in AD. Accumulating data suggest that NMDA receptor overactivity may contribute, via enhanced calcium ion influx, to the neuronal death that characterizes AD. On the other hand, excessive glutamate-mediated activation of receptors appears to be necessary for normal cognitive function. All in all, it is assumed that a fine equilibrium among NMDA-mediated processes should be achieved in order to maintain proper cognitive functioning. Memantine has a low to moderate affinity for the NMDA receptor, where it acts as a non-competitive antagonist that appears to block pathological , but not physiological, activation of the NMDA receptor. Memantine holds promise for the treatment of moderate to severe AD. It has been shown to improve symptoms and to reduce the rate of clinical deterioration in patients with moderate to severe AD,1 which is quite unique and does not characterize the other approved treatments for AD. Attention is now being turned towards preventive treatments for AD, such as vitamin E, estrogen, lipid-lowering agents, and immunization against amyloid. These treatments are designed to modify the amyloid load6 associated with AD. Other treatment options focus on other areas of neurochemical activity, such as oxidative damage and inflammation. However, none of these approaches has yielded satisfying results so far.7

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7.2 Drugs effective for the treatment of extrapyramidal side-effects (EPS) Suggested mechanisms involved in EPS and potential drug treatments

Dyskinesias Parkinsonism

Dystonia

Akathisia

Hypersensitization of the D2 receptors may cause (1) movement disorders (e.g. TD), (2) compensatory stimulation of NE/5-HT receptors, and (3) compensatory hypercholinergic transmission

Chronic APD treatment (blockade of D2 receptors) causes hypodopaminergic neurotransmission as well as a relative imbalanced dopaminergic–cholinergic neurotransmission (i.e. hypodopaminergic versus intact cholinergic transmission)

D2

D2

5-HT rec.

NE rec.

ACh-R

APDs

APDs

Excess acetylcholine (compensatory to the suppressed dopaminergic transmission caused by the blockade of D2 receptors by the APDs)

Daily fluctuations in serum APD levels occur. At times of low serum APD concentration, D2 receptors are relatively unoccupied, leading to enhanced dopaminergic transmission

Legend

Stimulates

5-HT

Serotonin

ACh-R

Dopamine Acetylcholine Norepinephrine Upregulated receptor

150

APD

Serotonin Acetylcholine receptor Antipsychotic drug

D2

Dopaminergic receptor subtype

NE

Norepinephrine

rec. TD

Receptor Tardive dyskinesia

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Notes about the scheme Extrapyramidal side-effects (EPS) can be caused by practically all antipsychotic drugs (APDs). However, patients receiving first-generation APDs are much more prone to develop these disturbing and often incapacitating adverse effects as compared with those receiving second-generation APDs (SGAs). The exact mechanism underlying the evolution of EPS is not fully understood, although it is apparent that it involves, at least in part, altered manipulation of the dopaminergic system. Thus, a somewhat schematic conceptualization of EPS involves the following cascade of reactions: 1.

2.

3.

4.

5. 6.

Normally, and as long as the subject does not receive APD treatment, the basal ganglia, caudate, putamen, and globus pallidus receive balanced cholinergic versus dopaminergic neural inputs. Following administration of APDs, the drugs antagonize dopaminergic neurotransmission in the nigrostriatal pathway (from the substantia nigra to the basal ganglia), causing imbalanced dopaminergic–cholinergic neurotransmission. This relative ’hypodopaminergic’ and ‘hypercholinergic’ state is believed to be a major factor in drug-induced parkinsonism. Dopaminergic receptors, following chronic APD treatment (probably as a compensatory mechanism), are upregulated and become hypersensitive. This phenomenon is partially effective in recovering the baseline balanced dopaminergic–cholinergic activity, but on the other hand it might be responsible for the tardive movement disorders (dyskinesia) seen most frequently with long-term treatment with first-generation APDs. Normal administration of APDs is characterized by fluctuating serum drug levels. When APD serum levels are temporarily decreased (and while the dopaminergic receptors are steadily hypersensitive), a relative hyperdopaminergic state exists. A possible compensatory cholinergic receptor hypersensitivity occurs, leading in some individuals to dystonic reactions. As a parallel reaction to the relative dopaminergic hypersensitivity, a noradrenergic and probably serotonergic compensatory hyperactivity occurs, leading to akathisia.

Thus, all current available treatments for EPS focus on suppressing one or more of the above-

mentioned overactivated neurotransmitter systems (dopaminergic, noradrenergic, cholinergic, and/or serotonergic).

Benzodiazepines These, via enhancing GABAA receptors, have an inhibitory effect on most brain areas, including on the hyperexcitability of the noradrenergic, serotonergic, and cholinergic systems.

b-adrenergic antagonists These (atenolol, metoprolol, nadolol, and propranolol) are beneficial in the treatment of akathisia (with about a 75% response rate) by blocking the presumed hyperadrenergic activity. They are regarded as first-line agents for this problem, and are considered to be superior to all other anti-akathisia modalities.

Clonidine This is a selective a2-adrenergic agonist that suppresses the release of norepinephrine from presynaptic vesicles into the synaptic cleft, thus reducing its concentration, with a consequent improvement in akathisia.

Anticholinergic drugs These agents block the acetylcholine muscarinic receptors, centrally and peripherally, thereby decreasing cholinergic activity and alleviating adverse effects such as acute dystonia and parkinsonism. The main drugs used for this purpose are benztropine, biperidone, procyclidine, and trihexphenidyl.

Dopaminergic agents These exert their effects by enhancing dopaminergic transmission. Among these are monoamine oxidase inhibitors (MAOIs) (type B). Specifically, selegiline, a MAOI type B that inhibits the degradation of dopamine (thus increasing its availability for synaptic transmission) has shown some beneficial effects in ameliorating EPS. Its exact mechanism is unknown, although it is presumed to act as a dopamine reuptake inhibitor and/or dopamine releaser. Bromocriptine acts as a postsynaptic dopamine agonist.

Zolmitriptan This is a selective 5-HT1D agonist that suppresses the release of serotonin from presynaptic neurons. It is usually used for treating migraine headaches. However, anecdotal data suggest that it is quite beneficial in alleviating akathisic symptoms. This notion is further supported by accumulated data about the beneficial effects of other, albeit nonselective, serotonergic antagonists (cyproheptadine, mianserin, mirtazapine, ritanserin, and trazodone) in treating akathisia.8–11 151

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7.3 Drugs effective for the treatment of extrapyramidal side-effects (EPS) Comparative clinical and side-effect profile

20–70

15–180 30–120 6–8

10–12

⬍72 h

~60

~60

60–90

~60

24

14–25

~4

3–5

6–12

Efficacy in

5-HT2 antagonist AChM1 antagonist ACh non-M1 antagonist a2-ADR antagonist b-ADR antagonist DA releaser DA reuptake inhibitor DA agonist GABAA agonist H1 antagonist NE reuptake inhibitor NMDA antagonist

Legend

5-HT2 Strongest affinity/efficacy

Weakest affinity/efficacy

AChM1

Subtype of serotonergic receptor Acetylcholine muscarinic receptor subtype

ADR

Adrenergic

DA

Dopamine

EPS

Extrapyramidal side-effects

Data not established

GABAA

* Can be given intravenously for faster onset of effects

H1

Histaminergic receptor subtype

NE

Norepinephrine

NMDA

152

Trihexphenidyl

Diazepam 15–60

24

Propranolol

Cyproheptadine ⬍48 h

18–50

Procyclidine*

Clonazepam 60–240

1–8

Orphenadrine

Biperidin 10–30

24

Mianserin

Benztropine 60–120

11–15

Lorazepam

Amantadine ⬎48 h

Akathisia Akinesia Dystonia Rigidity Tremor Onset of action (min) Duration of action (h)

Mechanism of action

Diphenhydramine

Anti-EPS drugs

c-Aminobutyric acid receptor subtype

N-Methyl-D-asparate

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7.4 Electroencephalogram (EEG) Findings associated with specific drugs

a Awake

b

h

d

Eyes closed

Normal EEG

Eyes open Asleep

a

b

h

d

Drugs

a

b

h

d

Antipsychotic drugs

?

Encephalopathy

Benzodiazepines

Encephalopathy

In normal therapeutic doses

Lithium SSRIs Stimulants TCAs

Drugs

?

?

?

a

b

h

d

Antipsychotic drugs Benzodiazepines Lithium

?

SSRIs

?

In toxic doses

Stimulants TCAs

Legend

a wave; 8–13 Hz; medium amplitude

SSRI


TCA


b wave; ⬎13 Hz; low amplitude h wave; 4–7 Hz; medium amplitude d wave; ⬍3 Hz; high amplitude

?

Not enough evidence

Increased prevalence of the specific waves Decreased prevalence of the specific waves

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7.5 Drugs effective for the treatment of obesity Suggested mechanisms involved in obesity and potential drug treatments

Fat-rich diet Increased energy (fat) stores Decreased energy (fat) stores

O

Histamine (by activating central H1 receptor)

?

Ghrelin

Leptin

S 5–HT2c ObRb

GHSR GABA

5–HT2C

ObRb

D2(?)

a1

S GABAergic neuron

POMC/CART neurons

NPY/AgRP neurons

? NPY or AgRP

a-MSH

Anorexogenic ('weight-losing') substances

TRH ACh CCK

MCH

GLP1 5HT NE

OX-A OX-B

Orexigenic ('weight-gaining') substances

S

Legend Action potential

5-HT 5-HT2C ACh AgRP

Stimulates Inhibits

APD a1 a-MSH

S

Sibutramine

O

Orlistat

?

154

CART CCK GABA

Not well established

GLP1

Serotonin

GHSR

Growth hormone secretagogue receptor

MCH

Melanin-concentrating hormone

Serotonergic receptor subtype Acetylcholine Agouti-related gene product

NE

Norepinephrine

NPY

Neuropeptide Y

Antipsychotic drug Noradenergic receptor subtype Melanocortin-stimulating hormone Cocaine- and amphetamineregulated transcript Cholecystokinin c-Aminobutyric acid Glucagon-like peptide 1

ObRb OX-A/B POMC TRH

Functional long leptin receptor Orexin A/B Propiomelanocortin Thyroid stimulating hormone (TSH)-releasing hormone

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In many industrialized nations, obesity is considered an epidemic, resulting in accelerated morbidity and mortality. Obesity is associated with an increased risk of coronary artery disease as well as a metabolic syndrome comprising abdominal obesity, increased fasting blood glucose levels, dyslipidemia, and hypertension, all of which are recognized cardiovascular risk factors. Diet, exercise, and lifestyle changes constitute important recommendations for treatment. Unfortunately, although they are effective in some individuals, these recommendations have proven to be ineffective in adequately addressing the broad, enlarging scope of this public problem. Sibutramine, an inhibitor of serotonin and norepinephrine reuptake, and orlistat, a gut lipase inhibitor, have been approved by the US FDA for body weight loss. Ongoing studies are continuing to evaluate other drug treatments that may result in body weight reduction through a number of different mechanisms.12

Notes about the scheme Sibutramine is a serotonin and norepinephrine reuptake inhibitor (SNRI) and represents a new class of agents approved by the FDA for the treatment of obesity. It induces weight loss by affecting the physiological process of satiety and stimulating thermogenesis. Its mode of action is far from being established. However, accumulating data suggest that it may increase the concentration of anorexogenic substances (i.e. norepinephrine and serotonin), it may act at the level of the hypothalamus by interfering with neuropeptide Y activities, and it may enhance the activity of leptin (which is a peripheral factor that relays the status of fat stores and is a key modulator of the ‘anorexogenic cycle’)13 in that it induces satiety. All in all, the reduction in body weight and adiposity induced by sibutramine is achieved by both a reduction in food intake and an increase in energy expenditure.

Orlistat inhibits pancreatic lipase and can block 30% of triglyceride hydrolysis in subjects eating a 30% fat diet. Several orlistat and sibutramine weightloss studies have been performed to date. Compared with placebo, orlistat-treated patients lose about 3 kg and patients on sibutramine lose about 4 kg. Orlistat causes gastrointestinal side-effects (e.g. diarrhea, and frequent and fatty stools) and sibutramine is usually associated with small increases in blood pressure and pulse rate.14–16 Other substances are currently being evaluated for treating obesity. One of these is: zonisamide, an antiepileptic agent that has serotonergic and dopaminergic activity in addition to blockade of sodium and calcium channels.17 It has been demonstrated to induce more weight loss than placebo when combined with a hypocaloric diet. Topiramate, an antiepileptic agent that suppresses appetite in some patients, is a potential therapeutic agent for the treatment of obesity.18 Bupropion (an antidepressant licensed as an aid for smoking withdrawal) inhibits the reuptake of norepinephrine and dopamine and has appetite-suppressant properties (demonstrated to be more effective than placebo for weight reduction).19,20 Leptin, a hormone produced by adipocytes that inhibits food intake, has undergone clinical trials, and analogs are currently being developed. Other agents include amylin, CB1 antagonists, melanocortin-4 receptor agonists, neuropeptide Y antagonists, b3adrenergic agonists, and glucagon-like peptide-1 agonists. As some redundancy exists in the central regulatory system controlling body weight, some agents might need to be used in combination in order to exert more beneficial responses. All in all, it is of paramount importance to combine a balanced diet and moderate exercise under the supervision of the treating physician together with antiobesity drugs in order to achieve optimal results.12

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7.6 Electroconvulsive therapy (ECT) Supposed mechanism of action

ECT At neuronal level

Unknown EAA

At brain level

?Ca

NMDA rec.

2⫹

G-protein

AChM

Restores hemispheric imbalance Acts as a zeitgeber (resynchronizes abnormal endogenous rhythms) Alters several sleep parameters Increases cerebral blood flow Increases permeability of BBB

2⫹

b-ADR

Increased Ca

5-HT2

Decreased AC, PLC

Increased synaptic

5-HT, BDNF, GABA, NE and the production of an unknown

Increases seizure threshold Suppresses limbic kindling

endogenous anticonvulsant

5-HT/5-HT2

Legend

Changes Stimulates Inhibits Upregulates

AC AChM BBB BDNF b-ADR

Downregulates EAA GABA NE NMDA rec. PLC

156

Serotonin/serotonergic receptor subtype (upregulated during ECT) Adenylate cyclase Acetylcholine muscarinic receptor (downregulated during ECT) Blood–brain barrier Brain-derived neurotrophic factor Noradrenergic receptor subtype (downregulated during ECT) Excitatory amino acid (unknown) c-Aminobutyric acid Norepinephrine N-Methyl-D-aspartate receptor Phospholipase C

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Electroconvulsive therapy (ECT) is probably the most effective treatment for major depressive disorder (MDD) with psychotic features, with average response rates of 70–90%, compared with only about 40% for ‘regular’ antidepressant medications. The response rates for MDD without psychosis are comparable between ‘regular’ medications and ECT (about 70–75%). ECT is usually given to patients whose condition is refractory to or who are intolerant of antidepressant medication. However, ECT may be considered the firstline option for specific severe cases such as suicidal patients, catatonically stuporous patients, or those refusing food and fluids. Additionally, ECT is highly effective for mania, catatonic states, and certain cases of schizophrenia. Moreover, it has been reported to ameliorate the motor symptoms of Parkinson’s disease and various other movement disorders, such as tardive dyskinesia and neuroleptic malignant syndrome (NMS).21

Notes about the scheme ECT affects both intracellular and intercellular functioning. The most consistent alterations in intracellular functions are certain modulations of receptor functioning, among them stimulation of the N-methyl-D-aspartate (NMDA) receptor for glutamate, downregulation of postsynaptic b-adrenergic and acetycholine muscarinic receptors, and upregulation of postsynaptic 5HT2A serotonergic receptors. Moreover, ECT inhibits the coupling of various neurotransmitters to their corresponding Gproteins, with a consequent decrease in phospholipase C and adenylate cyclase activities. It has also been proposed that ECT induces the production of an endogenous anticonvulsant that, when released into the synaptic cleft, might increase the seizure threshold and/or suppress limbic kindling. The mechanism underlying the clinical efficacy of ECT in several syndromes, and especially in affective disorders, is unclear as yet. Animal studies support the observation that ECT stimulates the release of various cathecholamines (especially norepinephrine and serotonin) into

the synaptic cleft, with a consequent increase in their availability for neuronal transmission. Moreover, ECT is also suggested to suppress both presynaptic a2-adrenergic and postsynaptic 5-HT1A serotonergic receptors, leading to increased secretion of norepinephrine, serotonin, and dopamine. Furthermore, long-term ECT treatment, as with most of the various antidepressant modalities, is associated with increased and continuous expression of certain neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). The role of these factors in depression is discussed in detail in Sections 2.1 and 2.3. Seizure induction is the most relevant and necessary event that has to take place in order to achieve the therapeutic effects of ECT. It is a very safe procedure (the death rate due to treatment is approximately 1 in 10 000 patients). Although ECT has no absolute contraindications, relative contraindications include the presence of a brain tumor, increased intracranial pressure, unstable myocardial infarction, and American Society of Anesthesiology risk level 4 or 5.22,23 In contrast to the rarity of medical complications associated with ECT, memory disturbances of varying severity are common and are by far the most bothersome adverse effects. Alterations in global brain functioning or in interneural transmission are also evident during ECT. Some data, based mainly on neuropsychological testing, suggest that MDD might be associated with right-hemispheric dysfunction, while ECT has been shown to normalize these functions. Furthermore, certain mood disorders are associated with desynchronization of certain circadian rhythms, such as the ‘24-hour biological clock’, and ECT has been shown to normalize such dysregularities, thus serving as an exogenous zeitgeber. Several abnormal sleep parameters are also normalized following ECT, especially the short rapid eye movement sleep latency, the reduced slow-wave sleep, and the high nocturnal temperature associated with depressive disorders. Other and less consistent evidence suggests that ECT is associated with increased cerebral blood flow and increased permeability of the blood–brain barrier.

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7.7 Major depressive disorder with seasonal pattern (MDDSP) Supposed mechanism of action of light therapy in major depressive disorder as part of MDDSP

Delay

Light therapy Phase-delay

MDDSP

SCN

24-hour clock

Normal timing of circadian rhythms

Advance

Legend

Induces 'phase-advance' Induces 'phase-delay'

Notes about the scheme Major depressive disorder with seasonal pattern (MDDSP) is characterized, clinically, by a depressed mood that occurs at the same time each year, virtually every year since the disorder was first experienced. These depressive states (usually modest) are often termed ‘winter depression’ since they worsen as the duration of light hours is reduced during the year. The prevalence of MDDSP is estimated to be around 5% in the USA and women are affected five times more than men. As the population is located further from the equator, more people are affected. The pathophysiology of MDDSP is not fully understood, although it is assumed to be associated with altered circadian rhythms. Basic circadian rhythms are regulated by several endogenous or exogenous pacemakers. The major endogenous pacemaker is probably located in the suprachiasmatic nucleus (SCN) of the hypothalamus. One of the major exogenous pacemakers is the light–dark cycle, in which different durations of light or dark hours affect

158

MDDSP Major depressive disorder with seasonal pattern SCN Suprachiasmatic nucleus of hypothalamus

the timing of sleep induction, hormone secretion, and many other biological rhythms. In healthy, euthymic subjects, the ratio of light to dark hours triggers the SCN to induce certain activities, including sleep, hormone secretion, and the secretion of melatonin (which may only serve as a marker associated with changes related to MDDSP) via stimulating the pineal gland. MDDSP is characterized, among other things, by a basic state of ‘phase-delay’ circadian rhythm. This means that the same triggered activities (by the SCN) are induced at a later time in the day (24-hour clock) than in nonMDDSP patients. Empirical data suggest that when a person is exposed to bright light during the light hours, the SCN is stimulated to induce its activities at an early time in the 24-hour cycle. This is termed ‘phase-advance’ circadian rhythm. If it is administered to a MDDSP patient, the ‘phase-advance’ is superimposed on a ‘phasedelay’ status, which may bring the system (e.g. the SCN) to an equilibrium, normalizing circadian rhythms, and at the same time ameliorating the depressive symptoms of MDDSP.24–26

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References 1. Zhang X. Cholinergic activity and amyloid precursor protein processing in aging Alzheimer’s disease. Curr Drug Targets CNS Neurol Disord 2004; 3: 137–152. 2. Ferris SH. Evaluation of memantine for the treatment of Alzheimer’s disease. Expert Opin Pharmacother 2003; 4: 2305–2313. 3. Birks JS, Harvey R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev 2003; (3): CD001190. 4. Rasler M, Anand R, Cicin-Sain A et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease. N Engl J Med 348; 14: 1333–1341. 5. Maelicke A, Samochocki M, Jostock R et al. Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer’s disease. Biol Psychiatry 2001; 49: 279–288. 6. Sano M. Noncholinergic treatment options for Alzheimer’s disease. J Clin Psychiatry 2003; 64(Suppl 9): 23–28. 7. Mintzer JE. The search for better noncholinergic treatment options for Alzheimer’s disease. J Clin Psychiatry 2003; 64(Suppl 9): 18–22. 8. Tandon R, Jibson MD. Extrapyramidal side effects of antipsychotic drug treatment: scope of problem and impact and outcome. Ann Clin Psychiatry 2002; 14: 123–129. 9. Poyurovsky M, Weizman A. Serotonin-based pharmacotherapy for acute neurolepticsinduced akathisia: a new approach to an old problem. Br J Psychiatry 2001; 179: 4–8. 10. Isseroff–Gross R, Magen A, Shiloh R et al. The 5-HT1D receptor agonist zolmitriptan for neuroleptics induced akathisia: an open label preliminary study. Int Clin Psychopharmacol 2005; 20: 23–25. 11. Stryjer R, Strous RD, Bar F et al. Treatment of neuroleptics induced akathisia with the 5-HT2A antagonist trazodone. Clin Neuropharmacol 2003; 26: 137–141. 12. Bays H, Dujovne C. Pharmacotherapy of obesity: currently marketed and upcoming agents. Am J Cardiovasc Drugs 2002; 2: 245–253. 13. Bouret SG, Simerly RB. Minireview: Leptin and development of hypothalamic feeding circuits. Endocrinology 2004; 145: 2621–2626.

14. Padwal R, Li Sk, Lau DC. Long term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev. 2003; (4): CD004094. 15. Sahu A. Minireview: A hypothalamic role in energy balance with special emphasis on leptin. Endocrinology 2004; 145: 2613. 16. Appolinario JC, Bacaltchuk J, Sichiera R et al. A randomized, double blind, placebocontrolled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry 2003; 60: 1109–1116. 17. Gadde KM, Franciscy DM, Wagner HR et al. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 2003; 9; 289: 1820–1825. 18. Chengappa KN, Gershon S, Levine J. The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder. Bipolar Disord 2001; 3: 215–232. 19. Jain AK, Kaplan RA, Gadde KM et al. Bupropion versus placebo with depressive symptoms. Obes Res 2002; 10: 1049–1056. 20. Anderson JW, Greenway FL, Fujoika K et al. Bupropion SR enhances weight loss: a 48-week double blind, placebo-controlled trial. Obes Res 2002; 10: 633–641. 21. Rasmussen KG, Shirlene M et al. Electroconvulsive therapy and newer modalities for the treatment of medication refractory illness. Mayo Clin Proc 2002; 77: 552–556. 22. American Psychiatry Association Committee on Electroconvulsive Therapy. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging, 2nd edn. Washington, DC: American Psychiatric Association, 2001. 23. Abrams R. Electroconvulsive Therapy, 3rd edn. New York: Oxford University Press, 1997. 24. Rosenthal NE, Sack DA, Gillin JC et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41: 72–80. 25. Neumeister A. Neurotransmitter depletion and seasonal affective disorder: relevance for the biologic effects of light therapy. Primary Psychiatry 2004; 11: 44–48. 26. Rudorfer MV, Skwerer RG, Rosenthal NE et al. Biogenic amines in seasonal affective disorder: effects of light therapy. Psychiatry Res 1993; 46: 19–28.

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Chapter 8 Drug interactions

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8.1 Tricyclic and tetracyclic antidepressant drugs Drug interactions

Acetaminophen (paracetamol) Alprazolam Cimetidine Contraceptives Diazepam Erythromycin Fluoxetine Fluvoxamine Haloperidol Levomepromazine Methylphenidate Paroxetine Perphenazine Tricyclic antidepressants Thioridazine Thyroxine

Antidiabetics Insulin Thioridazine Thiothixene (possibly other antipsychotics) Warfarin

Clonidine Guanethidine

Digoxin Heparin

Monoamine oxidase inhibitors (MAOIs) Selective serotonin reuptake inhibitors (SSRIs)

Alcohol (ethanol) abuse (chronic) Barbiturates Carbamazepine Clonazepam Fiber-rich diet Phenytoin Smoking

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Drugs that can increase the serum levels/effects of tricyclic antidepressants

Drugs whose serum levels/effects can be increased by tricyclic antidepressants

Drugs that can decrease the serum levels/effects of tricyclic antidepressants

Drugs whose serum levels/effects can be decreased by tricyclic antidepressants

Drugs whose therapeutic effects were shown to be opposed by tricyclic antidepressants

Drugs that can cause significant and severe side-effects due to additive impact (not due to toxicity)

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Alcohol (ethanol)

Benzodiazepines

Chronic abuse of alcohol can lead to enhanced activity of cytochrome P450 enzymes and a consequent decrease in tricyclic antidepressant (TCA) serum levels. Central receptor interactions between alcohol and TCAs can cause impaired motor abilities (evident with amitriptyline, clomipramine, doxepin, and nortriptyline).

Most studies have revealed no significant interactions with TCAs. Anecdotal reports suggest that alprazolam might increase the serum levels of imipramine by up to 30%. Clonazepam can decrease desipramine levels, while diazepam can increase amitriptyline serum levels in a few cases.

Anticoagulants

This lowers serum levels of TCAs (desipramine and doxepin), probably due to decreased gastrointestinal absorption of TCAs.

There are anecdotal reports of trazodone decreasing heparin serum levels by about 20%. Clomipramine, nortriptyline, and trazodone can raise warfarin serum levels up to 30%.

Anticonvulsants Phenytoin, a liver enzyme inducer, decreases serum levels of TCAs (especially desipramine and clomipramine). An increase in serum levels of nortriptyline and trazodone has also been reported. In these cases, the net effect of enzyme induction (by phenytoin) and enzyme inhibition (by TCAs) seem to be in ‘favor’ of the inhibitory effects. Carbamazepine also induces liver enzymes, with a consequent reduction in serum levels of TCAs (amitriptyline, desipramine, doxepin, and nortriptyline). These effects of carbamazepine have not been observed with clomipramine, but have been reported with selective serotonin reuptake inhibitors (SSRIs).

Antihypertensive agents The antihypertensive effects of clonidine are reduced by about 50% when it is co-administered with clomipramine or desipramine. The antihypertensive effects of guanethidine can be reduced by doxepin, amitriptyline, or desipramine, but not by maprotiline.

Antipsychotic drugs (APDs) Most APDs, as well as TCAs, are inhibitors of the cytochrome P450 enzymes, thus potentially increasing each other’s serum levels. For haloperidol, an increase in serum levels of TCAs (by about 2-fold) is found in up to 10% of patients treated with clomipramine or nortriptyline (but is not found with desipramine). Levomepromazine can significantly increase clomipramine serum levels. Perphenazine has been found to increase serum levels of amitriptyline, desipramine, and nortriptyline, while thioridazine has been reported to increase desipramine serum levels. Thiothixene levels are usually increased by TCAs such as doxepin, nortriptyline, and clomipramine (the latter combination increases the risk for tardive dyskinesia).

Barbiturates These can induce cytochrome P450 enzymes, with a consequent reduction in serum levels of TCAs (observed with amitriptyline, clomipramine, desipramine, and notriptyline).

Fiber-rich diet

Methylphenidate This can increase TCA serum levels (clomipramine and nortriptyline). Desipramine levels were not found to be impaired, although an additive adverse effect profile is evident (nausea, tremor, and tachycardia).

Monoamine oxidase inhibitors (MAOIs) Co-administration is usually safe and effective, although rare cases of serotonin syndrome are documented. Amitriptyline and nortriptyline are safer than clomipramine, desipramine, or imipramine. Clomipramine should be avoided. Additive toxicity is rare, and could be evidenced by hyperpyrexia, convulsions, cardiac collapse, and death. No significant interactions were found with amitriptyline or desipramine and moclobemide.

Morphine Amitriptyline, clomipramine, desipramine, and doxepin can enhance the analgesic and respiratory effects of morphine (mediated by serotonergic stimulation).

Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine inhibits cytochrome P450 liver catabolic enzymes, leading to increased TCA serum levels by 2–4-fold. This is most evident with amitriptyline, clomipramine, desipramine, and nortriptyline. Such changes were not found, even though tested, with the doxepin–fluoxetine regimen. More modest increases are found when fluoxetine is combined with trazodone. Fluvoxamine also inhibits cytochrome P450 liver catabolic enzymes, leading to potential increases in TCA serum levels by 1–2-fold. This is evident with amitriptyline, clomipramine, desipramine, and nortriptyline. With paroxetine, TCA levels could increase by up to 5-fold via inhibition of cytochrome P450 enzymes.

Smoking Components of cigarettes/tobacco are hepatic enzyme inducers, leading to a decrease in TCA serum levels (up to 50% reduction in serum levels of amitriptyline, clomipramine, or desipramine), although this is not evident with nortriptyline.1,2 163

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8.2.1 Selective serotonin reuptake inhibitors – citalopram/escitalopram Drug interactions

Fluvoxamine

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Antiarrhythmics b-blockers (alprenolol, bufanol, metoprolol, propranolol, timolol) Tricyclic antidepressants (TCAs) (relevant mainly with desipramine) Antipsychotic drugs (APDs) (levomepromazine)

Buspirone Monamine oxidase inhibitors (MAOIs) (documented with moclobemide) Sumatriptan

Drugs that can increase the serum levels/effects of (es)citalopram

Drugs whose serum levels/effects can be increased by (es)citalopram

Drugs that can decrease the serum levels/effects of (es)citalopram

Drugs whose serum levels/effects can be decreased by (es)citalopram

Drugs whose therapeutic effects were shown to be opposed by (es)citalopram


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Drug interactions Citalopram This selective serotonin reuptake inhibitor (SSRI) is N-demethylated to N-desmethylcitalopram, partially by the cytochrome P450 enzyme CYP2C19 and partially by CYP3A4, and N-desmethylcitalopram is further N-demethylated by CYP2D6 to the likewise inactive metabolite desmethylcitalopram. Current data suggest that citalopram is neither the source nor the cause of any clinically important pharmacokinetic drug–drug interactions. Other SSRIs (e.g. fluvoxamine, fluoxetine, and paroxetine) display greater in vitro inhibition of CYP3A4, CYP2D6, CYP2C19, and CYP1A2 than citalopram, and this is reflected in their drug interaction profile. This suggests that citalopram may be a better choice than the other SSRIs in patients who are at high risk of experiencing metabolic drug interactions, for example patients on polypharmacotherapy and particularly elderly patients, who may be more sensitive to alterations in drug concentrations.3,4

Antidepressants Addition of citalopram does not significantly affect the plasma concentration of tricyclic antidepressants (TCAs) such as amitriptyline, clomipramine, or imipramine. However, citalopram may increase desipramine plasma concentrations by up to 50%

Antipsychotic drugs (APDs) Citalopram does not interfere with the metabolism of APDs. At a dose of 40 mg/day, citalopram caused no significant changes in plasma concentrations of chlorpromazine, clozapine, haloperidol, perphenazine, thioridazine, or zuclopenthixol. Anecdotal data suggest that citalopram may increase the serum levels of levomepromazine.

b-adrenergic blockers Citalopram may increase plasma levels of various b-blockers (mainly evident with metoprolol).

Benzodiazepines There are no data of the effects of citalopram on the pharmacokinetics of benzodiazepines.

Buspirone There is one documented case report of serotonin syndrome when citalopram was combined with buspirone.

Lithium Citalopram does not appear to alter the kinetics of lithium when the two are co-administered.

Miscellaneous Neither citalopram nor selegiline appear to be affected by one another. Citalopram does not

have any significant effect on serum levels of digoxin. There have been no case reports or controlled studies investigating the pharmacokinetic interaction between citalopram and alcohol (ethanol). However, citalopram has been used in several studies as an adjunct treatment of alcohol dependence, where it seems to have clinical efficacy, and there appears to be no evidence for acute kinetic or dynamic interactions between alcohol and citalopram.

Moclobemide There have been a few documented cases of serotonin syndrome when citalopram was combined with moclobemide.

Other SSRIs There are no published data about pharmacokinetic interactions between citalopram and any of the other SSRIs.

Sumatriptan There is an increased risk of central nervous system toxicity when citalopram is combined with sumatriptan.

Warfarin Co-administration of warfarin and citalopram produces a small increase in mean prothrombin time. This probably has minor or no clinical significance. Escitalopram This may be considered one of the safest SSRIs with respect to pharmacokinetic drug interactions.

Antidepressants Escitalopram may increase desipramine plasma concentrations by up to 50%. This was explained by a weak inhibitory effect of desmethylcitalopram on CYP2D6, the isoform responsible for the 2-hydroxylation of desipramine.

APDs Escitalopram does not interfere with the metabolism of APDs.

b-adrenergic antagonists Escitalopram may increase plasma levels of metoprolol.

Lithium No pharmacokinetic interaction has been noted when escitalopram is combined with lithium.

Sibutramine A case of hypomania has been reported when citalopram/escitalopram were combined with sibutramine.

Sumatriptan There is an increased risk of central nervous system toxicity when escitalopram is combined with sumatriptan.5,6 165

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8.2.2 Selective serotonin reuptake inhibitors – fluoxetine Drug interactions

Benzodiazepines (metabolized by oxidation: alprazolam, chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, quazepam, temazepam, triazolam) b-blockers (alprenolol, bufanol, metoprolol, propranolol, timolol) Bupropion Carbamazepine Clozapine Haloperidol Cyclic antidepressants (not doxepin and less with trazodone) Methadone Morphine Phenytoin Risperidone Sertaline Trazodone Valproate Warfarin

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Antipsychotic drugs (clozapine, fluphenazine, perphenazine, sulpiride, thiothixene) Buspirone Lithium Monamine oxidase inhibitors (MAOIs)

Chlordiazepoxide Cyproheptadine

Drugs that can increase the serum levels/effects of fluoxetine

Drugs whose serum levels/effects can be increased by fluoxetine

Drugs that can decrease the serum levels/effects of fluoxetine

Drugs whose serum levels/effects can be decreased by fluoxetine

Drugs whose therapeutic effects were shown to be opposed by fluoxetine


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Alcohol (ethanol) The pharmacokinetics of alcohol are not significantly affected by fluoxetine.

Antidiabetic drugs There are anecdotal data indicating enhanced hypoglycemia capacity when fluoxetine is added to hypoglycemic agents or given to insulin-dependent patients.

Anticonvulsants Fluoxetine and its metabolite norfluoxetine are mild to moderate inhibitors of CYP3A4, the major cytochrome P450 enzyme involved in the metabolism of carbamazepine. The inhibitory effect of fluoxetine on carbamazepine metabolism might occur only at doses higher than 20 mg/day. Fluoxetine may impair phenytoin metabolism, resulting in phenytoin intoxication.

Antidepressants Fluoxetine at a dose of 20–60 mg/day, may cause a 2–4-fold increase in plasma concentration of tricyclic antidepressants (TCAs), possibly associated with signs of toxicity, including decreased energy, psychomotor retardation, sedation, dry mouth, and memory loss. The mechanism of this interaction may be attributed to the potent inhibitory effect of fluoxetine and norfluoxetine on the CYP2D6-mediated hydroxylation of TCAs. When given in combination with the heterocyclic antidepressant trazodone, fluoxetine was found to produce a significant elevation in plasma levels of both trazodone and its metabolite m-chlorophenylpiperazine (mCPP).

Antipsychotic drugs In a few cases, marked extrapyramidal sideeffects (akathisia, dystonia, and parkinsonism) have been reported with fluphenazine, perphenazine, sulpiride, and thiothixene when fluoxetine is added to the regimen. The mechanism is speculated to be the result of fluoxetine-induced further suppression of dopaminergic activity in the nigrostriatal pathways (serotonergic stimulation leads to decreased dopamine release), in addition to increases in their plasma concentration. Fluoxetine has been shown to increase haloperidol serum levels by about 20%, presumably via inhibition of cytochrome P450 enzymes. Fluoxetine can increase the risk of seizure induction when added to clozapine due to an increase in clozapine serum levels, or by additive effects. Concomitant treatment with fluoxetine and risperidone is associated with a mean 4-fold increase in the plasma concentration of risperidone.7

Benzodiazepines Fluoxetine may impair the elimination of some benzodiazepines such as diazepam and

alprazolam, potentially increasing their serum levels.

b-adrenergic blockers Fluoxetine has some capacity to inhibit the oxidative metabolism of b-adrenergic blockers (especially the lipophilic ones: metoprolol, pindolol, and propranolol), thus raising their serum levels. This might explain the occurrence of severe bradycardia or heart block.

Calcium-channel blockers The combination of fluoxetine with the calcium-channel blockers nifedipine and verapamil has been reported to be associated with signs of toxicity such as edema, nausea and flushing.

Bupropion A few cases have been reported suggesting that bupropion metabolism might be inhibited by fluoxetine, which could eventually lead to abrupt emergence of psychosis and seizure disorder.

Buspirone Fluoxetine can antagonize the anxiolytic effects of buspirone. Serotonin syndrome and seizure disorder have also been reported with this combination.

Cyproheptadine This can antagonize the antidepressant effects of fluoxetine, probably via the antiserotonergic properties of cyproheptadine.

Lithium Evidence is not conclusive. The combined lithium–fluoxetine regimen is generally considered as safe. Even so, a few isolated reports have described the emergence of lithium toxicity, seizure induction, delirious state, and serotonin syndrome with the combined lithium–fluoxetine regimen.

Methadone Fluoxetine may increase the serum levels of methadone.

Monoamine oxidase inhibitors (MAOIs) The concurrent use of fluoxetine and MAOIs (phenelzine and tranylcypromine) can induce a high incidence (up to 50%) of toxic reactions, including fatal serotonin syndrome.

Morphine Fluoxetine may increase the serum levels of morphine.

Warfarin There may be a marked elevation of the International Normalized Ratio (INR) and prolongation of prothrombin time when fluoxetine is combined with warfarin.4,8 167

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8.2.3 Selective serotonin reuptake inhibitors – fluvoxamine Drug interactions

Benzodiazepines (alprazolam, bromazepam, midazolam, triazolam) b-blockers (alprenolol, bufanol, metoprolol, propranolol, timolol) Carbamazepine Clozapine Haloperidol Methadone Mirtazapine Olanzapine Tricyclic antidepressants (TCAs) (amitriptyline, clomipramine, desipramine, imipramine, maprotiline, nortriptyline) Theophylline Warfarin

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168

Alcohol (ethanol) Levomepromazine Lithium Monoamine oxidase inhibitors (MAOIs) (phenelzine, tranylcypromine)

Coumarin

Drugs that can increase the serum levels/effects of fluvoxamine

Drugs whose serum levels/effects can be increased by fluvoxamine

Drugs that can decrease the serum levels/effects of fluvoxamine

Drugs whose serum levels/effects can be decreased by fluvoxamine

Drugs whose therapeutic effects were shown to be opposed by fluvoxamine


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Alcohol (ethanol) The pharmacokinetics of alcohol are not significantly affected by fluvoxamine.

Anticoagulants A potentially dangerous interaction may occur between fluvoxamine and warfarin. There is a 65% increase in plasma warfarin concentration and a significant prolongation of prothrombin time. The selective serotonin reuptake inhibitors (SSRIs) increase the risk of upper gastrointestinal bleeding, and this effect is potentiated by the concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. There are anecdotal reports of bleeding disorder with the concomitant use of nicoumalone (a coumarin derivate), ibuprofen, and warfarin.

Anticonvulsants Co-administration with fluvoxamine may result in increases in carbamazepine serum levels by up to 60%. The mechanism is not totally understood, since carbamazepine is metabolized mainly by the cytochrome P450 enzyme CYP3A4 while fluvoxamine is metabolized by CYP1A2. CYP3A4 is not significantly affected by fluvoxamine.

Antidepressants Fluvoxamine inhibits the cytochrome P450 liver catabolic enzymes (predominantly this is inhibition of N-demethylation), leading to an increase in tricyclic antidepressant (TCA) serum levels. Plasma levels of several antidepressant drugs (e.g. amitriptyline, clomipramine, desipramine, imipramine, maprotiline, and nortriptyline) have been reported to increase by up to 4-fold during co-administration with fluvoxamine. Fluvoxamine at a daily dose of 50–100 mg causes a 3–4-fold increase in the plasma concentration of mirtazapine.

Antipsychotic drugs Addition of fluvoxamine 50–300 mg to haloperidol results in a 1.8–4.2-fold increase in serum haloperidol concentration. Fluvoxamine may increase the plasma clozapine concentration by about 5–10-fold, possibly resulting in toxic effects. Fluvoxamine has also been found to increase olanzapine plasma concentration by approximately 2-fold. Fluvoxamine can increase the risk of seizure induction when combined with levomepromazine.

Benzodiazepines Fluvoxamine may decrease the metabolism of alprazolam and diazepam. However, most of the current data suggest that there are no

clinically significant pharmacokinetic interactions between fluvoxamine and benzodiazepines.

b-adrenergic blockers Co-administration of fluvoxamine 100 mg/day with propranolol 160 mg/day can result in up to a 5-fold increase in plasma propranolol concentrations (without major impairments in blood pressure or cardiac transmission). This is due, probably, to the fact that both propranolol and fluvoxamine are metabolized by hepatic CYP1A2.

Methadone In addicts on maintenance treatment with methadone, fluvoxamine but not fluoxetine was found to increase the plasma concentration of methadone by about 30–50%.

Lithium Established data are lacking. Lithium may enhance the serotonergic effects of fluvoxamine, and a few cases of hyperpyrexia and/or induction of seizure disorder were reported with a combined lithium–fluvoxamine regimen.

Monoamine oxidase inhibitors (MAOIs) Few data are available about fluvoxamine interactions with MAOIs, even though they might be comparable to those of fluoxetine. It must be remembered that the concurrent use of fluoxetine and MAOIs (phenelzine and tranylcypromine) can induce a high incidence (up to 50%) of toxic reactions, including fatal serotonin syndrome.

Reversible inhibitors of monoamine oxidase type A (RIMAs) To date, clinically significant or severe interactions between fluvoxamine and moclobemide have not been found in several relatively well-controlled studies.

Theophylline Concomitant treatment with fluvoxamine may cause a marked elevation in plasma theophylline levels associated with signs of theophylline toxicity, including ventricular tachycardia, anorexia, nausea, and seizures. This is due, probably, to the fact that both theophylline and fluvoxamine are metabolized (at least to some extent) by hepatic CYP1A2. As theophylline toxicity is a serious, sometimes fatal, condition, fluvoxamine should be avoided in patients taking theophylline. Even at low daily doses (10–20 mg), fluvoxamine inhibits the metabolism of caffeine, another methylxanthine.4,7,8 169

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8.2.4 Selective serotonin reuptake inhibitors – paroxetine Drug interactions

Antacids (paroxetine is exposed longer to carriers in the gastrointestinal tract, leading to enhanced absorption) Cimetidine Haloperidol Tricyclic antidepressants (TCAs) Thioridazine

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Benzodiazepines (alprazolam, midazolam, triazolam) b-blockers (alprenolol, bufanol, metoprolol, propranolol, timolol) Haloperidol Monoamine oxidase inhibitors (MAOIs) (tranylcypromine) Phenytoin Tricycle antidepressants (TCAs) Warfarin

Carbamazepine Phenytoin

Drugs that can increase the serum levels/effects of paroxetine

Drugs whose serum levels/effects can be increased by paroxetine

Drugs that can decrease the serum levels/effects of paroxetine

Drugs whose serum levels/effects can be decreased by paroxetine

Drugs whose therapeutic effects were shown to be opposed by paroxetine


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Drug interactions Paroxetine is metabolized by the hepatic cytochrome P450 enzyme CYP2D6. Hence, it is susceptible to pharmacokinetic interaction with drugs that either induce or inhibit this enzyme. In addition to being metabolized by CYP2D6, paroxetine inhibits this enzyme. This may lead to enhanced plasma concentrations of any co-administered drugs that are metabolized by CYP2D6.

Alcohol (ethanol) and sedative drugs Paroxetine does not appear to potentiate the sedative effects of psychomotor retardation induced by amylobarbital, alcohol, or oxazepam.

Antidiabetic drugs Paroxetine is highly protein-bound, and in vitro studies have shown that it does not significantly alter the protein binding of glibenclamide.

Anticonvulsants Serum levels of paroxetine can decrease when it is co-administered with anticonvulsants (some of which are enzyme inducers). The data are limited, but it seems that phenytoin may cause the greatest decrease, followed by carbamazepine. Valproate serum levels are unchanged by paroxetine co-administration.

Antidepressants Paroxetine levels might be increased (tricyclic antidepressants (TCAs) inhibit its metabolism); this is evident mainly with amitriptyline, desipramine, imipramine, and nortriptyline. Note that TCA levels could also increase, since paroxetine concomitantly inhibits their metabolism. Studies so far have confirmed this with desipramine and imipramine (whose half-life can increase by 5-fold).

Antipsychotic drugs A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are combined. Paroxetine has also been shown to increase haloperidol and perphenazine serum levels, with associated extrapyramidal side-effects. The mechanism is presumably via inhibition of hepatic enzymes. With respect to the second-generation antipsychotic drugs (SGAs), paroxetine at a dose of 20 mg/daily produces a 3–9-fold elevation in plasma risperidone. If paroxetine is administered with clozapine, mean plasma concentrations of clozapine and norclozapine may increase significantly (by about 30%).

b-adrenergic blockers In a number of interaction studies, paroxetine did not affect the pharmacokinetics of propranolol. However, the inhibition of

CYP2D6 by paroxetine may lead to accumulation of another b-blocker – metoprolol. Raised paroxetine levels after the addition of pindolol have also been reported, probably via CYP2D6 inhibition.

Benzodiazepines Paroxetine has not been found to alter the pharmacokinetics of diazepam or oxazepam. From a pharmacokinetic perspective, the combined use of paroxetine and benzodiazepines is considered relatively safe.

Cimetidine This can increase paroxetine serum levels by up to 50% (due to its inhibitory effects on hepatic microsomal enzymes), although the clinical significance is questionable.

Lithium No significant pharmacokinetic interactions have been found to date between lithium and paroxetine.

Monoamine oxidase inhibitors (MAOIs) Few data are available about paroxetine interactions with MAOIs, even though they might be similar to those of other selective serotonin reuptake inhibitors (SSRIs). Clinically significant or severe interactions have not been found to date. Administered together in patients with depression, moclobemide and paroxetine or fluoxetine appeared to produce adverse effects indicative of potentiated serotonergic activity.

Methadone Steady-state plasma methadone levels may rise with paroxetine, but only in poor CYP2D6 metabolizers.

Oral contraceptives No significant pharmacokinetic interactions have been found up to date between oral contraceptives and paroxetine.

Sumatriptan When combined with paroxetine, this may lead to weakness, hyperreflexia and incoordination. These adverse effects are not necessarily associated with hepatic drug–drug interactions.

Warfarin No significant pharmacokinetic interactions between paroxetine and warfarin have been found to date. However, anecdotal reports suggest that bleeding tendency may be increased by the co-administration of the two drugs. Clinically significant bleeding was observed in approximately 25% of healthy volunteers receiving paroxetine 30 mg/day and warfarin 5 mg/day for 14 days.4,7,8

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8.2.5 Selective serotonin reuptake inhibitors – sertraline Drug interactions

Cimetidine Fluoxetine Warfarin

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b-blockers (alprenolol, bufanol, metoprolol, propranolol, timolol) Clozapine (?) Olanzapine (?) Tricyclic antidepressants (TCAs) (desipramine) Tolbutamide Warfarin

Monoamine oxidase inhibitors (MAOIs) (described mainly with tranylcypromine but can be associated with other MAOIs as well)

Drugs that can increase the serum levels/effects of sertraline

Drugs whose serum levels/effects can be increased by sertraline

Drugs that can decrease the serum levels/effects of sertraline

Drugs whose serum levels/effects can be decreased by sertraline

Drugs whose therapeutic effects were shown to be opposed by sertraline


(?) Questionable interaction

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Alcohol (ethanol)

parameters. However, serotonin syndrome has been reported with the combined tranylcypromine–sertraline–clonazepam regimen.

Current data suggest no clinically significant pharmacokinetic interaction between sertraline and alcohol. This is due, probably, to the fact that alcohol is metabolized by the hepatic cytochrome P450 enzyme CYP2E1. The latter does not metabolize sertraline. Moreover, CPY2E1 rarely metabolizes any of the other regularly used ‘psychiatric’ drugs.

b-adrenergic blockers

Antidepressants

Cimetidine

Sertraline, at its usual effective dose of 50 mg/day, has been found to cause less pronounced modifications in plasma concentrations of tricyclic antidepressants (TCAs) as compared with other selective serotonin reuptake inhibitors (SSRIs) (mainly studies with fluoxetine, fluvoxamine, and paroxetine). However, since inhibition of the hepatic enzyme CYP2D6 is dose-dependent, significant increase in plasma concentration of TCAs may occur when higher doses of sertraline are administered. Acute liver damage possibly related to sertraline and venlafaxine ingestion has been reported.

Antidiabetic drugs In most studies, no clinically significant pharmacokinetic interactions were found with the combined use of tolbutamide and sertraline. Even so, some anecdotal data suggest clinically insignificant increases in serum tolbutamide levels when combined with sertraline. No pharmacokinetic interactions have been found with the combination of glibenclamide and sertraline. Thus, current data suggest that the co-administration of sertraline with hypoglycemic agents is generally safe.

Antipsychotic drugs Anecdotal reports have documented a moderate increase in the plasma concentration of clozapine after co-administration of sertraline. However, formal kinetic studies have indicated that sertraline does not significantly affect plasma concentrations of clozapine or olanzapine. Such findings are to be expected since both clozapine and olanzapine are metabolized mainly by CYP1A2, while sertraline is metabolized by other isoenzymes.

No pharmacokinetic interactions have been found with the combined sertraline–atenolol regimen. This can increase sertraline serum levels by about 25%. The data are limited and the clinical significance of such findings is currently questionable.

Dolasetron A serotonin syndrome has been reported with the combined use of both drugs.

Lithium Most studies have found that sertraline does not decrease lithium serum levels (or does so only negligibly). Hence, the co-administration of these two agents is considered relatively safe (with regard to pharmacokinetic interactions). To date, the most serious reported adverse effect of the combined regimen was the enhancement of lithium-induced tremor.

Monoamine oxidase inhibitors (MAOIs) Few data are available about sertraline interactions with MAOIs, even though they are expected to be similar to those of the other SSRIs. However, serotonin syndrome has been reported with the combined tranylcypromine–sertraline (and clonazepam also) regimen. At present, only this specific combination should be avoided.

Oxycodone Visual hallucinations and tremor induced by sertraline and oxycodone in a bone marrow transplant patient have been reported.

Tramadol Serotonin syndrome has been reported when tramadol was combined with sertraline.

Sumatriptan

Sertraline at a dose of 200 mg/day does not alter the pharmacokinetic parameters of carbamazepine (metabolized by CYP3A4) and phenytoin (metabolized by CYP2C9).

This is a 5-HT1D agonist (inhibiting the release of serotonin from presynaptic nerve terminals). Hence, even though it suppresses central serotonergic transmission (opposite to the effect of sertraline), there is an increased risk of central nervous system toxicity. Thus, the combined use of sertraline and sumatriptan is not usually recommended.

Benzodiazepines

Warfarin

There is no evidence of a metabolic interaction between sertraline and benzodiazepines. With regard to this, in healthy volunteers, co-administration of sertraline 50–200 mg/day with diazepam or alprazolam caused no significant modifications in their pharmacokinetic

Sertraline has been found to produce small increases in the free fraction of warfarin and a modest (~9%) increase in prothrombin time, which are considered clinically insignificant. Of the SSRIs, sertraline is assumed to exert the least effect on warfarin.4,7,8

Anticonvulsants

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8.3 Serotonin–norepinephrine reuptake inhibitors (SNRIs) Drug interactions

Cimetidine Diphenhydramine Fluoxetine (?) L-Mepromazine Paroxetine

Risperidone (?)

Carbamazepine

Monoamine oxidase inhibitors (MAOIs)

Legend

174

Drugs that can increase the serum levels/effects of SNRIs

Drugs whose serum levels/effects can be increased by SNRIs

Drugs that can decrease the serum levels/effects of SNRIs

Drugs whose serum levels/effects can be decreased by SNRIs

Drugs whose therapeutic effects were shown to be opposed by SNRIs



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Venlafaxine is rapidly absorbed after oral administration, with food or fasting dietary conditions minimally affecting the rate and extent of absorption. It is widely distributed in the body, with only limited protein binding (30% for both parent drug and metabolite). Upon absorption, venlafaxine undergoes extensive first-pass metabolism to a major metabolite (O-desmethylvenlafaxine), which is equal in antidepressant activity to the parent compound, and to two minor metabolites (N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine). Formation of the O-desmethyl metabolite is mediated by the cytochrome P450 CYP2D6 isoenzyme, whereas the majority of N-demethylation seems to be via CYP3A4. Venlafaxine is extensively metabolized by CYP2D6.

Benzodiazepines Single-dose venlafaxine does not alter the single-dose pharmacokinetic profile of drugs metabolized by CYP3A4 (alprazolam and diazepam). When milnacipran was administered with lorazepam in healthy volunteers, no changes in the pharmacokinetics of any drug were detected.

Caffeine Single-dose venlafaxine does not alter the single-dose pharmacokinetic profile of caffeine (metabolized by CYP1A2).

Cimetidine

Venlafaxine does not alter the pharmacokinetic disposition of alcohol in healthy volunteers.

The steady-state plasma concentration of venlafaxine increases by 61% when it is combined with cimetidine. Therefore, caution is advised with the use of cimetidine and venlafaxine in elderly patients, in patients with pre-existing hypertension, and in patients with hepatic or renal dysfunction.

Antidepressants

Diphenhydramine

Alcohol (ethanol)

Paroxetine has been shown to moderately increase duloxetine concentrations. To date, there are no other reported interactions between any of the serotonin–norepinephrine reuptake inhibitors (SNRIs) and antidepressant drugs. However, when switching from fluoxetine to venlafaxine, the general recommendation is to start on no more than one-half of the usual dose and after that to titrate the dose of venlafaxine upward over a few weeks as the norfluoxetine (metabolite of fluoxetine) levels gradually decrease. The reason for titrating the venlafaxine dose is that fluoxetine inhibits both CYP2D6 and CYP3A4, and the way in which venlafaxine and its major metabolite O-desmethylvenlafaxine are metabolized in the liver by these enzymes may reduce the clearance of both the parent drug and its active metabolite, leading to a higher concentration of venlafaxine in the blood.

Antipsychotic drugs At steady state, venlafaxine weakly inhibits the metabolism of risperidone; however, this interaction is unlikely to be of clinical significance. Co-administration of milnacipran and levomepromazine increases the milnacipran plasma concentration because of a modification of the apparent total clearance of the drug.

This drug significantly increases the plasma concentration of venlafaxine. The oral clearance of diphenhydramine, in both extensive and reduced metabolizers, is reduced by 6% and 18%, respectively.

Mood stabilizers Co-administration of milnacipran and carbamazepine decreases the milnacipran plasma concentration because of a modification of the apparent total clearance of the drug. Because milnacipran has low and nonsaturable protein binding and is not metabolized by the hepatic cytochrome P450 system, the potential for drug interactions is reduced compared with drugs that are metabolized by this system. When milnacipran was administered with lithium in healthy volunteers, no changes in the pharmacokinetics of any drug were detected.

Monoamine oxidase inhibitors (MAOIs) Combinations of venlafaxine and MAOIs have been reported to cause or be associated with serotonin syndrome. Hence, such combinations must be considered carefully, if at all. To date, there are no other reported interactions between any of the other SNRIs (i.e. duloxetine and milnacipran) and MAOIs.

SNRIs To date, there are no reported interactions between the SNRIs.4,7,9,10

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8.4 Norepinephrine reuptake inhibitors – bupropion and reboxetine Drug interactions

Carbamazepine

Legend

176

Desipramine

Antipsychotic drugs (APDs) (especially low-potency) Clozapine Monoamine oxidase inhibitors (MAOIs) Nicotine Tricyclic antidepressants (TCAs) (especially maprotiline) Theophylline

Drugs that can increase the serum levels/effects of bupropion

Drugs whose serum levels/effects can be increased by bupropion

Drugs that can decrease the serum levels/effects of bupropion

Drugs whose serum levels/effects can be decreased by bupropion

Drugs whose therapeutic effects were shown to be opposed by bupropion


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Drug interactions Bupropion Bupropion is metabolized to hydroxybupropion primary by the cytochrome P450 CYP2B6 isoenzyme and to a much lesser extent by CYP1A2, -2A6, -2C9, -2E1, and -3A4. Bupropion and hydroxybupropion inhibit CYP2D6 in vitro.

Alcohol (ethanol) Bupropion administered as a single dose of 100 mg did not exhibit clinically significant pharmacokinetic interactions with alcohol.

Antidepressants Desipramine is metabolized by CYP2D6 and when co-administered with bupropion, its plasma half-life is prolonged by approximately 2-fold. The concurrent administration of bupropion and a monoamine oxidase inhibitor (MAOI) is contraindicated because studies in animals have shown that the acute toxicity of bupropion is enhanced by concomitant administration of the MAOI phenelzine.

Anticonvulsants Carbamazepine decreases the plasma concentration of bupropion to about 90% even after a single dose of 150 mg of carbamazepine. Long-term administration of valproate (a weak inhibitor of hepatic metabolism) has no effect on bupropion plasma concentration. It has been shown that bupropion does not cause clinically relevant changes in the pharmacokinetics of a single dose of 100 mg of lamotrigine.

Antipsychotic drugs Bupropion can considerably lower the seizure threshold. Hence, it should be administered cautiously to patients taking medications (e.g, low-potency neuroleptics, clozapine, or olanzapine) or undergoing treatment regimens that may also lower the seizure threshold.

Cimetidine General enzyme inducers co-administered with bupropion could theoretically induce the metabolism of bupropion. However, results of clinical studies have been inconsistent regarding this possibility. For example, cimetidine has not been found to affect the pharmacokinetics of bupropion.

Cyclophosphamide Potential interactions between bupropion and cyclophosphamide (affected by CYP2B6) may be expected. L-Dopa

(levodopa)

The administration of bupropion and L-dopa increases the incidence of adverse experiences

such as gastrointestinal effects, excitement, and restlessness compared with the use of L-dopa alone.

Nicotine It has been observed that the incidence of treatment-emergent hypertension is elevated among patients treated concurrently with bupropion and nicotine patches compared with patients treated with bupropion alone.

Orphenadrine Potential interactions between bupropion and orphenadrine (affected by CYP2B6) may be expected.

Seizure-inducing agents Bupropion should be administered cautiously to patients taking medications or undergoing treatment regimens that may lower the seizure threshold (e.g. antidepressants, antipsychotics, systemic corticosteroids, and theophylline. Reboxetine Reboxetine has a complex hepatic biotransformation in humans, including hydroxylation, O-dealkylation, and oxidation, followed by glucuronidation and sulfoconjugation. In vitro hepatic experiments have indicated that CYP3A4 is the major enzyme responsible for the metabolism of reboxetine. In addition, reboxetine was found to be a weak in vitro inhibitor of the activity of CYP2D6 and CYP3A4. The inhibitory effect of reboxetine on CYP2D6 and CYP3A4 is unlikely to be relevant in vivo because it occurs at concentrations well above those achieved clinically.

Antidepressants Reboxetine does not affect the pharmacokinetic parameters of fluoxetine.

Antipsychotic drugs In a study of patients with schizophrenia or schizoaffective disorder, co-administration of reboxetine 8 mg/day did not affect the plasma levels of either clozapine or risperidone.

Benzodiazepines Studies in healthy subjects have shown that reboxetine does not significantly interfere with the pharmacokinetics of alprazolam or lorazepam.

Dextromethorphan Studies in healthy volunteers have shown that reboxetine 8 mg/day does not interfere with the pharmacokinetics of dextromethorphan.4,8,11,12

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8.5.1 Mood stabilizers – lithium Drug interactions

ACEIs (captopril, enalapril) Bupropion Carbamazepine Diuretics (K sparing : amiloride, spironolactone, triamterene; thiazide : chlorothiazide) Fluoxetine L-dopa Mazindol Metronidazole Non-steroidal anti-inflammatory drugs (NSAIDs) Phenytoin Spectinomycin Tetracyclines Vasopressin

Anticonvulsants (carbamazepine, phenytoin, primidone) Muscle relaxants (including those used during ECT: pancuronium bromide, succinylcholine bromide, vancuronium bromide)

Alcohol Antipsychotic drugs (APDs) Benzodiazepines Carbamazepines Clozapine Diltiazem ECT Fluvoxamine Hydroxyzine Iodine Pancuronium Succinycholine Tricyclic antidepressants (TCAs) Tranylcypromine Verapamil

Acetazolamide Antacids Aminophylline Caffeine Cotrimoxazole Sertaline Theophylline Verapamil

Chlorpromazine (lithium delays its gastric emptying with a consequent longer exposure to gut wall catabolic enzymes)

Digoxin Nifedipine

Legend

178

ACEI

Angiotensin-converting enzyme inhibitor

ECT

Electroconvulsive therapy

Drugs that can increase the serum levels/effects of lithium

Drugs whose serum levels/effects can be increased by lithium

Drugs that can decrease the serum levels/effects of lithium

Drugs whose serum levels/effects can be decreased by lithium

Drugs whose therapeutic effects were shown to be opposed by lithium


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Alcohol (ethanol) and sedative–hypnotics The effects of alcohol do not appear to be potentiated by the simultaneous administration of lithium.13 There are no clinically relevant interactions between lithium and benzodiazepines or other sedatives.14

Antibacterials and antineoplastics Increases in serum lithium concentration have been reported in patients receiving antibacterials (e.g., metronidazole, spectinomycin, tetracyclines, and ticarcillin.15 Regular monitoring of lithium plasma levels is advised when it is combined with cisplatin in cancer patients.16

Antidepressants When tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) are combined with lithium, a worsening of lithium-induced tremor may occur, as well as an increased risk of extrapyramidal side-effects and seizures.14 Regarding the selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, there are anecdotal reports of serotonin syndrome when they are combined with lithium.17,18 There is a risk of bradycardia when fluoxetine and lithium are combined. Pharmacokinetic interactions between lithium and newer antidepressants seem to be of no clinical importance.14

Antipsychotic drugs There is an increased frequency of neurotoxic symptoms in patients treated with lithium and antipsychotics (mainly described with lithium and haloperidol) or high-dose thioridazine.14,19 Marked electroencephalogram changes and tonic–clonic seizures have been observed when lithium has been combined with clozapine.20,21

Anticonvulsants Some anecdotal reports have suggested that phenytoin or carbamazepine can possibly increase the frequency and intensity of lithiuminduced adverse events.22

Caffeine Heavy caffeine consumption may increase the renal clearance of lithium. Therefore, withdrawal from caffeine can result in increased serum lithium concentration.23

Diuretics and cardiovascular drugs One of the best-known lithium interactions is the clinically relevant reduction of renal lithium clearance by combined administration of the drug with diuretics.24 Special caution is advised when long-term thiazides are combined with lithium.14 The potassium-sparing diuretics such as spironolactone can also increase plasma

lithium concentrations.24 In contrast, furosemide and possibly xanthine derivatives such as caffeine do not possess such action and may even increase lithium excretion.14 Verapamil usually increases lithium clearance.25 Nevertheless, some clinicians consider the combination of lithium and calcium-channel blockers potentially hazardous. No adverse interactions have been reported in patients treated with lithium and b-adrenoreceptor antagonists, whereas methyldopa has been reported to induce neurotoxic symptoms in some lithium-treated patients.26–29 There is a risk of lithium intoxication with simultaneous administration of angiotensin-converting enzyme inhibitors (ACEIs); lithium clearance may be reduced by up to 25%.30 Losartan, an angiotensin II antagonist, was anecdotally reported to induce lithium intoxication.31

Electroconvulsive therapy (ECT) A lithium-free interval of 24–48 hours is recommended before surgical intervention or narcosis, since the lithium-treated patient is generally endangered by the necessary restriction of water intake prior to such interventions, especially in polyuric patients.14 The action of muscle relaxants that are used during general anesthesia or ECT (pancuronium bromide, succinylcholine bromide, and vancuronium bromide) can be prolonged by lithium.32,33 There are reports of increased central nervous system adverse reaction such as delirium and amnestic reaction when lithium and muscle relaxants are combined.34,35

Monoamine oxidase inhibitors (MAOIs) Few cases of tardive dyskinesia have been reported with the combined used of tranylcypromine and lithium. No apparent interactions have been observed with moclobemide or phenelzine.

Non-steroidal anti-inflammatory drugs (NSAIDs) Various NSAIDs, such as ibuprofen, indomethacin, ketoprofen, phenylbutazone, piroxicam, and oxyphenbutazone, can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations.14

Theophylline Serum levels of lithium can be decreased by as much as 20–30% when theophylline is combined with lithium.

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8.5.2 Mood stabilizers – carbamazepine Drug interactions

Acetazolamide Cimetidine Danazol Diltiazem Erythromycin Fluoxetine Fluoxamine Isoniazid Lithium Ranitidine Valproate Verapamil

Lithium

Loxapine (?) Phenytoin Tricyclic antidepressants (TCAs) Tranylcypromine Theophylline

Ciprofloxacin Fluoxetine Fluvoxamine Lithium

Legend

180

Alprazolam Antipsychotic drugs (APDs) (reported with: aripiprazole, chlorpromazine, clozapine, fluphenazine, perphenazine, olazapine, risperidone) Birth control pills Bupropion Clonazepam Dexamethasone Digoxin Indinavir Paracetamol Saquinavir Tricyclic antidepressants (TCAs) Theophylline (?) Valproate Warfarin


Drugs that can increase the serum levels/effects of carbamazepine

Drugs whose serum levels/effects can be increased by carbamazepine

Drugs that can decrease the serum levels/effects of carbamazepine

Drugs whose serum levels/effects can be decreased by carbamazepine

Drugs whose therapeutic effects were shown to be opposed by carbamazepine


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Acetazolamide This can increase the serum levels of carbamazepine by up to 50%, with the possible development of toxicity (mechanism unclear).

Anti-infective drugs Ciprofloxacin can greatly increase the risk of seizure induction in patients taking anticonvulsants. Erythromycin produces a rapid 100–200% rise in carbamazepine levels. There is a possibility of reduced plasma levels of the protease inhibitors indinavir and saquinavir with carbamazepine. Isoniazid increases carbamazepine serum levels, and leads to the possible emergence of toxicity (disorientation and aggression). Mefloquine may antagonize the anticonvulsant effect of carbamazepine. Ritonavir, a protease inhibitor, may cause toxicity by raising carbamazepine plasma levels.

Anticonvulsants Valproate has some inhibitory effects on hepatic metabolism, and when co-administered with carbamazepine it can increase the serum levels and effects of the latter. Carbamazepine has been reported to reduce valproate serum levels by about 60%.

Antidepressants Carbamazepine induces hepatic catabolic enzymes, with a consequent reduction in serum levels of antidepressants (mainly described with amitriptyline, desipramine, doxepin, imipramine, mianserin, and nortriptyline). A decrease in bupropion serum levels was also reported with carbamazepine. These effects were not observed with clomipramine. Fluoxetine and fluvoxamine inhibit the metabolism of carbamazepine and valproate (up to 30% and 50% increases in serum levels, respectively). No significant interaction has yet been found between paroxetine and carbamazepine or valproate.

Antipsychotic drugs Carbamazepine was found to decrease the plasma levels of phenothiazines by as much as 50% (described with chlorpromazine, perphenazine, and fluphenazine). It has been reported to decrease the serum levels of clozapine by about 60–85% due to its hepatic cytochrome P450 (CYP) enzyme-inducing properties. Loxapine may induce carbamazepine metabolism. Carbamazepine has been shown to reduce the plasma levels of risperidone by as much as 50%, while it increases olanzapine clearance by 44% and reduces its half-life by 20%. Carbamazepine increases aripiprazole metabolism through CYP3A4 induction. Thus, the aripiprazole dose should be doubled.

Benzodiazepines These have complex interactions with anticonvulsants. The co-administration of

carbamazepine can (infrequently) cause significant (up to 50%) decreases in serum levels of clonazepam or alprazolam.

Calcium-channel blockers Diltiazem and verapamil have inhibitory effects on hepatic microsomal enzymes, and so can increase serum levels of carbamazepine. Nifedipine has not been studied as well as the other calcium-channel blockers, but present data suggest that it probably does not interact significantly with carbamazepine.

Cyclosporine The metabolism of cyclosporine is accelerated by carbamazepine to give reduced plasma levels.

Danazol This inhibits the hepatic microsomal enzymes; thus, carbamazepine serum levels can increase by up to 2-fold.

Digoxin Carbamazepine increases the risk of cardiac conduction disturbances (digoxin serum levels can decrease).

H2 blockers Transient elevation of carbamazepine plasma levels is evident with cimetidine (due to the latter’s cytochrome P450 inhibition capacity).

Lithium Carbamazepine and lithium can elevate each other’s serum levels (the mechanism is unknown). Toxicity is possible while blood levels are within the normal range, and is partially associated with pre-existing brain abnormalities. The diuretic effect of lithium outweighs the antidiuretic effect of carbamazepine. Carbamazepine does not protect against lithium-induced diabetes insipidus. Lithium can enhance carbamazepine-induced hyponatremia.

Monoamine oxidase inhibitors (MAOIs) Phenelzine, tranylcypromine, and moclobemide have no clinically significant interactions with carbamazepine.

Oral contraceptives Carbamazepine has been shown to increase the hepatic metabolism and to decrease the effects and safety of oral contraceptives. Higher doses of estrogen are vital to secure safety.

Ranitidine This has little/no interaction with carbamazepine.

Theophylline Isolated data suggest that theophylline might decrease carbamazepine serum levels.

Warfarin Serum levels and anticoagulant effects may be decreased due to the effect of carbamazepine on the hepatic metabolism of warfarin.1,36 181

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8.5.3 Mood stabilizers – valproate Drug interactions

Aspirin

Lamotrigine

Benzodiazepines Clozapine (?) Lamotrigine Methylphenidate (?) Rifampin

Carbamazepine Phenobarbital Phenytoin

Legend

182

Drugs that can increase the serum levels/effects of valproate

Drugs whose serum levels/effects can be increased by valproate

Drugs that can decrease the serum levels/effects of valproate

Drugs whose serum levels/effects can be decreased by valproate

Drugs whose therapeutic effects were shown to be opposed by valproate



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Antibiotics Rifampin is a prototype inducer of the cytochrome P450 enzyme CYP3A4. This induction of microsomal enzymes by rifampin is thought to increase the production of toxic metabolites, contributing to the potential of valproate to cause hepatotoxicity, although this clinical outcome is rare. Valproate inhibits glucuronidation of zidovudine and increased events from zidovudine are possible.

Antidepressants The combined use of valproate and paroxetine has not been found to result in any significant drug–drug interaction.

Antiepileptic drugs The most extensive investigation of drug interactions with valproate has been with regard to its combination with antiepileptic drugs, especially as the use of combination pharmacotherapy for treatment of epilepsy is common. Of the three metabolic pathways of valproate elimination – glucuronide conjugation, cytochrome P450 oxidation, and mitochondrial beta oxidation – the first two have been shown to be inducible by other drugs (carbamazepine, phenobarbital, and phenytoin), resulting in increased clearance of valproate. Phenobarbital or carbamazepine co-administration leads to higher clearance of valproate, with corresponding reductions in plasma valproate concentrations ranging from 30% to 40% in adults. Valproate increases lamotrigine plasma concentrations. Special caution should be used in patients who receive valproate and lamotrigine, because a severe rash reaction has been reported to occur due, probably, to increased lamotrigine concentration.

Antipsychotic drugs The combination of antipsychotics and valproate is frequently used in patients, including children, with mood disorders and aggressive behavior. Among the secondgeneration (‘atypical’) antipsychotic drugs (SGAs), an effect of valproate on inhibiting the glucuronidation of olanzapine might be anticipated. Valproate has an insignificant effect on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. Valproate has been reported to cause thrombocytopenia. Thus, although the combination of valproate and clozapine is considered relatively safe, careful attention should be given to a potential increased risk of

valproate and clozapine. Combined use of valproate and haloperidol or chlorpromazine has not been found to result in any significant drug–drug interaction.

Aspirin An interaction involving protein binding displacement may occur with aspirin. Children given antipyretic doses of aspirin co-administered with valproate were found to exhibit a decrease in protein binding and an inhibition of the metabolism of valproate. The common use of aspirin should alert to the need for caution if these drugs are co-administered. Interaction with other non-steroidal anti-inflammatory drugs (NSAIDs) may not be so prominent.

Benzodiazepines Valproate in combination with clonazapem was reported to result in increased absence seizures in children. Valproate inhibits diazepam metabolism and alters its plasma protein binding. The interaction between valproate and lorazepam is marginal. While limited data appear to document interactions between valproate and benzodiazepines, the addition of valproate to pre-existing pharmacotherapy that includes a benzodiazepine should be accompanied by increased monitoring for effects such as sedation.

Lithium The combined use of valproate and lithium was not found to result in any significant drug–drug interaction.

Methylphenidate Two patients aged 4 and 6 years old experienced tics and dyskinetic movements after starting on methylphenidate added to pre-existing treatment with valproate. Both patients improved when methylphenidate was no longer administered.

Oral contraceptives There is no substantial evidence for enzyme-inducing properties of valproate. Therefore, it should not interfere with the normal metabolism of steroid contraceptives, nor should it decrease the effective plasma concentrations of other drugs.

Ranitidine/cimetidine Combinations of valproate and ranitidine or cimetidine have not been found to result in any significant interaction that is likely to be clinically important.37,38

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8.6 Lamotrigine and topiramate Drug interactions

Cimetidine Felbamate Fluconazole Omeprazole Selective serotonin reuptake inhibitors (SSRIs) (i.e. fluoxetine and fluvoxamine) Teniposide Tolbutamide Troglitazone Valproate

Acetaminophen (paracetamol) Carbamazepine Phenobarbital Phenytoin

Phenytoin Valproate

Digoxin (?) Phenytoin

Legend

184

Acetazolamide Alcohol (ethanol) Contraceptives Dichlorphenamide Sertraline

Drugs that can increase the serum levels/effects of lamotrigine or topiramate

Drugs whose serum levels/effects can be increased by lamotrigine or topiramate

Drugs that can decrease the serum levels/effects of lamotrigine or topiramate

Drugs whose serum levels/effects can be decreased by lamotrigine or topiramate

Drugs whose therapeutic effects were shown to be opposed by lamotrigine or topiramate



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Lamotrigine Oral lamotrigine is readily bioavailable (98%), and undergoes minimal first-pass metabolism. Absorption of lamotrigine is unaffected by food. Linear pharmacokinetics show the peak lamotrigine concentration to occur 1–3 hours after a dose. Lamotrigine is extensively metabolized in the liver, predominantly via N-glucuronidation. Lamotrigine pharmacokinetics appear not to be significantly altered by many commonly used psychotropic agents.39

Acetaminophen (paracetamol) This may reduce serum concentrations of lamotrigine. The phenomenon is relevant only in long-term use. The mechanism is not clear.

Anticonvulsants Enzyme-inhibiting drugs such as valproate increase the plasma concentration of lamotrigine, while enzyme-inducing drugs such as carbamazepine, phenobarbital, and phenytoin may decrease it. Lamotrigine may increase the serum concentration of the epoxide metabolite of carbamazepine. Lamotrigine enhances the metabolism of valproate.

Lithium Lamotrigine has not been found to alter the pharmacokinetics of lithium.

Selective serotonin reuptake inhibitors (SSRIs) Toxicity has been anecdotally reported with the combined use of lamotrigine and sertraline. Data about potential interactions with other SSRIs are currently not available. Topiramate Absorption of topiramate is rapid and unaffected by food intake, with peak plasma concentrations being achieved approximately 2 hours after administration of a 400 mg dose. Metabolism of topiramate is not extensive and its oral plasma clearance is slow, with approximately 70% of an administered dose being eliminated unchanged by the kidneys. When used as monotherapy, topiramate has a

long elimination half-life of 19–25 hours. Clearance in adults is not affected by age, sex, or race; however, patients with moderate or several renal impairment show 42% and 52% reductions, respectively, in creatinine clearance. Hepatic impairment may also decrease clearance.40

Alcohol (ethanol) Because of the depressant effects of topiramate on the central nervous system, extreme caution is advised when administering the combination of topiramate and alcohol.

Anticonvulsants Topiramate interacts with other antiepileptic agents, including carbamazepine, phenytoin, and valproate, resulting in more rapid metabolism and elimination and reduced plasma concentration of topiramate. Carbamazepine can reduce topiramate serum levels by up to 25%. Phenytoin can lower topiramate serum levels by up to 25%, while topiramate has been shown to increase phenytoin serum levels by about 50%.

Carbonic anhydrase inhibitors The concomitant use of topiramate with carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide may increase the risk of renal calculi.

Oral contraceptives Topiramate may compromise the efficacy of oral contraceptive drugs.

CYP2C19 inhibitors Drugs such as cimetidine, felbamate, fluconazole, fluoxetine, fluvoxamine, omeprazole, teniposide, tolbutamide, and troglitazone that inhibit the cytochrome P450 enzyme CYP2C19 thereby inhibit the metabolism of topiramate and can increase its serum levels.

Digoxin Concomitant use of topiramate and digoxin has been shown to decrease the area under the concentration–time curve (AUC) for plasma digoxin by 12%, although the clinical relevance is unclear.39–41

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8.7 Monoamine oxidase inhibitors (MAOIs) Drug interactions

Paroxetine

Barbiturates (especially amibarbital) Phenylephrine Sympathomimetics (indirectly acting: amphetamines, cocaine, ephedrine, methylphenidate, pemoline, pseudoephedrine, phenylpropanolamine) Warfarin (?)

Amphetamines Buspirone Cocaine Dextromethorphan Guanthidine L-dopa L-tryptophan Meperidine (pethidine) Methyldopa MAOIs Phenylephrine Propranolol Reserpine Selective serotonin reuptake inhibitors (SSRIs) Serotonin reuptake inhibitors (SRIs) Tricyclic antidepressants (TCAs) (clomipramine, desipramine, imipramine) Tyramine-containing diet High tyramine content: aged cheeses, smoked or pickled meats/fish/poultry, aged putrefying meats/fish/ poultry, yeasts, meat extracts, red wines, fava beans Moderate tyramine content: meat extracts, ripe avocado, pasteurized light and pale beers Low tyramine content (permissible): distilled spirits (scotch, gin, rye, vodka), creamed/cottage cheese, chocolate, caffeine, fruits, yogurt, sour cream

Legend

186


Drugs that can increase the serum levels/effects of MAOIs

Drugs whose serum levels/effects can be increased by MAOIs

Drugs that can decrease the serum levels/effects of MAOIs

Drugs whose serum levels/effects can be decreased by MAOIs

Drugs whose therapeutic effects were shown to be opposed by MAOIs


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Antidepressants Antidepressant drugs with dominant serotonergic enhancement capacity (i.e. serotonin reuptake inhibitors, SRIs) should, where possible, be avoided as adjuvants to monoamine oxidase inhibitors (MAOIs) due to the potential induction of the serotonin syndrome. Few data are available about potential interactions between the newly introduced antidepressant drugs and MAOIs (due, most likely, to the relative avoidance in clinical practice of such regimens). Even so, there are many reported cases of serotonin syndrome, including some that became fatal when selective serotonin reuptake inhibitors (SSRIs: paroxetine and sertraline) were combined with MAOIs. The concurrent use of fluoxetine and MAOIs (phenelzine and tranylcypromine) is considered highly dangerous, with up to 50% of patients having toxic reactions (including serotonin syndrome). Hence, present data suggest that antidepressants (at least the serotonergic drugs) should not be combined with MAOIs. If an antidepressant is to be given with a MAOI, then the tricyclic antidepressants (TCAs) are conceived as relatively safer (especially amitriptyline and nortriptyline).

Antipsychotic drugs Many reports, including well-controlled studies, have found no averse interaction with phenothiazines, except rare reports of fatal adverse effects when an MAOI (pargyline or tranylcypromine) was given with methotrimeprazine.

collapse/arrhythmias, nausea, tremor, muscle spasm, and impaired consciousness/coma developed within minutes to a few hours of ingesting agents containing dextromethorphan, eventually leading to death (in some cases). L-dopa

(levodopa)

Low-dose L-dopa with carbidopa or benserazide seems safe, but higher doses should be avoided, as should L-dopa as sole agent.

Meperidine (pethidine) Many cases of serious (some fatal) adverse effects have been reported when meperidine is added to an MAOI (phenelzine or tranylcypromine). The most commonly encountered adverse and serious symptoms are hyperpyrexia, respiratory failure, and impaired consciousness (including coma and death). Even so, there are many published cases and studies that have not revealed any interaction between MAOIs and meperidine. All in all, combined therapy is relatively contraindicated. The mechanism of the potentially fatal reactions is unknown.

Morphine Anecdotal data describe marked hypotension and impaired consciousness when morphine is added to tranylcypromine. Many studies have shown no clinically significant interactions with isocarboxazid, phenelzine, tranylcypromine, and morphine, including in patients with known adverse reactions to meperidine.

Phenylephrine

MAOIs (mainly tranylcypromine) have been shown, in isolated reports, to enhance the activities of barbiturates (mainly amybarbital), probably by inhibition of microsomal enzymes.

Life-threatening hypertensive crisis has been reported with combinations of phenelzine or tranylcypromine and phenylephrine. This is due to the inhibited gut monoamine oxidase, which does not detoxify the ingested phenylephrine.

Benzodiazepines

Sympathomimetics (indirectly acting)

Barbiturates

Although there are isolated cases of MAOI toxicity, edema, and hepatotoxicity, this is normally considered a safe combination.

b-adrenergic blockers Propranolol used with MAOIs may cause severe hypertension and slight bradycardia. The combination should be monitored carefully, especially in the elderly.

Combining MAOIs with agents such as amphetamines, cocaine, ephedrine, methylphenidate, pemoline, pseudoephedrine, phenylpropanolamine, and others (including many cold and allergy medications) can cause a potentially fatal hypertensive crisis.

Sympathomimetics (directly acting)

Isolated cases of non-fatal hypertensive reactions (with phenelzine or tranylcypromine) have been reported. Clinicians should monitor patients closely when using this combination.

Combining MAOIs with agents such as epinephrine or norepinephrine is relatively safe since MAOIs cause them to accumulate in the nerve terminal (thus, they do not directly act on postsynaptic receptors).

Dextromethorphan

Warfarin

A few fatal cases and a couple of severe adverse effects have been reported with the combination of phenelzine and dextromethorphan. Hyperpyrexia, cardiovascular

No interactions have been reported to date. However, tranylcypromine is known to inhibit CYP2C19 and some potential for such an interaction exists.7

Buspirone

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8.8 Reversible inhibitors of monoamine oxidase type A (RIMAs) Drug interactions

Cimetidine

Legend

188

Opiates (fentanyl, morphine)

Amantadine (?) Citalopram (?) Clomipramine (?) Imipramine (?) Meperidine


Drugs that can increase the serum levels/effects of RIMAs

Drugs whose serum levels/effects can be increased by RIMAs

Drugs that can decrease the serum levels/effects of RIMAs

Drugs whose serum levels/effects can be decreased by RIMAs

Drugs whose therapeutic effects were shown to be opposed by RIMAs


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Drug interactions

Alcohol (ethanol)

Dextromethorphan

To date, no clinically significant interactions have been reported concerning the combined use of moclobemide and alcohol.

Unlike the combined monoamine oxidase inhibitor (MAOI) and dextromethorphan regimen (where fatal interactions are well documented), there is only limited evidence from animal studies supporting potentially dangerous interactions between dextromethorphan and moclobemide.

Amantadine There has been an isolated report of a hypertensive reaction when amantadine was combined with moclobemide and other agents. This effect was not confirmed in other studies. The mechanism is unknown and the clinical significance questionable.

Anticonvulsants

Digoxin No interaction has been reported.

Diuretics

Only a few published cases concerning the combined use of carbamazepine and moclobemide have reported to date, and no clinically significant interactions have been observed.

Only a few published cases concerning the combined use of diuretics and moclobemide have been reported. Hydrochlorothiazide was shown to have no significant interactions with moclobemide and there are no significant changes in the efficacy of either regimen.

Antidepressants

Hypoglycemic agents

A few cases of fatal and rapidly developing serotonin syndrome have been reported with the combined use of citalopram and moclobemide. Clinically significant or severe interactions have not been found to date (in several well-controlled trials) with the combined use of fluoxetine, fluvoxamine, and moclobemide, nor with amitriptyline or desipramine when given with moclobemide. One case has been reported of serotonin syndrome with the combined use of moclobemide and imipramine and another of suspected serotonin syndrome when moclobemide was given with clomipramine.

Antipsychotic drugs Many reports have found no adverse pharmacokinetic interactions with most of the butyrophenones, phenothiazines, clopenthixol, clozapine, and sulpiride.

b-adrenergic blockers Moclobemide can further enhance the hypotensive properties of metoprolol, but the effect is usually mild and clinically insignificant.

Benzodiazepines Data on the co-administration of benzodiazepines with moclobemide have revealed contradictory results: some reports suggest that there are no clinically significant interactions with the combined use, but other studies suggest a greater risk (incidence increasing by up to 100%) of developing adverse effects, usually related to moclobemide (mainly sedation).

Calcium-channel blockers To date, no clinically significant interactions have been reported concerning the combined use of moclobemide and calcium-channel blockers (mostly examined with nifedipine).

Cimetidine This can increase moclobemide serum levels by 40–100%, due to its inhibitory effects on hepatic microsomal enzymes.

Numerous hypoglycemic agents (including chlorpropramide, glibenclamide, and metformin) have been co-administered with moclobemide, and no clinically significant interactions have been noticed.

Ibuprofen This has no clinically significant interactions with moclobemide, even though some inconsistent interactions were evident in animal studies. L-dopa

(levodopa)

Moclobemide has a negligible capacity to increase dopaminergic neurotransmission, but studies so far have revealed no significant interactions or major adverse side-effects when moclobemide is co-administered with L-dopa.

Lithium Preliminary data suggest that there are no significant pharmacokinetic interactions between moclobemide and lithium.

Meperidine (pethidine) Many cases of serious (some fatal) adverse effects have been reported when pethidine is added to a RIMA.

Morphine Moclobemide is alleged to potentiate the effect of opiates, and dose reduction of morphine and fentanyl should be considered.

Oral contraceptives Co-administration of moclobemide with several types of oral contraceptives has not shown any significant interaction, and there does not appear to be any alteration in the efficacy of either agent.

Tyramine Moclobemide does not appear to significantly potentiate the pressor effects of tyramine. Dietary restrictions are generally not required, but patients should avoid eating excessive amounts of tyramine-containing foods, especially if they have pre-existing hypertension.7 189

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8.9.1 First-generation ('typical') antipsychotic drugs – phenothiazines Drug interactions

Paroxetine Propranolol (?)

Fluoxetine (?) Paroxetine Phenytoin Tricyclic antidepressants (TCAs) (amitriptyline, clomipramine, desipramine, imipramine, nortriptyline)

Antacids Barbiturates Carbamazepine Disulfiram Orphenadrine Vitamin C (?)

Barbiturates

Legend

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Pimozide Phenylpropanolamine Trazadone

Drugs that can increase the serum levels/effects of phenothiazines

(?) Questionable Drugs whose serum interaction levels/effects can be increased by phenothiazines

Drugs that can decrease the serum levels/effects of phenothiazines

Drugs whose serum levels/effects can be decreased by phenothiazines

Drugs whose therapeutic effects were shown to be opposed by phenothiazines


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Alcohol (ethanol) An increased risk of emergence of acute dystonic reactions has been described, mainly with fluphenazine and trifluoperazine, and is believed to be the consequence of an alcohol-induced lower neurological threshold or to be due to increased plasma levels of the antipsychotics. Chlorpromazine and thioridazine have not been found, to date, to alter alcohol metabolism (in contrast to haloperidol, which can increase alcohol levels).

Antacids Chlorpromazine serum levels can be rapidly decreased by about 50% (due to its absorption onto gel) when coadministered with antacids.

Anticholinergic drugs The combined use of phenothiazines (reported mainly with chlorpromazine) that have marked anticholinergic properties with other anticholinergic drugs can induce heat stroke, especially in hot and humid conditions. The rise in body temperature might be the result of suppressed sweat gland activity regulated by parasympathetic cholinergic innervation. Other serious adverse and additive effects of such combined regimens are the induction of paralytic ileus and atropine-like psychosis.

Anticonvulsants Carbamazepine induces hepatic microsomal enzymes that can decrease the steady-state plasma levels of phenothiazines (reported mainly with chlorpromazine, fluphenazine, and perphenazine). Chlorpromazine and thioridazine may increase the serum levels of phenytoin due to its inhibition of hepatic mono-oxygenase activities.

Antidepressants Most antipsychotic drugs as well as tricyclic antidepressants (TCAs) are inhibitors of the chytochrome P450 liver catabolic enzymes, thus potentially increasing each other’s serum levels. Chlorpromazine increases imipramine serum levels. Levomepromazine can cause a significant increase in clomipramine serum levels. Perphenazine has been reported to increase the serum levels of amitriptyline, desipramine, imipramine, and nortriptyline. Thioridazine has also been shown to increase TCA serum levels (mainly desipramine). Marked extrapyramidal sideeffects have been reported in a few cases with fluphenazine or perphenazine when fluoxetine was added to the regimen. The mechanism is not known. A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are

combined. Severe hypotension was evident in few cases when trazodone was added to chlorpromazine or trifluoperazine.

Barbiturates The serum levels of both barbiturates and phenothiazines (chlorpromazine and thioridazine) can be reduced by about 30%, presumably because barbiturates are potent hepatic catabolic enzyme inducers.

Disulfiram There is an anecdotal report of a more than 50% decrease in perphenazine serum levels when disulfiram was added to the regimen.

Hydroxyzine The antipsychotic effect of phenothiazines may be decreased.

Lithium There are a few reports of rapid development of extrapyramidal side-effects (parkinsonism and tremor) or neurotoxicity (delirium and seizures) when lithium was co-administered with fluphenthixol, fluphenazine, haloperidol, thioridazine, or thiothixene. Some of these events were apparent while lithium serum levels were within the normal range. Chlorpromazine serum levels are reduced in the presence of lithium.

Naltrexone There are anecdotal reports of prolonged and severe lethargy when naltrexone was co-administered with thioridazine.

Orphenadrine This induces hepatic oxidizing enzymes and has been reported to lower chlorpromazine serum levels.

Phenylpropanolamine There are anecdotal reports of fatal cardiac arrhythmia (ventricular fibrillation) with a combined phenylpropanolamine and thioridazine regimen.

Pimozide Pimozide and both chlorpromazine and thioridazine can prolong the QTc interval.

Propranolol Isolated data suggest that propranolol might reduce the elimination of chlorpromazine and thioridazine, with a consequent increase in their serum levels/therapeutic effects.

Vitamin C There are anecdotal reports of a 25% decrease in serum levels of fluphenazine when vitamin C was added to the regimen (probably not of clinical significance).7 191

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8.9.2 First-generation ('typical') antipsychotic drugs – haloperidol and others Drug interactions

Buspirone Chlorpromazine Fluoxetine Paroxetine

Alcohol (ethanol) Tricyclic antidepressants (TCAs) [clomipramine, nortriptyline (with haloperidol); doxepin (with thiothixene)]

Lithium

Antacids (noted with sulpiride) Carbamazepine Phenobarbital Phenytoin Rifampin Smoking

Valproate

Guanethidine

Legend

192

Drugs that can increase the serum levels/effects of haloperidol/ miscellaneous

Drugs whose serum levels/effects can be increased by haloperidol/ miscellaneous

Drugs that can decrease the serum levels/effects of haloperidol/ miscellaneous

Drugs whose serum levels/effects can be decreased by haloperidol/ miscellaneous

Drugs whose therapeutic effects were shown to be opposed by haloperidol/ miscellaneous


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Drug interactions Haloperidol

Antidepressants An increase (about 2-fold) in serum levels of tricyclic antidepressants (TCAs) is found in up to 10% of treated patients (most established with clomipramine and nortriptyline). Such serum level abnormalities are not observed with desipramine. Marked extrapyramidal sideeffects have been reported (a few cases only) with haloperidol when fluoxetine is added to the regimen. Fluoxetine and paroxetine have been shown to increase haloperidol serum levels (by about 20%), presumably via inhibition of cytochrome P450 enzymes.

Anticonvulsants Phenytoin and carbamazepine have been reported to decrease haloperidol serum levels by about 50% due to their hepatic cytochrome P450-inducing properties. Preliminary data suggest that haloperidol can lower valproate serum levels.

Barbiturates

side-effects, delirium, hyperthermia, dyskinesia, and some permanent brain damage). These effects are presumed to be mediated by additive effects of both agents on the basal striatal adenylate cyclase system or simply to be a manifestation of lithium toxicity. Some data suggest that old age and administration during the acute phase of a manic episode hold a greater risk for developing these effects. However, there is opposing and substantial evidence that the concurrent use of these agents is safe.

Rifampin This can increase haloperidol elimination, with a concomitant decrease in serum levels by about one-third.

Smoking Components of cigarettes/tobacco are hepatic enzyme inducers (mainly CYP1A2), leading to a decrease in haloperidol serum levels (haloperidol is also metabolized by CYP1A2) and established data suggest that the average serum levels of haloperidol are about halved.

Phenobarbital can lower haloperidol serum levels via inhibition of hepatic enzymes.

Miscellaneous APDs (not haloperidol)

Buspirone

Antacids

A few uncontrolled studies have shown an increase of about 50% in haloperidol serum levels.

Aluminum hydroxide can reduce the absorption of sulpiride and lower its serum levels.

Chlorpromazine

Antidepressants

This may significantly increase haloperidol levels, probably via inhibition of the cytochrome P450 enzyme CYP2D6.

Thiothixene levels are usually increased by TCAs (doxepin and nortriptyline). Additive adverse effects have also been reported when co-administered with clomipramine (rapid development of tardive dyskinesia). Marked extrapyramidal side-effects have been reported (a few cases only) with sulpiride or thiothixene when fluoxetine is added to the regimen. Unlike the established interactions between most phenothiazines and TCAs, in which serum levels of both agents could increase, no apparent interaction is evident to date between flupenthixol and imipramine or any other TCA.

Alcohol (ethanol) Numerous reports suggest that combined antipsychotic drug (APD)–alcohol consumption further impairs driving abilities and cognitive or neuromotor functioning, and this effect is noted mostly with chlorpromazine and flupenthixol, and (to a lesser extent) sulpiride, thioridazine, and haloperidol. Alcohol serum levels could be elevated by concurrent use of haloperidol.

Guanethidine The antihypertensive effects of guanethidine can be opposed by the concurrent use of haloperidol.

Indomethacin Isolated cases of severe drowsiness and fatigue have been reported when indomethacin was co-administered with haloperidol.

Lithium There are anecdotal and rare reports of severe adverse effects induced by the combined haloperidol–lithium regimen (extrapyramidal

Benzodiazepines Most data are consistent with relatively safe use of combined APDs and benzodiazepines (with respect to pharmacokinetic interactions).

Benzotropine There is an isolated case of reversible esophageal atonia and dilatation with thiothixene, due probably to additive anticholinergic effects. There is another isolated report of impaired esophageal contractility with increased upper esophageal sphincter pressure with molindone.7

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8.9.3 Second-generation ('atypical') antipsychotic drugs (SGAs) – amisulpiride, aripiprazole, clozapine and olanzapine Drug interactions

Caffeine Ciprofloxacin Erythromycin Fluoxetine Ketoconazole Paroxetine Quinidine Risperidone Valproate (?) (it may also lower clozapine serum levels)

Caffeine

Captopril (may enhance the risk of bone marrow suppression when combined with clozapine) Carbamazepine (may enhance the risk of bone marrow supression when combined with clozapine)

Carbamazepine Phenytoin Ritonavir Smoking Valproate (?) (may also raise clozapine serum levels)

Legend

194

Drugs that can increase the serum levels/effects of SGAs

Drugs whose serum levels/effects can be increased by SGAs

Drugs that can decrease the serum levels/effects of SGAs

Drugs whose serum levels/effects can be decreased by SGAs

Drugs whose therapeutic effects were shown to be opposed by SGAs



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Anticonvulsants These can decrease clozapine serum levels by about 60% (carbamazepine) and 85% (phenytoin) due to hepatic cytochrome P450-inducing properties. Plasma concentrations of clozapine and its metabolites have been reported to be either slightly decreased or increased when combined with valproate. Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its halflife by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate.

Antidepressants Fluvoxamine, a potent inhibitor of the cytochrome P450 enzymes CYP1A2 and CYP2C19 and a moderate inhibitor of CYP3A4, has been reported to cause a 5–10-fold elevation of plasma clozapine concentration. Fluoxetine and paroxetine may also increase plasma clozapine concentrations, while citalopram and sertraline have been reported to cause minimal or no elevation of plasma levels of clozapine. To date, in vivo studies with a combined olanzapine–imipramine regimen have not revealed any pharmacokinetic interactions.

Anti-inflammatory drugs Ketoconazole decreases aripiprazole metabolism, and so the aripiprazole dose should be decreased by about half during co-administration. Quinidine decreases aripiprazole metabolism, and so the aripiprazole dose should also be halved.

Antipsychotic drugs Anecdotal cases have been described of a substantial (about 2-fold) increase in clozapine serum levels following the co-administration of risperidone.

Benzodiazepines The combined regimen is safe and effective, although severe cardiovascular or respiratory adverse effects may occur with high doses of clozapine when combined with diazepam and lorazepam. There are no reports of pharmacokinetic interactions between olanzapine and benzodiazepines (studied mainly with diazepam).

Caffeine There is a potential interaction between clozapine and caffeine, due probably to a competitive pharmacokinetic interaction

between clozapine and caffeine at the CYP1A2 enzyme, resulting in an increased concentration of one or both drugs.

Ciprofloxacin Anecdotal data suggest that low doses (250 mg twice daily) of ciprofloxacin, a potent inhibitor of CYP1A2, result in a moderate elevation (about 30%) of clozapine plasma levels. There are anecdotal data suggesting that the addition of ciprofloxacin 250 mg twice daily almost doubles the plasma concentration of olanzapine.

Diuretics There is an increased risk of bone marrow suppression with a combined captopril–clozapine regimen, since each agent alone has the capacity to induce this side-effect.

Erythromycin Anecdotal data suggest that erythromycin can increase clozapine serum levels (via CYP1A2 blockade), with toxic effects.

Lithium To date, no pharmacokinetic interactions have been reported between aripiprazole and lithium.

Smoking Components of cigarettes are hepatic enzyme inducers (especially of CYP1A2), leading to a decrease in clozapine serum levels or therapeutic/side-effects. Close monitoring is suggested, especially if smoking is stopped. Cigarette components also accelerate the metabolism of olanzapin, increasing its renal clearance and reducing its plasma half-life by as much as 40%.

Ritonavir Administration of ritonavir, an HIV-1 protease inhibitor known to inhibit CYP3A4 and to reduce CYP1A2 at a dose of 300–500 mg twice daily, may decrease olanzapine plasma levels by about 50%.

Warfarin To date, the combined olanzapine–warfarin regimen has not revealed any pharmacokinetic interactions. No interactions have been reported to date between aripiprazole and warfarin.1,4,7 Amisulpiride Biotransformation in humans involves N-dealkylation and oxidation, but the isoenzymes involved in these reactions are as yet unidentified. As a consequence of its limited metabolic elimination, amisulpiride is unlikely to be involved in clinically relevant pharmacokinetic drug interactions.4

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8.9.4 Second-generation ('atypical') antipsychotic drugs (SGAs) – quetiapine, risperidone, sertindole and ziprasidone Drug interactions

Fluoxetine Fluvoxamine Ketoconazole Paroxetine

Sertindole

QTc-prolonging agents (should not be given in combination with sertindole or ziprasidone): Amiodarone Astemizole Clarithromycin Lovastatin Quinidine Sertindole Sotalol Thioridazine Ziprasidone

Barbiturates Carbamazepine Phenytoin Rifampin Thioridazine

Legend

196

Drugs that can increase the serum levels/effects of SGAs

Drugs whose serum levels/effects can be increased by SGAs

Drugs that can decrease the serum levels/effects of SGAs

Drugs whose serum levels/effects can be decreased by SGAs

Drugs whose therapeutic effects were shown to be opposed by SGAs


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Amiodarone Since ziprasidone is associated with slight prolongation of the QTc interval, caution may be required when co-administered with potent inhibitors of the cytochrome P450 enzyme CYP3A4 since sertindole is extensively metabolized by CYP2D6 and -3A4 and is a weak CYP2D6 and -3A4 inhibitor. It is contraindicated in patients receiving drugs affected by the same enzymes or known to prolong the QTc interval, such as amiodarone.

Anticonvulsants Carbamazepine, phenytoin, and barbiturates are all inducers of CYP3A4 and may accelerate the metabolism of quetiapine, decreasing its plasma concentrations and potentially leading to reduced efficacy. Carbamazepine, an inducer of drugmetabolizing enzymes, has been reported to decrease the plasma concentrations of risperidone and its metabolite (9-hydroxyrisperidone) by 50–80%. The clinical relevance of this interaction was documented in a case study concerning a patient with chronic schizophrenia, in whom the addition of carbamazepine to pre-existing risperidone therapy resulted in a marked decrease in the plasma concentration of both risperidone and 9-hydroxyrisperidone and in an acute exacerbation of psychotic symptoms. To date, there have been no reports on the effects of other CYP3A4 inducers, such as phenytoin and phenobarbital, on risperidone disposition.

Anti-infective agents Rifampin induces CYP3A4, consequently accelerating quetiapine metabolism and decreasing its plasma concentration. Ketoconazole is a potent inhibitor of CYP3A4 and may increase quetiapine plasma blood levels by 235–522%. Ketoconazole also causes a modest increase in ziprasidone plasma levels. Since ziprasidone is associated with slight prolongation of the QTc interval, caution may be required when it is co-administered with other potent CYP3A4 inhibitors such as clarithromycin, dexamethasone, erythromycin, fluconazole, and itraconazole. QTc prolongation by sertindole makes the combination of sertindole and macrolides a contraindication.

Antidepressants Imipramine is a substrate of hepatic CYP2D6, but present data suggest that it has no

significant effect on the pharmacokinetics of quetiapine. Fluoxetine, a potent CYP2D6 inhibitor and moderate CYP3A4 inhibitor, causes a minimal or statistically insignificant increase in quetiapine plasma levels. Since ziprasidone is associated with slight prolongation of the QTc interval, caution may be required when it is co-administered with potent CYP3A4 inhibitors such as fluoxetine or fluvoxamine (even though there are no concrete date about actual interactions). When administered with fluoxetine/paroxetine, plasma levels of sertindole are reported to increase by about 2–3-fold, probably via CYP2D6 inhibition. Hence, lower maintenance doses might be needed. Formal kinetic studies in patients with schizophrenia have demonstrated that concomitant treatment with risperidone together with fluoxetine or paroxetine (both of which are potent inhibitors of CYP2D6) may cause a significant elevation in the plasma concentration of risperidone, with possible occurrence or worsening of extrapyramidal symptoms. Other antidepressants with a weaker inhibitory effect on CYP2D6, including amitriptyline, citalopram, mirtazapine, reboxetine, and venlafaxine, have been found not to modify significantly the total plasma risperidone concentration.

Antipsychotic drugs Thioridazine at a dose of 400 mg/day significantly decreases quetiapine (given at 600 mg/day) serum levels by about 70%. On the other hand, the serum levels of haloperidol 15 mg/day or risperidone 6 mg/day are not altered by the addition of quetiapine. Sertindole is extensively metabolized by CYP2D6 and -3A4 and is a weak CYP2D6 and 3A4 inhibitor. It is contraindicated in patients receiving antipsychotic drugs known to prolong the QTc interval (e.g. thioridazine and ziprasidone).

Lovastatin A prolonged QTc interval has been reported with the combination of quetiapine and lovastatin (both of which undergo hepatic metabolism by CYP3A4).

QTc-prolonging drugs Sertindole is contraindicated in patients receiving drugs known to prolong the QTc interval, such as amiodarone, astemizole, quinidine, sotalol, thioridazine, and ziprasidone.1,4,7

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8.10 Benzodiazepines Drug interactions

Oral contraceptives Cimetidine (affects, mainly alprazolam, diazepam, chlordiazepoxide, flurazepam, nitrazepam, traizolam) Disulfiram Erythromycin Heparin Isoniazid Ketoconazole (?) Selective serotonin reuptake inhibitors (SSRIs) Probenacid Valproate

Digoxin (?) Phenytoin Tricyclic antidepressants (TCAs) (observed with desipramine and imipramine)

Ethanol Opiates

Acetazolamide Theophylline

Legend

198

Drugs that can increase the serum levels/effects of benzodiazepines

Drugs whose serum levels/effects can be increased by benzodiazepines

Drugs that can decrease the serum levels/effects of benzodiazepines

Drugs whose serum levels/effects can be decreased by benzodiazepines

Drugs whose therapeutic effects were shown to be opposed by benzodiazepines



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Acetazolamide

H2 blockers

This improves oxygenation at high altitudes. Benzodiazepines antagonize this effect due to an impaired respiratory response to hypoxia. Concomitant use should be avoided at high altitudes.

Cimetidine inhibits the liver enzymes associated with oxidative metabolism. Hence, the serum levels of most benzodiazepines affected by this metabolic pathway (alprazolam, diazepam, chlordiazepoxide, flurazepam, nitrazepam, and triazolam) were found to be increased when cimetidine was co-administered. Benzodiazepines metabolized by glucuronide conjugation (lorazepam, oxazepam, and temazepam) are not affected by cimetidine. Ranitidine probably has no significant interaction with most benzodiazepines.

Alcohol (ethanol) Alcohol and benzodiazepines produce synergistic central depression, probably via separate activity on the c-aminobutyric acid (GABA) type A receptor.

Antacids A few cases have been reported of slight and insignificant delays in the absorption of benzodiazepines (chlordiazepoxide and diazepam) and possibly more significant delays in absorption with clorazepate (activated by acid conditions).

Antibiotics/antifungal drugs There are many cases of increased serum levels of midazolam or triazolam when co-administered with erythromycin. The cytochrome P450 enzyme CYP3A4 is speculated to be inhibited by erythromycin. Isoniazid reduces the clearance of diazepam and triazolam, with a possible enhancement of their therapeutic or adverse effects. For ketoconazole, there is an isolated report of about 40% reduction in the clearance of chlordiazepoxide. Rifampin is a potent catabolic enzyme inducer, thus enhancing the elimination of many agents, including benzodiazepines such as diazepam and nitrazepam (whose half-lives decrease to about 15–35% of baseline). Temazepam (an agent that undergoes metabolism via hepatic glucuronidation) was found not to be affected.

Anticonvulsants The co-administration of carbamazepine can infrequently cause significant decreases in serum levels of some benzodiazepines (described with alprazolam and clonazepam). Valproate displaces diazepam from plasma protein binding and possibly inhibits its metabolism, leading to increased serum levels. A few studies have suggested that chlordiazepoxide, clonazepam, and diazepam may elevate serum levels of phenytoin.

Digoxin Diazepam was noted, anecdotally, to increase digoxin serum levels. The clinical significance of this interaction merits further investigation.

Disulfiram This inhibits the metabolism of diazepam and chlordiazepoxide, leading to enhancement of their therapeutic and/or adverse effects. The effects of lorazepam and oxazepam are practically unchanged. Isolated data suggest that disulfiram does not affect the metabolism of alprazolam.

Heparin This increases the free fraction of chlordiazepoxide, diazepam, lorazepam, and oxazepam. The mechanism is probably via induction by heparin of concomitant free fatty acid changes, which consequently alter benzodiazepine pharmacokinetics.

Lithium To date, there are no reports suggesting clinically relevant interactions between lithium and benzodiazepines.

Opiates There is an increased risk of death from respiratory failure.

Oral contraceptives These inhibit oxidative metabolism and at the same time enhance glucuronidation. Consequently, the half-lives of benzodiazepines such as alprazolam, chlordiazepoxide, diazepam, and triazolam were found to be increased, and the half-life of lorazepam, and to a lesser extent that of oxazepam, can be significantly reduced.

Probenecid This inhibits the hepatic glucuronidation metabolism and the renal excretion of many drugs, including benzodiazepines. As a result, elimination half-lives of agents such as lorazepam have been reported to increase (up to 2-fold).

Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine can raise the serum levels of alprazolam and diazepam, but has no apparent effect on the pharmacokinetics of clonazepam or triazolam.

Theophylline This can antagonize the sedative or anxiolytic effects of benzodiazepines (e.g. diazepam), probably via direct excitant action.

Tricyclic antidepressants Alprazolam has been found to increase imipramine and desipramine serum levels by about 25%. The mechanism is unknown.7 199

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8.11 Alcohol (ethanol) Drug interactions

Cimetidine

Amitriptyline

Acetaminophen

Haloperidol

Lithium

Nifedipine

Nifedipine

Antipsychotic drugs (APDs)

Ranitidine

Phenytoin (during acute alcohol intake)

Verapamil

Benzodiazepines* Mianserin Non-steroidal anti-inflammatory drugs (NSAIDs) Opiates* Tricyclic antidepressants (TCAs) (amitriptyline, clomipramine, doxepin, nortriptyline) Trazodone

Phenytoin (during chronic alcohol abuse) Propranolol Tricyclic antidepressants (TCAs)

Legend

200

Drugs that can increase the serum levels/effects of alcohol

Drugs whose serum levels/effects can be increased by alcohol

Drugs that can decrease the serum levels/effects of alcohol

Drugs whose serum levels/effects can be decreased by alcohol

Drugs whose therapeutic effects were shown to be opposed by alcohol


* Increase risk of respiratory depression

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Acetaminophen Alcohol can stimulate the conversion of acetaminophen (paracetamol) to hepatotoxic derivatives, thereby worsening hepatic damage. Heavy drinkers, especially, are at a greater risk.

complementary action on the c-aminobutyric acid (GABA) type A receptor.

Calcium-channel blockers

These can reduce some of the impairments attributed to alcohol abuse (memory, attention, recognition, reaction time, and decision making).

Nifedipine and verapamil can increase alcohol serum levels by about 15–50%. The mechanism is speculated to be via inhibition of hepatic alcohol metabolism. Some data suggest that alcohol might also inhibit the metabolism of nifedipine, thus raising its serum levels with consequent effects.

Anticonvulsants

Disulfiram

Amphetamines

Acute alcohol consumption increases serum phenytoin levels, while chronic alcohol abuse can decrease them

Antidepressants With tricyclic antidepressants (TCAs), chronic use of alcohol can enhance activity of the cytochrome P450 liver catabolic enzymes, with a consequent decrease in TCA serum levels. However, a few studies have found alcohol to increase the serum levels of amitriptyline by up to 2-fold (due, possibly, to inhibition of amitriptyline metabolism). Some data suggest central receptor interactions between alcohol and TCAs that can cause impaired motor abilities (evident with amitriptyline, clomipramine, doxepin, and nortriptyline). Mianserin and trazodine can aggravate impaired driving skills caused by alcohol, while no clinically significant interactions between mirtazapine, nefazodone, and alcohol have been observed. To date, there are no established data suggesting clinically significant pharmacokinetic interactions between alcohol and reboxetine or venlafaxine. Fluoxetine, fluvoxamine, and paroxetine do not interact significantly with alcohol. Isolated reports suggest that fluvoxamine and paroxetine can slightly augment the motor, attention and functioning impairements caused by alcohol.

Antipsychotic drugs Numerous reports suggest that a combined antipsychotic–alcohol regiment further impairs driving abilities and cognitive or neuromotor functioning, this effect being noted mostly with chlorpromazine and flupenthixol and, to a lesser extent, with haloperidol, sulpiride, and thioridazine. Haloperidol can increase alcohol serum levels. Enhanced central nervous system sedation would be expected with olanzapine and quetiapine. Raised heart rate and increased postural hypotension have been reported with quetiapine. An increased incidence of acute dystonic reactions has been suggested with the combined use of alcohol and fluphenazine or trilfuoperazine.

Benzodiazepines Alcohol and benzodiazepines produce synergistic central nervous depression due to

This antagonizes aldehyde dehydrogenase (which metabolizes acetylaldehyde, the first metabolite of alcohol), leading to accumulation of acetaldehyde with a consequent anti-abuse reaction (flushing, weakness, vertigo, headaches, nausea, vomiting, dyspnea, hypotension, and tachycardia), 10–30 minutes following the ingestion of alcohol.

Buspirone A minimal interaction and slightly increased sedation have been reported.

H2 blockers Some, but not all, studies have found that cimetidine and ranitidine can increase serum alcohol levels by 10–300% (perhaps via inhibition of alcohol dehydrogenase in the gastric mucosa, leading to enhanced alcohol absorption).

Lithium Impaired driving skills have been reported, although no clinically significantly adverse interactions have actually been reported. Alcohol may produce a slight (12%) increase in peak lithium levels.

Non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen has not been found to interact significantly with alcohol, although there are anecdotal data about the emergence of acute renal failure with combined alcohol–ibuprofen use. The risk of gastrointestinal bleeding is enhanced by concomitant use of alcohol and NSAIDs (and aspirin). The mechanism involves the damaging effects of both agents on gastric mucosal cells.

Propranolol Alcohol may slightly reduce propranolol absorption and increase excretion.

Zolpidem and zopiclone To date, no clinically significant pharmacokinetic interactions between alcohol and zopiclone have been reported. Zolpidem enhances alcohol performance impairment (the effect appears to be short-lived).7 201

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8.12 Electroconvulsive therapy (ECT) Drug interactions

b-adrenergic blockers Anticholinergic drugs (TCAs, low-potency phenothiazines, clozapine, olanzapine; all may increase cognitive impairments) Benzodiazepines Bupropion, clozapine, low-potency phenothiazines, maprotiline, TCAs (all have the capacity to significantly decrease seizure threshold and may cause prolonged seizure activity) Fluoxetine (?) Lithium (may interfere with pseudocholinesterase (the enzyme that degrades succinylcholine) and cause prolonged muscle paralysis) Monamine oxidase inhibitors (MAOIs) (may impair blood pressure management and might also inhibit pseudocholinesterase) Methylphenidate, dextroamphetamine, pemoline Nefazodone (?) Reboxetine (?) TCAs, TeCAs (?) – those drugs that block the reuptake of norepinephrine at the transporter site Vanlafaxine (?) Verapamil

Benzodiazepines Carbamazepine Gabapentin Lamotrigine Topiramate Valproate

Legend

202

Drugs that can increase the effects of ECT

Drugs whose serum levels can be increased by ECT

TCA


TeCA

Tetracyclic antidepressant

(?)

Questionable interaction or significance

Drugs that can decrease the effects of ECT

Drugs whose serum levels can be decreased by ECT

Drugs whose therapeutic effects were shown to be opposed by ECT


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Anesthetic induction agents

more) drugs with sedative properties (benzodiazepines in combination with thiopental sodium or propofol). The presence of benzodiazepines and b-blockers can reduce seizure duration.

These (e.g. methohexital, propofol, thiopental sodium) rapidly induce hypnosis, without significantly shortening seizure activity or causing hemodynamic instability, and thus allow for rapid emergence from anesthesia. Small to moderate doses of these drugs have all been used successfully for this purpose, with methohexital probably being the most preferred agent.

To date, no clinically significant interactions have been reported with the combination of ECT and buspirone.

Anticonvulsants

CNS stimulants

Buspirone

Central nervous system stimulants such as dextroamphetamine, methylphenidate, and pemoline pose a potential risk for potentiating seizure activity, thereby leading to prolonged seizures or the risk of status epilepticus.

The anticonvulsant action of valproate may prevent ECT treatment from being effective by preventing seizure activity. This is also a theoretical/practical concern with carbamazepine, gabapentin, lamotrigine, and topiramate. As a rule of thumb, the co-administration of an anticonvulsant and ECT should be considered very cautiously: (1) because the opposing effects of the anticonvulsant on seizure induction and (2) if the patient receives an anticonvulsant drug because of an underlying epilepsy, then there is an increased risk that the ECT may stimulate epileptic foci, which can further progress into ‘status epilepticus’.

To date, no clinically significant interactions have been reported with the combination of ECT and various dopaminergic drugs (e.g. amantadine).

Antidepressants

Lithium

Some antidepressant drugs (e.g. tricyclics) inhibit the sodium/potassium adenosine triphosphatase (ATPase)-dependent pump that is important for membrane stabilization, and they may therefore cause dysrhythmias and heart block. Patients with cardiac disease who receive ECT along with such antidepressants may have a significantly higher rate of cardiac complications during ECT than do patients without cardiac complications. Bupropion and trazodone can prolong seizure duration. Among the selective serotonin reuptake inhibitors (SSRIs), fluoxetine may prolong seizure duration. Excessive seizure activity causes a higher incidence of unwanted adverse effects such as confusion and memory impairment.

Antipsychotic drugs These may enhance the effects of central nervous system depressants. Therefore, the doses of anesthetics drugs need to be titrated (usually reduced) to the effect required.51

b-adrenergic blockers The presence of b-blockers can reduce seizure duration. Therefore, routine administration of these agents during ECT is not advisable.

Benzodiazepines Most drug interactions with benzodiazepines are predictable and reflect the effects of two (or

Estrogen To date, no clinically significant interactions have been reported with the combination of ECT and estrogen compounds .

Dopaminergic drugs

This acts presynaptically, via activation of ATP-sensitive potassium channels, to inhibit neuromuscular transmission and acts at the muscle membrane to inhibit muscle contraction. Prolongation of neuromuscular block has been reported in patients receiving lithium and depolarizing and non-depolarizing neuromuscular blockers. Hence, the combination of lithium and ECT is relatively contraindicated.

Muscle relaxants These should be rapid in onset, profound in intensity, and short in duration. Succinylcholine is the only muscle relaxant that meets all of these requirements. If its use is contraindicated, mivacurium is currently the preferred short-acting alternative.

Verapamil This is a calcium-channel antagonist, which can produce potentiation of suxamethonium and non-depolarizing neuromuscular blockers at doses within the therapeutic range. Verapamil also exacerbates the increase in serum potassium levels after the administration of suxamethonium. To date, there are no established data about such interactions between other calcium-channel blockers and ECT.42–44 203

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8.13 Acetylcholinesterase inhibitor (donepezil) Drug interactions

Inhibitors of CYP2D6 Amiodarone (also due to inhibition of CYP3A4) Cimetidine (also due to inhibition of CYP3A4) Delaviradine Selective serotonin reuptake inhibitors (SSRIs) (especially fluoxetine (also due to inhibition of CYP3A4) and paroxetine) Propafenone Inhibitors of CYP3A4 Erythromycin Diltiazem Fluvoxamine Metronidazole Nefazodone Verapamil

Carbamazepine Dexamethasone Phenobarbital Phenytoin Rifampin St John's wort

Legend

204

Drugs that can increase the effects of donepezil

Drugs whose serum levels/effects can be increased by donepezil

Drugs that can decrease the effects of donepezil

Drugs whose serum levels/effects can be decreased by donepezil

Drugs whose therapeutic effects were shown to be opposed by donepezil


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References 1. Preskorn SH, Flockhart D. 2004 guide to psychiatric drug interactions. Primary Psychiatry 2004; 11: 39–60. 2. BeBattista C, Schatzberg AF. 2003 psychotropic dosing and monitoring guidelines. Primary Psychiatry 2003; 10: 80–84, 87–96. 3. Brosen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 2001; 11: 275–283. 4. Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fund Clin Pharmacol 2003; 17: 517–538. 5. Waugh J, Goa KL. Escitalopram, a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 2003; 17: 343–362. 6. Wengel SP, Burke WJ. Escitalopram: What does it have to offer? Primary Psychiatry 2003; 10: 67–70. 7. Bazire S. Psychotropic Drug Directory, 2003/2004. Mental Health Matters: 271–366. 8. Prakash SM, Gupta S. Long term side effects of newer generation antidepressants: SSRIs, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann Clin Psychiatry 2002; 14: 175–182. 9. Spencer CM, Wilde MI. Milncipran. Drugs 1998; 56: 405–427. 10. Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fund Clin Pharmacol 2003; 17: 517–538. 11. Zyban (bupropion hydrochloride) sustainedrelease tablets: product information. GlaxoSmithKline UK, 2001. 12. Fagerstrom K. Smoking cessation treatment with sustained released bupropion: optimizing approaches to management. Drugs Suppl 2002; 62: 1–70. 13. Linnoila M, Saario I, Maki M. Effects of treatment with diazepam or lithium and alcohol on psychomotoric skills related to driving. Eur J Clin Pharmacol 1974; 7: 337–342. 14. Muller-Oerlinghausen B. Drug interactions with lithium. CNS Drugs. 1999; 11: 41–48. 15. Jefferson JW, Greist JH, Acherman DL. Lithium Encyclopedia for Clinical Practice, 2nd edn. Washington, DC: American Psychiatric Press, 1987. 16. Vincent F, Bensousan TA, Levy V et al. Lithium concentration during cisplatinbased chemotherapy: evidence for renal interaction. Cancer chemother Pharmacol 1995; 6: 533–534.

17. Bauer M. The combined use of lithium and SSRIs. J Serotonin Res 1995; 2: 69–76. 18. Mekler G, Woggon B. A case of serotonin syndrome caused by venlafaxine and lithium. Pharmacopsychiatry 1997; 30: 263–264. 19. Goldman RD, Spencer ND. Safety of the combination of lithium and neuroleptics drugs. Am J Psychiatry 1986; 143: 882–884. 20. Helmchen H, Kanoeski S. EEGVeranderunger unter Lithium Therapie. Nervenarzt 1971; 42: 144–148. 21. Garcia G, Crismon ML, Dorson PG. Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol 1994; 14: 426–427. 22. Chaudry RP, Waters BGH. Lithium and carbamazepine interaction. J Clin Psychiatry 1983; 44: 30–31. 23. Mester R, Toren P, Mizrachi I et al. Caffeine withdrawal increases lithium blood levels. Biol Psychol 1995; 37: 348–350. 24. Jefferson JW, Greist JH, Baudhuin M. Lithium: interactions with other drugs. J Clin Psychopharmacol 1981; 1: 124–34. 25. Weinrauch LA, Belok S, D’Elia. Decreased serum lithium during verapamil therapy. Am Heart J 1984; 108: 1378–1379. 26. Byrd GJ. Lithium carbonate and methyldopa: apparent interaction in man. Clin Toxicol 1977; 11: 1–4. 27. Yassa R. Lithium methyldopa interaction. Case Report. CMAJ 1986; 134: 141–142. 28. Finley PR, Warner MD, Peabody CA. Clinical relevance of drug interaction with lithium. Clin Pharmacokinet 1995; 29: 172–191. 29. Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1988; 155: 15–21. 30. Finley PR, O’Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol 1996; 16: 68–71. 31. Blanche P, Raynaud E, Kerob D et al. Lithium intoxication in an elderly patient after combined treatment with Losartan. Eur J Clin Pharmacol 1997; 52: 501. 32. Hill GE, Wong KC, Hodges MR. Lithium carbonate and neuromuscular blocking agents. Anesthesiology 1977; 46: 122–126. 33. Saarnivaara L, Ertama P. Interactions of lithium/rubidium and six muscle relaxants. A study on the rat phrenic-hemidiaphregm preparation. Anesthetist 1992; 41: 760–764. 34. Lippman SB, El-Mallakh R. Can electroconvulsive therapy be given during lithium treatment? Lithium 1994; 168: 241–243. 35. Jha AK, Stein GS, Fenwick P. Negative interactions between lithium and

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36. 37.

38.

39. 40.

electroconvulsive therapy: a case–control study. Br J Psychiatry 1996; 168: 241–243. Suppes T, Majeres K. Dosing and monitoring guidelines for anticonvulsants. Primary Psychiatry 2004; 11: 53–70. DeVane CL. Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 2003 (Summer); 37: 25–42. Gara L, Roberts W. Adverse response to methylphenidate in combination with valproic acid. J Child Adolesc Psychopharmacol 2000; 10: 39–43. Goldsmith DR, Wagstaff AJ, Ibbotson T. Spotlight on lamotrigine in bipolar disorder. CNS Drugs 2004; 18: 63–67. Bialer M, Doose DR, Murthy B et al.

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Pharmacokinetic interactions of topiramate. Clin Pharmacokinet 2004; 43: 763–780. Waught J, Goa KL. Topiramate as monotherapy in newly diagnosed epilepsy. CNS Drugs 2003; 17: 985–992. Naguib M, Koorn R. Interactions between psychotropics, anaesthetics and electroconvulsive therapy. CND Drugs 2002; 16: 229–247. Alexander HE Jr, McCarty K, Giffen MB. Hypotension and cardiopulmonary arrest associated with concurrent haloperidol and propofol therapy. JAMA. 1984; 252: 87–88. Fuller MA, Sajatovic M. In: Drug Information Handbook for Psychiatry. Cleveland, OH: Lexi-Comp Inc., 2002: 322–323.

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Chapter 9 Treatment strategies (evidence based)

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Treatment strategies (evidence-based)

9.1 Major depressive disorder (MDD) (non-resistant) Main reactions relevant for psychiatric pharmacotherapy

If mild–moderate depression, consider

Cognitive–behavioral therapy

If not relevant

Avoid, as much as possible, Choose from one of the following classes:

TCAs SSRI, NARI, SNRI, TCA, Atypical Chose on basis of patient's background [former response to drugs, age, gender, concomitant 'physical' disorders, concomitant drugs (hepatic metabolism, protein-binding capacity, synergistic adverse effects) and physician's experience]

If suicidal

due to their relative high lethality/ cardiotoxicity compared with the other classes of antidepressants

Consider augmentation with

Switch to alternative agent (from different class):

SSRI, NARI, SNRI, TCA, Atypical Lithium or with Triiodothyronine (T3), L-tryptophan,

Switch to alternative agent (from different class):

pindolol

MAOI, ECT, RIMA

Legend

Name of modality

Well-established efficacy

Name of modality

Some (less-established) efficacy

Name of modality

Efficacy not well established If partial response

ECT MAOI NARI RIMA SNRI

If no response SSRI Atypical

208

Atypical antidepressant (see text for details)

TCA

Electroconvulsive therapy Monoamine oxidase inhibitor Noradrenaline (norepinephrine) reuptake inhibitor Reversible inhibitor of monamine oxidase type A Serotonin–norepinephrine reuptake inhibitor Selective serotonin reuptake inhibitor Tricyclic antidepressant

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9.2 Major depressive disorder (MDD) with psychotic features Treatment strategies (evidence-based)

If there are no relative contraindications to ECT (1), or if there are contraindications to pharmacotherapy (2), consider

Electroconvulsive therapy (ECT)

If not relevant at that stage

Consider antipsychotics, preferably

If not relevant at that stage

Atypical antipsychotic

Consider

Consider adding an antidepressant agent

Amoxapine (3)

Antidepressant drug (4)

Legend

1

Recent myocardial infarction, increased intracranial pressure, prior serious adverse effects following ECT, concomitant treatment with lithium, comorbid epilepsy

Name of modality


Name of modality


2

Allergic reactions, lack of response to previous drug therapy

Name of modality

Efficacy not well established

3

Due to its dual antipsychotic and antidepressant properties

If partial response

4

Try to use selective serotonin reuptake inhibitors (SSRIs), at least in mild–moderate cases. The use of tricyclic antidepressants (TCAs) should be left for more severe cases

If no response

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9.3 Major depressive disorder (MDD) with atypical features Treatment strategies (evidence-based)

If patient can be given an MAOI (good dietary compliance, no clinically significant hypotension, not diabetic, not asthmatic), consider

MAOI or try a

RIMA

If severe depression and patient can tolerate adverse effects of TCAs, consider

If patient cannot tolerate side effects of TCAs, is obese, or suffers from seizure disorder, consider

TCA

SSRI

Try augmentation; consider

Lithium, triiodothyronine (T3)

Legend

Name of modality


MAOI


Name of modality


RIMA

Reversible inhibitor of monoamine oxidase type A

Name of modality


SSRI


TCA


If no response If partial response If not relevant

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Unipolar depressive disorder or major depressive disorder (MDD) is characterized by depressive symptoms without any history of a manic, mixed, or hypomanic episode. MDD is a severe mood disorder, associated with significant morbidity and mortality that affects individuals of all ages and races. The mean age of onset of MDD is approximately 30 years. The disorder has a median life prevalence of 4.5–18%. It occurs in about 5–10% of the adult population, with women being at a higher risk than men (the ratio is approximately 2 : 1). Female gender, a previous episode of major depression, and a first-degree family history of depression are the most consistently described risk factors for a depressive episode. Untreated MDD has decreasing episode cycles with increasing episode number. Although the prognosis of MDD is generally considered quite favorable (e.g. most patients return to normal functioning with pharmacologic treatment), up to 20–30% of patients suffer chronically from at least some of their symptoms.1

Notes about Schemes 9.1–9.3 The treatment of MDD corresponds to three stages: acute phase, continuation phase, and maintenance phase.2 The gross treatment options should follow the strategies listed in Scheme 9.3. The following are only suggestions, which are based mainly on specific data from accumulated research. The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are usually considered as first-line treatments. Amitriptyline and clomipramine are second-line treatments. Other tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs) are third-line treatments. For MDD with atypical features, fluoxetine, moclobemide, and sertraline are the first-line treatments. Phenelzine is the second-line treatment. Imipramine is the third-line treatment. For MDD with melancholic features, paroxetine and venlafaxine are the first-line treatments. TCAs and moclobemide are the second-line treatments. Citalopram and fluoxetine are third-line treatments. For MDD with psychotic features, electroconvulsive therapy (ECT) or an

antipsychotic plus an antidepressant are first-line treatments. Olanzapine plus an antidepressant is second-line treatment. For MDD with seasonal pattern (MDDSP), bright-light therapy is the first-line treatment. Fluoxetine and moclobemide are second-line treatments. Bupropion, citalopram, and tranylcypromine are third-line treatments. For MDD with severe anxiety, mirtazapine, TCAs, trazodone, and benzodiazepines should be considered as adjunctive therapy.3 If the patient is not at least moderately improved after 4–8 weeks, the treatment regimen should be reappraised. Compliance should be checked. It is important to consider pharmacokinetic/pharmacodynamic factors (this may require an evaluation of serum levels of the antidepressant medication), general medical comorbidities, and comorbid psychiatric disorders, including substance abuse and significant psychosocial problems. The initial therapeutic treatment dose should be gradually maximized. For partial responders, the trial should be extended by 2–4 weeks. For non-responders on moderate doses or those with low serum levels, the dose should be increased and the patient monitored for increased side-effects. It may be necessary to add, change, or increase the frequency of psychotherapy. If there is no response to the first trial, medication should be switched to another non-MAOI, preferably from a different class. If only a partial response is achieved, augmentation with lithium, pindolol (see Section 2.7), or thyroid hormone should be considered. If the second trial, fails, treatment should be augmented with a non-MAOI antidepressant from a different class or another adjuvant medication (anticonvulsants, lithium, pindolol, psychostimulants, or thyroid hormone). If the second trial fails even with augmentation therapy, medication should be switched to an MAOI. If this fails, ECT should be instituted.2 The required washout periods between trials of antidepressant medications and the use of MAOIs are as follows: when switching from/to an MAOI to/from a drug with a long-half-life metabolite (e.g. fluoxetine), the minimum period is 5 weeks; when switching from/to an MAOI to/from other antidepressants (e.g. fluvoxamine, paroxetine, TCAs, and venlafaxine), the minimum period should be 2 weeks.3

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9.4 Major depressive disorder (MDD) (treatment-resistant) Treatment strategies (evidence-based)

Use an antidepressant agent that has not been used before. Select from one of the following main classes of antidepressants:

TCAs, TeCAs, SSRIs, SNRIs, NARI, MAOIs, 'atypical' ADs

Switch to another agent from the main classes listed above but with different pharmacodynamics. If not relevant, try augmentation with

Lithium, SGAs, ECT

Try different augmentation/other drugs. The following combinations have shown some efficacy:

Bromocriptine; bupropion ⫹ yohimbine carbamazepine ⫹ lithium; clomipramine ⫹ L-tryptophan MAOI ⫹ (amphetamine/TCA) SSRI ⫹ (buspirone/lithium/trazodone) TCA ⫹ (amphetamine/CBZ/lithium/MAOI/ SGAs/SSRI/triiodothyronine (T3))

Legend Name of modality


Name of modality


Name of modality

Efficacy not well established If partial response If no response

212

AD CBZ ECT MAOI NARI SGA SNRI SSRI TCA TeCA

Antidepressant drug Carbamazepine Electroconvulsive therapy Monoamine oxidase inhibitor Selective noradrenaline (norepinephrine) reuptake inhibitor Second-generation antipsychotic Serotonin–norepinephrine reuptake inhibitor Selective serotonin reuptake inhibitor Tricyclic antidepressant Tetracyclic antidepressant

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Treatment-resistant depression typically refers to an inadequate response to at least one antidepressant trial of adequate dose (superior to placebo in controlled clinical trials) and duration (e.g. 6–12 weeks). Treatment-resistant depression is a relatively common occurrence in clinical practice, with up to 50–60% of patients not achieving an adequate response following antidepressant treatment. Although the more traditional view of treatment resistance has focused on non-response, from the perspective of clinicians and patients, not achieving remission despite adequate treatment represents a significant challenge. In addition, response without remission has a potentially poor outcome, as residual symptoms are associated with poorer outcome and increased relapse risk. With this treatment approach in mind, inadequate response implies that the treatment has failed to achieve remission; from the clinician’s and patient’s perspective, remission typically implies achieving a relatively asymptomatic state.4

Notes about the scheme Generally, patients with non-psychotic unipolar major depressive disorder start treatment with antidepressant monotherapy. However, when their symptoms fail to achieve full remission during an adequate course of treatment, switching, augmenting, and combining various pharmaceutical agents can be effective management strategies. Advantages of switching include improved compliance, reduced medication costs, and fewer drug interactions. Advantages of augmentation or combination include rapid response, no necessity for titration, and maintenance of initial improvement. Most patients are started on a selective serotonin reuptake inhibitor (SSRI); switching to another SSRI may be beneficial but such a strategy has not been studies as yet in a wellcontrolled trial. Another possibility is to switch to a selective noradrenaline (norepinephrine) reuptake inhibitor (NARI, i.e. reboxetine), a tricyclic antidepressant (TCA), or a serotonin–norepinephrine reuptake inhibitor (SNRI, e.g. venlafaxine). However, there are limited data indicating that a switch from an SSRI to reboxetine/TCA can be

useful. Switching from an SSRI to an SNRI (e.g. venlafaxine) may be a very effective strategy, even in very resistant patients (failing to respond to at least three adequate trials of antidepressants). The evidence about switching from an SSRI (or any other antidepressant) to bupropion is more limited. Mirtazapine is a safe and effective alternative when other antidepressant treatments fail. Switching to an irreversible monoamine oxidase inhibitor (MAOI) requires a 2-week washout period (a 5-week washout period switching from fluoxetine). Augmentation and combination strategies are particularly helpful in managing treatment-resistant patients. These strategies allow the patient to maintain the improvement already achieved, and positive effects may appear more rapidly. Of all the augmentation strategies, lithium has been best researched, and it is considered the preferred augmentation to TCAs, although it has also demonstrated its efficacy as augmentation to SSRIs. Thyroid hormone is another possibility. Some data suggest that it might be more beneficial in patients with a family history of thyroid disorder. Other augmentation strategies include the addition of buspirone or bupropion to SSRIs; this has given mixed results. Pindolol augmentation of SSRIs is another option (see Section 2.7). However, well-controlled studies have not found consistent evidence for its beneficial effects. Other anecdotal augmentations include dopaminergic receptor agonists (e.g. bromocriptine, pramipexole, ropirinole, and pergolide) or methylphenidate. Combination strategies include the combination of noradrenergic tricyclic agents (e.g. desipramine or nortriptyline) or bupropion with SSRIs. Adding an a2-adrenergic antagonist such as yohimbine is another approach to managing treatment-resistant depression. The combination of an SSRI and mirtazapine may also be an effective strategy. The combination of yohimbine and mianserin may be useful in some cases. Combining risperidone or olanzapine and an SSRI has shown some promise. Electroconvulsive therapy (ECT) remains one of the most effective treatments for treatment-resistant depression.4,5

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9.5 Major depressive disorder in the geriatric population Treatment strategies (evidence-based)

Consider one of the following, choosing on the basis of side-effect profile, comorbid 'physical' disorders, past response, physician experience:

SSRI (most effective/tolerable are citalopram, escitalopram, fluvoxamine, sertraline) or mirtazapine or reboxetine or trazodone or venlafaxine

Consider switching to

Tricyclic antidepressant (TCA) (most tolerable and effective are desipramine and nortriptyline)


ECT, fluoxetine (third-line only due to its very long half-life*), paroxetine (third-line only due to its relative high anticholinergic capacity among the SSRIs)



Name of modality


Name of modality


214

ECT SSRI *

Electroconvulsive therapy Selective serotonin reuptake inhibitor The average time required for a decrease of 50% in serum levels of the compound

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Depression is often overlooked as a clinical diagnosis in older patients because it is mistakenly assumed to be a ‘normal’ response to aging, physical deterioration, or other lifeevents. However, medical intervention for depression is appropriate in this population, especially in those patients with severe chronic disease. Community studies have shown that 25% of elderly persons report having depressive symptoms, and between 1% and 9% meet the criteria for major depressive disorder. Higher prevalence rates are reported in the hospitalized elderly population (36–46%) and about 10–22% in patients hospitalized in long-term facilities. In the evaluation of a first or recurrent episode of depression, numerous medical conditions, medications, and other factors associated with age should be considered. Among these are hypothyroidism, diabetes, cancer, macular degeneration, myocardial infarction, use of b-blockers, interferon-a, or many anticancer drugs, parkinsonism, Alzheimer’s disease, multiple sclerosis, stroke, Huntington’s disease, microvascular disease, and cognitive decline.6

Notes about the scheme The selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment of depression in the elderly. Compared with tricyclic antidepressants (TCAs), they are much safer in overdose and, for the most part, their sideeffects are better tolerated. The antidepressants that have been shown, in controlled studies, to be effective in geriatric major depression are the SSRIs fluoxetine, paroxetine, and sertraline, the TCAs clomipramine and nortriptyline, and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine. Given that most antidepressants are effective in the elderly, the choice of drug is based on its side-effect profile and its potential to interact with other medications. Anticholinergic side-effects are particularly troublesome to elderly patients. Dry mouth promotes dental decay and denture problems;

papillary dilatation increases the risk of developing closed angle glaucoma. Constipation, an increasing problem with age, may lead to laxative abuse, ileus, or intestinal obstruction. Enlarged prostates are at risk of urinary retention. Anticholinergic effects on cognition can be significant and additive from multiple drugs, and may result in delirium or other cognitive decline. Sedation and increased appetite due to histamine blockade and hypotension from adrenergic blockade are also causes for concern. Many of the geriatric population receive numerous concomitant medications (i.e. ‘non-psychiatric’). Most regularly used drugs (‘psychiatric’ and ‘nonpsychiatric’) are metabolized by the hepatic cytochrome P450 enzymes CYP2D6 or CYP3A4. Therefore, in order to eliminate, as much as possible, drug–drug interaction, the best drugs to give a geriatric patient are those that are not metabolized by either CYP2D6 or CYP3A4. A second option is to take drugs that are metabolized by other hepatic enzymes in addition to CYP2D6/3A4, so that the influence of CYP2D6/3A4 is less dominant. Taking this into account, the best drugs with respect to drug–drug interactions are probably citalopram, escitalopram, fluoxetine, fluvoxamine, reboxetine, and venlafaxine. Among the TCAs, desipramine and nortriptyline are the most recommended, since they have few anticholinergic side-effects.6 Sertraline has been studied in a placebo-controlled randomized trial and is considered one of the safest drugs for elderly patients post myocardial infarction, since it has no negative impact on cardiac measures.7 A number of placebo-controlled studies of post-stroke depression have shown efficacy for citalopram at doses of 10 mg and for nortriptyline (but not for fluoxetine). Venlafaxine may also be considered; however, it should be used with caution since in 3–5% of patients it increases blood pressure. Mirtazapine may be used in patients with insomnia and decreased appetite due to its sedative side-effects and its promotion of increased appetite.6

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9.6 Premenstrual dysphoric disorder (PMDD) Treatment strategies (evidence-based)

If the patient exhibits a less severe form of the disorder or refuses pharmacological treatments, reduce stimulating factors of PMDD:

Reduce alcohol, caffeine, chocolate, refined sugars Increase exercise, relaxation techniques Consider cognitive therapy, light therapy, marital counseling, sleep deprivation

Consider pharmacotherapy

Calcium, magnesium, mefenamic acid, naproxen vitamin B6, vitamin E

Consider switching to SSRIs (citalopram, fluoxetine, paroxetine, sertraline)

Alprazolam, buspirone venlafaxine Or agents that prevent ovulation: danazol, GnRH agonists, leuprolide, oral contraceptives, progesterone



Name of modality


Name of modality


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SSRI GnRH

Selective serotonin reuptake inhibitor Gonadotrophin-releasing hormone

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Premenstrual dysphoric disorder (PMDD) occurs in 2–9% of women of reproductive age and requires clear impairment of functioning in order to be diagnosed. Even though the symptoms of PMDD vary from woman to woman, the symptoms experienced by each individual have been shown to be relatively consistent from cycle to cycle. PMDD starts in the early to mid 20s, although it may begin at menarche. It is characterized by mood symptoms that are sufficiently severe that they result in significant disruption of a women’s normal level of functioning. The current predominant hypothesis is that those women who develop PMDD have an underlying vulnerability in the central nervous system. Many of the typical symptoms of PMDD – most notably irritability, impulse dyscontrol, depressed mood, and carbohydrate craving – have been linked to serotonergic dysfunction. Hence, treatment of PMDD is usually based on selective serotonin reuptake inhibitors (SSRIs).8

Notes about the scheme In patients with less severe PMDD, non-pharmacological strategies are usually warranted, among them reduction of caffeine, salt, chocolate, refined sugars, and alcohol, increased exercise, relaxation and stress reduction techniques, cognitive therapy, martial counseling, light therapy (bright, full-spectrum lights), biofeedback, and sleep deprivation. In addition, miscellaneous agents should be tried, such as vitamin B6 100–200 mg/day, calcium 1000–1200 mg/day, magnesium 200 or 360 mg/day, vitamin E 400–800 IU/day, and over-the-counter analgesics such as naproxen and mefenamic acid. For patients with severe PMDD with comorbid psychiatric disorders such as depressive or anxiety disorder, continuous dosing (daily dose) is recommended; the SSRIs fluoxetine at a dose of 20 mg/day or sertraline at a dose of 25–50 mg/day are considered first-line treatment (the doses are somewhat lower than those used in other

psychiatric disorders such as major depressive disorder and obsessive–compulsive disorder). Effectiveness for PMDD has also been reported with other SSRIs (e.g. citalopram, fluvoxamine, and paroxetine). The benefit of SSRIs appears usually within 2–3 days. Alprazolam at a daily dose of 0.25 mg twice a day up to 0.5 mg three times a day during the luteal phase or buspirone at continuous dosing are considered second-line treatment. Venlafaxine has also been reported to exert significant efficacy at doses of 50–200 mg/day. For patients with PMDD without comorbid psychiatric disorders, intermittent premenstrual dosing is highly effective and very well tolerated, and is likely to be the treatment of choice. Intermittent premenstrual dosing is typically initiated approximately 14 days prior to the anticipated onset of menstrual bleeding and is continued to the menstrual flow. Fluoxetine and sertraline are considered first-line treatment at 20 mg/day and 50–100 mg/day, respectively. Symptoms of PMDD may remit if ovulation is suppressed. The various treatments that have been employed to achieve an anovulatory state include danazol, gonadotrophin-releasing hormone (GnRH) agonists, leuprolide, and progesterone. However, the fact that chronically low estrogen levels increase the risks of both cardiovascular illness and osteoporosis makes these regimens less advised. Oral contraceptives prevent ovulation and should be effective for the treatment of PMDD. However, limited evidence does not support efficacy for oral contraceptive agents containing progestins derived from 19-nortestosterone. The combination of the estrogen and progestin may produce symptoms similar to PMDD, such as water retention and irritability. There is preliminary evidence that oral contraceptive pills containing low-dose estrogen and the progestin drospirenone (a spironolactone analog) instead of a 19-nortestosterone derivative can reduce symptoms of water retention and other side-effects related to estrogen excess.8

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9.7 Dysthymic disorder Treatment strategies (evidence-based)

Consider treatment with

MAOI (phenelzine)

If there is a relative contraindication to MAOIs / MAOIs cannot be administered, consider SNRI (venlafaxine), SSRIs [citalopram, fluoxetine, sertraline (best data)] or a TCA (desipramine)



Lithium, triiodothyronine (T3)

TCA (amitriptyline, imipramine)


Bupropion, reboxetine, RIMA, SGA (e.g. amisulpiride), SSRIs (other than those listed above)



Name of modality


Name of modality


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MAOI Monoamine oxidase inhibitor RIMA Reversible inhibitor of monoamine oxidase type A SGA Second-generation antipsychotic drug SNRI Serotonin–norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitor TCA


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The essential feature of dysthymic disorder is a chronically depressed mood that occurs for most of the day more days than not for at least 2 years. The lifetime prevalence of dysthymic disorder is approximately 6%, with females being affected almost twice as much as males. It has an early and insidious onset as well as a chronic course (the disorder may last up to 20 years, with a median duration of about 5 years).9 Patients may suffer from ‘superimposed’ major depressive disorder, an entity known as ‘doubledepression’. In that case, the prognosis of the disorder worsens considerably. All in all, the prognosis of treated dysthymic disorder is variable. Some data suggest that only 20–25% of patients attain complete remission a year following diagnosis. Moreover, up to 20–25% of patients suffer from a chronic, non-remitting course of the disorder.

Notes about the scheme Traditionally, dysthymic disorder has not been the focus of pharmacotherapeutic interventions, given its chronicity and the presumed non-biological personality variables associated with it. Psychotherapy and psychoanalysis were generally considered the first-choice treatment options, although these treatment modalities have not been well studied in controlled trials.10 However, as a result of a series of placebocontrolled medical trials, this attitude has been changed.11 Among the antidepressants found to be superior to placebo are the selective serotonin reuptake inhibitors (SSRIs, with results being evident so far with fluoxetine and sertraline), the tricyclic antidepressants (TCAs) amitriptyline, desipramine, and imipramine (with a 40–60% favorable response), and the reversible and irreversible monoamine oxidase inhibitors (MAOIs) moclobemide and phenelzine, respectively. Of these, phenelzine has been shown (although not in very large and well-controlled studies) to be the most effective drug for dysthymic disorder (with 30–70% beneficial results). Other antidepressants (e.g.

amineptine, bupropion, citalopram, mirtazapine, nefazodone, reboxetine, and venlafaxine) have also been reported in case reports, small case series studies, and open-label trials to exert some beneficial effects in dysthymia. Although the optimal length of pharmacotherapy in dysthymia has not been studied in a controlled trial, a course of treatment with an antidepressant for at least 2–3 years is recommended. Recommended doses for dysthymia are similar to those given for acute treatment of a major depressive episode. The SSRIs, due to their superior tolerability and side-effect profile, are currently considered the first-line treatment for the long-term treatment of dysthymic disorder. In the case of failure or intolerance to SSRIs, the TCAs amitriptyline, desipramine, and imipramine or the reversible MAOI moclobemide should be tried. The reversible MAOI phenelzine has shown superior effectiveness to imipramine in one double-blind study.12 However, it should be reserved as third-line therapy due to its less-favorable side-effect profile and dietary restrictions. Electroconvulsive therapy (ECT) has been suggested by some clinicians as the third-line option in dysthymic disorder. However, to date, there are no well-established or consistent data about its efficacy for this condition. Currently, most of the suggested treatment algorithms do not include ECT as an option. The third-line options are usually second-generation antipsychotics (SGAs) and combination therapies. Among the SGAs, the recently introduced amisulpiride has shown the most consistent beneficial effects in dysthymic disorder, especially when given in low doses (e.g. 50 mg/day). At these dosages, amisulpiride is believed to block mainly the presynaptic dopaminergic autoreceptors, with consequent enhanced secretion of dopamine. Some other data suggest the efficacy of olanzapine in dysthymia, particularly if there is comorbidity with borderline personality disorder.10,11

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9.8 Major depressive disorder as part of bipolar I disorder Treatment strategies (evidence-based)

If the patient is on lithium therapy, not suicidal, or ECT is not relevant (e.g. patient disagrees, previous non-responsive, etc.)

If the patient is suicidal and ECT is relevant (e.g. patient agrees, previous response, etc.)

If good adherence and low lithium levels, increase dose

If hypothyroidism (may also be effective in euthyroid patient)

Lithium

T3

If on lithium / carbamazepine / valproate, discontinue and start a course of

ECT

Choose on basis of past response, side-effect profile, pharacodynamic profile, physician's experience:

SNRI, SSRI, TCA

Bupropion, MAOI, nefazodone, reboxetine, TeCA, trazodone

Legend

Name of modality


Name of modality


Name of modality

Efficacy not well established If partial response If no response If relevant

220

ECT MAOI

Electroconvulsive therapy Monoamine oxidase inhibitor

SNRI

Serotonin–norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitor T3 Triidothyronine

TCA TeCA

Tricyclic antidepressant Tetracyclic antidepressant

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The primary goal of treatment of major depressive disorder (MDD) as part of bipolar I disorder, as with unipolar depression, is remission of the symptoms of major depression with return to normal levels of psychosocial functioning. An additional focus of treatment is to avoid precipitation of a manic or hypomanic episode. One reason patients with bipolar I depression do not receive effective care is that this condition has long been overlooked because clinicians tend to recognize mania more readily than bipolar I disorder. Recognition and treatment of bipolar I disorder is of paramount importance since most suicides among patients with this condition occur during the depressive phase of the disorder.13,14 Systematic studies of bipolar I disorder, and especially of the role of pharmacotherapy while on lithium maintenance therapy, are quite limited. To date, many of the treatment strategies concerning major depressive disorder (unipolar) are applicable, to some extent, in bipolar I disorder.

Notes about the scheme The first-line pharmacological treatment for MDD as part of bipolar I disorder is either to add an antidepressant drug to ongoing lithium (or another mood stabilizer) treatment or, if the patient is not receiving a mood stabilizer, to administer an antidepressant drug as a sole agent. If the administration of an antidepressant drug is not relevant, one of the following treatments might be appropriate: lamotrigine, lithium, olanzapine, or olanzapine plus fluoxetine. Besides antidepressants, the best supported of the above treatment options is lithium. While standard antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have shown good efficacy in the treatment of unipolar depression, for bipolar I disorder they have generally been studied only as add-ons to medications such as lithium or valproate. Thus, antidepressant monotherapy is probably recommended and efficient, given the

risk of precipitating a switch to mania. In patients with life-threatening inanition, suicidality, or psychosis, electroconvulsive therapy (ECT) represents a reasonable alternative. In addition, ECT is a potential treatment for severe depression during pregnancy, treatment-resistant depressive episodes, or those episodes with catatonic or psychotic features. For patients who, despite receiving maintenance medication, suffer a breakthrough depressive episode, the first-line intervention should be to optimize the dose of the maintenance medication. For patients who do not respond to optimal maintenance treatment, the next step is to switch to another antidepressant from a different class or to combine two first-line treatments. The addition of valproate should also be considered (the combination of lamotrigine with valproate should be avoided, since it may cause Stevens–Johnson or other severe rash), as might one of the second-generation antipsychotic drugs (e.g. aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone). If there is no response to a combination of firstline treatments, and the patient does not suffer from rapid cycling, an antidepressant such as bupropion or an SSRI could be added (tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) should be avoided, as they may increase the risk of switching to mania). If the patient suffers from rapid cycling bipolar I disorder and the combination of two first-line treatments fails, olanzapine or valproate should be added. Other options include the administration of non-TCAs such as reboxetine, trazodone, or an MAOI. However, the efficacy of these regimens in bipolar I disorder has not been studied in well-controlled trials, and they should be left for incapacitating symptoms in patients who have received practically all other possibilities. Most patients with bipolar I disorder may also benefit from psychological treatments in addition to any pharmacological treatment.13,14

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9.9 Acute manic episode Treatment strategies (evidence-based)

If no indication for a specific drug

If good prognostic signs for lithium exist (1)

If good prognostic signs for carbamazepine exist (2)

If good prognostic signs for valproate exist (3)

Carbamazepine

Valproate

Lithium

Lithium

Carbamazepine, valproate

Lamotrigine, topiramate

Electroconvulsive therapy (ECT)

Clonazepam, second-generation antipsychotic drugs (SGAs)

Calcium-channel blockers, clonidine

1

Euphoric mania, first-degree relatives with mood disorders, less than 3 previous manic episodes, absence of psychosis, good previous response

2

Dysphoric mania, mixed episode, rapid cycling (most probably better than lithium but not as efficient as valproate), part of schizoaffective disorder, comorbid substance abuse, absence of psychosis, obesity

3

Rapid cycling, dysphoric mania, mixed episode, stable or decreasing number of manic exacerbations



Name of modality


Name of modality


222

At any time, consider adding an antipsychotic agent (preferably a second-generation drug) if the patient is dangerously psychotic, aggressive, or with known good previous response to antipsychotics. A benzodiazepine (e.g. clonazepam) may also be effective in severe agitation/aggressiveness

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Patients experiencing a manic episode show elevated mood, expansiveness, flight of ideas, decreased sleep, heightened self-esteem, and grandiose ideas. For patients experiencing a manic or mixed episode, the primary goal of treatment is the control of symptoms to allow a return to normal levels of psychosocial functioning. Rapid control of agitation, aggression, and impulsiveness is particularly important to ensure the safety of patients and those around them.15

Notes about the scheme Lithium and valproate are usually considered the first-line treatment options for acute exacerbation of non-psychotic mania. Lithium is most effective in euphoric mania and valproate is probably more effective in mixed states. Moreover, good prognostic signs for lithium may include: ● ●

● ●

first-degree relatives with mood disorders; euphoric mania (60–80% will respond favorably to lithium, while among patients with dysphoric mania only about 20% will respond favorably); less than three lifetime manic episodes; good responses to lithium in previous exacerbations.

Good prognostic signs for valproate may include: ● ●

rapid cycling or dysphoric mania; stable or decreasing frequency of manic exacerbations.

Carbamazepine may also be effective in specific cases of acute manic episode. Good prognostic signs for carbamazepine are: ● ● ● ●

●

secondary mania (due to brain disorder or pharmacotherapy); comorbid substance abuse; mixed or dysphoric mania; rapid cycling (for which carbamazepine is probably better than lithium but less effective than valproate); manic episode as part of schizoaffective disorder.

The time of onset of action of lithium may be somewhat slower than that of valproate

although data are not well established. The combination of an antipsychotic with either lithium or valproate may be more effective than any of these agents alone in patients with severe mania (associated aggression, agitation, impulsiveness, and psychotic symptoms). For less severe mania, but still with psychotic features, lithium, olanzapine, risperidone, or valproate may be sufficient. Alternatives with less supporting evidence for treatment of manic or mixed states include other secondgeneration antipsychotics (SGAs) such as quetiapine or ziprasidone, or a combination of quetiapine and carbamazepine. Short-term adjunctive benzodiazepines may be also helpful in managing symptom relief. Antidepressants may precipitate or exacerbate manic or mixed episodes, and generally should be tapered and discontinued if possible.16 Hence, various factors may lead the clinician to choose a particular medication, among them the type of mania (i.e. euphoric, dysphoric, mixed, or rapid cycling). As mentioned before, some evidence suggests a greater efficacy of carbamazepine, olanzapine, risperidone, olanzapine, or valproate compared with lithium in the treatment of mixed states.15,16 For severely ill, psychotic, or agitated patients, antipsychotics may be needed. SGAs are favored because of their more benign side-effect profile.15,16 For patients who experience a ‘breakthrough’ episode, the medication dose should first be optimized. When first-line medications at optimal dose fail to control symptoms, recommended treatment options include the addition of another first-line medication. Alternative treatment options include adding carbamazepine or oxcarbazepine in lieu of an additional first-line medication, adding an antipsychotic if not already prescribed, or changing from one antipsychotic to another. Of the antipsychotics, clozapine may be particularly effective for treatment of refractory illness. Electroconvulsive therapy (ECT) may also be considered for patients with severe or treatment-resistant illness. In addition, ECT is a potential treatment for patients with mixed episodes or for severe mania experienced during pregnancy.

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9.10 Panic disorder (PD) Treatment strategies (evidence-based)

If (1) consider Selective serotonin reuptake inhibitors (SSRIs)(2)

If (4) consider

Benzodiazepines If (3) consider Tricyclic antidepressants (TCAs) ⴞ CBT

Change to a different class of agent:


MAOI or SSRI or TCA

Benzodiazepine or lithium or TCA

Consider switching to one of the following:

Benzodiazepines (low-potency), carbamazepine, inositol, mirtazapine, nefazodone, reboxetine, reversible inhibitors of MAO type A (RIMA), valproate, venlafaxine or to a SGA (olanzapine)

Legend

1

If there are no relative contraindicators to SSRIs

Name of modality


2

Mostly studied with citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Name of modality


3

Name of modality


If there are moderate symptoms, no prominent cardiovascular pathologies, no concomitant seizure disorder, and the patient is not suicidal

4

If there are severe, frequent and incapacitating symptoms

If good response If partial response

CBT MAO(I)

If no response

224

SGA

Cognitive–behavioral therapy Monoamine oxidase (inhibitor) Second-generation antipsychotic drug

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Panic disorder (PD) is a chronic, distressing, and disabling condition that often appears to require ongoing treatment in clinical practice. Up to 50% of panic attacks as part of PD begin with attacks consisting of 3 or fewer symptoms out of the 13 possible symptoms eligible for the diagnosis of PD according to DSM-IV. Up to 20% of panic attacks appear without any sense of anxiety. Although a variety of pharmacological and cognitive–behavioral treatments appear to be effective for the acute treatment of PD, a significant number of patients do not fully respond to initial treatment, and others relapse when treatment is discontinued.17 For example, among studies examining the long-term efficacy of pharmacotherapy for PD, about one-third of patients achieved continuous remission during the 4-year follow-up period, 50% continued to have mild to moderate symptoms or intermittent periods of remission, and 19% suffered from persistent, severe symptoms.18

Notes about the scheme Accumulating data, including well-controlled studies, suggest that the selective serotonin reuptake inhibitors (SSRIs) are efficacious and well-tolerated for PD (studied mainly with paroxetine and sertraline).19,20 However, despite the current guidelines recommending the use of SSRIs for PD,21 many clinicians use benzodiazepines as first-line therapy, despite their abuse potential and the fact that well-controlled data suggest that patients taking SSRIs have a comparable clinical course to those taking benzodiazepines.22,23 Tricyclic antidepressants (TCAs) such as imipramine and clomipramine were regularly used for the treatment of PD up to the early 1990s; however, the side-effect burden of TCAs is a major hindrance to treatment in many patients, and they are now considered second-line treatment for PD. Since then, the SSRIs as sole agents or in combination with benzodiazepines (e.g. alprazolam and clonazepam) have been more commonly used.17

Benzodiazepines are commonly coprescribed with SSRIs/serotonin reuptake inhibitors (SRIs)20 in the hope of reducing initial anxiogenic effects caused by the latter agents. However, data on combined treatment do not suggest evidence of better ultimate outcome compared with monotherapy.22,23 The benefit of combined therapy is associated with acceleration of response rather than ultimate outcome,23,24 and combined therapy is mostly recommended in patients who are in need of an immediate anxiolytic effect even if it increases the chance of addiction (e.g. patients whose symptoms are very severe, incapacitating, and frequent). For maximizing the chances of remission in long-term treatment, the three most common interventions are the addition of cognitive–behavioral therapy (CBT), adding a benzodiazepine (either alprazolam or clonazepam) to an SSRI, or increasing the dose of the SSRI. However, as yet, there are few systemic data addressing the relative benefit of partial responders or non-responders to initial therapy. CBT offers the hope that once patients learn its principles and applications, they will be able to serve as their own therapists in the event that symptoms emerge with continuation of medication.17 For treatment-resistant patients who do not respond to SSRIs or TCAs, or to the combination of TCAs/SSRIs with benzodiazepines, other antidepressants have shown at least some beneficial effects in alleviating PD symptoms (e.g. mirtazapine, moclobemide, nefazodone, phenelzine, reboxetine, and venlafaxine). Other agents have also been reported to exert beneficial effects in PD, especially when combined with SSRIs/TCAs (lithium, pindolol, and propranolol). In cases where all treatments have failed, valproate or olanzapine should be considered.25–30 In order to optimize treatment, patients should avoid or reduce the consumption of compounds that could potentially induce/exacerbate panic attacks (e.g. caffeine, alcohol, and nicotine) and should exercise regularly.31

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9.11 General anxiety disorder (GAD) Treatment strategies (evidence-based)

Consider one of the following, on the basis of side-effect profile, comorbid 'physical' disorders, past response, physician experience:

SSRI (most studied with paroxetine), imipramine, venlafaxine or buspirone, hydroxyzine

Consider adding/switching to

Benzodiazepines [(e.g. either long-acting chlordiazepoxide, clonazepam, diazepam) or short-acting (e.g. alprazolam, lorazepam, oxazepam)], buspirone, hydroxyzine, monoamine oxidase inhibitor (MAOI), SNRI and SSRI (combined), trazodone

Abecarnil, opipramol, pregabalin



SNRI

Name of modality


SSRI

Name of modality


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Serotonin–norepinephrine reuptake inhibitor Selective serotonin reuptake inhibitor

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The main features of generalized anxiety disorder (GAD) are excessive anxiety and worry. Patients suffer from somatic symptoms as well as from restlessness, irritability, difficulty in concentrating, muscle tension, sleep disturbances, and being easily fatigued. Patients who suffer from GAD may express various worries, all of which are non-delusional and non-bizarre in nature. Such a worry can be that a patient’s relative may suffer, become ill, have an accident, etc. Hence, worries are realistic in nature – the problem is that they are excessive.32

Notes about the scheme Currently accepted (US FDA-approved) first-line treatments for GAD are the serotonin and nonepinephrine reuptake inhibitor (SNRI) venlafaxine (75–225 mg/day).33,34 or the selective serotonin reuptake inhibitor (SSRI) paroxetine (20–50 mg/day).35 However, it seems that the other SNRIs/SSRIs may prove to be as efficient. Among the tricyclic antidepressants (TCAs), imipramine (75–200 mg/day) has been the most widely studied and has shown beneficial results. However, due to its relatively unfavorable side-effect profile compared with venlafaxine and the SSRIs, this drug might be the second choice in treating GAD. In treatment-resistant cases, benzodiazepines, either long-acting (diazepam, clonazepam, and chlordiazepoxide) or short-acting (alprazolam, oxazepam, and lorazepam) may be used when the patient does not have a history of addictive behavior. Also, they can be combined with SNRIs/SSRIs in the first weeks of treatment before the onset of the therapeutic effects of the latter. Benzodiazepines as monotherapy may not be as robust as assumed. Among patients responding to treatment, less than two-thirds will go into remission, and a number of studies have indicated, despite early improvements in anxiety symptoms, that the effect of benzodiazepines may not be different from placebo after 4–6 weeks of treatment.

Moreover, the benefit of benzodiazepines extends primary to the relief of somatic symptoms, rather than the psychological symptoms, which include worry, a key feature of GAD. The efficacy of buspirone (a 5-HT1A partial agonist; see Section 3.8) for GAD at doses of 15–60 mg/day has been shown in a number of relatively small studies. However, current data are not well established.36 The antihistminergic drug hydroxyzine (37.5–75 mg/day) may also exert some beneficial effects in GAD, even compared with buspirone.37 In general, long-term studies in GAD patients are lacking, with the exception of venlafaxine. If first-line drugs such as venlafaxine, paroxetine, and imipramine fail, a trial with second-line drugs such as buspirone and hydroxyzine is warranted. Other anxiolytics may be useful, such as trazadone and nefazodone.36 A limited number of studies have evaluated the efficacy of other agents in the treatment of GAD. These have included partial benzodiazepine receptor agonists such as abecarnil and suriclone, which are speculated to retain the anxiolytic efficacy of benzodiazepines but to be devoid of the potential for causing sedation, interacting with alcohol, or inducing dependence. The most extensively studied of these agents, abecarnil, may produce a rapid anxiolytic effect within 1 week of commencing treatment.36 However, these data have not been established via large and well-controlled studies. Opipramol, an antagonist of sigma receptors, has been shown to be superior to placebo and equally effective as alprazolam in the treatment of GAD.36 Pregabalin interacts with the same binding site and has a similar pharmacological profile as its predecessor gabapentin, and thus it may be useful for the short-term treatment of GAD.38 However, pregabalin is not yet available for routine clinical use. Due to the lack of studies, it remains unclear whether a combination of cognitive behavioral therapy (CBT) and drug therapy is advantageous over each of the modalities alone.32

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9.12 Obsessive–compulsive disorder (OCD) Treatment strategies (evidence-based)


Serotonin reuptake inhibitor (SSRI or clomipramine) ⴞ CBT


Pindolol, risperidone

Or switch to/add one of the following:

Buspirone, clonazepam, clonidine, inositol, lithium, MAOI (most studied with phenelzine), olanzapine, SSRI with clomipramine (combined), trazodone, tryptophan, venlafaxine



Name of modality


Name of modality


228

CBT MAOI SSRI

Cognitive–behavioral therapy Monamine oxidase inhibitor Selective serotonin reuptake inhibitor

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Obsessive–compulsive disorder (OCD) is an intriguing and often debilitating syndrome characterized by obsessions and compulsions. Data from epidemiological and clinical studies suggest that OCD typically begins during late adolescence or early adulthood. For most patients, OCD is chronic and lifelong, with fluctuations in the severity of symptoms over time. Over the past decades, the availability of the serotonin reuptake inhibitors (SRIs) and the introduction of selective serotonin reuptake inhibitors (SSRIs), along with the presence of effective behavioral treatments using exposure-response prevention techniques, has led to a significant improvement in the prognosis of patients suffering from OCD.39

Notes about the scheme Advances in pharmacotherapy in the past decade have provided clinicians with many safe and effective medications for the treatment of patients with OCD. The SSRIs and clomipramine (an SRI) are the first-line pharmacological therapies for patients with OCD. The treatment of OCD patients with SSRIs is unique in that a selective efficacy exists (other non-SRI antidepressants are ineffective in OCD), a longer therapeutic lag occurs, and higher doses are often required than in treating patients with major depression or other anxiety disorders. The SSRIs provide clinically significant relief in up to 70% of OCD patients, although most do not reach full remission. Clinical experience with the SSRIs suggests that they alleviate the symptoms of OCD, but they do not ‘cure’ the illness. No one SSRI has been demonstrated to be superior to the others in head-to-head trials. About 40% of patients with OCD do not completely respond to adequate trials of SSRIs. Hence, augmentation strategies are necessary for SSRI partial and non-responders.40 As mentioned above, up to 65–70% of patients with OCD have a clinically meaningful response to their first SSRI therapy. Moreover, with

sequential trials, as many as 90% of patients will respond favorably (improvement varies, but as many as 30–60% of long-term treated patients complain of some residual symptoms).40 In cases of partial or non-response, an attempt should be made to combine cognitive–behavioral therapy (CBT) with pharmacological treatments. Data are not well established concerning the efficacy of such combinations. Non-response to treatment in OCD is associated with substantial impairment and is defined as poor or non-response to two or more trials of SSRIs. However, a trial of clomipramine up to 200–300 mg/day for at least 10 weeks should always be considered before viewing a patient as refractory to treatment. In cases of non-response, family therapy should also be suggested, in order to assess the family dynamics. However, and as with the combination of SRIs and CBT, to date there are no well-established data to support/favor such combination. Augmentation is called for when there is partial or non-response to the above approaches. Combinations of SSRIs with buspirone, clonazepam, clonidine, inositol, lithium, pindolol, olanzapine, risperidone, trazodone, tryptophan, and venlafaxine have been reported, with limited benefit.41 To date, only two augmenting agents have been found to be effective in double-blind studies: risperidone42 and pindolol.43 Augmentation of SSRIs with clomipramine (or vice versa) is a common practice in non-responders; however, this combination may lead to a substantial increase in the level of tricyclics in the blood and/or increase the risk of serotonin syndrome. Phenelzine may be helpful in symmetry-related or other atypical obsessions. Electroconvulsive therapy (ECT) should be reserved for severely depressed and suicidal OCD patients. Neurosurgery is the last resort; current operations include anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy.41 The outcome of such operations is questionable.

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9.13 Post-traumatic stress disorder (PTSD) Treatment strategies (evidence-based)


SSRI (most studied are fluoxetine, paroxetine, sertraline) or TCA (most studied are amitriptyline, imipramine) or MAOI (most studied is phenelzine)

Consider augmentation with or switching to

Alprazolam (note that generally benzodiazepines are not recommended in PTSD), anticonvulsants (carbamazepine may reduce re-experiencing, aggressive behavior and valproate may improve avoidance/numbness; data about lamotrigine are less specific), antipsychotics (olanzapine and quetiapine in low doses might be effective in reducing intrusive recollections, avoidance/numbness, irritability, and brief psychotic episodes), clonidine, guanfacine, prazosin, propranolol, tiagabine, venlafaxine



Name of modality


Name of modality


230

MAOI SSRI TCA

Monamine oxidase inhibitor Selective serotonin reuptake inhibitor Tricyclic antidepressant

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Since its introduction as a formal diagnosis in 1980, post-traumatic stress disorder (PTSD) has been shown to have a lifetime prevalence of about 8% in the USA, with a much higher prevalence in countries affected by civil war, genocide, forced migration, and terrorism. Furthermore, evidence continues to accumulate indicating that, in addition to its public health significance as a prevalent psychiatric disorder, PTSD is a risk factor for many medical illnesses. Pharmacotherapy is only one of several treatment options for PTSD, especially in view of the great success of cognitive–behavioral therapy (CBT). Medication may be a good choice when patient acceptability of such an approach is high, when comorbid conditions are present that are responsive to pharmacotherapy (e.g. depression, panic disorder, social phobia, and obsessive–compulsive disorder), or when CBT is not applicable.44

Notes about the scheme Selective serotonin reuptake inhibitors (SSRIs) are the first-line therapy for PTSD. Efficacy for fluoxetine, paroxetine, and sertraline has been demonstrated in well-designed double-blind placebo-controlled studies to reduce all symptom domains (intrusive recollection, avoidance/numbness, and hyperarousal).45–47 Other treatment options include the tricyclic antidepressants (TCAs) amitriptyline and imipramine and the irreversible monoamine oxidase inhibitor (MAOI) phenelzine, which have been shown to reduce re-experiencing. However, in comparison with SSRIs, TCAs and phenelzine are associated with a higher incidence of side-effects, risk of overdose, and poor compliance.48 Alprazolam has demonstrated anecdotal efficacy; however, regular use of benzodiazepines is not recommended.49 Benzodiazepines can be used on an ‘as-needed’ basis for specific symptoms (e.g. sleep disturbances). CBT has shown beneficial effects in relatively well-controlled studies, while the results with exposure therapy are

inconsistent.48 The magnitude of effect achieved by the various pharmacological options for PTSD is often limited, and remission is rarely achieved. In cases of non-response to the above medications, other drugs can be tried, such as lamotrigine and venlafaxine,48 as well as the second-generation antipsychotics (SGAs) olanzapine, quetiapine, and risperidone, which have shown some effectiveness at low doses – especially for reducing intrusive recollection, avoidance/numbness behavior, irritability, aggressive behavior, and brief psychotic episodes (this is mostly evident when they are used as augmenters to partial or non-responders to SSRIs and other second-line agents).44,49 Anticonvulsants might prove to play a role in alleviating some symptoms of PTSD. This notion is based on a neurobiological model that assumes sensitization of regions related to anxious behavior following exposure to traumatic events and, vice versa, densensitization following anticonvulsant therapy. However, to date, there are no well-controlled studies about anticonvulsants and their potential beneficial effect in PTSD. Even so, anecdotal data suggest that carbamazepine may reduce re-experiencing and aggressive behavior, while valproate seems to be more effective for reducing avoidance/numbing symptoms.44 There are no systematic data about lithium in respect to PTSD; thus, at present, lithium cannot be recommended as treatment for PTSD.44 Other options include antiadrenergic agents such as the postsynaptic b-adrenergic antagonist propranolol, the postsynaptic a1-antagonist prazosin (both of which block, postsynaptically, the activities of norepinephrine, which is presumed to be overly secreted in anxious states of PTSD), and the presynaptic a2-agonists clonidine and guanfacine (which decrease secretion of norepinephrine from presynaptic neurons). The best research on this class of agents has focused on prazosin, which has produced marked reduction in traumatic nightmares and improved sleep.44

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9.14 Specific phobia Treatment strategies (evidence-based)

Consider

Cognitive–behavioral therapy (CBT)


b-adrenergic antagonists [atenolol, propranolol (less efficacious)]

Benzodiazepines (can reduce fear avoidance. They probably have no effect on autonomic symptoms)

Selective serotonin reuptake inhibitors (SSRIs) (mostly studied with fluoxetine, paroxetine)



Name of modality


Name of modality


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A specific phobia is a circumscribed, persistent, and unreasonable fear of a particular object or situation. Exposure to the phobic stimulus is associated with an acute and severe anxiety reaction. Therefore, despite the fact that individuals with specific phobias recognize that their fear is unrealistic, most adjust their lifestyle so that they can completely avoid or at least minimize this contact. The population prevalence of specific phobias is approximately 10%, with women being two to three times as likely to be affected as men. Although there is a variation according to subtype, most cases are characterized by early onset and a chronic course. Even though effective treatments are available, less than 20% of affected individuals seek help. DSM-IV has defined four subtypes on the basis of phobic stimulus: animal, situational, blood injury, and nature–environment. There are currently three main etiological approaches to specific phobias: modified conditioning, the non-associative model, and the psychoanalytical model. The classic conditioning model of specific phobias was developed in the 1920s. It was observed that one could teach (condition) an animal or infant to respond fearfully to a harmless object or situation by repeatedly pairing the harmless stimulus (conditioned stimulus) with a frightening one (unconditioned stimulus). For example, a rat could be taught to be afraid of a soft buzzing noise if that noise were repeatedly followed by an electric shock. Following the conditioning sessions, the rat would become frightened on hearing the buzzing, even if the shock did not follow. Observing that specific phobics are also unrealistically afraid of situations that others deem harmless, the behaviorists suggested that this disorder might result from a similar process, and that specific phobias are conditioned fear. Non-associative models are derived from the observation that each species seem to have certain fears that are part of development and can occur even in individuals who have had no previous direct or indirect experience with a

phobic stimulus. There is considerable evidence of a variety of ‘innate’ (or unlearned) fears in both humans and animals. The psychoanalytic model is based on the assumption that an unconscious trauma or fear is displaced to a conscious object as a defense mechanism.50 Treatment of specific phobia is based on cognitive–behavioral therapy (CBT) and/or pharmacotherapy, which includes principally antidepressants.50

Notes about the scheme A few regimens have been studied with various degrees of success in specific phobia; however, to date, there is no definitive established treatment of specific phobia. Benzodiazepines (alprazolam, diazepam, lonazepam, and lorazepam) reduce fear avoidance, but have little effect on autonomic symptoms. The use of these agents in specific phobia is usually aimed at helping patients to engage in an exposure program and in the case of a specific phobic condition. Selective serotonin reuptake inhibitors (SSRIs: fluoxetine and paroxetine) have shown some benefit in preliminary reports.51–53 b-adrenergic antagonists have not been found to be efficacious in augmentation behavioral treatments. They have been demonstrated to have some efficacy in performance anxiety; however, prescription of these drugs should be done with caution due to the cardiopulmonary side-effects. They are contraindicated in asthma and chronic pulmonary disease, severe bradycardia, and atrioventricular block, and relatively contraindicated in diabetes mellitus. Before prescribing b-adrenergic antagonists, a baseline ECG should be performed. In the case of a depressed patient with performance anxiety, b-adrenergic antagonists that are lipid-soluble (e.g. propranolol) may cause depressive states, therefore it is preferable to prescribe a b-adrenergic antagonist that is water-soluble with a low central nervous system side-effect profile, such at atenolol.54,55

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9.15 Social anxiety disorder (SAD) Treatment strategies (evidence-based)

Consider starting with cognitive–behavioral therapy (CBT) If possible, combine it with pharmacotherapy for maximal efficacy

Cognitive–behavioral therapy (CBT)

SSRI [most studied are fluoxetine (in USA), fluvoxamine, paroxetine, sertaline] or MAOI (most studied is phenelzine)

Consider augmentation with a benzodiazepine or switching to

Anxiolytic 'antidepressants' (trazodone, venlafaxine), clonazepam (or other benzodiazepines; note that, generally, benzodiazepines are not recommended for long-term use in SAD), gabapentin, MAOI (tranylcypromine), RIMA (moclobemide)



Name of modality


Name of modality


234

MAOI RIMA SSRI

Monamine oxidase inhibitor Reversible inhibitor of monoamine oxidase type A Selective serotonin reuptake inhibitor

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Social anxiety disorder (SAD) is characterized by marked, persistent, and unreasonable fear of being observed or evaluated negatively by others in social performance or interaction situations, and is associated with somatic and cognitive symptoms. The feared situations are avoided or else are endured with intense anxiety or distress. These situations include fear of speaking in public, speaking to unfamiliar people, or being exposed to possible scrutiny by other people. Although SAD is a severely disabling disorder, it is typically underdiagnosed and undertreated in healthcare settings. This may result from a trend for SAD patients to present for help for comorbid disorders, such as depression or other anxiety disorders, rather than SAD per se, and a tendency by clinicians to dismiss reported SAD as normal shyness.56 SAD only entered the DSM nosology in 1980 with the publication of DSM-III. Prior to this, SAD had been recognized in DSM as a form of general phobia or anxiety neurosis rather than as a qualitatively distinct disorder. The term ‘social anxiety disorder’ may have a number of advantages over ‘social phobia’, including a less pejorative sound. DSM-IV-TR notes that shyness and performance anxiety (or ‘stage fright’) are common in the general population and should not be diagnosed as SAD unless they are associated with clinically significant impairment or marked distress. While there is overlap between SAD and excessive shyness, the two are not the same constructs: people can be extremely shy without meeting a SAD diagnosis or can have a specific social phobia (e.g. of writing in front of others) but not be shy in other situations. SAD should therefore not be dismissed as normal shyness. Certain forms of SAD are particularly poorly recognized, for example paruresis or shy bladder syndrome. In the general population, the gender ratio is approximately 1.5–2 : 1 female-to-male, but in clinical samples, there is a more even gender distribution. The onset of SAD most commonly occurs before the age of 25 years, with the mean age at onset being between 14 and 16 years, a developmental period in

which social relationships become more important.

Notes about the scheme As with most other Axis I psychiatric disorders, and especially with the anxiety disorders, the treatment for the anxiety caused by the disorder is usually symptomatic and there are no known pharmacological interventions that target the specific disorder (e.g. SAD). Selective serotonin reuptake inhibitors (SSRIs) are regarded as first-line treatment in social phobia.56 Fluvoxamine, paroxetine, and sertraline have been shown to be effective in double-blind placebocontrolled studies.57–59 The irreversible monoamine oxidase inhibitor (MAOI) phenelzine shows robust results in terms of efficacy60 and has demonstrated (at least anecdotally), its efficacy in improving some of the cognitive aspects associated with SAD. However, phenelzine is usually less well tolerated than alternative treatments due to its associated dietary restrictions and adverse side-effect profile, including sedation and postural hypotension. Results with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide are inconsistent. Benzodiazepines are not recommended as first-line agents in treating social phobia, because they are associated with abuse and long-term dependence. However, they may play a role as adjunctive agents or for patients refractory to other treatments. They may be used as adjuncts to antidepressant therapy during the first period of 2–3 weeks before the onset of efficacy of these drugs. SAD patients who are refractory to treatment with SSRIs may benefit from second-line treatment such as clonazepam, moclobemide, and phenelzine. Other agents may be used in cases of failure or intolerance of second-line treatment, among these are gabapentin, venlafaxine, and the MAOI tranylcypromine. The combination of pharmacological treatment and cognitive–behavioral therapy (CBT) may be advantageous.56

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9.16 Acute psychotic exacerbation of schizophrenia Treatment strategies (evidence-based)

If the patient is very agitated, or has a known history of severe EPS, a history of NMS, or a previous good response to low-potency APDs

If (1), consider

If previous good response to an APD and good present adherence

Low-potency APDs, SGAs, clozapine (2)

Highpotency APDs, SGAs (3)

Previously beneficial APD

Consider adding / augmenting with

Antidepressants (4), benzodiazepines (5), lithum

Clozapine (6), ECT, sulpiride

Buspirone, divalproex, propranolol (7)

Legend

Name of modality


Name of modality


Name of modality


APD ECT EPS NMS SGA

If partial response

1

If no response

2 3 4

If relevant

5 6 7

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Antipsychotic drug Electroconvulsive therapy Extrapyramidal side-effects Neuroleptic malignant syndrome Second-generation antipsychotic Cardiac illness, elderly, glaucoma, history of hepatitis/jaundice, seizure disorder, hypotension, suicidal Usually a third-line drug to its potential severe adverse effects Especially amisulpiride, aripiprazole, resperidone, zotepine If dominant depressive symptoms/'negative' symptoms/ obsessive compulsive symptoms If agitated or aggressive Especially if on sulpiride May reduce severity of recurrent hostility/aggression

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Schizophrenia is a chronic illness that can influence many aspects of life in affected persons. Therefore, treatment planning should have several main goals: ● ● ●

reduction or elimination of symptoms; maximizing quality of life and adaptive functioning; promoting and maintaining recovery from the debilitating effects of illness to the maximum extent possible.

Accurate diagnosis has enormous implications for short- and long-term treatment planning, and it is essential to note that diagnosis is a process rather than a one-time event.61 With the widespread use of secondgeneration antipsychotics (SGAs) as first-line treatment, the management of schizophrenia has improved with regard to side-effects, adherence with medication, and, in many cases, efficacy in comparison with the first-generation antipsychotics.

Notes about the scheme The goals of treatment during an acute psychotic exacerbation of the disorder are to prevent harm, to control disturbed behavior, and to reduce the severity of psychosis and associated symptoms (e.g. agitation, aggression, negative symptoms, and affective symptoms). In first-episode psychosis, it is recommended that every patient have a thorough physical and laboratory evaluation as first screen in order to exclude an ‘organic’ etiology. In most cases, SGAs (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) are the first-line treatment for a psychotic exacerbation. Among the SGAs, risperidone is most widely preferred as first-line drug due to its relatively tolerable side-effect profile, as well as its favorable cost/benefit ratio.62 First-episode patients are generally more sensitive to the therapeutic effects and side-effects of medication, and often require lower doses than patients with chronic schizophrenia. In

treatment-resistant patients, patients with predominant negative symptoms or persistent suicidal ideation or behavior, and patients with persistent hostility and aggressive behavior, clozapine might be recommended. In patients with a history of sensitivity to extrapyramidal side-effects or hyperprolactinemia, one of the SGAs (except risperidone at high doses) should be administered. In patients with significant weight gain and/or sensitivity to hyperglycemia, or with hyperlipidemia, ziprasidone or aripiprazole may be the preferred agent. In patients with a history of repeated non-adherence to pharmacological treatment, long-acting injectable antipsychotic drugs (APDs) are recommended.61 Other psychoactive medications are commonly added to APDs in the acute phase to treat comorbid conditions or associated symptoms such as agitation, aggression, and side-effects. Benzodiazepines may be used to treat catatonia as well as to manage both anxiety and agitation until the APDs achieve therapeutic goals. The most agitated patients may benefit from an oral or parenteral benzodiazepine; lorazepam has the advantage of reliable absorption when it is administered either orally or parenterally.63 There is some evidence that divalproex (semisodium valproate) and b-adrenergic blockers (pindolol and nadolol) may be effective in reducing the severity of recurrent hostility and aggression.64–66 Major depression and obsessive–compulsive disorder (OCD) are common comorbid conditions in patients with schizophrenia, and may respond to antidepressants (OCD-like symptoms may respond to serotonin reuptake inhibitors (SRIs)). Sleep disturbances are common in acute psychotic exacerbations, and while controlled studies are lacking, there is anecdotal evidence that a sedating antidepressant (e.g. mirtazapine or trazodone) or a sedative–hypnotic benzodiazepine may be helpful.62 Electroconvulsive therapy (ECT) in combination with APDs may be considered for treatment of resistant and/or suicidal schizophrenia patients.61

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9.17 Schizoaffective disorder – depressed type Treatment strategies (evidence-based)

If, besides having MDD, the patient is also psychotic, consider

Increasing the dose of FGA (if already on FGA) or starting an SGA (mostly studied with aripiprazole, olanzapine, quetiapine)

If on APDs, add an antiparkinsonian drug (parkinsonian side-effects may mimic some of the depressive symptoms)

If, besides having MDD, the patient is not currently psychotic, consider

Antidepressant drugs [most studied are the SRIs (e.g. clomipramine) or the SSRIs]

Try adding/augmenting with

Carbamazepine, lamotrigine

Lithium, ECT



Name of modality

Some (less established) efficacy

Name of modality


238

APD

Antipsychotic drug

ECT


FGA First-generation antipsychotic drug MDD

Major depressive disorder

SGA Second-generation antipsychotic drug SRI

Serotonin reuptake inhibitor

SSRI


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Notes about the scheme Patients with schizoaffective disorder, depressed type, are often treated with an antipsychotic drug (APD) plus an antidepressant. For acute psychotic exacerbations of schizoaffective disorder, depressed type, APDs given as sole agents appear to be as effective as APDs plus antidepressants. For major depressive disorder as part of schizoaffective disorder, the situation is somewhat different. This is true especially with the combined use of first-generation (‘typical’) APDs (FGAs) and antidepressants versus FGAs/antidepressants alone. In such instances, the expected response rate (of one regimen alone) is only about 40%. However, there are some accumulating data suggesting the superior efficacy of second-generation (‘atypical’) antipsychotic drugs (SGAs) over FGAs, due, probably, to their mood-stabilizing effect. Consequently, some data suggest that the use of SGAs as sole regimens in schizoaffective disorder, depressed type is almost as effective as the combined F/SGA–antidepressant regimen. A patient with major depressive disorder (as part of schizoaffective disorder) who is not on ongoing treatment with APDs should begin a trial with APDs first. It is almost always advisable to administer one regimen at a time (for side-effect evaluation and treatment response). For patients who develop a major depressive episode after remission of acute psychosis, the addition of an antidepressant drug should be considered (following a few days of evaluating potential adverse effects). Before administering an antidepressant, the clinician should consider the possibility of neuroleptic-induced parkinsonism. This side-effect can mimic some depressive symptoms. Therefore, an attempt to optimize APD doses and/or add an antiparkinsonian regimen should be made. Another probable assumption is the emergence of so-called ‘negative symptoms’. If so, lowering the neuroleptic dose might not be sufficient, and a switch to one of the SGAs (aripiprazole, olanzapine, quetiapine, or risperidone) should be considered if the patient has already been treated with FGAs.67,68 The role of electroconvulsive therapy (ECT) in schizoaffective disorder, depressed type

is not well established, but should be considered. ECT has a proven efficacy in the treatment of affective disorders and is also beneficial in some of the psychotic disorders, especially if affective components are present (catatonia, psychotic mania, or major depressive disorder with psychotic features). Therefore, ECT might prove to be a beneficial tool for the treatment of depressive episodes as part of schizoaffective disorder.69 There is little evidence to support the addition of lithium to ongoing APD and/or antidepressant treatment for the emergence of acute major depressive disorder. Lamotrigine seems to be more effective than lithium in such cases, especially taking into consideration the proven greater efficacy of lamotrigine in the treatment of bipolar depression.70 Carbamazepine, an anticonvulsant with known mood-stabilizing capacity, also seems to be superior to lithium in schizoaffective disorder, depressed type,71 and it may also be used in subsequent prophylaxis. There are too few sufficiently well-established data concerning the maintenance treatment of schizoaffective disorder, depressed type (especially with concomitant psychotic features). A logical practice, although not proven in well-controlled trials, is to continue with the same regimen that improved the acute depressive exacerbation. As in the maintenance treatment of other chronic psychotic disorders, the long-term use of high-dose APDs should be questioned due to the increased risk of developing severe adverse side-effects (e.g. tardive dyskinesia) and the fact that long-term high-dose APD treatment has not been proven, to date, more effective in preventing relapse or improving prognosis in any other way. Therefore, the present recommendation is to lower the APD dose to the minimum effective dose (to about a chlorpromazine equivalent of 300 mg/day or a haloperidol equivalent of 2–4 mg/day). These estimates were tested in maintenance treatment following acute schizophrenic exacerbation, and their validity for schizoaffective disorder should be challenged. In schizophrenia patients, the above-mentioned doses were found to lengthen the time between exacerbations and to lower the risk for relapse.67,68

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9.18 Schizoaffective disorder – manic type treatment strategies (evidence-based)

If there is no indication for a specific drug

If good prognostic signs for lithium exist (1)

If good prognostic signs for carbamazepine exist (2)

If good prognostic signs for valproate exist (3)

Carbamazepine

Valproate

Lithium

Carbamazepine, valproate

Lithium

Lamotrigine, topiramate

Electroconvulsive therapy (ECT) SGAs (mostly studies with olanzapine, risperidone, ziprasidone) Clozapine (consider for resistant patients only)

Legend

Name of modality


Name of modality


Name of modality


1

Euphoric mania, first-degree relatives with mood disorders, less than 3 previous manic episodes, absence of psychosis, good previous response

2

Dysphoric mania, mixed episode, rapid cycling (most probably better than lithium but not as efficient as valproate), part of schizoaffective disorder, comorbid substance abuse, absence of psychosis, obesity

3

Rapid cycling, dysphoric mania, mixed episode, stable or decreasing number of manic exacerbations

If partial response If no response If relevant SGA Second-generation antipsychotic drug

240

At any time, consider adding an antipsychotic agent (preferably an SGA: olanzapine, risperidone, ziprasidone) if the patient is psychotic, aggressive, or with good previous response to antipsychotics. A benzodiazepine may also be effective in severe agitation/aggresiveness

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Notes about the scheme In patients with acute psychotic (including manic psychosis) exacerbation of schizoaffective disorder, manic type, the second-generation antipsychotics (SGAs) clozapine, olanzapine, risperidone, and ziprasidone are considered first-line treatment. However, among these, clozapine should be reserved only for specific patients (e.g. resistant ones) due to its potential severe adverse side-effects (hematological or seizure-inducing properties). The combination of an antipsychotic with either lithium or valproate may be more effective than any of these agents alone in patients with severe mania (associated aggression, agitation, impulsiveness, and psychotic symptoms). In non-psychotic patients, oxcarbazepine and valproate have been shown to exert similar efficacy in controlling mood symptoms in schizoaffective disorder. It is reasonable (although not tested) to use them in combination with SGAs in iller patients. Carbamazepine seems to be equipotent to lithium in controlling mood symptoms; however, lithium is probably less effective than carbamazepine in improving depressive episodes as part of schizoaffective disorder. All in all, lithium and valproate are the first-line treatment of acute non-psychotic mania. Lithium is most effective in euphoric mania and valproate is probably more effective in mixed states. The time to onset of action of lithium may be somewhat slower than that of valproate, although data are not well established. In resistant patients, the combination of SGAs and lithium or carbamazepine seems a reasonable approach. Carbamazepine is contraindicated as augmentation therapy to clozapine, due to their synergistic effects on bone marrow suppression. Electroconvulsive therapy (ECT) may also be considered for patients with severe or treatment-resistant

illness. In addition, ECT is a potential treatment for patients with mixed episodes or for severe mania experienced during pregnancy. During remissions, lithium has been found to be an efficient modality for schizoaffective disorder, especially when the following factors exists: ● ● ●

●

predominant mood symptoms; serum levels above 0.6 mmol/l; better efficacy (as a prophylactic agent) in schizoaffective disorder, manic type as compared with depressed type; when a family history of mood disorders is evident.

If the patient cannot tolerate lithium, maintenance treatment should be continued with the antipsychotic drug (APD). Doses should be gradually decreased, if possible, to a ‘lower effective’ dose (equivalent to chlorpromazine 300 mg/day or haloperidol 2–4 mg/day). When the acute episode has been controlled and the clinical state stabilized, an attempt should be made to taper down the mood stabilizer regimen to the minimum effective dose. For patients who experience a ‘breakthrough’ when first-line medications at optimal doses fail to control symptoms, recommended treatment options include the addition of another first-line medication. Alternative treatment options include adding carbamazepine or oxcarbazepine in lieu of an additional first-line medication, adding an APD if not already prescribed, or changing from one APD to another. Of the APDs, clozapine may be particularly effective for the treatment of refractory illness. Short-term adjunctive benzodiazepines may also be helpful in managing symptoms relief. Antidepressants may precipitate or exacerbate manic or mixed episodes and generally should be tapered and discontinued if possible.72–76

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9.19 Delusional disorder Treatment strategies (evidence-based)

Start low dose of

SGAs (most studied are clozapine, olanzapine, quetiapine, risperidone) or FGAs (most studied are chlorpromazine, pimozide)

Add or start a benzodiazepine (especially if the patient is severely anxious)

Consider (especially if somatic type) switching to

SSRIs (mostly studied with fluoxetine, fluvoxamine, paroxetine)

Clomipramine, clomipramine ⫹ pimozide, ECT



ECT


Name of modality


FGA

Name of modality


SGA

First-generation antipsychotic drug Second-generation antipsychotic drug

If partial response If no response

242

SSRI


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Delusional disorder is characterized, mainly, by persistent delusions (usually one major delusion that is non-bizarre in nature) along with an absence of prominent hallucinations, thought disorder, or mood symptoms. The age of onset is usually between 40–50 years and females are slightly more affected than males. The prognosis for delusional disorder is usually moderate–poor and complete remission of delusional symptoms is relatively rare. Even so, the subpopulation of patients who suffer from acute onset of persecutory delusions may be more responsive to pharmacotherapy.77

Notes about the scheme Delusional disorder is a relatively difficult entity to study since patients suffering from the disorder are most often seen (if at all) in ambulatory settings, their insight is usually poor, and they tend not to cooperate. Hence, all present data are based on anecdotal reports or relatively small open-label studies. The present data suggest that the delusional themes should be treated with antipsychotic drugs (APDs) even if the overall prognosis is moderate–poor. Moreover, the available data imply that an initial response to pharmacotherapy cannot be achieved before 8 weeks of treatment with adequate doses. Because of the relative moderate–poor response to APDs, some clinicians believe that after failure of two or three consecutive trials of APDs, these APDs might be withdrawn (mainly due to adverse side-effects, either acute or chronic, which can reduce patient compliance in the long run). In such cases, benzodiazepines, especially if the patient is severely anxious, can have a beneficial effect. The second-generation antipsychotics (SGAs; mostly described with clozapine, olanzapine, quetiapine, and risperidone) are considered first-line treatment due to their better side-effect profile.79 However, well-established data are not available concerning the efficacy of these SGAs in delusional disorder. The data about first-generation APDs (FGAs) are somewhat better established. Among the FGAs, pimozide seems, in a few reports, to

exert a relative good response. However, it has not proved superior to other more commonly used APDs such as chlorpromazine in controlled studies. All APDs should be given in low doses (usually a haloperidol equivalent of 2–5 mg/day), and if no response is observed within 6–8 weeks (with proper adherence), then a change in medication should be considered.79 Since delusional themes are relatively resistant to pharmacotherapy and patient compliance is usually lacking, if the predominant clinical symptoms are agitation or anxiety, or if the patient is prone to experience acute adverse side-effects (dystonia parkinsonism) or has a history of ongoing tardive dyskinesia, the best regimen might be a benzodiazepine (for relief of the acute symptoms and for a relatively immediate response that could improve compliance).80 Specific benzodiazepines have not been studied in well-controlled studies. Their abuse potential is not usually a major concern in those patients. In patients with delusional disorder, somatic type, a trial of a selective serotonin reuptake inhibitor (SSRI; described mainly with fluoxetine, fluvoxamine, and paroxetine) at high doses and for at least 12 weeks is warranted. Serotonergic manipulation is relevant since an association between somatic delusions and serotonergic dysfunction has been suggested; this is supported by reports of the beneficial effect of clomipramine in symptoms associated with delusional disorder (especially somatic delusions) resistant to pimozide treatment, and has been further demonstrated in double-blind placebo-controlled trials in which fluoxetine and fluvoxamine have been shown to improve delusional body dysmorphic disorder.81–83 The role of electroconvulsive therapy (ECT) in delusional disorder has not been studied. However, it has proven efficacy in psychotic depression, and is very efficacious in affective disorders (major depressive disorder, bipolar I). Thus, since delusional disorder has psychotic and possibly affective components, ECT may be considered a good candidate in specific cases.

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9.20 Anorexia nervosa (AN) Treatment strategies (evidence-based)

Start CBT with family therapy. Evaluate patient's weight

If the patient is severly underweight Avoid, as much as possible, TCAs

Consider adding one of the following pharmacological agents:

SSRIs (mostly studied with fluoxetine), amitriptyline (especially for binge eating/purging type), cyproheptadine, lithium, olanzapine

Antipsychotics (preferably SGAs such as risperidone, or low-potency agents such as chlorpromazine; some data support the beneficial effects of pimoxide), clonidine, gastric prokinetic agents (claspride, domperidone), naltrexone

Legend Well-established efficacy

CBT

Cognitive–behavioral therapy

Name of modality


SGA

Second-generation antipsychotic

Name of modality


SSRI


TCA


Name of modality

If relevant

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Anorexia nervosa (AN) involves a pathological body image along with an aversion to food that could lead to a state of starvation and emaciation. Patients with AN have an intense fear of gaining weight, even if they are severely underweight. Patients have a distorted image of their own weight or shape and deny the serious health consequences of their low weight. Usually, AN patients lose about 15–60% of their normal body weight. AN is estimated to occur in 0.5–3% of all teenagers, usually in adolescence with peaks at 13–14 and 17–18 years of age. Females are much more prone to develop AN (9 : 1 F/M ratio). However, the prevalence of AN in males appears to be increasing as awareness of the possibility that men might be affected is improving. To date, there are no pharmacological agents that have consistently been shown, in double-blind, placebo-controlled trials, to significantly improve AN.84 The overall prognosis is variable. Some patients exhibit spontaneous recovery, some respond favorably to psychotherapy/pharmacotherapy, but a relatively major subgroup exhibits a chronic deteriorating course that might lead to starvation and death (mortality rates are estimated to be 3–20%).

Notes about the scheme Food remains the ‘drug of choice’ for this population. A healthy goal weight in women is the weight at which normal menstruation and ovulation are restored or, in premenarchal girls, the weight at which normal physical and sexual development resumes. Psychotropic medications should not be relied on as the sole or primary treatment of AN. Establishing and maintaining a psychotherapeutically informed relationship with the patient is important and beneficial. Decisions concerning the use of medications should often be deferred until weight has been restored, because many symptoms (including depression) diminish considerably when weight is gained. Bupropion should be avoided in patients with eating disorders because of an increased risk of seizures. Tricyclic antidepressants (TCAs) should be avoided as much as possible in underweight patients due to side-effects

(mainly sedation and postural hypotension). Cardiovascular consultation may be helpful if there is concern about the potential medication’s cardiovascular side-effects.84 Lithium has been shown in one well-controlled trial to be statistically better than placebo in a small group of patients.85 However, the potential risks of lithium treatment in AN seem to be far greater than the possible benefits, largely due to the danger of lithium toxicity secondary to dehydration and electrolyte imbalances from starvation, compulsive exercising, and/or purging. Another study found amitriptyline statistically better than placebo for patients who are both bulimic and anorexic, while cyproheptadine was reported to be more beneficial for restricting anorexia.86 Although the use of antidepressant medications in AN seems theoretically sound, the results from randomized controlled trials have been dismal. In addition, the cardiac effects of TCAs include prolongation of the QT interval, which can already be prolonged in patients with AN, and might be a prelude to sudden death. Selective serotonin reuptake inhibitors (SSRIs) might seem applicable given their safety profile and usefulness in major depression and obsessive–compulsive disorder, as well as the profound central serotonergic disturbances reported in AN.87,88 Moreover, they seem to help in cases of secondary anxiety/dysphoria, which are very common in AN. Fluoxetine has been shown to have absolutely no effect on weight, body image, anxiety, or mood in low-weight patients with AN.89 However, once patients’ weight is recovered, some data indicate that relapse (which is common) can be significantly reduced with fluoxetine in comparison with placebo.90 It is hypothesized that fluoxetine (or any monoamine reuptake inhibitor) cannot work in low-weight patients because central serotonin levels are profoundly depleted in anorectic patients as a direct result of starvation and weight loss.87–89 Hence, agents such as the second-generation antipsychotic drug (SGA) olanzapine may be beneficial via enhancement of appetite and weight gain, as well as via its presumed anxiolytic and antidepressant properties.90

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9.21 Bulimia nervosa (BN) Treatment strategies (evidence based)

Start cognitive–behavioral therapy

Avoid TCAs (in suicidal patients), MAOIs, lithium

Consider adding one of the following pharmacological agents:

SSRIs (especially studied with fluoxetine and fluvoxamine)

TCAs (especially studied with desipramine and imipramine)

Bupropion, antidepressants (mirtazapine – due to its observed capacity to reduce binging/purging), naltrexone (especially with comorbid alcohol abuse and/or self-injurious behavior), ondansetron (its 5-HT3 blockade may reduce binge eating/purging), topiramate

Legend

246

Name of modality


5-HT3


Name of modality


MAOI


Name of modality


SSRI


If relevant

TCA


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Bulimia nervosa (BN) is more common than anorexia nervosa and usually begins early in adolescence. Estimates of the prevalence of BN among young women range from 3% in adolescents to 10% in young adults. More than 95% of patients with BN are females.84 The core feature of the disorder is recurrent episodes of binge eating accompanied by the feeling of being out of control. Even so, and mainly due to compensatory measures taken by patients in order to reduce weight, about 70% of affected patients remain within the normal range of body weight. There are various axis I and II disorders associated with BN. The lifetime prevalence of major depressive disorder among BN patients is about 60% and they also exhibit increased prevalence of borderline and histrionic personality disorders and (to a lesser extent) obsessive–compulsive or avoidant personality disorders. The prognosis is variable, and the disorder is often chronic with a waxing and waning course. Even so, about 70% of BN patients display moderate–good relief of symptoms during long-term follow-up.

Notes about the scheme Cognitive–behavioral therapy (CBT) is the most empirically validated treatment for BN.84 However, several antidepressant agents have shown some beneficial results in BN. The antibulimic effects of antidepressants have been shown in several studies to be independent of the drugs’ antidepressant effects per se. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment of BN;91 those studied in BN using randomized controlled trials are fluoxetine (FDA-approved) and fluvoxamine. The doses of both fluoxetine and fluvoxamine required to achieve an antibulimic effect are similar to those used for the treatment of obsessive–compulsive disorder.92,93 Both desipramine and imipramine have been found to be effective in short-term, randomized

controlled trials, and may be used as second-line treatment.94 Although bupropion has been found anecdotally to be effective in reducing bingeing and purging frequency, the risk of seizures far outweighs its potential benefits.95 Therefore, its use in BN (as well as in anorexia nervosa) is relatively contraindicated. Tricyclic antidepressants (TCAs) should be used with caution for patients at high risk of suicide. Monoamine oxidase inhibitors (MAOIs) should also be avoided, since chaotic bingeing and purging preclude the necessary dietary restrictions accompanying the use of these agents. Lithium has shown its capacity as an augmenter in various axis I disorders. However, its use in BN has not been properly examined, probably due to its relative narrow therapeutic window and particularly because its serum levels can shift markedly with rapid volume changes, as often happens in BN.85,91 There are a few other classes of drugs that have been found, mostly anecdotally, to improve some aspects of BN. Ondansetron, a potent 5-HT3 antagonist and an antiemetic indicated for the treatment of chemotherapy-induced nausea and vomiting in patients with cancer, has been found to be effective in reducing bingeing and purging when compared with placebo.96 Hence, although very costly, it is worth considering in refractory or severe cases. Another option, theoretically relevant but not examined as yet, is the use of mirtazapine, an antidepressant drug with marked 5-HT3 antagonistic capacity (like ondansetron) that enhances appetite. The anticonvulsant topiramate has also been reported to be effective in reducing binge and purge frequencies in comparison with placebo.97 However, bothersome side-effects such as paresthesias, impaired cognition, and renal calculi may lessen its usefulness. Naltrexone is a possible adjunct in patients who are refractory to SSRIs, especially those with comorbid alcoholism and/or self-injurious behavior.98

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9.22 Attention deficit hyperactivity disorder (ADHD) – adult type Treatment strategies (evidence-based)

Start with either

Methylphenidate, amphetamine

Consider atamoxetine. If not relevant, consider: pemoline (less indicated due to its hepatotoxicity)

Consider

Bupropion, clonidine, guanfacine, modafinil, reboxetine

TCAs (desipramine, imipramine, nortriptyline), venlafaxine



Name of modality


Name of modality


248

TCAs


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Attention deficit hyperactivity disorder (ADHD) is known to affect approximately 4–12% of children and continues into adulthood for approximately 20–50% of those diagnosed in childhood. Prevalence is estimated at about 5% of the adult population. Males are affected 3–5 times more than females. In adults, just as in children, the symptoms of ADHD are described by the deficits associated with the core syndrome. As the demands for planning increase with age, the difficulties related to ADHD become increasingly prominent over the lifetime. The most common clinical symptoms in adult ADHD are inattention, impulsivity, intrusiveness, distractibility, low frustration tolerance, impatience, day-dreaming, forgetfulness, and frequent shifts in activities. High divorce rates and poor academic or occupational functioning are also commonly observed. Treatment of adult ADHD should include a medication trial and restructuring of the patient’s environment to address any residual impairment and facilitate functional and developmental improvements.99

Notes about the scheme A critical part of the assessment must be to determine the patient’s impairment at various times throughout the day to ensure that medication coverage overlaps with the time when the patient is most likely to benefit. As with all medication trials, it is important to start with a low dose of medication and keep increasing it slowly until the optimal risk-tobenefit ratio has been determined. Stimulant medication (methylphenidate, mixed amphetamine salts, and pemoline) and atomoxetine (a non-stimulant selective norepinephrine reuptake inhibitor, approved by the FDA for adult ADHD) are the first-line treatments of adult ADHD. Pemoline is not recommended as first-line treatment due to the risk of hepatoxicity. Stimulant drugs used to treat adults with ADHD are considered safe and effective, and have been well studied. There are several new long-acting formulations of

stimulant medication, lasting 6–12 hours, which facilitates compliance by eliminating frequent dosing. Potential side-effects of stimulant medication in adults with ADHD include appetite loss, insomnia, nervousness, a mild increase in pulse and blood pressure, irritability, dysphoria, and rebound worsening of symptoms. Adults may be more vulnerable to mild elevations in blood pressure or heart rate if they have occult or borderline hypertension or other cardiovascular effects. Patients with a past history of substance abuse, unresponsive patients, and those with intolerable side-effects (dysphoria, anxiety, and severe rebound) may react better to atomoxetine, which causes less rebound, and its once-daily dosing provides full coverage even into the evening.99 Non-stimulant medications (except atomoxetine) are second-line treatment for adult ADHD. Tricyclic antidepressants (TCAs) such as desipramine, imipramine, and nortriptyline have been shown to exert some beneficial effects in ADHD. Moreover, the TCAs may still take priority in a subgroup of ADHD patients with tics and/or Tourette’s syndrome, especially ADHD patients who have experienced tic exacerbation with stimulants. Bupropion, an antidepressant that inhibits the reuptake of dopamine and norepinephrine, is an effective alternative in the relatively small subgroup of ADHD patients who suffer from bipolar disorder, due to its low risk of inducing mania. Venlafaxine has also shown some benefit in adult ADHD, as well as the a2-adrenergic agonist clonidine, which has been used for many years for the treatment of ADHD despite debate regarding its efficacy and safety (rebound hypertension). Controversy exists as to whether it exerts its therapeutic effect via improvement in cognition or whether it simply has a non-specific sedative effect. Since clonidine is often quite sedative, guanfacine (also an a2-adrenergic agonist) may be an alternative due to its better side-effect profile compared with clonidine. Anecdotal reports suggest that modafinil, a stimulant used for the treatment of narcolepsy, is also beneficial in adult ADHD.100,101

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9.23 Neuroleptic malignant syndrome (NMS) Treatment strategies (evidence-based)

If NMS is suspected, rule out major causes of NMS-like syndromes (e.g. heat stroke, lethal catatonia, malignant hyperthermia, viral encephalitis). At the same time:

Withdraw the offending agent (most probably APD) immediately Institute supportive measures (cooling blankets, ice-water enema, oxygen) Monitor vital functions (serum electrolytes, renal/hepatic/cardiac functions) Low-dose heparin (if patient is immobilized) Continue anticholinergic drugs

Consider aministering one of the following (or in combination):

Dantrolene, benzodiazepine (e.g. lorazepam), ECT

Amantadine, bromocriptine, nifedipine

When in remission (and part of schizophrenia)

When in remission (and part of bipolar I disorder)

Bromocriptine, carbamazepine, lithium, valproate

APDs (low-potency or SGAs), bromocriptine



Name of modality


APD

Antipsychotic drug

Name of modality


ECT


If partial response

SGA

Second-generation antipsychotic drug

If no response If remitted

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Neuroleptic malignant syndrome (NMS) continues to be an unpredictable and rare – but potentially fatal – complication associated with the use of antipsychotic drugs (APDs).102 Presumably linked to dopamine blockade, and more common with first-generation antipsychotics (FGAs), it nonetheless also occurs in patients receiving second-generation antipsychotics (SGAs), albeit less frequently. The incidence rates of NMS are between 0.07% and 0.9%. It usually appears early in the course of neuroleptic treatment (about 80% of cases are evident within the first 2 weeks of treatment). The cardinal features of NMS are hyperthermia, rigidity, autonomic instability, and altered consciousness. If either rigidity or temperature elevation is mild or absent, a diagnosis of NMS is questionable. The associated features of NMS include akinesia, tremor, dystonias, dysphagia, dyspnea, sialorrhea, fluctuating blood pressure, tachycardia diaphoresis, incontinence, pallor, and flushing. Leukocytosis may occur, with white blood cell counts commonly ranging from 10 000 to 20 000/mm3.

Notes about the scheme The most enduring theory about the pathophysiology of NMS is that the central and peripheral manifestations of NMS are the oftennoted consequences of dopamine blockade. Discontinuation of amantadine, an indirect dopamine enhancer, or discontinuation of anticholinergic agents (cholinergic rebound induces relative dopamine deficit) have also been associated with triggering NMS. Early and aggressive supportive interventions are the cornerstone of managing NMS. When the syndrome is suspected, a complete medical and neurological work-up is necessary. It is most prudent to discontinue potentially contributing medications even before the diagnosis is definite. Abrupt discontinuation of antipsychotic drugs (APDs) is warranted despite the potential for precipitating psychotic relapse. Stopping anticholinergic medication

abruptly is not advised, since cholinergic rebound resulting from withdrawal of anticholinergics may contribute to the syndrome itself. The same goes for amantadine in patients who receive the drug for the management of extrapyramidal side-effects (EPS), since withdrawal of amantadine may exacerbate NMS and amantadine itself may be used for the treatment of NMS.102–105 Other non-pharmacological interventions should begin as soon as possible, such as mechanical cooling. If dysphagia or dyspnea secondary to dystonia of throat and chest musculature is present, oral intake should be avoided, intravenous fluid replacement should be given, and intubation and ventilatory support should be considered. Antipyretics are not useful, since the temperature elevation is not associated with the action of pyrogens. The most effective pharmacological interventions include bromocriptine and other dopaminergic agents (amantadine and L-dopa (levodopa) in combination with carbidopa) and dantrolene sodium. Dantrolene sodium is a directly acting skeletal muscle relaxant; its mechanism of action is blockade of intracellular calcium efflux, causing excessive skeletal muscle contraction coupling. It reduces heat production and begins taking effect within minutes. Benzodiazepines are best used in prominent catatonic symptoms. However, they are anecdotally reported to exert beneficial effects in NMS, although their mechanism of action here is unclear. Electroconvulsive therapy (ECT) might be effective in the treatment of NMS; however, it is most recommended when other treatments have failed or when severe or ‘lethal’ catatonia is in the differential diagnosis.102 Management of the post-NMS patient demands judicious use of medications, since recurrent NMS has been reported with FGAs and SGAs, including clozapine. In such cases, clinicians are advised to use low-potency APDs or APDs with marked anticholinergic properties.104 Anecdotal data suggest the efficacy of the relatively newly introduced aripiprazole or the vesicular monoamine transporter inhibitor tetrabenazine in NMS.102

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9.24 Tardive dykinesia (TD) Treatment strategies (evidence-based)

SGAs (especially studied with clozapine)

Reserpine, tetrabenazine, vitamin E

APDs (increase dose of current APD), benzodiazepines, botulinum toxin, calcium-channel blockers (diltiazem, nifedipine, nimodipine, verapamil), ECT, essential fatty acids, estrogens, lithium, naloxone, periactin, phenylalanine, piracetam, tryptophan

Legend

252

Name of modality


APD

Antipsychotic drug

Name of modality


ECT


Name of modality


SGA

Second-generation antipsychotic drug

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Tardive dyskinesia (TD) is a hyperkinetic, repetitive, purposeless, persistent drug-induced movement disorder, mostly of the face, caused by long-use of antipsychotic drugs (APDs). It is most commonly observed with first-generation antipsychotics (FGAs), but also with second-generation antipsychotics (SGAs), albeit less frequently. The prevalence of TD is about 5–20% of chronic APD-treated patients, but it is as high as 70% in populations at risk (the elderly, females, and those with comorbid mood disorder, diabetes, concurrent brain injury, or concomitant anticholinergic medications). TD can appear at any time following APD treatment (between weeks and a few years). The mean time for appearance is about 7 years. When TD was first described in the middle of the 20th century, it was considered to be a new syndrome and quite rare. Although there are unanswered questions concerning the role of antipsychotic drugs in TD, there is no debate about the role played by neuroleptics in inducing certain movement disorders. The most widely accepted theory focuses on dopamine receptor hypersensitivity. This hypothesis proposes that dopamine receptors located on neurons of the nigrostriatal dopaminergic pathway develop increased sensitivity to dopamine as a consequence of chronic blockade resulting from prolonged use of either FGAs or SGAs.

Notes about the scheme Once TD has developed, spontaneous improvement occurs in 30–50% of cases within 2 years after discontinuation of the APD. The main goal in treating TD is to desensitize the hyperactive dopaminergic receptors or to counterbalance their activities. Because prolonged and complete drug withdrawal is often difficult, total or partial substitution with SGAs (especially clozapine) is proposed as the first-line strategy for patients who have to continue APDs. It is assumed that SGAs,

especially clozapine, produce less blockade of dopaminergic receptors, or that SGAs have reduced affinity to the nigrostriatal pathway, therefore causing less hypersensitization of the dopaminergic receptors (see Section 4.4). Another option is to administer ‘dopaminergic depletors’ such as tetrabenazine and reserpine, which have been found to reduce the severity of TD. However, depression is well recognized during treatment with tetrabenazine and especially with reserpine. Another possible step is to increase the APD dose, although this has the consequence of an unpleasant feeling of entering a vicious cycle. There is a growing interest in using non-dopaminergic agents in an attempt to reduce the severity of TD, but this strategy is less effective in controlling the disorder. Benzodiazepines may have something to contribute to patients with TD, but at present their use should be considered experimental.106 Cholinergic drugs are of interest to researchers, but currently have little place in routine clinical work.107 Small trials with uncertain quality of randomization indicate that vitamin E protects against deterioration of TD, but there is no evidence that it improves TD.108 Based on anecdotal data, calcium-channel blockers such as diltiazem, nifedipine, nimodipine, and verapamil are beneficial for treating TD. However, before evaluation of these drugs in larger randomized controlled trials, clinicians should carefully weigh up the possible benefits against their potential adverse effects.109–111 Different treatments such as botulinum toxin, cyproheptadine, estrogens, essential fatty acids, ganglioside, lithium, naloxone, phenylalanine, piracetam, stepholidine, tryptophan, neurosurgery, and electroconvulsive therapy (ECT) have been tried for TD. There is no strong evidence to support the use of any of these agents in TD; however, because of the small sample sizes, the results must be considered inconclusive.112

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9.25 Acute neuroleptic-induced akathisia (NIA) Treatment strategies (evidence-based)

If it is possible to reduce dose of APDs and/or there is significant cardiac illness

If there is no significant cardiac illness and no depression/ asthma (in the case of propanolol)

If there is no significant cardiac illness, asthma, and/or it is not possible to lower dose of APD

Propranolol

Lower dose of currently used APD

Anticholinergics (1) 5-HT2A antagonists (2)

5-HT2A antagonists, preferably mianserin, mirtazapine

Zolmitriptan

Consider adding/switching to Benzodiazepines (e.g. clonazepam, diazepam, lorazepam)

Amantadine, clonidine



Name of modality


Name of modality


254

5-HT2A APD 1 2

Postsynaptic serotonergic receptor subtype Antipsychotic drug Benztropine, biperidin, trihexyphenidyl Cyproheptadine, mianserin, mirtazapine, ritanserin, trazodone

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Neuroleptic-induced akathisia (NIA) is characterized by a subjective sense of inner restlessness and objective fidgety movements. It is a major extrapyramidal side-effect that is mostly associated with the use of firstgeneration antipsychotic drugs (FGAs) and to a lesser extent second-generation antipsychotics (SGAs). Despite its high incidence (20–45%), the underlying mechanisms have not yet been adequately explained, although it seems to be associated with hypernoradrenergic and/or serotonergic transmission in the central nervous system. Early detection and adequate treatment of NIA are important because of its negative clinical consequences and serious adverse effects. Akathisia is thought to be a risk factor for the development of tardive dyskinesia, it may be predictive of more severe psychopathology, and it seems to herald a poor response and non-adherence to treatment. Moreover, it may be a contributing factor in the suicidal and violent behavior of patients with schizophrenia.113

Notes about the scheme The diagnosis of NIA may be difficult owing to the existence of various forms of NIA, namely acute, chronic, withdrawal, and tardive, along with diurnal variations in its expression and its common association with other symptoms, such as agitation and restlessness. When NIA is diagnosed, there are two first-line treatment options: ●

●

If there is no necessity to maintain the specific drug/dose the antipsychotic drug (APD) regimen can be changed, by reducing the dose of the APD, switching to a low-potency FGA such as thioridazine, or switching to an SGA such as aripiprazole, olanzapine, quetiapine, or risperidone. If there is no response a change to clozapine can be considered. Addition of anti-akathisia agents: either propranolol (usually up to 40–120 mg/day) or a postsynaptic 5-HT2A serotonergic antagonist such as cyproheptadine (8–16 mg/day),

mianserin (15–30 mg/day), mirtazapine (15 mg/day),116 ritanserin (5–20 mg/day), or trazodone (50–100 mg/day). Recent data also suggest the substantial efficacy of presynaptic inhibitory 5-HT1Db receptor agonists. Such drugs (e.g. zolmitriptan, usually indicated for the treatment of migraine) act on the presynaptic serotonergic receptor and inhibit the secretion of serotonin to the synaptic cleft. Thereby, they decrease the presumed enhanced serotonergic transmission that is thought to be associated with NIA. Among the b-adrenergic blockers, only the more lipophilic drugs (betaxolol, pindolol, and propranolol) have been found, to date, to be effective in alleviating symptoms of NIA. The more hydrophilic b-adrenergic blockers (metoprolol and nadolol) are practically inefficient. Since passage through the blood–brain barrier is probably directly correlated with drug lipophilicity, this implies that a central mechanism is a predominant factor in inducing NIA. The b-adrenergic blockers should be avoided, as much as possible, in patients with diabetes/glucose intolerance and in the hypotensive population. Second-line treatment usually includes the anticholinergic benzotropine (1.5–8 mg/day), biperiden (4–12 mg/day), and trihexyphenidyl (2–10 mg/day). These are mainly advised in patients with concurrent parkinsonism. If there is a partial response (mainly in patients with marked distress) to first- and/or second-line treatment, a benzodiazepine such as clonazapem (0.5–1 mg/day), diazepam (5–15 mg/day), or lorazepam (1–2 mg/day) can be added. Accumulating data suggest that the combined benzodiazepine–anticholinergic drug regimen is more effective than either of the drugs alone. The anxiolytic buspirone has shown conflicting effects in NIA and is currently not a recommended treatment. Amantadine (100 mg/day) and clonidine (up to 0.15 mg/day) may also exert some beneficial response in selective patients, and they might be considered as fourth-line therapy.113–116

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9.26 Delirium Treatment strategies (evidence-based)

Address underlying cause (e.g. drugs, infections, fluid/electrolyte imbalance, metabolic/endocrine disorders, hypoxia, sensory deprivation, urinary retention, trauma). Administer supportive care

Benzodiazepines (if alcohol/sedative–hypnotic withdrawal-induced delirium) SGAs (olanzapine, quetiapine, risperidone, ziprasidone) or FGAs (less preferred; best studied is haloperidol)

Donepezil, rivastigmin (these are acetylcholinesterase inhibitors, which increase cholinergic transmission in the central nervous system), trazodone

Legend

256

Name of modality


FGA

Name of modality


SGA

Name of modality


First-generation antipsychotic drug Second-generation antipsychotic drug

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Delirium is a clinical syndrome manifested by altered consciousness, global disturbances of cognition, fluctuating course with rapid onset, perceptual abnormalities, and evidence of a physical cause. Delirium can be caused by numerous etiologies, about 85% of which are extracranial. The mechanism is unclear but it involves, at some stage, decreased cholinergic activity, especially in the dorsal tegmental area of the brainstem’s reticular formation (believed to be a major site for regulation of attention and arousal). The clinical picture is so characteristic that a confident diagnosis of delirium can be made even if the underlying cause is not firmly established. In addition to a history of an underlying physical or brain disease, evidence of cerebral dysfunction, such as an abnormal electroencephalogram (EEG), usually but not invariably shows a slowing of background activity. The prevalence of delirium increases with age – from 0.4% in those over the age of 18 to 13.6% in those over 85. Risk factors in delirium can be categorized according to whether they are predisposing factors or more immediate precipitating factors. For example, a chest infection (precipitating factor) may be sufficient to cause an episode of delirium in a person with pre-existing cognitive impairment (predisposing factor) but not in a person who is cognitively normal.117

Notes about the scheme Delirium is a medical emergency, and prompt attention to obvious precipitating factors should be the first aim of management. Four key steps have been described: addressing the underlying cause, maintaining behavioral control, preventing complications, and supporting functional needs. In practice, the commonest causes are drugs, infections, fluid balance and metabolic disorders, cerebral hypoxia, pain, sensory deprivation, urinary retention, and fecal impaction (especially in people with pre-existing dementia). Many drugs may cause delirium, but

particularly psychotropic drugs with strong anticholinergic effects such as tricyclic antidepressants (TCAs). While there are no randomized controlled trials of interventions such as noise control, light intensity, reassurance, and stimulus modification, these manipulations are still recommended as an integral part of the management of delirium. Antipsychotic drugs (APDs) are the mainstay of treatment and are effective in all types of delirium, except in cases of delirium caused by alcohol or sedative hypnotic withdrawal. In many older patients, oral drug treatment is accepted and obviously preferred to a parenteral route. Haloperidol is the preferred drug when the parenteral route is necessary. Haloperidol in doses of 0.5–10 mg/day (intramuscularly or intravenously) improves most symptoms of delirium and is especially effective in the control of more severely disturbed and aggressive patients. Second-generation antipsychotics (SGAs: olanzapine, quetiapine, risperidone, and ziprasidone) are the first-line treatment if the oral route is possible (olanzapine and risperidone are available in liquid formulations and as orodispersible tablets). The adage in psychopharmacology in older patients is ‘start low, go slow’, and, if the patient’s clinical condition allows, starting doses of 0.5 mg/day of haloperidol or risperidone and olanzapine at 2.5 mg/day are recommended.117 Benzodiazepines may be particularly helpful if the delirium is caused by withdrawal of alcohol or sedatives. Benzodiazepines with rapid onset and short duration of action, such as lorazepam, are preferred and may be given orally or intravenously, with a recommended upper limit of 2 mg intravenously every 4 hours.118 Donepezil and rivastigmine, an acetylcholinesterase inhibitor (which thus enhances cholinergic transmission), may be helpful in delirium superimposed on dementia or parkinsonism,119,120 while serotonin antagonists such as trazodone have also been found helpful anecdotally.121

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9.27 Tobacco smoking Treatment strategies (evidence-based)

Nicotine replacement therapy (NRT) (e.g. gum, transdermal patch, nasal spray, lozenge) or bupropion

Antidepressant drugs (best results are reported with nortriptyline. Some data suggest that nortriptyline is as effective as bupropion with respect to long-term abstinence from smoking. Other TCAs may also be beneficial), clonidine (was found especially effective for relapse prevention; it induces its 'anti-smoking' effects via an unknown mechanism)

Legend

258

Name of modality


Name of modality


Name of modality


TCA

Trycyclic antidepressant

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Treatment for tobacco dependence involves a combination of behavioral therapies and pharmacological treatment. The most common pharmacological treatments involve nicotine replacement therapy (NRT) and non-nicotine medications, including antidepressants. The antidepressant with the greatest weight of evidence for efficacy in the treatment of tobacco dependence is bupropion. The efficacy of bupropion for the treatment of tobacco dependence is attributed to the blockade of dopamine reuptake in the mesolimbic dopaminergic system. This area of the brain is believed to mediate reward for nicotine use and for other drug dependences. Nortriptyline, a tricyclic antidepressant (TCA), is a non-selective norepinephrine reuptake inhibitor, and long-term abstinence outcomes are not significantly different from bupropion. However, only NRT and bupropion are currently approved by the FDA for the treatment of tobacco dependence.122

Notes about the scheme The most common pharmacological treatment for tobacco dependence is NRT. Nicotine is believed to result in tobacco dependence through its effects on both the dopaminergic and noradrenergic systems, known as the ‘reward center’ of the brain. These systems involve both the mesolimbic dopaminergic system and the locus ceruleus, which is the largest noradrenergic nucleus in the brain.123 Increased levels of dopamine in the mesolimbic system are thought to mediate or signal pleasure rewards from nicotine as well as other drugs of abuse. The nicotine-stimulated noradrenergic system enhances vigilance and task performance, thereby reinforcing nicotine use. Available forms of NRT (e.g. gum, transdermal patch, nasal spray, inhaler, and lozenge) increase smoking cessation compared with placebo by 50–100%. However, despite the positive results from these studies, fewer than one in five smokers making an attempt to quit do so with the aid of NRT.

Another efficient modality for smoking cessation is bupropion.122 The antidepressant activity of bupropion is achieved through its effects on the levels of dopamine and norepinephrine in the brain (the effects of bupropion are mediated by blocking the reuptake of both dopamine and norepinephrine124). These effects are thought to underlie its positive results in clinical trials of patients with tobacco dependence (bupropion about doubles long-term abstinence rates compared with placebo). Increased brain levels of dopamine and norepinephrine would be expected to counteract the deficiency of these neurotransmitters during nicotine withdrawal and thereby aid in smoking cessation. Bupropion appears to reduce nicotine withdrawal symptoms and may simulate the actions of nicotine on the brain reward system.125 The most common side-effects related to bupropion are insomnia (30–45% at a dose of 300 mg/day) and dry mouth. Other commonly reported adverse events include hypertension, headache, and nausea. Seizures are a known risk associated with the use of somewhat higher doses compared with other antidepressants (0.1–0.4%), especially for the immediate-release form of the drug and when given at dosages of 450 mg/day or higher. Bupropion, unlike the TCAs, is virtually free of adverse cardiovascular effects,122 which makes it quite attractive for specific populations. Although the greater weight of evidence supporting efficacy favors bupropion, long-term abstinence outcomes in clinical trials of bupropion and nortriptyline are not significantly different. However, nortriptyline is not FDA-approved for tobacco use and dependence. It carries the risk of postural hypotension, cardiac arrhythmia, and serious toxicity with overdose.126 Clonidine, a central a2-adrenergic agonist, has anecdotally been reported to be effective in smoking relapse prevention. The mechanism of clonidine in smoking relapse prevention is not understood, and larger, well-controlled studies are needed to further establish its potential role in smoking cessation.127

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9.28 Borderline personality disorder Treatment strategies (evidence-based)

Avoid, as much as possible Benzodiazepines (due to their addictive potential) or tricyclic antidepressants (TCAs) To date, they have not shown any beneficial results in alleviating depressive symptoms (vs. placebo) in well-controlled studies

If predominant affective dysregulation, impulsiveness

Legend

If predominant psychosis, aggressiveness, or cognitive dyscontrol

SSRIs

SGAs*

Carbamazepine, lithium, MAOI, SSRI ⴙ benzodiazepine (use with caution due to the addictive potential of benzodiazepines), SSRI ⴙ low-dose SGA, valproate

Carbamazepine, SSRI, SSRI ⴙ lithium, MAOI, valproate

Name of modality


Name of modality


Name of modality


MOAI

Second-generation antipsychotic drug (clozapine, olanzapine, quetiapine, risperidone)

SSRI


If no response *

If partial response If relevant

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SGA

Depot preparations of 'typical' neuroleptics can be very useful (as well as long-acting preparations of SGAs)

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Borderline personality disorder (BPD) belongs to cluster B – the ‘dramatic’ cluster (along with narcissistic, histrionic, and antisocial personality disorders). The disorder is usually characterized by stormy interpersonal relations, unstable affect, and behavior dyscontrol. The prevalence of BPD is about 2% in the general population and up to 20% in psychiatric inpatients. BPD is the most studied personality disorder because it is clinically common and it is responsive, at least to some extent, to pharmacological interventions. BPD is most likely a collection of different illnesses placed under a single moniker, as is the case with other major disorders according to DSM-IV criteria. The treatment of BPD focuses on selecting specific symptoms/syndromes that are known to be responsive to pharmacological interventions. Among them are affective dysregulation, impulsive behavior, psychosis, aggression, and comorbid disorders such as substance abuse, anxiety disorders, eating disorders, and major depressive disorder.128,129

Notes about the scheme As mentioned above, pharmacological intervention in BPD is directed at particular behavioral dimensions or psychiatric symptoms/syndromes. Affective dysregulation and impulsivity/aggression are risk factors for suicidal behavior, self-injury, and assaultiveness, and are given high treatment priority. Prevalent psychotic symptoms might point as first-line treatment to the use of a second-generation antipsychotic (SGA). Mood swings and impulsive behavior dyscontrol may prompt the selection of selective serotonin reuptake inhibitors (SSRIs).128,129

Affective dysregulation symptoms These should be treated initially with an SSRI, and data suggest that, in most cases, at least 12 weeks are needed in order to achieve beneficial effects. If response is suboptimal, the medication should be switched to a different SSRI. The addition of a benzodiazepine (especially clonazepam) should be considered when affective dysregulation presents as anxiety. However, benzodiazepines should be used with great caution due to their addictive

properties. For disinhibited anger coexisting with other affective symptoms, SSRIs are the treatment of choice. For severe behavioral dyscontrol, the addition of a low-dose SGA should be considered. Monoamine oxidase inhibitors (MAOIs) are effective but are not considered first-line treatment because of their side-effects and concerns about non-adherence with dietary restrictions. Mood stabilizers (carbamazepine, lithium, and valproate) are also second-line treatments. Electroconvulsive therapy (ECT) should be considered for comorbid severe depression refractory to pharmacotherapy.

Impulsive behavioral dyscontrol The SSRIs are the treatment of choice. If severe symptoms are present, the addition of a low-dose SGA may be beneficial. If one SSRI is ineffective, another SSRI should be considered. In cases of partial response to an SSRI, the addition of lithium has shown a beneficial response in several studies. If an SSRI fails, medication could be switched to an MAOI after an appropriate washout period. Carbamazepine, valproate, or an SGA could also be considered. Clozapine may be warranted after other treatments have failed.129

Cognitive–perceptual symptoms There is a growing body of evidence to support the efficacy of low-dose SGAs in decreasing impulsivity, aggression, self-injury, affective instability, and psychosis in BPD.130 If response is suboptimal within 4–6 weeks, the dose can be increased to the range used for Axis I disorders. Over the past few years, olanzapine (5–20 mg/day) has been the most thoroughly studied SGA for treating BPD. Olanzapine has benefited patients in all measured domains, except for depression reduction.131,132 Risperidone (1–4 mg/day) has been shown to reduce impulsive/aggressive behavior,133 and anecdotal reports have been published on the beneficial effect on quetiapine (25–300 mg/day) in self-injury. Open-label studies/case reports also point to the efficacy of clozapine (300–550 mg/day) in BPD in reducing psychosis, self-injury,129 and hostility, and improving social adaptability. However, because of its side-effect profile and adherence problems, clozapine should be reserved for the most severe cases.129

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Index 5-HT1A antagonist, pindolol 38–9 abbreviations list xii–xiii absorption 18–19 absorption–precipitation 19 gastrointestinal pH 19 gut motility 19 absorption–precipitation 19 abuse, substance see substance abuse AC see adenylate cyclase acetylcholinesterase (AChE) inhibitors 148–9 drug interactions 204 acute intoxication, substance abuse 140–1 acute manic episode lithium 222–3 treatment strategies 50–1, 222–3 valproate 222–3 acute NIA, treatment strategies 254–5 acute psychotic exacerbation, schizophrenia 236–7 adenosine diphosphate (ADP), signal transduction 7 adenosine triphosphate (ATP), signal transduction 7 adenylate cyclase (AC) postsynaptic nerve 4–5 signal transduction 6 ADHD see attention deficit hyperactivity disorder ADP see adenosine diphosphate adrenergic system, sexual function 106–7 adverse effects amphetamines 118–19 anticholinergic 42 antidepressant drugs 42–3 antihistaminergic drugs 78–9 antipsychotic drugs 95, 100–1, 150–2 BDZs 77 cardiovascular 43 central nervous system 42 cocaine 120–1 EPS 150–2 gastrointestinal 43 sexual function 112 topiramate 59 trazodone 28–9, 42, 43

affective dysregulation symptoms, BPD 260–1 akathisia 150–2 antipsychotic drugs 95 alcohol (ethanol) abuse 126–7 dependence mechanisms 126–7 drug interactions 200–1 intoxication symptoms 140–1 treatment options 126–7 withdrawal symptoms 126–7, 142 Alzheimer’s disease (DAT) 148–9 amisulpiride, drug interactions 194–5 amphetamines abuse 118–19 adverse effects 118–19 dependence mechanisms 118–19 intoxication symptoms 140–1 treatment options 118–19 withdrawal symptoms 118–19, 142 anorexia nervosa (AN), treatment strategies 244–5 anticholinergic drugs, EPS 151 anticholinergic effects, antidepressant drugs 42 antidepressant drugs 26–49 see also major depressive disorder; mood stabilizers adverse effects 42–3 affinities, comparative 40 anticholinergic effects 42 antiglutamatergic agents 49 Bcl-2 48–9 cardiovascular effects 43 cellular changes following treatment 30–1 chronic use 30–1 classification 28–9 CNS effects 42 CREB 48–9 CYP enzymes 41 dopamine function 48–9 dual-acting 32–3 efficacy 30–1 escitalopram 36–7, 164–5 future developments 48–9 gastrointestinal effects 43 MAOIs 28–9, 46–7, 70–1, 186–7 mechanisms of action 28–9, 30–1

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Index antidepressant drugs cont. mirtazapine 32–3, 34–5 pindolol 38–9 recently developed 32–3, 34–5, 36–7 receptor/transporter affinities 40 response 49 sexual function effects 44 sleep effects 45 SNRIs 32–3, 154–5, 174–5 TCAs 70–1, 106–7, 162–3, 260–1 transporter/receptor affinities 40 antiglutamatergic agents, antidepressant drugs 49 antihistaminergic drugs adverse effects 78–9 anxiolytics 78–9 clinical profile 78–9 antimanic treatments 50–1, 222–3 antipsychotic drugs 90–103 adverse effects 95, 100–1, 150–2 atypical 96–7, 98–9, 150–2, 194–7 characteristics comparison 98–9 drug interactions 190–7 EPS 150–2 mechanism of action, atypical drugs 96–7 mechanism of action, typical drugs 94–5 receptor affinity 102 schizophreniform disorder 90–3 typical 94–5, 98–9, 150–2, 190–3 anxiety disorders, GAD 226–7 anxiolytics 68–87 antihistaminergic drugs 78–9 b-adrenergic blockers 71 barbiturates 74–5 BDZs 70–1, 72–3, 74–5, 84 buspirone 80–1 development 72–3 ‘fear’ network 68–9 GABA 74–6 hypnotics 77 MAOIs 70–1 mechanism of action 70–1 neurosteroids 74–5 OCD 82–3 sedatives 77 serotonin 68–9 SSRIs 69, 71 TCAs 70–1 aripiprazole, drug interactions 194–5 ARs see autoreceptors ATP see adenosine triphosphate attention deficit hyperactivity disorder (ADHD) adult type 248–9 treatment strategies 248–9 autoreceptors (ARs), presynaptic nerve terminal 2–3 b-adrenergic antagonists anxiolytics 71 EPS 151 pindolol 38–9 268

B-cell lymphoma protein 2 (Bcl-2), antidepressant drugs 48–9 barbiturates, anxiolytics 74–5 basic principles, drug action 1–24 Bcl-2 see B-cell lymphoma protein 2 benzodiazepines (BDZs) abuse 132–3 adverse effects 77 anxiolytics 70–1, 72–3, 74–5 BPD 260–1 cf. buspirone 81 buspirone 132–3 clinical profile 77 dependence mechanisms 132–3 drug interactions 198–9 EPS 151 hepatic metabolism 84 intoxication symptoms 140–1 treatment options 132–3 withdrawal symptoms 132–3, 142 bipolar disorders 50–61 MDD 220–1 BN see bulimia nervosa borderline personality disorder (BPD) affective dysregulation symptoms 260–1 cognitive–perceptual symptoms 260–1 impulsive behavioral dyscontrol 260–1 treatment strategies 260–1 bulimia nervosa (BN), treatment strategies 246–7 bupropion, drug interactions 176–7 buspirone anxiolytics 80–1 cf. BDZs 81 BDZs 132–3 mechanism of action 80–1 cAMP see cyclic adenosine monophosphate cAMP-dependent protein kinase activation opiates 116–17 signal transduction 7 cAMP-response element-binding protein (CREB), antidepressant drugs 48–9 cannabis abuse 128–9 dependence mechanisms 128–9 intoxication symptoms 140–1 treatment options 128–9 withdrawal symptoms 128–9, 142 carbamazepine drug interactions 180–1 mood stabilizers 54–5 cardiovascular effects, antidepressant drugs 43 CBT see cognitive–behavioral therapy cellular changes following treatment, antidepressant drugs 30–1 central nervous system (CNS), antidepressant drugs 42 cholinergic nerve terminal 9 cholinergic system, sexual function 106–7 chronic use, antidepressant drugs 30–1

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Index citalopram drug interactions 164–5 cf. escitalopram 37 cf. mirtazapine 35 clonidine, EPS 151 clozapine, drug interactions 194–5 CNS see central nervous system cocaine abuse 120–1 adverse effects 120–1 dependence mechanisms 120–1 intoxication symptoms 140–1 treatment options 120–1 withdrawal symptoms 142 cognitive–behavioral therapy (CBT) BN 246–7 SAD 234–5 specific phobia 232–3 cognitive–perceptual symptoms, BPD 260–1 CREB see cAMP-response element-binding protein cyclic adenosine monophosphate (cAMP) 6 postsynaptic nerve 4–5 signal transduction 7 cyclic guanosine monophosphate (cGMP), postsynaptic nerve 4–5 cytochrome P450 (CYP) enzymes 20–2 antidepressant drugs 41 blockers 22 pharmacokinetics 22 DAG see diacylglycerol DAT see dementia of Alzheimer’s type delirium, treatment strategies 256–7 delusional disorder, treatment strategies 242–3 dementia of Alzheimer’s type (DAT) 148–9 deoxyribonucleic acid (DNA), signal transduction 8 depressed type, schizoaffective disorder 238–9 depressive disorders see also antidepressant drugs; major depressive disorder mood regulation 26–7 diacylglycerol (DAG), postsynaptic nerve 4–5 distribution 18–19 DNA see deoxyribonucleic acid donepezil 148–9 drug interactions 204 dopaminergic activity, schizophreniform disorder 91 dopaminergic agents, EPS 151 dopaminergic nerve terminal 9 dopaminergic system, sexual function 106–7 drug action principles 1–24 see also mechanism of action drug interactions 162–206 AChE inhibitors 204 alcohol (ethanol) 200–1 amisulpiride 194–5 antipsychotic drugs 190–7 aripiprazole 194–5

BDZs 198–9 bupropion 176–7 carbamazepine 180–1 citalopram 164–5 clozapine 194–5 donepezil 204 ECT 202–3 escitalopram 164–5 fluoxetine 166–7 fluvoxamine 168–9 haloperidol 192–3 lamotrigine 184–5 lithium 178–9 MAOIs 186–7 mood stabilizers 178–83 norepinephrine reuptake inhibitors 176–7 olanzapine 194–5 paroxetine 170–1 phenothiazines 190–1 quetiapine 196–7 reboxetine 176–7 RIMAs 188–9 risperidone 196–7 sertindole 196–7 sertraline 172–3 SNRIs 174–5 SSRIs 164–73 TCAs 162–3 tetracyclic antidepressant drugs 162–3 topiramate 184–5 valproate 182–3 ziprasidone 196–7 dual-acting antidepressant drugs 32–3 duloxetine 32–3 dyskinesias 150–2 TD 252–3 dysthymic disorder, treatment strategies 218–19 dystonia 150–2 antipsychotic drugs 95 ecstasy (MDMA) see MDMA ECT see electroconvulsive therapy EEG see electroencephalogram efficacy, antidepressant drugs 30–1 electroconvulsive therapy (ECT) 156–7 drug interactions 202–3 electroencephalogram (EEG) 153 enzymes, CYP see cytochrome P450 enzymes EPS see extrapyramidal side-effects escitalopram 36–7 cf. citalopram 37 drug interactions 164–5 excretion 18–19 extrapyramidal side-effects (EPS) 150–2 adverse effects 150–2 drug treatments 150–2 mechanisms 150–1 ‘fear’ network, anxiolytics 68–9 fluoxetine, drug interactions 166–7 fluvoxamine, drug interactions 168–9 269

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Index future developments, antidepressant drugs 48–9 c-aminobutyric acid (GABA) anxiolytics 74–6 degradation 11 hypofunction 91–3 macromolecular complex 74–6 neurotransmission 11 schizophreniform disorder 91–3 synthesis 11 G-protein complex postsynaptic nerve 4–5 signal transduction 6 GABA see c-aminobutyric acid GAD see general anxiety disorder galantamine 148–9 gastrointestinal effects, antidepressant drugs 43 gastrointestinal pH, absorption 19 GC see guanylate GDP see guanosine diphosphate gene expression, signal transduction 8 general anxiety disorder (GAD), treatment strategies 226–7 glutamate antiglutamatergic agents 49 degradation 9 neurotransmission 10 synthesis 9 GTP see guanosine triphosphate guanosine diphosphate (GDP), signal transduction 6 guanosine triphosphate (GTP), signal transduction 6 guanylate (GC), postsynaptic nerve 4–5 gut motility, absorption 19 haloperidol, drug interactions 192–3 heteroreceptors (HRs), presynaptic nerve terminal 2–3 hypnotics see sedatives/hypnotics IAR see inhibitory autoreceptor IHR see inhibitory heteroreceptor impulsive behavioral dyscontrol, BPD 260–1 inhalants (volatile solvents) abuse 138–9 dependence mechanisms 138–9 treatment options 138–9 withdrawal symptoms 138–9 inhibitory autoreceptor (IAR), presynaptic nerve terminal 2–3 inhibitory heteroreceptor (IHR ), presynaptic nerve terminal 2–3 inositol trisphosphate (IP3), postsynaptic nerve 4–5 interactions, drug see drug interactions intoxication symptoms, abused substances 140–1 IP3 see inositol trisphosphate ketamine, schizophreniform disorder 93 270

lamotrigine 60–1 drug interactions 184–5 light therapy, MDDSP 158–9 lithium 52–3 acute manic episode 222–3 drug interactions 178–9 lysergic acid diethylamide (LSD) abuse 130–1 dependence mechanisms 130–1 intoxication symptoms 140–1 treatment options 130–1 withdrawal symptoms 130–1, 142 major depressive disorder (MDD) with atypical features 210–11 bipolar 1 disorder 220–1 cellular changes following treatment 30–1 depressive state – no treatment 26–7 ECT 156–7 geriatric population 214–15 mechanisms 26–7 non-resistant 208, 211 with psychotic features 209, 211 SSRIs 28–9 treatment-resistant 212–13 treatment strategies 208–15 major depressive disorder with seasonal pattern (MDDSP) 158–9 mania acute manic episode 222–3 antimanic treatments 50–1, 222–3 manic type, schizoaffective disorder 240–1 MAO see monoamine oxidase MAOIs see monoamine oxidase inhibitors MDD see major depressive disorder MDDSP see major depressive disorder with seasonal pattern MDMA (ecstacy) abuse 122–3 dependence mechanisms 122–3 treatment options 122–3 withdrawal symptoms 122–3 mechanisms of action antidepressant drugs 28–9, 30–1 antipsychotic drugs, atypical 96–7 antipsychotic drugs, typical 94–5 anxiolytics 70–1 buspirone 80–1 MAOIs 28–9 selegiline 28–9 trazodone 28–9 VMAT2; 12–13 memantine 148–9 mesolimbic/mesocortical pathways, schizophreniform disorder 95 messenger ribonucleic acid (mRNA), signal transduction 8 metabolism, drug pathways 18–19 milnacipran 32–3 mirtazapine 32–3, 34–5 cf. citalopram 35

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Index cf. SSRIs 35 modulatory systems, presynaptic nerve terminal 2–3 monoamine oxidase inhibitors (MAOIs) 46–7 anxiolytics 70–1 drug interactions 186–7 mechanism of action 28–9 monoamine oxidase (MAO), presynaptic nerve terminal 2–3 monoamines degradation 9 neurotransmission 9 synthesis 9 mood regulation 26–7 mood stabilizers 52–62 see also antidepressant drugs carbamazepine 54–5, 180–1 comparative profile 62 drug interactions 178–83 lamotrigine 60–1, 184–5 lithium 52–3, 178–9, 222–3 topiramate 58–9, 184–5 valproate 56–7, 182–3, 222–3 mRNA see messenger ribonucleic acid N-methyl-D-aspartate (NMDA) DAT 148–9 schizophreniform disorder 92–3 neuroleptic-induced akathisia (NIA), treatment strategies 254–5 neuroleptic malignant syndrome (NMS), treatment strategies 250–1 neurosteroids, anxiolytics 74–5 neurotransmission postsynaptic nerve 4–5 presynaptic nerve terminal 2–3 neurotransmitters 9–11 GABA 11 glutamate 9–10 monoamines 9 NIA see neuroleptic-induced akathisia nicotine abuse 134–5 dependence mechanisms 134–5 intoxication symptoms 140–1 treatment options 134–5 treatment strategies, smoking 258–9 withdrawal symptoms 134–5, 142 nicotine replacement therapy (NRT) 258–9 nigrostriatal pathways, schizophreniform disorder 95 NMDA see N-methyl-D-aspartate NMS see neuroleptic malignant syndrome noradrenergic nerve terminal 9 norepinephrine reuptake inhibitors, drug interactions 176–7 NRT see nicotine replacement therapy obesity drug treatments 154–5 mechanisms 154–5

obsessive–compulsive disorder (OCD) anxiolytics 82–3 treatment strategies 228–9 olanzapine, drug interactions 194–5 opiates abuse 116–17 dependence mechanisms 116–17 intoxication symptoms 140–1 treatment options 116–17 withdrawal symptoms 116–17, 142 panic disorder (PD), treatment strategies 224–5 parkinsonism 150–2 antipsychotic drugs 95 paroxetine, drug interactions 170–1 PCP see phencyclidine personality disorder, borderline see borderline personality disorder pharmacokinetics 18–19 CYP enzymes 22 phencyclidine (PCP) abuse 124–5 dependence mechanisms 124–5 intoxication symptoms 140–1 schizophreniform disorder 93 treatment options 124–5 withdrawal symptoms 124–5, 142 phenothiazines, drug interactions 190–1 phobia, specific, treatment strategies 232–3 phospholipase C (PLC), postsynaptic nerve 4–5 pindolol 38–9 plasma membrane transporter (PMT), presynaptic nerve terminal 2–3 PLC see phospholipase C PMDD see premenstrual dysphoric disorder PMT see plasma membrane transporter post-traumatic stress disorder (PTSD), treatment strategies 230–1 postsynaptic nerve alterations, antidepressant drugs 30–1 drug action principles 4–5 premenstrual dysphoric disorder (PMDD), treatment strategies 216–17 presynaptic nerve terminal alterations, antidepressant drugs 30–1 drug action principles 2–3 modulatory systems 2–3 VMAT2; 2–3 principles, drug action 1–24 protein phosphorylation opiates 116–17 signal transduction 7 psilocybin abuse 136–7 dependence mechanisms 136–7 treatment options 136–7 withdrawal symptoms 136–7 PTSD see post-traumatic stress disorder quetiapine, drug interactions 196–7

271

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Index reboxetine, drug interactions 176–7 receptor affinity antidepressant drugs 40 antipsychotic drugs 102 receptor-mediated psychiatric symptoms/ syndromes 16 receptor/transporter-mediated ‘non-psychiatric’ symptoms 17 receptors activation 14–15 intracellular modifications following activation 14–15 roles in non-psychiatric symptoms 17 roles in psychiatric syndromes 16 reversible inhibitors of monoamine oxidase type A (RIMAs), drug interactions 188–9 ribonucleic acid (RNA), signal transduction 8 RIMAs see reversible inhibitors of monoamine oxidase type A risperidone, drug interactions 196–7 rivastigmine 148–9 RNA see ribonucleic acid SAD see social anxiety disorder schizoaffective disorder depressed type 238–9 manic type 240–1 treatment strategies 238–41 schizophrenia, acute psychotic exacerbation 236–7 schizophreniform disorder 90–3 dopaminergic activity 91 dopaminergic pathways 95 GABAergic hypofunction 91–3 ketamine 93 mesolimbic/mesocortical pathways 95 nigrostriatal pathways 95 NMDA receptor activity 93 PCP 93 serotonergic involvement 91 tuberoinfundibular pathways 95 sedatives/hypnotics adverse effects 77 anxiolytics 77 clinical profile 77 selective serotonin reuptake inhibitors (SSRIs) 32–3 anxiolytics 69, 71 drug interactions 164–73 MDD 28–9 cf. mirtazapine 35 OCD 82–3 pindolol 38–9 sexual function 106–7, 109–11 selegiline, mechanism of action 28–9 serotonergic involvement, schizophreniform disorder 91 serotonergic nerve terminal 9 serotonergic system, sexual function 106–7 serotonin and norepinephrine reuptake inhibitors (SNRIs) antidepressant drugs 32–3 272

drug interactions 174–5 obesity 154–5 serotonin, anxiolytics 68–9 serotonin reuptake inhibitors (SRIs), OCD 82–3 sertindole, drug interactions 196–7 sertraline, drug interactions 172–3 sexual function 106–13 adrenergic system 106–7 adverse effects, drugs 112 antidepressant drugs 44 cholinergic system 106–7 dopaminergic system 106–7 ejaculation 108–11 erectile dysfunction 108–9 male 108–11 modulators 106–7 neurobiology 106–7 PDE5 inhibitors 108–9 premature ejaculation 108–9 serotonergic system 106–7 SSRIs 106–7, 109–11 side effects see adverse effects signal transduction 4–5, 6–8 cAMP-dependent protein kinase activation 7 gene expression 8 protein phosphorylation 7 second messengers activation 6 sleep effects, antidepressant drugs 45 smoking see nicotine SNRIs see serotonin and norepinephrine reuptake inhibitors social anxiety disorder (SAD), treatment strategies 234–5 solvents see inhalants specific phobia, treatment strategies 232–3 SRIs see serotonin reuptake inhibitors SSRIs see selective serotonin reuptake inhibitors substance abuse 116–45 alcohol 126–7 amphetamines 118–19 BDZs 132–3 cannabis 128–9 cocaine 120–1 inhalants (volatile solvents) 138–9 intoxication, acute 140–1 LSD 130–1 MDMA 122–3 nicotine 134–5 opiates 116–17 PCP 124–5 psilocybin 136–7 withdrawal symptoms 142 tardive dyskinesia (TD), treatment strategies 252–3 TCAs see tricyclic antidepressants TD see tardive dyskinesia tetracyclic antidepressant drugs, drug interactions 162–3 TF see transcription factor tobacco smoking see nicotine

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Index topiramate 58–9 adverse effects 59 drug interactions 184–5 transcription factor (TF), signal transduction 8 transfer ribonucleic acid (tRNA), signal transduction 8 trazodone adverse effects 28–9 mechanism of action 28–9 treatment strategies 208–66 acute manic episode 50–1, 222–3 acute NIA 254–5 ADHD 248–9 AN 244–5 BN 246–7 BPD 260–1 delirium 256–7 delusional disorder 242–3 dysthymic disorder 218–19 GAD 226–7 MDD 208–15 NIA 254–5 NMS 250–1 OCD 228–9 PD 224–5 phobia, specific 232–3 PMDD 216–17 PTSD 230–1 SAD 234–5

schizoaffective disorder 238–41 smoking 258–9 specific phobia 232–3 TD 252–3 tobacco smoking 258–9 tricyclic antidepressants (TCAs) anxiolytics 70–1 BPD 260–1 drug interactions 162–3 sexual function 106–7 tRNA see transfer ribonucleic acid tuberoinfundibular pathways, schizophreniform disorder 95 valproate acute manic episode 222–3 drug interactions 182–3 mood stabilizers 56–7 venlafaxine 32–3 vesicular monoamine transporter type 2 (VMAT2) drugs affecting 13 mechanism of action 12–13 presynaptic nerve terminal 2–3 withdrawal symptoms, substance abuse 142 ziprasidone, drug interactions 196–7 zolmitriptan, EPS 151

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Atlas of Psychiatric Pharmacotherapy, Second Edition

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