Pharmacotherapy.2nd.edition

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Atlas of

Psychiatric

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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

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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.: 44 (0) 207 017 6000 Fax.: 44 (0) 207 017 6699 E-mail: [email protected] Website: 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

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1.1 Principles of drug action – 2 presynaptic nerve terminal

Main reactions relevant for psychiatric pharmacotherapy

1.2 Principles of drug action – 4 postsynaptic nerve

1.3 Signal transduction (I) 6

G-protein complex and activation of second messengers

1.4 Signal transduction (II) 7

Activation of cAMP-dependent protein kinase and subsequent protein phosphorylation

1.5 Signal transduction (III) 8

Gene expression

1.6 Neurotransmitters (I) 9

Monoamines – synthesis and degradation

1.7 Neurotransmitters (II) 10

Glutamate (excitatory) – synthesis and degradation

1.8 Neurotransmitters (III) 11

GABA (inhibitory) – synthesis and degradation

1.9 Vesicular monoamine transporter 12 type 2 (VMAT2)

Main mode of action

1.10 Intracellular modifications 14 following activation of various

receptors (I)

Changes in intracellular compounds following activation of major receptors

1.11 Intracellular modifications 15 following activation of various

receptors (II)

Changes in intracellular compounds following activation of major receptors

1.12 Receptor-mediated psychiatric 16 symptoms/syndromes

Assumed roles of specific receptors in major psychiatric syndromes

1.13 Receptor/transporter-mediated 17 ‘non-psychiatric’ symptoms

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

1.14 Drug pharmacokinetics 18

Main pathways of drug metabolism

1.15a Cytochrome P450 (CYP) hepatic 20 enzymes (I)

Major CYP enzymes responsible for metabolizing various drugs

1.15b Cytochrome P450 (CYP) hepatic 21 enzymes (II)

1.16 Drug pharmacokinetics 22

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

References 23

List of abbreviations

xii

Chapter 1

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2.1 Major depressive disorder 26

Depressive state – no treatment

2.2 Antidepressant drugs 28

Schematic classification according to main mode of therapeutic action

2.3 Major depressive disorder 30

Cellular changes following antidepressant treatment

Recently developed antidepressants (I) – SNRIs

Recently developed antidepressants (II) – mirtazapine

Recently developed antidepressants (III) – escitalopram

2.7 Pindolol – 5-HT1Aand b-adrenergic 38

antagonist

Supposed mode of accelerating and augmenting the antidepressant effect of SSRIs

Comparative affinities for various receptors/transporters

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

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

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

Effects on sexual function

Effects of antidepressant drugs on various sleep parameters

Monoamine oxidase inhibitors

Potential future developments

2.16 Antimanic drugs 50

Supposed mechanism of action

2.17 Mood stabilizers 52 Lithium 2.18 Mood stabilizers 54 Carbamazepine 2.19 Mood stabilizers 56 Valproate

2.20 Mood stabilizer-like drugs 58

Topiramate

2.21 Mood stabilizer-like drugs 60

Lamotrigine 2.22 Mood stabilizers 62 Comparative profile References 63

Chapter 3 Anxiolytic drugs

3.1 Anxiolytics (I) 68

The ‘fear’ network and the role of serotonin in suppressing anxiety

3.3 Anxiolytics (III) 72

New approaches for developing anxiolytic drugs

Chapter 2

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3.5 c-Aminobutyric acid (GABA) 76 macromolecular complex (II)

Agents that suppress chloride channel/GABAAreceptor activity

(cause anxiety)

3.6 Sedatives and hypnotics 77

Comparative clinical and side-effect profile

3.7 Antihistaminergic drugs 78

3.8 Buspirone 80

Supposed mechanism of action in anxiety disorders

3.9 Obsessive–compulsive disorder (OCD) 82

Supposed mechanism of action of anti-OCD drugs 3.10 Benzodiazepines 84 Hepatic metabolism References 85

Chapter 4 Antipsychotic drugs

Chapter 3 Anxiolytic drugs (cont.)

4.1 Schizophreniform disorder 90

No treatment

4.2 Schizophreniform disorder 92

The potential role of GABAergic hypofunction 4.3 Antipsychotic drugs 94 Typical (first-generation) antipsychotic drugs – mechanism of action 4.4 Antipsychotic drugs 96 Second-generation (atypical) antipsychotic drugs – mechanism of action 4.5 Antipsychotic drugs 98

Schematic characteristics: typical versus atypical antipsychotic drugs

4.6 Antipsychotic drugs 99

Specific characteristics: typical versus atypical antipsychotic drugs

4.7 Antipsychotic drugs 100

Main adverse side-effects (I)

Main adverse side-effects (II)

Comparative affinity for different receptors

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5.1 Neurobiology of sexual function 106

Assumed modulators of sexual function

5.2 Male sexual function (I) 108

Drugs that can maintain/induce erection

5.3 Male sexual function (II) 110

Main drugs affecting ejaculation

5.4 Drugs affecting sexual function 112

Sexual adverse side-effects associated with various psychotropics

References 113

Chapter 5 Drugs affecting sexual function

Chapter 6 Drugs for the treatment of symptoms related to

substance abuse

6.1 Abused substances – opiates 116

Supposed mechanism of dependence, withdrawal symptoms, and treatment options

6.2 Abused substances – 118

amphetamines (I)

amphetamines (II)

Supposed mechanism of dependence, adverse effects, and treatment options

6.3 Abused substances – cocaine 120

6.4 Abused sustances – MDMA (ecstasy) 122

6.5 Abused substances – phencyclidine 124 (PCP)

6.6 Abused sustances – alcohol 126

6.7 Abused substances – cannabis 128

6.8 Abused substances – lysergic 130 acid diethylamide

6.9 Abused substances – benzodiazepines 132

6.10 Abused substances – nicotine 134

6.11 Abused substances – psilocybin 136

6.12 Abused substances – inhalants 138 (volatile solvents)

acute intoxication (I)

Frequently encountered ‘non-psychiatric’ symptoms

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6.14 Abused substances – 141 acute intoxication (II)

Frequently encountered ‘psychiatric’ symptoms

withdrawal symptoms

Frequently encountered withdrawal symptoms

Chapter 8 Drug interactions

Chapter 7 Miscellaneous drugs/treatment modalities

Chapter 6 Drugs for the treatment of symptoms related to

substance abuse (cont.)

8.1 Tricyclic and tetracyclic 162 antidepressant drugs

Drug interactions

8.2.1 Selective serotonin reuptake 164 inhibitors (SSRIs) – citalopram/

escitalopram

Drug interactions

8.2.3 Selective serotonin reuptake 168 inhibitors (SSRIs) – fluvoxamine

Drug interactions

8.2.4 Selective serotonin reuptake 170 inhibitors (SSRIs) – paroxetine

Drug interactions

8.2.5 Selective serotonin reuptake 172 7.1 Drugs for the treatment of 148

dementia of Alzheimer’s type (DAT)

Suggested mechanisms involved in DAT and potential drug treatments

7.2 Drugs effective for the treatment of 150 extrapyramidal side-effects (EPS)

Suggested mechanisms involved in EPS and relevant drug treatments

7.3 Drugs effective for the treatment of 152 extrapyramidal side-effects (EPS)

7.4 Electroencephalogram (EEG) 153

Findings associated with specific drugs

7.5 Drugs effective for the treatment 154 of obesity

Suggested mechanisms involved in obesity and potential drug treatments

7.6 Electroconvulsive therapy (ECT) 156

Supposed mechanism of action

7.7 Major depressive disorder with 158 seasonal pattern (MDDSP)

Supposed mechanism of action of light therapy in major depressive disorder as part of SAD

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8.3 Serotonin–norepinephrine 174 reuptake inhibitors (SNRIs)

Drug interactions

8.4 Norepinephrine reuptake inhibitors – 176 bupropion and reboxetine

Drug interactions

8.5.1 Mood stabilizers – lithium 178

Drug interactions

8.5.2 Mood stabilizers – carbamazepine 180

Drug interactions

8.5.3 Mood stabilizers – valproate 182

Drug interactions

8.6 Lamotrigine and topiramate 184

Drug interactions

8.7 Monoamine oxidase inhibitors 186 (MAOIs)

Drug interactions

8.8 Reversible inhibitors of monoamine 188 oxidase type A (RIMAs)

Drug interactions

8.9.1. First-generation (‘typical’) 190 antipsychotic drugs – phenothiazines

Drug interactions

8.9.2 First-generation (‘typical’) 192 antipsychotic drugs – haloperidol

and others

Drug interactions

8.9.3 Second-generation (‘atypical’) 194 antipsychotic drugs (SGAs) –

amisulpiride, aripiprazole, clozapine, and olanzapine

Drug interactions

8.9.4 Second-generation (‘atypical’) 196 antipsychotic drugs (SGAs) –

quetiapine, risperidone, sertindole, and ziprasidone Drug interactions 8.10 Benzodiazepines 198 Drug interactions 8.11 Alcohol (ethanol) 200 Drug interactions

8.12 Electroconvulsive therapy (ECT) 202

Drug interactions 8.13 Acetylcholinesterase inhibitor – 204 donepezil Drug interactions References 205

Chapter 8 Drug interactions (cont.)

Chapter 9 Treatment strategies (evidence-based)

9.1 Major depressive disorder (MDD) 208 (non-resistant)

Treatment strategies (evidence-based)

9.2 Major depressive disorder (MDD) 209 with psychotic features

9.3 Major depressive disorder (MDD) 210 with atypical features

9.4 Major depressive disorder (MDD) 212

9.6 Premenstrual dysphoric disorder 216 (PMDD)

9.7 Dysthymic disorder 218

9.8 Major depressive disorder as part 220 of bipolar I disorder

9.9 Acute manic episode 222

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9.12 Obsessive–compulsive disorder 228 (OCD)

9.13 Post-traumatic stress disorder (PTSD) 230

9.14 Specific phobia 232

9.15 Social anxiety disorder (SAD) 234

9.16 Acute psychotic exacerbation of 236 schizophrenia

9.17 Schizoaffective disorder – 238 depressed episode

9.18 Schizoaffective disorder – 240 manic episode

9.19 Delusional disorder 242

9.20 Anorexia nervosa (AN) 244

9.21 Bulimia nervosa (BN) 246

9.22 Attention deficit hyperactivity 248 disorder (ADHD)

9.23 Neuroleptic malignant 250

syndrome (NMS)

9.24 Tardive dyskinesia (TD) 252

9.25 Acute neuroleptic-induced akathisia 254

9.26 Delirium 256

9.27 Tobacco smoking 258

9.28 Borderline personality disorder 260

Chapter 9 Treatment strategies (evidence-based)

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AC Adenylate cyclase Acetyl-CoA Acetyl coenzyme A

ACh Acetylcholine

AChE Acetylcholinesterase

AChM1,... Acetylcholine muscarinic receptor

subtypes

AChN Acetylcholine nicotinic receptor ACPD 1-Aminocyclopentyl-1,3-dicarboxylate

AD Alzheimer’s disease

ADHD Attention deficit hyperactivity disorder

ADP Adenosine diphosphate

ADR Adrenergic receptor

AgRP Agouti-related gene product

a-KG a-Ketoglutarate

AMPA a-Amino-3-hydroxy-5-methylisoxazole-4-propanoic acid

a-MSH Melanocortin-stimulating hormone

AN Anorexia nervosa

AP4 2-Amino-4-phosphonobutyrate

APD Antipsychotic drug

ATP Adenosine triphosphate

Bcl-2 B-cell lymphoma protein 2 BDNF Brain-derived neurotrophic factor

BDZ Benzodiazepine

BN Bulimia nervosa

BuChE Butylcholinesterase

cAMP Cyclic adenosine monophosphate

CART Cocaine- and amphetamine-related transcript

CBT Cognitive–behavioral therapy

CCK Cholecystokinin

CCKA Cholecystokinin receptor, type A

cGMP Cyclic guanosine monophosphate

CNS Central nervous system

CNTF Ciliary neurotrophic factor COMT Catechol-O-methyltransferase

CRE cAMP-response element

CREB cAMP-response element-binding protein CRF Corticotrophin-releasing factor

CVS Cardiovascular system

CYP ... Cytochrome P450 enzyme isoforms

D1,... Dopaminergic receptor subtypes

DAG Diacylglycerol

DMT N,N-Dimethyltryptamine

DNA Deoxyribonucleic acid

DSM Diagnostic and Statistical Manual (American Psychiatric Association)

ECT Electroconvulsive therapy

EKG Electrocardiogram

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

drug

GC Guanylate cyclase

GDP Guanosine diphosphate

GHSR Growth hormone secretogogue receptor GIT Gastrointestinal tract

GLP Glucagon-like peptide 1

5’-GMP Guanosine 5’-monophosphate GnRH Gonadotrophin-releasing hormone GSK-3b Glycogen synthase kinase 3b

GTP Guanosine triphosphate

GU Genitourinary

H1,2 Histaminergic receptor subtypes

5-HIAA 5-Hydroxyindole acetic acid 5-HT 5-Hydroxytryptamine (serotonin) 5-HT1,... Serotonergic receptor subtypes

HVA Homovanillic acid

INR International Normalized Ratio (blood coagulation test)

IP1 Inositol monophosphate

IP3 Inositol trisphosphate

LAAM L-a-Acetylmethadol

LC Locus ceruleus

LSD Lysergic acid diethylamide

MAO Monoamine oxidase

MAOI MAO inhibitor

MCH Melanin-concentrating hormone

mCPP m-Chlorophenylpiperazine

MDD Major depressive disorder MDDSP MDD with seasonal pattern mRNA Messenger ribonucleic acid

NAc Nucleus accumbens

NARI Selective noradrenaline (norepinephrine) reuptake inhibitor

NE Norepinephrine (noradrenaline)

NGF Nerve growth factor

NK1 Neurokinin receptor, type 1

(receptor for substance P) NK2 Neurokinin receptor, type 2

(receptor for neurokinin A)

NMDA N-Methyl-D-aspartate

NMS Neuroleptic malignant syndrome

NO Nitric oxide

NPY Neuropeptide Y

NRT Nicotine replacement therapy NT-3/4/5 Neurotropin-3/4/5

ObRb Functional long leptin receptor OCD Obsessive–compulsive disorder

OX-A/B Orexin A/B

PD Panic disorder

PDE4/5 Phosphodiesterase-4/5

PK Protein kinase

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RNA Ribonucleic acid

SAD Social anxiety disorder SCN Suprachiasmatic nucleus of

hypothalamus

SGA Second-generation (‘atypical’) antipsychotic drug

SNRI Serotonin–norepinephrine reuptake inhibitor

SRI Serotonin reuptake inhibitor

SSAD Succinic semialdehyde dehydrogenase

TCA Tricyclic antidepressant

TD Tardive dyskinesia

TeCA Tetracyclic antidepressant

trkB Receptor for brain-derived neurotrophic factor (BDNF)

TRH Thyroid-stimulating hormone

(TSH)-releasing hormone tRNA Transfer ribonucleic acid

VMAT2 Vesicular monoamine transporter type 2

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Chapter 1 Basic principles of

psychiatric

pharmacotherapy

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1.1 Principles of drug action – presynaptic nerve terminal

Axon

IAR

PMT

IHR

Nerve

terminal

Metabolites First messengers Mitochondria VMAT2 Plasma membrane Plasma membrane transporter (reuptake site)

Available for postsynaptic interaction

From adjunct neuron MAO MAO ~30% ~70% Neurotransmitter Inhibits Monoamine oxidase

IAR Inhibitory autoreceptor IHR Inhibitory heteroreceptor PMT Plasma membrane transporter

VMAT2 Vesicular monoamine transporter type 2

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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

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:

● the availability of the neurotransmitter and the

proper functioning of the sites of its reuptake into the presynaptic nerve;

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).

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

● 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

Table 1.1

Biogenic amines Amino acids Peptides Miscellaneous

Acetylcholine Aspartate Angiotensin Oxcytocin Adenosine

Dopamine Glutamate Bombesin Prolactin Adenosine triphosphate (ATP) Histamine Glycine Bradykinin Somatostatin Nitric oxide

Norepinephrine c-Aminobutyric acid (GABA) Cholecystokinin Tachykinins Carbon monoxide (noradrenaline) Homocysteate Endorphins Vasoactive intestinal

Serotonin Melatonin peptide

Table 1.2

Nerve type Inhibitory AR Inhibitory HR Stimulatory AR Stimulatory HR

Cholinergic Muscarine type 2 (M2) a2-adrenoreceptor; Nicotinic N-methyl-D-aspartate (NDMA)

dopamine type D2/D3;

serotonin type 5-HT3

Dopaminergic Dopamine type D2/D3 Muscarinic type 2 (M2); Nicotinic: N-methyl-D

-serotonin type 5-H3? aspartate (NMDA)

GABAergic (releases GABA type B (GABAB)

c-aminobutric acid)

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1.2 Principles of drug action – postsynaptic nerve

G-protein complex

Activation of specific protein kinases

Specific intracellular responses

Neurotransmitter Membrane receptor linked to G-protein PLC AC GC DAG cAMP cGMP IP3 Signal transduction Intracellular Ca2 storage vesicle Activates/stimulates Second messengers Adenylate cyclase Cyclic guanosine monophosphate Cyclic adenosine monophosphate DAG Diacylglycerol GC Guanylate AC cAMP cGMP IP3 Inositol trisphosphate PLC Phospholipase C

Legend

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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 receptor-gated 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-messenger-dependent. 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

Catalytic domain

(inactive when covered by the regulatory domain)

Regulatory domain

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

G-protein complex GDP GDP Inactive AC Activated AC ATP cAMP S b _b c a _c a a S S

Inactive membrane receptor

linked to G-protein _{(e.g. by neurotransmitter)}Activated receptor

GTP GTP cAMP-dependent protein kinase Activates/stimulates Dissociates Neurotransmitter Various subunits of the G-protein complex

AC Adenylate

cAMP Cyclic adenosine monophosphate

GDP Guanosine diphosphate GTP Guanosine triphosphate

Legend

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Inactive

protein kinase

Active

protein kinase

cAMP ATP ADP cAMP-dependent protein kinase

(inactive; without cAMP attached)

Alters intracellular functioning

(e.g. may affect lipid/protein/glucose metabolism, cell division/differentiation, permeability/excitability

of cell membrane, secretory processes, gene expression)

Inactive (not phosphorylated) protein

or transcription factor

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

(cAMP attached)

Catalytic domain Phosphate residue Regulatory domain Metabolic pathway

ADP Adenosine diphosphate ATP Adenosine triphosphate

,

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1.5 Signal transduction (III)

Gene expression

Cell nucleus

Double-stranded DNA mRNA tRNA Protein Active TF Active TF RNA polymerase II Activates Regulatory element Transcribed region

RNA Ribonucleic acid

DNA Deoxyribonucleic acid mRNA Messenger ribonucleic acid

tRNA Transfer ribonucleic acid TF Transcription factor

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Noradrenergic nerve terminal

Dopaminergic nerve terminal

Serotonergic nerve terminal

Cholinergic nerve terminal

Tyrosine L-dopa L-dopa NE-PMT MHPG DA 5-HIAA Tryptophan 5-OH-tryptophan NE a₂-ADR a2-ADR _5-HT1D Mit. Mit. 5-HT NE 1 3 1 2 3 1–3 2 Tyrosine hydroxylase Tryptophan hydroxylase

Amino acid decarboxylase Dopa decarboxylase

DA-b-hydroxylase

Tyrosine

Acetic acid Choline Choline-PMT HVA DA-PMT Dopamine Acetylcholine Acetyl-CoA D2,3 AChM2 Mit. Tyrosine hydroxylase Choline acetyltransferase Dopa decarboxylase Name Acetylcholinesterase

(on postsynaptic membrane)

Enzymes Inhibits

Receptors Stimulates

MAO type A COMT MAO type A/B COMT MAO type A aldehyde dehydrogenase

5-HIAA 5-Hydroxyindole acetic acid 5-HT 5-Hydroxytryptamine (serotonin)

ADR Adrenergic

COMT Catechol-O-methyltransferase DA Dopamine

HVA Homovanillic acid MAO Monoamine oxidase

MHPG 3-Methoxy-4-hydroxyphenylglycol Mit. Mitochondria

NE Norepinephrine (noradrenaline) PMT Plasma membrane transporter AChM2 Acetycholine muscarinic

receptor subtype

Acetyl-CoA Acetyl coenzyme A

D2,3 Dopaminergic receptor subtype

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1.7 Neurotransmitters (II)

Glutamate (excitatory) – synthesis and degradation

Presynaptic

glutamatergic

nerve

terminal

Postsynaptic

nerve

Mit. Pyruvate Glutamate (any kind) Glutamate

Increased cation influx

(causes excitatory response)

Cations (mainly Ca2) AP4 NMDA receptor complex Glutamate-PMT Combination of glycine and 2 molecules of glutamate is needed

to properly open the cation channel Inhibits Stimulates Glycine Ketamine, phencyclidine (PCP), Mg2 AP4 2-Amino-4-phosphonobutyrate (inhibitory autoreceptor)

NMDA N-methyl-D-aspartate

PMT Plasma membrane transporter Mit. Mitochondria

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SC SSA Glutamate a-KG

Presynaptic

GABAergic

nerve terminal

Postsynaptic

nerve

(any kind) Inside the mitochondria

Mitochondria GABA GABA SSAD GABA-T Gl u ta m ic acid deca rboxylase GABA GABAA Increased Cl influx

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

Acetyl-CoA SC macromolecular complex SSA Glutamate Name a-KG GABA-PMT GABAB Pyruvate Cl ions Pyruvate Enzymes Inhibits Stimulates a-KG a-Ketoglutarate GABA c-Aminobutyric acid

Acetyl-CoA Acetyl coenzyme A

PMT Plasma membrane transporter SC Succinate

SSA Succinic semialdehyde

SSAD Succinic semialdehyde dehydrogenase GABA-T GABA ketoglutarate transaminase

(aminotransferase)

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1.9 Vesicular monoamine transporter type 2 (VMAT2)

Main mode of action

Presynaptic

nerve terminal

Metabolites Mitochondria Storage vesicle Neurotransmitter

(i.e. biogenic amine)

VMAT2 30% MAO 70% PMT Inhibits Tetrabenazine

Serine residue of VMAT2 Neurotransmitter

Hydroxyl group Attaches to hydroxyl

group of neurotransmitter

Stimulates

Reserpine

MAO Monoamine oxidase

PMT Plasma membrane transporter

VMAT2 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,

tetraphenyl-phosphonium, 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

(29)

1.10 Intracellular modifications following activation of various

receptors (I)

Changes in intracellular components following activation of major receptors

Affected intracellular components

Activated

membrane

receptors

Na a1-ADR a2-ADR d, j, l opioid j opioid 5-HT1A 5-HT1D 5-HT2A 5-HT2C 5-HT3 5-HT4,6,7 A1 A2 AChM1,3 AChM2 AChM4 AChN b1–3-ADR K Cl cAMP cGMP IP3 DAG Ca2 Increased concentration of intracellular component Decreased concentration of intracellular component

5-HT1–7 Serotonergic receptor subtypes

A1,2 Adenosine receptors

cGMP Cyclic guanosine monophosphate

DAG Diacylglycerol IP3 Inositol trisphosphate

a1,2/b1–3-ADR Adrenergic receptor subtypes

AChM1–4 Acetylcholine muscarinic receptor subtypes

AChN Acetylchlorine nicotinic receptor

(30)

Affected intracellular components

Activated

membrane

receptors

Increased concentration/activity of intracellular component Decreased concentration/activity of intracellular component ACPD1,2

CCKA Cholecystokinin receptor

D1–5 Dopaminergic receptor subtypes

IP3 Inositol trisphosphate

DAG Diacylglycerol

H1,2 Histaminergic receptor subtypes

NK1 Neurokinin receptor, type 1

(receptor for substance P)

NK2 Neurokinin receptor, type 2

(receptor for neurokinin A)

NMDA N-Methyl-D-aspartate

cGMP Cyclic guanosine monophosphate

Na K cAMP ACPD1 ACPD2 CCKA D1,5 D2 GABAA GABAB H1 H2 NK1 NK2 D3,4 AMPA Kainate NMDA cGMP DAG Cl IP3 Ca2

Glutamatergic receptor subtypes (1-aminocyclopentyl-1,3-dicarboxylate)

AMPA Glutamatergic receptor subtype

(a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)

GABAA,B c-Aminobutyric acid receptor

subtypes

(31)

1.12 Receptor-mediated psychiatric symptoms/syndromes

Assumed roles of specific receptors in major psychiatric syndromes

Psychiatric symptoms/syndromes

Stimulated

receptors

Anxiety spectrum Pre-synaptic Post-synaptic Ge n e ralized a n xiety 5-HT1A 5-HT1A 5-HT2A/2C a1-ADR 5-HT1D D2 GABAA Obsessive– co m p u lsive Pa n ic attacks Phobia (social) Bu limia Dep ression Psychosis Sex u al dys fu nc tion

Improved symptom (by activation of the correspondent receptor)

Worsened symptom (by activation of the correspondent receptor)

5-HT1A,1D,2A,2C Serotonergic receptor subtypes

a1-ADR Adrenergic receptor subtype

D2 Dopaminergic receptor subtype

GABAA c-Aminobutyric acid receptor, type A

(32)

Stimulated/inhibited receptors/transporters

5-HT 1A 5-HT 1D 5-HT 2A/2C 5-HT 2A/2C 5-HT -PMT DA-PMT 5-HT 3 5-HT 3 AChM 1 D2 GABA A H1 NE-PMT a2 -ADR a1 -ADR a1 -ADR

CNS

CVS

GIT

GU

Others

Agitation Akathisia Dry mouth EPS (c) Headache (c) Headache (p) Hyperthermia Hypothermia Insomnia Memory impairment (c) Prolactinemia Sedation Seizures (c) Sweat (c) Sweat (p) Hypertension Hypotension Tachycardia 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 Blurred vision Photophobia Tremor EPS (p)

Presynaptic Postsynaptic Transporters

Data fairly well established Data not well established Green-colored receptor/transporter Stimulated receptor/transporter

Red-colored receptor/transporter Inhibited receptor/transporter

(c) Causes specific symptom

a1,2-ADR Adrenergic receptor subtypes

CNS Central nervous system CVS Cardiovascular system

EPS Extrapyramidal side-effects

GABAA c-Aminobutyric acid receptor, type A

GIT Gastrointestinal tract GU Genitourinary

H1 Histaminergic receptor subtype

NE-PMT

D2 Dopaminergic receptor subtype

(p) Protects from specific symptom 5-HT1A,1D,2A,2C,3 Serotonergic receptor subtypes

5-HT-PMT Plasma membrane transporter for serotonin

AChM1 Acetylcholine muscarinic

receptor, type 1

DA-PMT Plasma membrane transporter for dopamine

Plasma membrane transporter for norepinephrine

(33)

1.14 Drug pharmacokinetics

Main pathways of drug metabolism

Systemic

circulation

GIT

Liver

Renal tubules A A Excreted in the urine Excreted in the feces Biliary tract Free (active) form CYP CYP Drug Metabolite/s (following phase I) Drug (albumin-bound) Drug (conjugated; following phase II)

CYP Cytochrome P450 GIT Gastrointestinal tract

(34)

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

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.

(35)

1.15a Cytochrome P450 (CYP) hepatic enzymes (I)

CYP enzymes

Substrates

1A2 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 2B6 2C19 2C9 2D6 2E1 3A4

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

DHEA Dehydroepiandrosterone

(36)

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

Substrates

CYP enzymes

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

Warfarin (R/S) Specific isomers of warfarin

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

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1.16 Drug pharmacokinetics

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

Various

inhibitors of

CYP enzymes

Antidepressant drugs Antipsychotic drugs

Various stimulators of CYP enzymes

RIMA

Affected

CYP enzymes

Strongest effect Medium effect Little effect

* Reboxetine appears to be devoid of any

inducing/inhibiting effects on major hepatic metabolizing enzymes

** Cigarette smoking; through the action of

polyaromatic hydrocarbons

RIMA Reversible inhibitor of

monoamine oxidase type A 1A2 2C 2D6 3A4 Amitriptyline Clomipramine Desipramine Fluoxetine Fluvoxamine Nefazodone Reboxetine* Paroxetine Sertraline Venlafaxine Fluphenazine Haloperidol Perphenazine Thioridazine Moclobemide Carbamazepine Phenobarbital Smoking**

Legend

(38)

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Chapter 2 Antidepressant drugs

and mood stabilizers

(41)

2.1 Major depressive disorder

Depressive state – no treatment

Presynaptic

nerve terminal

Postsynaptic

nerve

IAR Upregulated inhibitory autoreceptors (e.g. a2-adrenergic) Low synaptic NE and/or 5-HT Rec. trkB Soma Nerve terminal Loss of dendrites/ changes in morphology SM CREB Nucleus

Low synaptic neurotrophic factor (e.g. BDNF) BDNF

BDNF

Feedback inhibition (enhanced)

Loss of dendrites and/or change in morphology

Low concentration

5-HT Serotonin

BDNF Brain-derived neurotrophic factor IAR Inhibitory autoreceptor

NE Norepinephrine Rec. Receptor

SM Second messenger (e.g. cAMP) trkB Receptor for BDNF

CREB Cyclic adenosine monophosphate

(cAMP)-response element-binding protein

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-HT1Aserotonergic

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,2Creceptors suppress 5-HT1A

receptor functions).

All of the above mentioned reactions are supposed to play a role in maintaining proper neuroplasticity.1–13

(43)

2.2 Antidepressant drugs

Schematic classification according to main mode of therapeutic action

Presynaptic nerve terminal

Postsynaptic

nerve

PMT IAR AD AD AD AD Reuptake inhibitors of NE: MAO (e.g. a2-adrenergic receptors) NARI (reboxetine)

SNRIs (duloxetine, milnacipran venlafaxine)

TCAs (e.g. amitriptyline,

clomipramine, doxepin, imipramine, nortriptyline, desipramine)

TeCAs (e.g. amoxapine, maprotiline) Inhibitors of MAO Inhibitors of presynaptic IAR Inhibitors of postsynaptic 5-HT receptors RIMA: Moclobemide Mianserin, mirtazapine, trazodone Mianserin, mirtazapine, nefazodone, trazodone MAOIs: Isocarboxazid, phenelzine, tranylcypromine of 5-HT:

SSRIs (e.g. citalopram, fluoxetine, fluvoxamine, paroxetine, setraline) SNRIs TCAs of both NE and 5-HT: NE/5-HT receptors 5-HT2 receptors SNRIs Others (nefazodone) Inhibition Enhanced secretion Inhibits 5-HT Serotonin

MAO Monamine oxidase MAOI MAO inhibitor

NE Norepinephrine

PMT Plasma membrane transporter RIMA Reversible inhibitor of MAO type A

SNRI Serotonin–norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitor

T/TeCA Tri/tetracyclic antidepressant

NARI Seletive noradrenaline (norepinephrine) inhibitor

AD Antidepressant drug IAR Inhibitory autoreceptor