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Atlas Psihiatrie

Atlas Psihiatrie

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Atlas of Psychiatric Pharmacotherapy

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, MRCP, FRCPsych, FMedSci
Professor of Psychopharmacology School of Medical Sciences University of Bristol UK

Graphics Roni Shiloh

TaylorS* Francis
Taylor & Francis Croup LONDON AND NEW YORK

©2006 Taylor & Francis, an imprint of the Taylor & Francis Group Taylor & Francis Croup is the Academic Division of Informa pic 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 0X14 4P.N Tel.: Fax.: E-mail: Website: +44 (0) 207 01 7 6000 +44(0)207 017 6699 info.medicine@tandf.co.uk 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 W1 P OLP. 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
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Tel: 800 272 7737; Fax: 800 374 3401
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Tel: 561 994 0555; Fax: 561 361 6018 E-mail: orders@crcpress.com 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: salesorder.tandf@thomsonpublishingservices.co.uk Composition by J&L Composition, Filey, North Yorkshire Printed and bound in Italy by Printer Trento

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Chapter 1 Basic principles of psychiatric pharmacotherapy .

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Chronic use of these drugs leads to a relative depletion of amine stores. Regional localization of VMAT2 is consistent with the known monoamine nerve terminal density. reduced VMAT2 gene expression). serotonin in specific vesicles in serotonergic nerves. There is some evidence for the existence of two conformations of VMAT2. Acetyjcholine undergoes an extracellular catabolic process catalyzed by acetylcholinesterase. Having entered the presynaptic nerve terminal. histamine) with practically equivalent affinity. norepinephrine. It is thought that transport of biogenic amines is dependent on the pH gradient_between the cytoplasm and the intravesicular space. 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. The cytoplasm is a relatively high-pH region compared with the intravesicular space (low-pH region. and that hydroxyl groups on the different biogenic amines serve as substrates that are recognized by the serine residues. while MAO type B metabolizes dopamine. About 70% of the neurotransmitters taken up by the PMT are restored in intracellular vesicles located in the presynaptic nerve terminal. which is why they can cause depression. as well as agents such as tacrine. Some is retransported into the presynaptic nerve terminal by the plasma membrane transporter (PMT).8-¹6 . verapamil. A fraction of the released neurotransmitter binds to the corresponding post. substantia nigra pars compacta.g. it is highest in the striatum. The way in which estrogen and progesterone affect VMAT2 is unclear. The most studied are reserpine and tetrabenazine. Other possible inhibitors of VMAT2 activity are cytotoxic compounds such as ethidiutn. respectively). which is transported in the opposite direction. etc. acetylcholine. Several substances are known to affect VMAT2. pH = 4-5). and rhodamine. and both of its extremities are located in the cytoplasmatic site. isometamidium. and locus ceruleus. and might be via an indirect action (e. VMAT2 is a protein with 12 membrane segments. with a consequent secondary intracellular change. serotonin. can be involved in several processes. and the hormones estrogen and progesterone. Reserpine and tetrabenazine have different binding sites on VMAT2 and are presumed to exert their inhibitory effects on biogenic amine transport via different mechanisms. 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. norepinephrine. it dissociates from the specific receptor back into the synaptic cleft. This means that when reserpine (or tetrabenazine) binds VMAT2.Notes about the scheme A neurotransmitter. it inhibits its capacity to uptake monoamines but at the same time prevents the binding of the other antagonist (tetrabenazine or reserpine.g. and epinephrine. dopamine. The mechanism of VMAT2 action is complex and only partially understood. lateral septum. once released from the presynaptic nerve into the synaptic cleft. Following this. Lower density is evident in the cerebral cortex and in the cerebellum. raphe nucleus. and it transports all biogenic amines (e. ready for reuptake into the presynaptic nerve or for further receptor interaction. Vesicular monoamine transporter type 2 (VMAT2) is located on the membrane of the intracellular storage vesicle. tetraphenyi-phosphonium. Each of these vesicles contains only a specific biogenic amine: norepinephrine is accumulated and stored in specific vesicles in noradrenergic nerves.or presynaptic receptors. Both inhibit VMAT2 activity with a consequent decrease in biogenic amine transport into storage vesicles. binding either reserpine or tetrabenazine. This results in a reduced amount of biogenic amine available for release into the synaptic cleft. 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.

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distribution. and hydrolysis (termed phase I). which can have opposite effects decreased gut motility.17-43 • • Distribution Once absorbed from the gastrointestinal tract. Once some of the free drug has been metabolized. Distribution is also affected by a drug's protein-binding properties. adipose). Significant drug-drug interactions are associated with drugs that are more than 90% bound to plasma proteins. altered absorption might prevent the expected therapeutic response (due to inability to reach the appropriate serum level). Absorption-precipitation. drugs pass through the liver via the portal circulation and are metabolized to various extents (the first-pass effect). it can be metabolized further by phase II. is subjected to metabolic processing and excretion. liver) exhibit a rapid blood-tissue equilibration of drugs. Excretion Most drugs are excreted via the bile/kidneys to be finally eliminated in the feces or the urine. These complexes are sometimes poorly absorbed. iron) – while passing via the gastrointestinal tract. partially active. The bound fraction is pharmacologically inactive.Notes about the scheme Pharmacokinetic interactions are subdivided into absorption. Absorption from the gastrointestinal tract (mostly from the proximal parts of the ileum) depends on the solubility of the agent (the more lipidsoluble. The rate of absorption is important if a rapid response is needed. kidneys. Absorption Orally administered drugs can undergo processing while passing through the gastrointestinal trace. In the case of a drug given in a single dose. a portion of the bound drug becomes unbound and can exert its pharmacological activities and. . acetic. Metabolism Metabolism is the biotransformation of a drug to another chemical and a less lipid-soluble form that is more easily excreted. Many agents may form a larger complex – precipitates with other particles such as metallic ions (aluminum. the better is the diffusion through the intestinal membrane) and on the electrical charge of the agent (the nonionized form usually diffuses well through the mucous membrane).9. This redistribution can mean that a drug with a long elimination halflife 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). highly perfused tissues (central nervous system. which may be still pharmacologically active. There are several factors governing absorption: • Gastrointestinal pH. particularly to albumin. Then. Phase I reactions change the parent compound into a more polar form. which generally leads to total inactivation of the parent compound. sulfuric or an amino acid. Initially. Phase II reactions involve the conjugation (coupling) of a drug with a polar substrate such as glucuronic. When a drug has been metabolized by phase I reactions. or it can be hydrophilic enough to be eliminated without further metabolism. cytochrome P450 (CYP)) located in microsomes of the endoplasmic reticulum of hepatic cells. It has little importance if the drug is given chronically or in multiple daily doses. causes the drug to spend more time in the gastrointestinal tract. or delayed emptying of the stomach. heart. at the same time. Changes in distribution can be evident if perfusion to a target organ or tissue is altered. and excretion. Many drugs alter the activities of these metabolic processes by either stimulating catabolic enzymes or inhibiting them.e. and conjugation (termed phase II). Most drugs are bound to plasma proteins. Some agents can alter gut motility. the drug may be redistributed to less-perfused tissues (muscle. or inactive. There are four main types of metabolic reactions: oxidation. calcium. reduction. The vast majority of metabolic processing is done by a group of enzymes (i. Following passage through the liver. with a need for an immediate response. bismuth. The gastrointestinal pH may alter these parameters. Gut motility. metabolism. Such processes may interfere with absorption by affecting the rate and total amount of drug absorbed. the drugs are distributed to the tissues by the systemic circulation. and many drug-drug interactions are due to this. 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).

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Dockens RC et al. Ereshefsky L. Fleishaker JC. Goff DC. Neurotransmitter transporters: recent progress. J Clin Psychopharmacol 1996. Eur J Clin Pharmacol 1994. 4. de Morais SMF. Rapid down regulation of beta adrenoreceptors by coadministration of desipramine and fluoxetine. 29. Pharmacokinetic optimisation of therapy with newer antidepressants. Kerr BM. Riesenman C. Thummel KE. Clin Pharmacokinet 1995. 57(Suppl 8): 1 7-25. Midha KK. . Landau EM. Baron BM. Hanson GR. Goldstein JA. 10. Imaging the vesicular monoamine transporter. Ereshefsky L. Riesenman C. 18. 15: 18-24. J Exp Biol. J Psychiatry Neurosci 2003. 23. 24. 154: 125-134. New directions in monoamine oxidase A and B: selective inhibitors and substrates. Baron BM. j Clin Psychiatry 1994. Pharmacogenetics 1994. Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffine granules. 38. 22.References 1. 28. Biochem Pharmacol 1990. Liu Y et al. DeVane CL. Jimenez ). Biochemistry 1989. Liu G. Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. Gram LF. 5. Presynaptic control of quantal size: kinetic mechanism and implications for synaptic transmission and plasticity. 27: 307-330. Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin re-uptake inhibitors: Part 1. 13: 324-331. You dim MBH. Science 2001. imipramine and lithium. 15: 399-408. Henry JP. Sindrup SH et al. Biol Psychiatry 2005. Curr Opin Neurobiol 2003. Preskorn SH. Neurotransmitter transporters: Why dance with so many partners? Curr Opin Pharmacol 2004. 41: 155-162. Clinicalpharmacokinetic profile of moclobemide and its comparison with other MAOinhibitors. 28: 247-250. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. 14. Rev Contemp Pharmacother 1994. Blitzer RD. Eur J Clin Pharmacol 1988. Ogden AM. Henry JP. Hulst LK. Siegel BW et al. Impact of psychostimulants on vesicular monoamine transporter function. 2. Kuhar MJ. Pharmacogenetics and drug metabolism of new antidepressant agents. Gonzalez Ml. Functional identification and molecular cloning of a human brain vesicle monoamine transporter. 1 7. jaudon P et al. Wurden Q et al. Postsynaptic signaling networks: cellular cogwheels underlying long term plasticity. 46: 35-39. Sagne C et al. Harvey AT. Antidepressant drug interactions and the cytochrome P450 system: the role of CYP2D6. 15. Scherman D. Siegel BW et al. 36. Human liver carbamazepine metabolism: 35. 25. JNeurochem 1993. Adv Neuroi 2001. J Biol Chem 1994. Frey KA. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Ogden AM. 7. Am J Psychiatry 1991. 8. 11. 294: 1024-1030. 16. GuentertTW. Neurotransmitter interactions in psychotropic drug action. Greenshaw AJ. Eiden LE. J Clin Psychiatry 1996. 5: 19-34. 1994. Greengard P. 196: 251-262. 20. Koeppe RA. The neurobiology of slow synaptic transmission. 33: 72-77. 13. 6. Greene DS. 26. Goodnick PJ. 25: 11 3-122. 12. Fleckenstein AE. Annu Rev Neurosci 1993. lyengar R. Salazar DE. Mayersohn M. Kilbourn MR. 55(12 Suppl): 3845. 37. Peter D. Scherman D. Mol Pharmacol 1984. Clin Pharmacokinet 1994. j Clin Psychopharmacol 1995. 29(Suppl 1): 10-19. Brotman AW et al. beyond dopamine and serotonin. Reserpine binding to chromaffin granules suggests the existence of two conformations of the monoamine transporter. 57: 11 3-119. Citalopram: interaction studies with levomepromazine. 21. Erickson JD. Scherman D. Robinson MB. Rapid down regulation of beta adrenoreceptors by coadministration of desipramine and fluoxetine. Henry JP. Amara SG. 28:1692-1697. 27. Lam YWF. Eur j Clin Pharmacol 1988. 154: 125-134. 148: 790-792. Coadministration of nefazodone and benzodiazepines: a pharmacokinetic interaction study with alprazolam. 269: 7231-7237. 16: 73-93. 4: 285-299. Reserpine binding to bovine chromaffin granule membranes with dihydrotetrabenazine binding. Hansen MGj. 19. 479:283-289. Biochemistry and molecular biology of the human CYP2C subfamily. 3. Mol Pharmacol 1988. Therap Drug Monitor 1993. Elevation of plasma concentrations of haloperidol after addition of fluoxetine. Darchen P. Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter. 16: 273-278. 9. Eur j Pharmacol 2003. 86: 237-247. 4: 30-35. Finberg JPM. Botton D. Lam YWP. 61: 2314-2317. Gasnier B.

Lemoine A.venlafazine and other 5-HT reuptake inhibitors.36(Suppl 5): S8-S13. Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide. Kelman AW et al. early trivial names of enzymes. 26: 144-160. 21: 51 7-520. Shami M. Aiavijeh MS. 40. Biochem Pharmacol 30. Burrows CD et al. 1994. 150: 1125-1126. accession numbers. Kronbach T. Clin Pharmacokinetics 1994. Trends Pharmacol 33. Elliot HL. Interactions between sertraline and tricyclic antidepressants. The pharmacokinetics of mianserin. 25 years since the discovery of presynaptic receptors: present knowledge and future perspectives. gene mapping. Kamataki T. Drugs 2004. Langer SZ. The pivotal role of drug metabolism and pharmacokinetics in the discovery and development of new medicines.Clin Pharmacokinet 1995.role of CYP3A4 and CYP2C8 in 10. 29: 292-332. Eur J Clin Pharmacol 1982. . and nomenclature. Mathys D. patients. Lillsunde P. Br j Clin Pharmacol 1983. Mol Pharmacol 1989. 18: 95-99. Levy RH. 31. Ball SE. Effects of carbamazepine on serum antidepressant concentrations in psychiatric 42. 36: 89-96. Cytochrome P450 isoenzymes and anti-epiieptic drug interactions. 43: 827-832. Leinonen E. DNACell Biol 1993. 34. catalyzed by cytochromes P450 1A2 and P450 3A4 in human liver. Extrahepatic metabolism of drugs in humans. Epilepsia 1995. A pharmacokinetic study of mianserin. Otton SV. Krishna DR. Mol Pharmacol 1993.11epoxide formation. Lydiard RB. Norman TR. J Clin Psychopharmacol 1991. Curr Opin Drug Discov Devel 2003. Waxman Dj et al. 6: 66-80. The P450 super-family: update on new sequences. 15: 313S-322S. Umeno M et al. Palmer AM. 32. Comparative inhibition of the polymorphic enzyme BYP2D6 by 41. GuentertTW. Clin Pharmacol Ther1994. Azoulay D et al. 12:1-51. Cunningham T. 11: 313-318. Major pathway of imipramine metabolism is 43. 39. Cheung SW et a!. Roberts SA. Am ] Psychiatry 1993. Gauthier JC. Drug metabolism and pharmacokinetics in drug discovery. 47: 1969-1979. Mayersohn M. 7: 755-763. Laukkanen V et al. Maguire KP.55: 141 (abst). Oxidation of midazolam and triazolam by human liver cytochrome P4503A4. Sci 1997. Anton RF. Klotz U. Nelson DR.

Chapter 2 Antidepresant drugs and mood stabilizers .

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4. nerve growth factor (NCF). All of the above mentioned reactions are supposed to play a role in maintaining proper neuroplasticity. nefazodone. Other mechanisms. recent evidence demonstrates that in mood disorders. Hence. 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). alterations in morphology and number of dendritic spjnes. Among them are proper _ regulation of postsynaptic 5-HT1A serotonergic receptors and concentration of intracelluiar Bcl2.2c receptors suppress 5-HTiA receptor functions). are supposed to be involved in the maintenance of euthymic mood.Present knowledge about the biological mechanism of normal mood has made much progress in recent years. mianserin. and ciliary neurotrophic factor (CNTF).and postsynaptic receptors/transporters. consequent gene expression. cAMP) and production of various neurotrophic brain factors. and the capacity of neurons to survive toxic and non-toxic abuses). intact signal transduction involving appropriate production/stimulation of intracellular messengers (e.4. The concept of neuroplasticity refers to the capacity of the CNS to adapt itself to changing external stimuli through appropriate signal transduction.5 (NT-3. and possibly the only. Although the precise cellular mechanism underlying these morphometric changes remain to be fully elucidated. synaptic connectivity. 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 (5HT2A. as yet less understood. it was assumed that decreased norepinephrine or serotonin in the synaptic cleft is the major.6. It is presumed that most antidepressant drugs that exert their antidepressant activity by antagonizing the postsynaptic 5-HT2A serotonergic receptors (e.2C serotonergic. data suggest a predominant role of altered neuronal plasticity and cellular resilience. among other things. Notes about the scheme MDD. normal regulation of mood is currently conceived as proper modulation of the adrenergic and/or serotonergic systems via: Correct signal transduction culminates in intact neuroplasticity and resilience in specific brain areas and results in maintenance of euthymic mood. cyclic adenosine monophosphate. factor involved in inducing major depressive disorder (MDD). although it is not yet fully understood. especially cAMP-response element-binding protein (CREB). However. which eventually leads.g.1-13 . and B-cell lymphoma protein 2 (Bcl-2). direction of axonal/dendritic outgrowth. to the production of CREB and BDNF.5).g.7 serotonergic receptors activate the adenylate cyclase-cAMP cascade. 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. • • • correct functioning of various pre. Postsynaptic β1 adrenergic and 5-HT4. and especially in MDD. CREB is also modulated by Ca2+dependent protein kinases stimulated by other postsynaptic receptors such as the αr adrenergic and the 5-HT2A. and the production of various neurotrophic factors responsible for normal cell connectivity. there is regional reduction in central nervous system (CNS) volume.g. mirtazapine. as well as neurotrophin-3. and trazodone. brain-derived neurotrophic factor (BDNF). is currently thought to derive from changes in neuronal plasticity and cellular resilience (e. appropriate secretion of norepinephrine and/or serotonin from presynaptic neurons.g. Decades ago. which has traditionally been conceptualized as a 'pure' neurochemical disorder. Thus. various neurochemical modifications (e.

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13 The MAOIs (isocarboxazid. Under normal conditions. mirtazapine. however. Postsynaptic blockade of various receptors modulates cellular activities and is presumably responsible for the antidepressive effects. although there are a few exceptions to this (e. cause the presynaptic neurons to release more neurotransmitter to the synaptic cleft.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.the SSRIs (citalopram. • MAO inhibitors (MAOIs). and dopamine taken up by the plasma transporters into the cytoplasm. Blockade of monoamine receptors (pre. all antidepressant drugs have comparable efficacy but different adverse effects profiles. Inhibition of the metabolism of the mitochondrial monoamine oxidase (MAO) responsible for the degradation of approximately 30% of cytoplasmic serotonin. When the MAOs are inhibited./the inhibition of MAO type B by selegisine increases the availability of dopamine in the synaptic cleft. and tranyicypromine) and reversible inhibitors of MAO type A (RIMAs: befloxatone. the excess neurotransmitters are stored and released again upon need.and postsynaptic. norepinephrine. paroxetine. while type B metabolizes dopamine. fluoxetine. and sertraline). amphetamines) that cause. specifically: • Inhibiting the transporters responsible for the uptake of monoamines (e. MAOs metabolize about 30% of serotonin. phenelzine. Receptor (both pre. and this effect probably accounts for some of its side-effects such as postural hypotension. α2-adrenergic). among other things. which include irreversible MAOIs (isocarboxaziid. phenelzine. when blocked. norepinephrine. some of the 30% of the neurotransmitters that were supposed to be metabolized are stored and are available for future release.g. MAO type A is the main metabolizing enzyme of serotonin and norepinephrine. and venlafaxine). These are dual-acting • . and the norepinephrine and dopamine reuptake inhibitor (bupropion). By blocking MAO. fluvoxamine. leading to excessive concentration of monoamines in the synaptic cleft.g.1 • antidepressants since (1) they block the α2 auto. Trazodone also inhibits the α1 postsynaptic receptor. or both). although there are some anecdotal reports of its efficacy in major depressive disorder6) or with some of the abused substances (e.g. which include the tricyclic and tetracyclic antidepressants (TCAs and TeCAs).1. duloxetine. the concentrations of serotonin. and trazodone. priapism and sedation. Therefore. euphoria. its main use is in parkinsonism. selective serotonin reuptake Inhibitors (SSRIs) are less efficacious in severe major depressive disorder). milnacipran. • Notes about the scheme Antidepressants are classified as: • Reuptake inhibitors. Most of the data about dopamine and depression come from clinical experience with various pharmacological agents that enhance dopaminergic transmission (e. Some of these are presynaptic inhibitory auto/heteroreceptors (e. the serotonin and norepinephrine reuptake inhibitors (SNRIs. while the other 70% are stored in vesicles to be released again when needed. and tranylcypromine) are irreversible inhibitors of MAO types A and B.g. and dopamine in the synaptic cleft increase following MAOI administration. moclobemide. norepinephrine.g. which include mianserin. escitalopram. and dopamine. and toloxatone). which. The antidepressants can be classified according to their mechanism of action.As a rule of thumb. reuptake inhibition of noradrenaline and/or serotonin).and postsynaptic) blockers.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. nefazodone.

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and the production of neurotrophic brain factors. while (b) postsynaptic downregulation of β1-adrenergic receptors occurs up to weeks before the clinical resolution of depression is observed. These effects on proliferation and survival of neurons (observed mainly in hippocampal regions) support the notion that alterations in hippocampal neurogenesis are fundarnental to the resolution of the clinical syndrome of depression. which takes between 4 and 8 weeks to develop. including a higher rate of relapse and suicidality. increases in synaptic norepinephrine and serotinin and downregulation of postsynaptic β1-adrenerqic receptors). intracellular second-messenger activation. and has crossed the bloodbrain barrier).Although antidepressant drugs are considered very effective (about 75% of treated patients respond favorably). decreased synaptic concentrations of both norepinephrine and serotonin (see Section 1. For example. are not merely normalization of previous morphology but rather a distinct new morphological setting. since (a) increased synaptic concentrations of serotonin and norepinephrine are observed immediately following drug administration (within a few minutes.g. followinq the normalization of intracellular CREB and BDNF. The chain of intra. changes in brain morphology (e. 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 brainderived neurotrophic factor (BDNF). However. the chronically 'treated' neurons have many more dendrites than the 'depressed' neurons and also more neurons than the premorbid 'euthymic' neurons. which begins with receptor targeting. As previously described. This chain of events corresponds chronologically to the resolution of depression.and intercellular events following chronic antidepressant administration corresponds chronologically to the resolution of depression. Among these were upregulation of presynaptic inhibitory auto/heteroreceptors such as the α2-adrenergic. This effect is acute and it is probably not associated with direct antidepressive action.g.and postsynaptic receptors that were thought to be associated with the development of major depressive disorder.2 . which correspond (at least chronologically) to the resolution of depression. which usually takes at least 4 weeks. Chronologically. Moreover. All of the above-mentioned morphological changes. These events modulate the neuroplasticity vital for the maintenance of normal mood and the resolution of the depressive mood. 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.2 Studies conducted decades ago demonstrated various alterations in pre. These components are uprequlated by antidepressant treatment at least in animal models of depression (e. growth of dendrites and their correct topographic position) as well as increased cell survival are evident.1). and upregulation of postsynaptic receptors. in mouse limbic regions). The achievement of a proper response is essential because residual symptoms are often associated with a myriad of risks.7 Notes about the scheme Chronic antidepressant administration causes a chain of events. gene expression. has entered the systemic circulation.g. especially the β1-adrenergic. it was even demonstrated that antidepressant treatment was associated with further alterations in these abnormal parameters (e. practically all antidepressants increase the monoamine concentration in the synaptic cleft. these antidepressant drugrelated changes could not fully explain the clinical resolution of depression. and reach proper intracellular concentrations following 4-6 weeks of treatment (chronologically comparable to the clinical resolution of depression). after the drug has been absorbed from the gastrointestinal tract.

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Mirtazapine also antagonizes post-synaptic 5-HT2A and 5-HT3 serotonergic receptors and it indirectly activates the postsynaptic 5-HT1A receptor. with a less potent effect on norepinephrine and dopamine. milnacipran. like the SNRIs (although via a different mechanism). It is associated with sustained hypertension in up to 1 3% of patients on higher doses. Mirtazapine is a potent antagonist of central α2-adrenergic auto. the SNRIs still enhance noradrenergic and serotonergic transmission by using the 'old' technique (i. dizziness. Recently. dry mouth.g. and dry mouth. TCAs) were aimed mainly at inhibiting the reuptake of norepinephrine. The lower affinity for norepinephrine transport requires dose elevation in order to achieve both serotonin and norepinephrine inhibition. mirtazapine. milnacipran has a higher incidence of headache. The most frequent reported adverse events are nausea. somnolence. Emerging evidence indicates that higher doses of venlafaxine (200-375 mg/day) may have a faster onset of action. especially the SSRIs. insomnia.5). while reboxetine and desipramine enhance predominantly norepinephrine). It lacks affinity for other neurotransmitter receptors. which usually dissipate with continued treatment. Venlafaxine is a potent reuptake inhibitor of serotonin.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. blockade of the plasma membrane transporter responsible for the reuptake of serotonin and/or norepinephrine). headache. tricyclics. and does not interact with other neurotransmitter receptors. There are four newgeneration dual-acting antidepressants: duloxetine. at low therapeutic doses. Even so. These dual-acting antidepressants are serotonin and norepinephrine reuptake inhibitors (SNRIs: duloxetine. newly developed dual-acting antidepressants have been introduced.18 . and its most frequent adverse side-effects include nausea. thus. although they exhibit a somewhat different mechanism of action compared with the older drugs. with weak effect on dopamine reuptake.The earliest antidepressant drugs (e. milnacipran. it is more potent at blocking the noradrenergic transporter (norepinephrine reuptake inhibition). and dysuria.g. there is no increased incidence of hypertension with duloxetine compared with placebo. while the later selective serotonin reuptake inhibitors (SSRIs) specifically block the reuptake of serotonin. It is a little more potent at blocking the reuptake of serotonin. somnolence. and sweating. it enhances the release of both norepinephrine and serotonin to the synaptic cleft. Compared with the SSRIs. and venlafaxine) and mirtazapine (see the following pages for the relevant schemes). 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.and heteroreceptors (see Section 2. and venlafaxine.14 Duloxetine is the most potent inhibitor of the reuptake of serotonin and norepinephrine (among the SNRIs). observed as early as 4 days to 1 week following treatment initiation. insomnia. Unlike duloxetine and venlafaxine. Hence. 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.e.14 . Unlike venlafaxine. it is more of a 'noradrenergic' drug. although at higher doses (within the therapeutic range) it is a relatively balanced reuptake inhibitor of both serotonin and norepinephrine. Milnacipran is a reuptake inhibitor of norepinephrine and serotonin with little effect on dopamine reuptake or other neurotransmitter receptors. sweating. SSRIs enhance mainly serotonin.

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The formulation is designed to increase compliance in patients who have difficulty in swallowing conventional capsules or tablets. and there was some evidence for an early onset of action of mirtazapine. Mirtazapine has also been found to be efficacious in the treatment of elderly patients with depression. mirtazapine 15 mg was given as an intravenous infusion over 1 hour once a day for 14 days. although it is not expected to have an effect on the protein binding of coadministered drugs. Statistically. As a consequence of its α 2-antagonistic action. and the drug reaches a steady state after 4-6 days of once-daily administration. The half-life is 37 hours in women compared with 26 hours in men. It also blocks the postsynaptic 5-HT2 and 5-HT3 receptors. with the 5-(+) enantiomer exhibiting an approximately 50-fold more potent effect than the R-(-) enantiomer at these receptors. depression improved significantly. leading to indirect enhancement of 5-HT1A-mediated neurotransmission. An orally disintegrating tablet formulation of mirtazapine has been developed (mirtazapine SolTab). and post-traumatic stress disorder. In a recent study. The predominant active metabolite. and 3A4. with the drug ingredients being microencapsulated into a quickly dissolving tablet. the drug is an antagonist at the α2-adrenergic receptor. mirtazapine may show an earlier onset of action (although data are currently not well established). Mirtazapine has a non-specific affinity for plasma proteins and is approximately 85% bound to them. mirtazapine i. Ndesmethylmirtazapine. At the end of the intravenous period. Adverse effects of mirtazapine administered intravenously did not differ from those reported in other trials of mirtazapine administered orally.v. Mirtazapine is at least as effective as the tricyclic antidepressants and trazodone in a wide range of patient subgroups. Food has minimal effects on the rate and extent of absorption of the drug. including in.and outpatient clinical settings. It is essentially completely absorbed orally and its bioavailability after oral administration is about 50%.14 -18 . there were no differences between mirtazapine SolTab and sertraline. the drug has been shown to increase both noradrenergic and serotonergic neurotransmission (the latter by_blockade of α2-adrenergic heteroreceptors located in serotonergic neurons). The efficacy of orally administered mirtazapine has been well established in controlled clinical trials in patients with moderate to severe depression in both in. A comparative study of mirtazapine SolTab versus the SSR1 sertraline was conducted in a large study of patients with a DSM-IV diagnosis of major depressive disorder.Notes about the scheme Mirtazapine is a tetracyclic antidepressant that is marketed as a racemic mixture of its optical isomers. After a washout of 3 days. social phobia. The drug is metabolized through hydroxylation and demethylation. due to first-pass effects. It was suggested that antagonism of presynaptic α 2-adrenergic receptors does not enhance serotonin neurotransmission directly. Pharmacologically. 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. but rather disinhibits the norepinephrine activation of serotonergic neurons and thereby increases serotonergic neurotransmission by a mechanism that may not require a timedependent desensitization of receptors. 1A2. Mirtazapine can be administered intravenously. mirtazapine combined with citalopram in obsessivecompulsive patients induced an earlier response when compared with citalopram plus placebo. When compared with the selective serotonin reuptake inhibitors (SSRIs). Mirtazapine is primarily metabolized by CYP450 2D6. is 5-10 times less active than the parent compound.and outpatients with moderate to severe depression. The bitter taste of the drug is disguised with an orange flavor in the case of mirtazapine SolTab. followed by glucuronidation. Mirtazapine has been shown to be effective in the treatment of panic disorder. In one study. was administered to patients with a DSM-IV diagnosis of major depression.

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it does not bind to or has low affinity for a range of ion channels. a. although the incidence of these events was not significantly higher than in patients receiving placebo. K+. and CYP2D6. insomnia. Antidepressant efficacy of escitalopram was observed in patients with major depression receiving 10-20 mg/day versus those receiving placebo . the capacity of citalopram to block the reuptake of serotonin is relatively weak compared with that of escitalopram. and panic disorder. escitalopram should be used with caution in patients with severe renal impairment. social anxiety disorder. 5desmethylcitalopram and 5didesmethyicitalopram. Discontinuation rates due to adverse events were similar in patients receiving escitalopram or placebo in several trials. presumably. which. The S enantiomer (escitaiopram) binds to a primary binding site of the serotonin plasma membrane transporter and blocks the reuptake of serotonin. histamine. and by doing so it more effectively blocks the reuptake of serotonin into the presynaptic nerve terminal. Nausea and ejaculatory problems were reported in both fully published trials in patients with major depression.noted as early as 1-2 weeks after starting therapy. diarrhea. No dosage adjustment is required in patients with mild to moderate renal impairment. With a favorable side-effect profile. Escitalopram appears to be a welltolerated and effective antidepressant. The adverse events profile for escitalopram is similar to that observed with RS-citaiopram in both major depression and anxiety disorders. a commonly prescribed selective serotonin reuptake inhibitor (SSRI). and Ca2+. The primary isoenzymes involved in the metabolism of escitalopram are cytochrome P450 (CYP) 2C19.e. including those for Na+. may be titrated up to 20 mg/day. 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 escitatopram and commencement of an irreversible MAGS and vice versa. dry mouth. Elimination of escitalopram is principally via hepatic and renal routes as metabolites. The oral clearance of R5citalopram was reduced by 37% and its halflife doubled in patients with hepatic impairment. At the same time. while recent reports hold promise for escitalopram in the treatment of obsessive-compulsive disorder. but by doing so. and upper respiratory tract infections were experienced by patients receiving escitalopram. allosteric) site on the serotonin transporter. there is some elevation in levels of coadministered desipramine and metoprolol. escitalopram also binds to a different (i. The R enantiomer binds to the primary binding site (like the S enantiomer). At 20 mg/day of escitalopram (twice the recommended daily starting dose). it interferes with the binding of the 5 enantiomer to the allosteric site. to its unique mode of action. headache. both of which are less potent than the parent drug. Escitalopram is transformed into two metabolites. The recommended dose of escitalopram for the treatment of major depression is 10 mg/day. Moreover. and is less highly protein-bound than other SSRls. Escitalopram has shown superior efficacy compared with placebo in patients with generalized anxiety disorder. it appears to be well tolerated even in patients who are intolerant of other SSRls. and due to its unique conformational state. which appear comparable to the effect of RS-citalopram.14 19 20 . Ch. In addition. Also.and p-adrenergic. and benzodiazepine receptors. Escitalopram may possess safety advantages. The oral clearance is 36 l/h (600 ml/min) and the elimination half-life is between 27 and 32 hours. the R enantiomer by itself is not sufficiently efficacious in blocking the reuptake of serotonin. however.Escitalopram is the therapeutically active S enantiomer of R5-citalopram. Hence. Escitalopram has no or very low affinity for a variety of other serotonin. depending on the individual patient response. 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. There is some evidence of greater efficacy than dtalopram and probably other SSRls due. Escitaiopram is the predominant plasma compound. CYP3A4. muscarinic. in that it appears to have potential for fewer drug-drug interactions due to little effect on the CYP system. Citalopram has an equal amount of the R and 5 enantiomers. dopamine.

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through a cascade of intracellular signal transduction. while β 2 is located predominantly in peripheral tissues such as the liver. the timing of which correlates with the delay in onset of action of SSRIs. SNRI) in patients with major depression. The current data regarding the clinical efficacy of pindoiol in speeding/augmenting the response to SSRIs is contradictory and not well established. reduced negative-feedback autoinhibition. Hence. it inhibits the autoinhibition caused by 5-HT1A receptors and thereby causes a net increase in synaptic 5-HT concentration. With repeated administration of SSRIs. and the potentially fatal consequences of pindolol overdose mean that pindolol augmentation of antidepressant therapy should be considered a third. β 3). and in the presence of ongoing serotonin reuptake inhibition at the synapse by SSRIs. The 5-HT1A autoreceptor is inhibitory in nature.Notes about the scheme Some of the β-adrenergic receptor antagonists have a potential use in psychiatric pharmacotherapy. There is good evidence that facilitation of serotonergic neurotransmission may act either directly or indirectly as a unifying mechanism of antidepressant treatment. it inhibits the release of serotonin from nerve terminals.21 . it responds to synaptic serotonin and inhibits. the current absence of selective compounds. Preclinical studies provide a plausible pharmacodynamic rationale for the addition of 5-HT1A antagonists to drug regimens for the treatment of depression. both of which are believed to respond to serotonergic enhancement therapies. pindolol might be useful as an augmentator in patients with obsessive-compulsive disorder and panic disorder. facilitates and perhaps even enhances antidepressant action. 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. resulting in inhibition of the neuron. While a number of selective 5-HT1A antagonists may become available for future clinical use. 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 conflicting results of 5-HT1A augmentation in the treatment of major depression. The β1 receptor is located mainly in the central nervous system and the heart.24 . β 2. and gastrointestinal tract. These receptors are found mainly in the mid and dorsal raphe nuclei of the midbrain and their main effect is inhibitory in nature. the depolarization of the cell. the initial rise in extracellular serotonin following SSRI administration feeds back onto 5-HT1A somatodendritic receptors in raphe nuclei. Pindolol is a lipophilic (quite easily crossing the blood-brain barrier) and selective pradrenergic 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. despite immediate uptake blockade/reduced metabolism of monoamines at a synaptic level. The action of pindolol speeds up the inhibition of the 5-HT1A receptors and thereby. pancreas. presumably.or fourthline augmentation strategy for the treatment of major depression. 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. When this occurs. and. The few controlled studies have revealed no beneficial results with such combinations. there is downreguiation of somatodendritic 5-HT1A receptors. blood vessels. Moreover. There are several distinct padrenergic receptors (β1. thus. pulmonary tree. The 5-HT1A receptors are a subgroup of C-protein-coupled serotonergic receptors that are present postsynaptically on the soma and dendrites of serotonergic neurons. and increased firing and serotonin synthesis. there is a facilitation of serotonergic neurotransmission and only then an antidepressant response. finally. when pindolol is administered. reduced firing and reduced serotonin synthesis. In effect.

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and orthostatic hypotension. and dopamine. hyperreflexia. cimoxatone. Hence. it is very well suited among the MAOIs for the treatment of depression. including among the elderly. Specifically. hallucinations. hyperpyrexia. and benzylamine. and may thereby alter the dynamics of regular monoamine transmitters. norepinephrine. 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. may substantially elevate blood pressure. restlessness. Since mociobemide does not induce orthostatic hypotension. moclobemide showed good results. a strict tyramine-reduced diet must be observed. Fewer adverse effects were reported among moclobemide-treated patients compared with selective serotonin reuptake inhibitor (SSRI)-treated patients. Two isoforms of MAO exist: MAO-A and MAO-B. Currently. 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. because the pressor effect of tyramine from food is only marginally potentiated compared with tranylcypromine. The use of sympathomimetic drugs in combination with MAOIs. In the GIT. The pressor sensitivity towards tyramine is normalized 4 weeks after cessation of tranylcypromine therapy and more than 11 weeks after cessation of phenelzine therapy. convulsions.Notes about the scheme Monoamine oxidase (MAO) is an enzyme present in the outer mitochondrial membrane of neuronal and non-neuronal cells. In the human brain. increased anxiety. Selegiline. Parkinson's disease (selegiline). moclobemide. and headaches. Moclobemide has limited potential to elicit a hypertensive crisis. The most frequently reported adverse effects of the reversible selective MAO-A inhibitor moclobemide are sleep disturbances. they inhibit the first-pass metabolism of exogenous tyramine. Selective MAO-B inhibitors and reversible MAO-A inhibitors are free from this potentially fatal interaction. the so-called 'cheese effect'. and dopamine. dyskinesia. can cause anorexia/nausea. most importantly. does not possess anticholinergic properties. The MAO enzymes are responsible for the oxidative deamination of endogenous and xenobiotic amines. anxiety disorders. and. This effect may occur more frequently in elderly than in younger patients. and toloxatone (all reversible). The non-selective and irreversible MAOIs have serious side-effects. and death. serotonin. more studies are needed before this combination can be recommended. and tissue distributions. MAO inhibition allows endogenous and exogenous substrates to accumulate. and MAO-B deaminates dopamine. tranylcypromine. dry mouth. the primary effect of MAO inhibitors (MAOIs) is to increase the availability of these neurotransmitters at the nerve terminal. The selective MAOIs are classified as MAO-A and MAO-B inhibitors. hypertensive crisis following the ingestion of foods containing tyramine. MAOIs are classified as selective and nonselective and as reversible and irreversible. β-phenylethylamine. nialamide. Presently. Monoamine oxidases (both MAO-A and MAO-B) also exist in peripheral tissue. Acute overdose with MAOIs causes agitation. The most dangerous MAOIs in overdose are the irreversible non-selective MAOIs. about 75% of MAO is of the B subtype. The main non-selective MAOIs include isocarboxazid. and phenelzine (all irreversible). orthostatic hypotension. MAO-A deaminates serotonin. inhibitor specificities. The pressor effect of tyramine is normalized within 3 days of cessation of treatment with moclobemide. particularly the irreversible non-selective MAOIs.13. When these compounds are used. such as norepinephrine. because the cardiovascular systems of the elderly are already compromised by age. Regarding toierability. 25 . MAOIs are used for the treatment of depressive disorders. and have different substrate preferences. and Alzheimer's disease (selegiline). The MAO-B selective inhibitors include pargyline and selegiline (deprenyl) (all irreversible). especially when used in combination with levadopa. and is not cardiotoxic. including hepatoxicity.27 . The MAO-A selective inhibitors include befioxatone. specifically the gastrointestinal tract (GIT).

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and may be part of the mechanism underlying antidepressant activity. Furthermore. Among the currently available antiglutamatergic agents (most are non-selective) are amantadine. The current approach to potentiating the CREB cascade is based on inhibition of phosphodiesterase-4 (PDE4). have direct and indirect inhibitory effects on the glutamatergic system. some current research for new treatment of major depressive disorder (MDD) is focused on developing antiglutamatergic agents43 and studying their potential antidepressant capacity. and brain-derived neurotrophic factor (BDNF)).A significant percentage of patients (40-50%) do not fully respond to standard treatment with antidepressant drugs. PDE4 metabolizes CREB under normal physiologic conditions.4 The monoamine-based therapies (i. atypical antipsychotic drugs. 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 monoaminebased strategies of the current antidepressants remain the mainstream of treatment. Hence. Examples of various non-selective enhancers of dopamine that also stimulate Bcl-2 are pergolide. the nucleus accumbens). A different strategy to address the intracellular components relevant for the treatment of MDD is to enhance the activities of CREB. and selegiline. mood stabilizers. while pramipexole may directly enhance Bcl-2.g. However. and increases in dendrite density and volume in limbic areas. including current 'conventional' antidepressants. The antidepressant effect exhibited by enhanced dopaminergic transmission is thought to be at least partially related to increased dopaminergic transmission in limbic structures (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).12 . its inhibition by agents such as rolipram increases intracellular concentrations of CREB and stimulates antidepressant effects. and up to one-third do not respond at all. all increase the synaptic concentration of norepinephrine and/or serotonin).1-2. which is associated with cAMPmediated gene transcription. eventually.e.3 . a probable component of any modality with antidepressant capacity. Another strategy is to directly enhance dopamine function as well as the activities of B-cell lymphoma protein 2 (Bcl-2). in the resolution of depression. cAMP-response element-binding protein (CREB). 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. Hence. new treatment strategies for the management of major depression are being evaluated in order to shorten the lag response and to improve remission rates. and riluzole. increased dopamine secretion in the striatum. '9 . and electroconvulsive therapy. The latter effects on dendritic morphology (and presumably functioning) are associated with improved neuroplasticity. The mechanism of action of practically all antidepressant agents currently in use is based on extracellular manipulation of the monoamine system (e. which is another important component that may play a role. accumulating data suggest that the antidepressant effects of drugs are associated with altering intracellular components (cyclic adenosine monophosphate (cAMP). memantine.g. Hence.8 Therefore. felbamate. The mechanism behind the NMDA antagonisminduced antidepressant effect is not fully understood. accumulating data suggest that modulation of intracellular calcium influx (via antagonism of the NMDA receptor) leads to enhanced serotonergic neurotransmission in limbic regions. ropinirole.

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However.28 . quetiapine. dysphoric. Refractory mania Clozapine has been shown to be efficacious in both euphoric and dysphoric mania.and intercellular alterations (the full mechanism is unknown as yet). especially since the demonstrated efficacy of the secondgeneration antipsychotics (e.28 Much progress have been made in the treatment of acute manic states. lithium may not be as effective as valproate.30"42 Dysphoric mania and mixed states So far there is limited evidence for the superiority of one drug over the other. especially in higher doses. and risperidone) for the treatment of acute mania.55 Anticonvulsants such as valproate and carbamazepine seem to be as efficacious as lithium. however. phenytoin.28 Notes about the scheme Treatment of acute manic states can be broadly classified according to the different types of mania.g. and risperidone in these patients.28 have failed on lithium prophylaxis. 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. zonisamide. Valproate shows equal overall efficacy in mania. high-dose thyroid hormone augmentation should be considered in such cases.30'34~37 The use of firstgeneration antipsychotics. fewer studies support its efficacy in euphoric mania compared with lithium. This can arise either from loss of inhibitory tonic orbitofrontal control of limbic neurons or from various intra. while other possibilities include the combination of either valproate or lithium with an antipsychotic agent. 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. topiramate.Acute mania as part of bipolar I disorder is supposed to result from overexcitation of limbic neurons. olanzapine. while a combination of valproate and lithium or clozapine (as sole agent) may be beneficial in refractory cases. which include calcium channel blockers. and mania with a rapid cycling course of the disease. Carbamazepine has also been reported to be effective in rapid cycling.28 Both the high-potency typical antipsychotics and the second-generation antipsychotics olanzapine and risperidone have demonstrated efficacy in the treatment of euphoric mania. clonazepam. clonidine. mixed (along with clinical manifestations of major depressive disorder). Manic episodes are often classified into euphoric (classical). evidence for superiority of one treatment over another is as yet limited.28 Electroconvulsive therapy (ECT) is a treatment modality frequently chosen and anecdotally found effective when other approaches have failed. resulting in firm evidence that lithium is especially effective in this type of mania. Euphoric (classical) mania Until recently. However. and new treatment strategies are in continuous development. and omega-3 fatty acids. Since a rapid cycling course appears more common in patients with hypothyroidism. olanzapine. oxcarbazepine. mania with psychotic/catatonic features.30 and who 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. treatment of acute manic states remains incomplete.38 Psychotic mania As for mixed states. most studies on antimanic agents were exclusively conducted in patients with bipolar I disorder and euphoric mania. may exacerbate dysphoric or depressive experiences and should probably be avoided.28 Small open studies and case reports exist on numerous alternatives. carbamazepine.

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and proper functioning of intracellular microtubule structures. In most cases. 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. Lithium can also alter the adenylate cyclase (AC) system. and hypothyroidism. it produces a subsensitivity of inhibitory 5-HTiA receptors.39 Long-term treatment of rats with lithium produces a doubling of Bcl-2 levels in the frontal cortex. It has some antidepressant capacity. Lithium also exerts antiaggressive effects in conduct disorder.39 Lithium also inhibits glycogen synthase kinase (GSK)-3(3. and it is suggested that these effects may underline its efficacy in potentiating diverse classes of antidepressants. 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. causing alterations in calcium. 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. Many calciumdependent systems may be affected by lithium. although this is not well established. and attention deficit hyperactivity disorder (ADHD). These effects initiate a cascade of secondary changes at different levels of the signal transduction process and gene expression in the central nervous system . The most commonly observed adverse side-effects of lithium are gastrointestinal (weight gain.39 Considerable data have shown that lithium can also affect neurotrophic signaling cascades (e.39^13 and enhance neurogenesis in the hippocampus. in unresponsive major depressive disorder. and can reduce behavioral dyscontrol and self-mutilation in mentally retarded patients. it exerts beneficial effects in many disorders as an adjuvant to other treatment modalities. among them regulation of receptor sensitivity. GSK-3p is also involved in regulating the phosphorylation of tau and P-catenin.39 . independent of any mood disorder.39"41 Lithium is the first-line drug for the treatment of bipolar disorder. It has been found to alter intracellular building stages essential for the proper production of inositol and consequently phosphatidylinositol bisphosphate (PIP2). Lithium may also reduce levels of the proapoptotic protein p53.44 Long-term treatment with lithium increases basal and stimulation-induced serotonin release. fine tremor. lithium may increase gray-matter volume in bipolar patients. increase the levels of Nacetylaspartate (a putative marker of neuronal viability) in bipolar patients and healthy volunteers. which can result in a net increase in serotonin release from presynaptic nerve terminals. the response to lithium augmentation is either considerable or not at all ('all-or-none' phenomenon). It acts predominantly through the phosphatidylinositol (PI) second messenger system. nausea. and for maintenance treatment of bipolar I disorder (mood stabilizer). enhancing the activity of B-cell lymphoma protein 2 (Bcl-2)). For example. both of which have been implicated in certain types of disease-related neuronal death. which regulates various cytoskeletal processes. but this action is probably related to its toxic effects. polyuria and polydipsia.g.effects that are ultimately responsible for the therapeutic efficacy of lithium. Such effects are apparent only if it is administered to an already pharmacologically treated patient. and diarrhea). the co-administration of lithium to an ongoing antidepressant treatment increases the response rate by up to 50%. bulimia nervosa. In addition. Some (currently not convincing) results have also been reported in unipolar depression.39 In addition. which further supports the role of lithium as a neuroprotective agent. parathyroid hormone release.and protein kinase C (PKC)-mediated processes. since it is efficacious in acute euphoric mania without psychotic features (beneficial in up to 80% of cases). moreover.Lithium is one of the group IA alkali metals (like potassium and sodium) and is not normally present in the body.41 Notes about the scheme The specific mode of action of lithium is not fully established.

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and. It appears that enhanced serotonin release may play a role in the efficacy of carbamazepine in the treatment of bipolar disorder. • acute manic episode as part of schizoaffective disorder. • comorbid substance abuse disorder. and the patient's clinical status) versus the disadvantages (teratogenicity and other sideeffects) of giving the drug. Carbamazepine may have weak GABAergic effects. and at therapeutic concentrations it markedly reduces the depolarization produced by NMDA.Carbamazepine is an anticonvulsant beneficial in the treatment of bipolar I disorder. has been associated with an increased risk of neural tube defects.44 .45 Clinically. • dysphoric mania. if good prognostic signs exist.46 . lithium and valproate). under certain instances. by inhibiting the inhibitory presynaptic a2.1 7 on lithium). Carbamazepine appears to have teratogenic effects and. like valproate. Carbamazepine and carbamazepineepoxide reduce the frequency of sustained repetitive firing action potentials in cultured mammalian central neurons. as in the case of valproate.g. carbamazepine does not have direct or indirect effect on the action of glycogen synthase kinase (GSK)-β3 (which regulates the phosphorylation of tau and βcatenin. • good previous response to carbamazepine. has been associated with an increased risk of neural tube defects. carbamazepine can. The main ones are: • secondary mania (due to pharmacotherapy. Carbamazepine acts as an antagonist at adenosine Ai receptors and as an agonist at adenosine A2 receptors. as well as the potential advantages (previous response to carbamazepine or to other drugs.g. be related to the potent interaction of carbamazepine with adenosine-binding sites in the brain. Carbamazepine also induces the release of serotonin by a mechanism that does not involve the serotonin transporter (e. It appears to have a teratogenic effect and. It has also been proposed that the therapeutic and prophylactic effects of carbamazepine in bipolar I disorder (but not its anticonvuisant effect) may. evidence is accumulating that carbamazepine also has calcium-antagonist properties (perhaps by inhibiting N-methyl-D-aspartate (NMDA) receptors and enhanced y-aminobutyric acid type A receptor (GABAA) effects. Hence. These activities are presumed to play a role in its mood stabilizing effects (especially its antimanic capacity). and should. Unlike lithium and valproate. Moreover. Even so. • absence of psychotic features. be given to pregnant women. Notes about the scheme The main targets of carbamazepine are voltage-dependent sodium channels. The clinician's decision whether to administer carbamazepine to a pregnant woman should take carefully into account the woman's own preference. like valproate. however. Chronic treatment with carbamazepine induces upregulation of adenosine A1 receptors in astrocytes and rats. both as an antidepressant effect (in major depressive disorder as part of bipolar I disorder) and as a suppressing neurotransmitter (in manic states). mixed episode. or trauma). and thus it does not protect the cell from the apoptotic reactions associated with abnormal function of cellular tau and β-catenin. Carbamazepine blocks NMDA-activated membrane currents in cultured neurons in a dose-dependent fashion. there are various possible good predictor signs (for beneficial effects of carbamazepine). carbamazepine inhibits the DNAbinding activity of the cyclic adenosine monophosphate (cAMP)-response elementbinding protein (CREB) transcription factor. unlike some other mood stabilizers (e. see Section 2. which appear to be confined to certain types of neurons.and p2-adrenergic autoand heteroreceptors). rapid cycling disorder. the overall decision is not a simple 'yes' or 'no'. it may be more advantageous than lithium in non-classical bipolar conditions such as mixed mood states and rapid cycling conditions. brain disorder. and. at least in part.

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These are assumed to be related to its antimanic and mood-stabilizing effects. It is proposed that it exerts its antimanic effects by suppressing the overexcitability of limbic neurons via enhancing γ-aminobutyric acid (GABA) neurotransmission. in comparison with those treated with selective serotonin reuptake inhibitors (SSRIs).Valproate is currently the most widely prescribed antiepileptic/mood-stabilizing drug and is being used increasingly in the treatment of bipolar I disorder. Unlike benzodiazepines and barbiturates. and decreased GABA turnover. being observed mainly in the substantia nigra. a region with one of the brain's highest rates of GABA synthesis. increased GABA synthesis. Such effects may be consistent with recent morphometric studies reporting localized atrophy and neuronal and glial cell loss in bipolar disorders. sedation. while some reports suggest that valproate can slow sodium conductance. Notes about the scheme There has been increasing interest in the potential of anticonvulsants and mood stabilizers to provide neuroprotective effects. and mild leukocytosis. The neural GABA membrane transporter.51 Even so. the main established mechanism of action of valproate is GABAergic. tremor.48 The mechanism of action of valproate as a mood stabilizer is not fully understood.47 It is effective as a mood stabilizer and appears to be more efficacious than lithium in rapid cycling mania and dysphoric mania. is more sensitive to valproate inhibition and probably plays a role in elevating synaptic GABA concentration. A direct effect on sodium channels has not been consistently shown. weight gain.47-52 . While the GABA-elevating effects of valproate were initially proposed to result from inhibition of GABA-T. Its antidepressive effects are less well understood. especially by blocking the reuptake of GABA into the presynaptic nerve terminal and by inhibiting GABA ketoglutarate transaminase (aminotransferase) (GABA-T). Valproate does not appear to have significant direct effects on calcium channels. more recent evidence suggests that valproate also inhibits the reuptake of GABA.50 These clinical data support the hypothesis that some of the therapeutic actions of valproate may involve neurotrophic/ neuroprotective effects. decreased liver function tests. it is found to be more efficacious in specific entities/settings. see Sections 2. who show prefrontal atrophy. 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. although this is yet not completely clarified. It is possible that its stimulation of various neuroprotective factors such as B-cell lymphoma protein 2 (Bc!-2.49 Crosssectional neuroimaging studies suggest that patients undergoing long-term valproate treatment do not show subgenual prefrontal cortex atrophy. this is still a matter of debate. It has been demonstrated that valproate increases brain concentration of GABA by three major mechanisms: inhibition of GABA degradation. the enzyme responsible for metabolizing the re-uptaken GABA. Increased GABA synthesis appears to be regionally selective. and in limbic regions. Valproate enhances GABA activity by various mechanisms. 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. valproate does not have any affinity for the GABAA receptor complex. Valproate can be used in various psychiatric diagnoses. especially in the USA.1 and 2. However.52 The main adverse side-effects of valproate are headaches. decreased platelet count. compared with the glial GABA transporter.15) is relevant.

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leading to neuronal hyperpolarization (similar to the effects of benzodiazepines).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. topiramate seems to have some efficacy as add-on therapy to an ongoing mood stabilizer for patients with treatment-refractory mood disorders.62 The most common side-effects of topiramate are paresthesia (27%). can be managed by gradual introduction and dose escalation. anorexia (11%).61 Topiramate has also anecdotally demonstrated efficacy in eating disorders. although this effect may not be a major feature of its antiepileptic/mood-stabilizing activity. topiramate is known to enhance γaminobutyric acid (GABA) activity through interaction with the postsynaptic GABAA receptor. Topiramate has been shown to exert beneficial effects in patients with acute mania. and very little is currently known about the mechanisms underlying its antidepressive effects. The GABAA receptor is located adjunct to a chloride channel and.65 Many of the central nervous system effects of topiramate. difficulty with concentration (7%). dizziness (14%). in patients with bipolar I disorder. Results of preliminary studies show a trend toward improvement. and the incidence of nephrolithiasis is estimated to be 2-4 times higher than that expected in a similar untreated population. as yet anecdotal. Third. topiramate has been associated with kidney-stone formation. and it also inhibits certain isoenzymes of carbonic anhydrase.66 Notes about the scheme The mechanism of action of topiramate has not been fully elucidated. topiramate is currently considered the least potent/efficacious in ameliorating both manic and/or depressive symptoms (see Section 2. fatigue (20%). and in some instances significant improvement. First.g. carbamazepme. there is some evidence. topiramate indirectly increases intracellular chloride ion concentration.63'64 As with other anhydrase inhibitors. Hence. as well as in patients with bipolar depression. based on current data. are depression (7%). a known mechanism by which neuronal excitability can be decreased. compared with the well-established group of 'mood stabilizers' (lithium.59 with a dosedependent response. and confusion (5%).60 . by decreasing neuronal excitability). causing increased ion influx. Second. . and weight loss (11%). and valproate).62 Furthermore.54 All in all.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. including cognitive complaints. but with important clinical implications. Topiramate also antagonizes the effects of glutamate at non-/V-methyl-D-aspartate (nonNMDA) receptors. upon activation it opens up the channel. somnolence (13%). headache (21%).53 . topiramate appears to antagonize the ability of kainite to activate the kainite/α-amino-3-hydroxy-5methylisoxazole-4-propanoic acid (AMPA) subtype of glutamatergic receptor.22). However. although three potential mechanisms are thought to be involved in its 'mood-stabiiizing'-like activity. Less common side-effects. such as improving multiple behavioral dimensions of bulimia nervosa. Consequently. most of the knowledge about the mode of action of topiramate concerns its potential antimanic activities (e. its role as a mood stabilizer is still under investigation and its mood-stabilizing capacity is not yet fully accepted. that topiramate limits repetitive ceil firing by blocking voltagedependent sodium channels.

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67 Many anticonvulsants enhance γ-aminobutyric acid (GABA)ergic inhibitory neurotransmission (barbiturates. valproate. In that respect.67 which some investigators hypothesize as being relevant to the mood-stabilizing effects of various drugs. lamotrigine might be specifically beneficial in a subpopulation of bipolar I depressed patients with predominant symptoms such as apathy. including absence seizures. activation. and valproate) are considered better antimanic agents than antidepressants. and valproate) appear to 'stabilize mood from above' in that they maximally impact manic or hypomanic symptoms in bipolar disorder. 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). significant weight gain. tremor. carbamazepine. tiagabine. nausea. They might also explain the predominant efficacy of lamotrigine in treating major depressive episodes as part of bipolar I ('stabilizes mood from below'). and hypersomnia. Thus.70 Lamotrigine has not shown antimanic activity and has not been associated with the induction of mania or of rapid cycling bipolar disorder. carbamazepine. and valproate). lamotrigine may 'stabilize mood from below'. psychomotor retardation. the older mood stabilizers (lithium.69 and treatment-resistant (primary rapid cycling) mood disorders. insomnia. it is hypothesized that the mood-stabilizing effect of lamotrigine is consistent with its glutamatergic action. weight loss.73 In addition. lithium. Taken together. and.67 Double-blind. The effects of lamotrigine on calcium channels compared with sodium channels are less prominent. with the most common adverse events being headache. all of which may cause. Hence. to a lesser extent. but are of potential interest in view of the beneficial use of calcium channel blockers (anecdotal data) in bipolar disorder. and possibly antidepressant and anxiogenic effects. and is indicated in both partial and generalized seizures. at least in some predisposed populations. Lamotrigine does not appear to cause body weight gain. benzodiazepines. Incidences of diarrhea and tremor are lower with lamotrigine than with lithium.e. tending to yield alertness. Lamotrigine is reported to be generally well tolerated in maintenance studies. In that respect.e.68 rapid cycling bipolar disorder. respectively.1% (including rare cases of Stevens-Johnson syndrome). In contrast. The incidence of serious rash with lamotrigine treatment is 0. it is also unique compared with the other mood stabilizers (i. at least hypothetically. In contrast. lamotrigine is unique among the mood stabilizers. gabapentin.74 .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. since the most widely used of these (i. and vigabatrin) and thereby induce calming or 'sedating' psychotropic profiles. These effects can result in a new increase in serotonin secretion and/or an increased concentration of serotonin in the synaptic cleft. lithium. placebo-controlled studies found lamotrigine to be most effective in bipolar depression (and much less so in manic episodes). lamotrigine attenuates calcium influx. carbamazepine. It has a broad spectrum of antiseizure activity. as opposed to manic states.Lamotrigine is the second drug after lithium to be approved in the USA for the maintenance treatment of bipolar I disorder (in 2001). lamotrigine may enhance glutamatergic excitatory neurotransmission and thus possess an 'activating' profile.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.

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Chapter 3 Anxiolytic drugs .

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following pathological processing of sensory data and inadequate response of target organs to such stimuli. The projection from the raphe neurons to the periaqueductal gray region appears to modify/inhibit escape/defense behavior.2 CO2. from the primary viscerosensory cortices and via corticothalamic relays allowing for higher-level neurocognitive processing and modulation of sensory information.1 • • • • These projections from the amygdala can be conceptualized as the 'fear network'.17 At the level of the amygdala. at least in part. Specifically. The serotonergic neurons originating in the dorsal and medial raphe nuclei project directly to the amygdala via the medial forebrain bundle. support this hypothesis by demonstrating that the entire 'fear network' is activated following administration of agents that cause panic attacks (e.4 fenfiuramine. and thereby contributing to physiological and behavioral arousal. Major efferent pathways of the amygdala relevant to anxiety include: • to the locus ceruieus (LC). Anxious behavior/disorders arise.specifically in panic disorder.16 a phenomenon found in long-term treatment with SSRIs. Accumulating data.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. 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 ceruieus is generally. and the parabrachial nucleus (influencing respiratory rate and timing). inhibiting excitatory inputs from the glutamatergic thalamic and cortical pathways. Serotonergic neurons originate in the brainstem raphe nucleus and project widely throughout the entire CNS. Most anxiolytic drugs have in common the capacity to enhance serotonergic transmission in the central nervous system (CNS).6 norepinephrine. allowing it to bind both pre. Because the amygdala is known to receive dense serotonergic input from the raphe. based mainly on pharmacological interventions both in human and in animal models.8 hypertonic sodium chloride.14 which is known to increase the firing rate of the locus ceruieus as well as the sensation of fear. by increasing serotonergic activity in the brain. including the 'prototype' .and postsynaptic receptors while increasing overall serotonergic transmission in the CNS.12 This suggests that SSRIs.g. to the periaqueductal gray regions (resulting in defensive behavior and postural freezing). from the thalamus.15 . it may be a prime site for the anxiolytic effect of the SSRIs.5 m-chlorophenylpiperazine (m-CPP). This blockade of serotonin reuptake effectively increases the amount of serotonin available in the synapse. SSRIs have in common the property of inhibiting the protein responsible for transporting serotonin back into the presynaptic neuron. increasing norepinephrine release.9 and cholecystokinin analogs10). viscerosensory information is conveyed to the amygdala by two major pathways: downstream.1 (SSRIs) can be discussed in this context. whereby an increase in serotonin inhibits excitatory cortical and thalamic inputs from activating the amygdala. to the hypothalamic paraventricular nucleus (activating the hypothalamic pituitaryadrenal axis. have a secondary effect of decreasing noradrenergic activity. inhibitory. the therapeutic effects of the • selective serotonin reuptake inhibitors . since SSRIs are the first-line treatment for many anxiety disorders.13 Projections to the hypothalamus suppress hypothalamic release of corticotrophinreleasing factor (CRF). sodium lactate.7 epinephrine. Hence. and upstream. the hypothalamic lateral nucleus (activating the sympathetic nervous system). and thus inhibiting the cardiovascular manifestations of panic attacks. releasing adrenocorticoids).panic disorder.3 yohimbine. which is abnormal in anxiety disorders . Contextual information is stored in the hippocampus and conveyed directly to the amygdala. serotonin modulates sensory input at the lateral nucleus of the amygdala.

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One of these findings is the increased firing rate from noradrenergic neurons arising from the locus ceruleus. which is followed (in the case of long-term MAOI/TCA administration) by downregulation of postsynaptic 5-HT1A. as might be expected. leading to a net decrease in noradrenergic neurotransmission. evidence from animal studies shows that MAOIs/TCAs. Selective serotonin reuptake inhibitors (SSRIs) These have two main mechanisms in common with the MAOIs/TCAs: • They increase the synaptic concentration of serotonin. Benzodiazepines These exert their anxiolytic effects by enhancing the activities of the γ-aminobutyric acid (GABA) type A receptor. decrease the firing rate of noradrenerqic neurons. decrease the release of GABA from presynaptic nerve terminals into the synaptic cleft. They downregulate presynaptic 5-HT1D receptors located on GABAergic neurons. evidence from animal studies shows that benzodiazepines.17 . following long-term use. downregulation of postsynaptic 5-HT1A/2 receptors. Furthermore. the end result of most clinically efficacious anxiolytic agents is believed to be associated with decreasing noradrenergic neurotransmission.a phenomenon that may explain their anxiolytic capacity. • • Both MAOIs and TCAs downregulate presynaptic 5-HT1D heteroreceptors located on GABAergic neurons. Stimulation of the GABAA receptor results in increased chloride influx into neurons (including noradrenergic). a phenomenon that explains their anxiolytic capacity.14). and cause. 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. The schematic mechanisms of action of the main classes of anxiolytic drugs are described below. and they are discussed in this section. It is assumed that the downregulated receptors cause less inhibition of cell excitability. which results in increased secretion of GABA into the synaptic cleft and consequent suppression of postsynaptic noradrenergic neurons. resulting in increased secretion of GABA into the synaptic cleft.4). it is not yet clear if this effect is clinically significant. once stimulated. which will eventually lead to decreased secretion into the synaptic cleft. and consequent suppression of noradrenergic neurons. The β-adrenergic blockers simply block excess norepinephrine from interacting with postsynaptic adrenergic receptors. increased GABAergic neuron excitability. The increased GABA stimulates postsynaptic GABAA receptors located on noradrenegic neurons arising from the locus seruleus. Even so. However.Notes about the scheme The pathophysiology of anxiety differs between the various anxiety disorders. there are some common pathological mechanisms/findings that are evident in many anxiety disorders.2 and 2. Therefore. It is assumed that increased norepinephrine in major brain regions plays a major role in modulating anxiety. 2 serotonergic receptors located on GABAergic cells. 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. because they do not decrease the firing rate of noradrenergic neurons or the concentration of norepinephrine in the synaptic cleft. like benzodiazepines. • β-adrenergic blockers The mechanism of action of these drugs is somewhat different from that of the other anxiolytics. Furthermore. Therefore. which leads to hyperpolarization and decreased excitability (see Section 3. with consequent suppression of their neurons. The 5-HT1D receptors are inhibitory in nature and. The downregulation of these receptors following long-term administration of MAOIs/TCAs decreases their inhibitory capacity. decrease the firing rate of noradrenergic neurons . one of the main enzymes modulating the synthesis of norepinephrine from tyrosine. pharmacological interventions that suppress one sort of anxiety do not necessarily exert the same anxiolytic effects in other anxiety disorders. Inhibition of tyrosine hydroxylase may result in a decreased concentration of norepinephrine in presynaptic storage vesicles.

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and intestines. 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.g. while the α2 subunit mediates their anxiolytic effect.33 Moreover. stress-related substances such as corticotrophin-releasing factor (CRF). Pagoclone is a partial BDZGABA receptor agonist that is under development for the treatment of panic and other anxiety disorders. Therefore. such as corticotrophin-releasing factor and substance P. Hence. Preclinical and clinical trials with tiagabine suggest that this agent may be useful as an anxiolytic. is capable of neurogenesis has led to more specific targets for anxiety interventions. Manipulation of GABA levels may be another effective antianxiety treatment. New neurons are generated from dividing progenitor cells in the dentate gyrus. Neurogenesis in the human hippocampus appears to be possible throughout life. so antagonists of these neurotransmitters may prove to be beneficial anxiolytics. glucocorticoids. 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. agents (e. Since BDZ-GABA receptors are ubiquitous throughout the central nervous system. including the human brain.19 . Several substance P antagonists (e. the amygdala appears to oversecrete stress-related factors such as CRF in anxiety disorders. and with a more favorable side-effect profile. 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. it may work by modulation of a subtype of calcium ion channel. Substance P is localized in the brain.31 . sensory afferents.g. and binds preferentially to the type 1 neurokinin receptor (NKi). Pregabalin has been shown to be effective for anxiety disorders in several controlled trials. L-760735. Accumulating data suggest that such treatments might be at least as effective as benzodiazepines (BDZs). benzodiazepines are effective anxiolytics due to their rapid suppression of excitatory neurotransmission everywhere in the brain.18 Notes about the scheme Benzodiazepines potentiate the effect of the inhibitory neurotransmitter GABA. which have been the traditional treatment of anxiety for the past 40 years. [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. Benzodiazepines and GABA also enhance the binding of one another to the BDZ-GABA receptor complex.Recent advances in neuroscience and understanding of the etiology of anxiety have led to new concepts for the treatment of anxiety.32 . a number of CRF antagonists (e. lungs. Anecdotal evidence suggests that blocking glutamate/CRF and/or stimulation of neurotrophic factors may restore normal neurogenesis and reverse stress. however. and glutamate are associated with anxious feeling and behavior. it can be impeded by stress. Subsequently.g.30 Although its mechanism of action in treating anxiety is not yet clear. The γ-aminobutyric acid (GABA) system has long been targeted in anxiety interventions via benzodiazepines. The anticonvuisant tiagabine is a selective GABA reuptake inhibitor. but not the side-effects. Other neurotransmitters. The GABAA receptor is composed of several different subunits.g. appear also to be abnormally regulated in patients with anxiety disorders. of benzodiazepines has led researchers to develop agents that partially stimulate BDZGABA receptors. The need for antianxiety treatments with the effectiveness. which is widely distributed in the brain and limbic system. pagoclone) that activate specific subunits (e. Substance P belongs to a group of neurotransmitters named neurokinins that are released in excess during times of emotional stress. The α1 subunit mediates the sedative but not the anxiolytic properties of benzodiazepines. the α 2 subunit) may be effective for the treatment of anxiety disorders.

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post-traumatic stress disorder. alcoholism. α2. Receptors with α2. α3.33 GABAB receptors comprise two seventransmembrane-spanning proteins that are coupled to either calcium or potassium channels via G-proteins26. Hence. . panic disorder. but does show some brain region specificity. Among the five subunits of the GABAA receptor. they exert their action via different pathways than the benzodiazepines.Notes about the scheme Alterations in benzodiazepine binding as well as in the γ-aminobutyric acid (CABA) system have been linked to the pathophysiology of most of the anxiety disorders. or α5 subunits appear mainly in the hippocampus. the various neurosteroids and barbiturates directly stimulate chloride channel opening and consequent chloride influx without the mediation of the GABAA receptor. The GABAA receptor is a known target of benzodiazepines and neurosteroids. leading to neuronal hyperpolarization. Receptors containing α1.24 while the involvement of the GABAB receptors in psychiatric disorders (especially in anxiety disorders) has yet to be determined. in the case of an overdose or extreme adverse side-effects of neurosteroids. while. which in turn opens up the chloride channel. The excess intracellular chloride concentration causes the membrane to hyperpolarize and results in neuronal inhibition. The barbiturates as well as various neurosteroids also suppress brain excitability by enhancing chloride influx in most brain regions. and generalized anxiety disorder) have reduced benzodiazepine binding in various brain regions. On the other hand.25 Receptors with the α2 or α3 subunits are thought to mediate the anxiolytic effects of the benzodiazepines.22 Specifically. α3. either calcium currents are suppressed or membrane potassium conductance is increased. the neurotransmitter GABA. and downregulated GABAergic systems20 in comparison with normal subjects.18 . the administration of receptor antagonists such as flumazenil is effective in alleviating many benzodiazepine-induced symptoms. and other psychiatric and neurological disorders.27 Receptor subunit distribution is heterogeneous within regions of the brain. resulting in an augmentation of chloride influx into the cell.24 Upon activation of the receptors. activation of GABAA receptors causes the opposite effect to GABAB stimulation. allowing enhanced chloride influx. is known to act on two main GABA receptor subtypes: GABAA and GABAB. The latter activate the GABAA receptor. which is inhibitory in nature. the α1 subunit preferentially binds zolpidem and other similar agonists with high affinity and has been linked to the sedative/hypnotic effects associated with benzodiazepine treatment. In the case of benzodiazepines. When activated. or α5 are all found also in the cortex. Pathologies associated with the GABAA receptor play a major role in anxiety disorders. the configuration of the chloride channel changes (it opens up) and it becomes more permeable to chloride ions. such differences might be clinically relevant in the case of patients consuming overdoses of such substances. epilepsy.18 .24 and their therapeutic effects are related mainly to their capacity to target the α2 and α3 subunits with consequent enhancement of the GABA-mediated inhibition of neuronal overexcitability that is thought to be present in many of the anxiety disorders. flumazenil is not effective in restoring the brain suppression and/or other side-effects. However.32 It is widely accepted that patients with anxiety disorders (e.g. 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. Hence. Receptors containing the on subunit constitute the majority of GABAA receptors and are expressed predominantly in the cerebellum and thalamus.23 The GABAA receptor is a pentameric transmembrane glycoprotein composed of five subunits that are arranged around a central chloride channel.

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The limited number of studies directed at disclosing the effects of firstgeneration antihistamines on sleep in patients with insomnia tend to discount these compounds for the treatment of chronic insomnia. there is substantial evidence that it plays a role in control of the sleep/wake cycle. mepyramine. promethazine (a phenothiazine). diphenhydramine. the development of acute tolerance to the sedative effects of firstgeneration H1 antagonists calls into question their effectiveness as sleep aids.34 Although these compounds were originally developed for the treatment of symptoms related to allergies and colds.Neuroanatomical. or indirectly. secondary to the use of this drug. and increased likelihoods of falling asleep and reduced concentration. For this reason. one always should bear in mind the possible (though rare) emergence of extrapyramidal side-effects. loss of alertness. They are well absorbed following oral administration. neurochemical. to date. The plasma half-life values range from a few hours for diphenhydramine and triprolidine to approximately 24 hours for hydroxyzine and chlorpheniramine. especially in long-term sleep disturbances. via other ascending pathways to the thaiamus and preoptic area. Three histamine receptors are known: histaminerelated functions in the central nervous system (CNS) are regulated at postsynaptic sites by the H1 and H2 receptors. Diphenhydramine. is still a matter of debate. Currently. hydroxyzine may be useful in the treatment of generalized anxiety disorder37. including their adverse effects. Peak plasma concentrations are achieved in 2-3 hours. hydroxyzine seems to be an exception to these agents.35 The H2 and H3 receptors are also distributed extensively and in a heterogeneous fashion in the CNS. due to the development of acute tolerance to their sedative effects. Acute administration of first-generation Hi receptor antagonists such as chlorpheniramine. the available evidence does not support the use of these agents for the treatment of transient (lasting several days). or long-term (lasting more than 3 weeks) insomnia. Moreover. It is present in all areas and layers of the cerebral cortex. However. via hypothalamocortical projections. while the H3 receptor exhibits the features of a presynaptic autoreceptor. caudate putamen.38 . thalamus. hypothalamus. hydroxyzine. and neuropharmacological studies support a role for histamine and especially the histamine Hi receptor in the control of the sleep/wake cycle.34 Notes about the scheme Histamine immunoreactive neurons have been identified in the tuberal region of the posterior hypothalamus (tuberomammilary nucleus). The H1 receptor is widely distributed in the CNS. and triprolidine produces somnolence. an increased likelihood of falling asleep. Diphenhydramine is the primary active ingredient in various proprietary preparations for insomnia that are sold over the counter in many countries. diphenhydramine. Their sedative effects led to the use of these drugs as over-thecounter medication to promote sleep and sedation/calmness. chlorpheniramine. mepyramine. and reduced concentration led to their use as sleep aids. Regarding the role of histamine in the CNS. hydroxyzine. and promethazine have the most marked sedative activity among these agents. including tardive dyskinesia. projecting to nearly all parts of the brain. and lower brainstem and spinal cord. the tendency to produce somnolence.36 The first-generation antihistaminergic drugs include brompheniramine. Whether the histaminergic system promotes the waking state directly. and readily cross the bloodbrain barrier. psychiatrists should be familiar with their pharmacological profile. and. tolerance has not been reported to develop following its long-term use. mediating the synthesis and release of histamine. and triprolidine. the concept is that in spite of their widespread use as over-the-counter medications. nucleus accumbens. Hence. limbic system. mesencephalon. Since promethazine is a phenothiazine. short-term (lasting 1-3 weeks).

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They have a relatively unique mechanism of action (i. and irritability respond better to buspirone than to benzodiazepines. buspirone has shown no drugdrug interactions with benzodiazepines or alcohol.43 To date. since most of the anxious population are given benzodiazepines first. which have more robust effects on the somatic symptoms of anxiety such as muscle tension and insomnia.46 . is its gradual.43 It does not cause respiratory depression. benzodiazepines can be given for a short period of time (to avoid. In addition. it is not yet clear whether this affinity for dopaminergic receptors contributes to its anxiolytic effect. very different from those of the selective serotonin reuptake inhibitors (SSRIs) and the other 'antidepressants' used to treat anxiety disorders.42 Buspirone has little or no potential for abuse or dependence. Notes about the scheme Buspirone acts as a partial 5-HTiA agonist at the postsynaptic population of serotonergic" receptors located in the hippocampus. Buspirone has also been shown to downregulate postsynaptic 5-HT2 serotonergic receptors. However. There is practically no withdrawal syndrome as seen with benzodiazepines. 1-(pyrimidinyl)piperazine (1 PP). buspirone has a moderate affinity for presynaptic D2 dopaminergic receptors. Psychic symptoms of anxiety such as worry.42 Binding to these receptors enables the drug to influence the activity of serotonergic neurons through modulating receptor activities. and headaches. The most frequent adverse effects of buspirone are dizziness. including the USA. nausea.44 .53 One of the most salient clinical features of buspirone. in contrast to most benzodiazepines. The excessive serotonergic transmission is probably associated with the anxiolytic effect of buspirone (see Section 3.39 . being 5-HT1A partial agonists). as much as possible. and is relatively safe in overdose.45 which is a therapeutic advantage in patients who suffer from chronic obstructive pulmonary disease. The clinician should remember to taper-off the benzodiazepines as soon as possible. buspirone could be considered as a first-line drug and it is often quite suitable for the treatment of GAD. This is a significant limitation. 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. compared with the benzodiazepines.54 . with α2-adrenergic antagonistic properties that have been related to improved sexual dysfunction in anxious patients. This effect may explain its moderate antidepressant properties. either from their general practitioners or from treating psychiatrists.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. Buspirone also has a weakly active metabolite. and at the 5-HTIA serotonergic autoreceptors located in the dorsal raphe nucleu. and it does not cause psychomotor or memory impairment.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. the antidepressant capacity of buspirone has not been well established and the drug is not proven as an antidepressant agent. Buspirone does not cause sedation and has minimal or no potential for abuse or dependence. relatively slow onset of action. However. One of the main limitations in using buspirone relates to the observed relative ineffectiveness of the drug in anxious patients formerly/currently on benzodiazepines. anger. resulting in enhanced serotonin secretion from these neurons. Even so. addiction to the drug) as adjuvants to buspirone if a patient suffers from incapacitating anxiety. Considering all of the abovementioned.1). 58 . with many patients taking 4-6 weeks to respond. drowsiness.e.

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Clomipramine (a potent SRI) and the selective serotonin reuptake inhibitors (SSRIs: serotonin reuptake inhibitors (SRls) citalopram. The striatum. Thus. escitalopram. Given the intimate connections between the amygdala and the striatum. the repetitive ritualized behaviors or compulsions might be the expression of aberrant or compensatory striatal activity. through its influence at the level of the thalamus. it has been suggested that activation of the amygdala during a state of fear or anxiety could readily effective in OCD. 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). which may normalize to some extent during treatment. and their respective roles. Moreover. or social activities. considerable evidence implicates corticostriatal circuitry in the pathophysiology of OCD. the role of enhanced serotonergic transmission in alleviating OCD symptoms is fairly well established. The selective response of OCD to induce stereotyped behaviors observed during striatal activation.62 In conclusion. paroxetine. Obsessions may be mediated by overactivity within the frontal cortex while stemming from impaired thalamic gating fundamentally attributable to deficient striatal function. In addition.60-61 desipramine. work. stereotyped cognitive processes on an implicit level. Functional brain imaging studies in OCD patients are also strongly suggestive of an abnormality in basal gangliathalamic-orbitofrontal-cortical circuitry. supporting the hypothesis that the antiobsessional effects of these various pharmacological agents result from their potent serotonergic reuptake blocking activity. fluvoxamine.62 Although it is unlikely that one neurotransmitter system can explain all the complexities of OCD. OCD is among the most common of mental disorders and its overall impact on society is tremendous.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. .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. the leading theories of OCD do not emphasize a central role for the amygdala. is believed to influence reciprocal thalamocortical interactions. Epidemiological studies demonstrate that 1-2% of the population has OCD. more complex. Rather. the striatum has been implicated in a variety of cognitive and affective functions. However. interactions are involved in OCD. the leading hypothesis is centered largely around the role of serotonin. focused the interest of researchers on the serotonergic system. Specifically. fluoxetine. In contrast to the various neurocircuitry models relevant for the other anxiety disorders. while other antidepressants with less potent inhibitory effects on serotonin reuptake (amitriptyline. it is believed to mediate repetitive. In addition to mediating motor activities. and sertraline) all have beneficial effects in OCD. 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. their anatomical proximity. and imipramine) are not Notes about the scheme Overactivity of corticostriatal circuitry is implicated in the pathophysiology of OCD. There is a strong evidence that neurobiological as well as psychologic factors play an important role in the pathogenesis of OCD.

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Chapter 4 Antipsychotic drugs .

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• . However. alogia. 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. possibly. it is accepted by most researchers that the neurotransmitter abnormalities are only a part. bizarre behavior. EPS are not evident in schizophrenia per se. • Plasma levels of homovanillic acid (HVA). with consequent potential reduction of 'negative' symptoms. maybe even only a small one. anhedonia. see Section 4. infectious. (b) the beneficial role of atypical APDs (drugs with enhanced capacity to block postsynaptic serotonergic receptors. often correlate with the severity of the psychotic symptoms in schizophrenia patients. the dopaminergic transmission in the nigrostriatal pathway (from the substantia nigra to the basal ganglia) is believed to be intact in schizophrenia (untreated). excessive serotonergic transmission from the raphe nuclei to this pathway. Notes about the scheme Among the above-listed abnormalities in schizophrenia. Possibie 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). Among these. but rather are the result of APD treatment. among them genetic. at least in part. Extrapyramidal side-effects (EPS) are a consequence of inhibited dopaminergic transmission in these regions. no specific abnormality. It is believed that enhanced serotonergic neurotransmission in the mesocortical pathway suppresses the dopaminergic neurons originating in the VTA and projecting to cortical regions. there is. γ-Aminobutyric acid (GABA) hypoactivity GABAergic neurons are inhibitory. 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. The efficacy of almost all antipsychotic drugs (APDs) has been found to be correlated with their ability to antagonize dopamine receptors. see Section 4. autoimmune. All in all.1 For a complete overview. a metabolite of dopamine. to date. neurotransmitter abnormalities (especially the dopamine/serotonin hypothesis of schizophrenia) are widely accepted as directly inducing or at least mediating certain symptoms of the disorder. of the biological pathology of schizophrenia. and asociality).2. has proved satisfactory in explaining the complex phenomena observed in schizophrenia. hallucinations. and possibly adrenergic). indistinguishable from the characteristic symptoms found in schizophrenia. cocaine. serotonergic. The major empirical observations concerning the role of abnormal neurotransmitter functioning in schizophrenia are as follows. can be induced by the use of dopaminergic agents such as amphetamines.4) in ameliorating psychotic symptoms. Atypical (second-generation) APDs block this excess serotonin. or combination. and with their consequent response to APD treatment. and neurotransmitter. and thought disorder) and it is a widely accepted/consistent abnormality. At the same time. L-dopa. There are many possible associated abnormalities in schizophrenia. specifically the D2 receptors. during either the acute psychotic exacerbation or the remission periods. the overactivity seen with other neurotransmitter systems (dopaminergic. Along with the decreased dopaminergic transmission in the mesocortical pathway. neurotransmitter abnormalities are the best studied and best understood. and phencyclidine (PCP). avolition. which relies mainly on the following findings: • Psychotic symptoms. causing 'negative' symptoms. seasonal. Hence. and a loss of these inhibitory effects can produce. bromocriptine.The term 'schizophreniform psychosis' refers to the clinical symptoms observed during the course of schizophrenia.

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hypoactive) glutamatergic receptor expression/function may contribute to the observed abnormalities. it produces delusions. hence.2 . possibly due to the action of clozapine in increasing the occupancy of the glycine modulatory site at the NMDA receptor. regulating the influx of cations (mainly Ca2+) via a cation channel located adjunct to the receptor). 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. Consistent with this model. respectively. and psychosis. accumulated data suggest that altered (i. associated presumably with the induction of 'negative' and 'positive' symptoms.to 15fold lower affinity for the NMDA receptor. The enhanced serotonergic transmission inhibits mesocortical dopaminergic pathway by acting at postsynaptic 5-HT2A serotonergic receptors located on their dopaminergic neurons. Evidence for hypoactivity of NMDA receptors in schizophrenia has led to therapeutic trials with agents (e. However. Within the channel. glycine. there seemed to be improvements in negative symptoms. PCP produces a syndrome in normal individuals that closely resembles schizophrenia and exacerbates symptoms in patients with chronic schizophrenia. leading to decreased activation of GABAB receptors located on presynaptic nerve terminals of dopaminergic neurons (in limbic regions) and serotonergic neurons (in the VTA). and thought disorder. their suppression leads to increased dopamine secretion in the mesolimbic pathway and increased serotonergic transmission in the VTA. with some beneficial results.and postsynaptic markers for glutamatergic neurons in schizophrenia patients. PCP binds to a site within the ion channel of the NMDA receptor that blocks the influx of cations. the addition of glycine site agonists to clozapine produced no changes in negative symptoms or cognitive function. there is a binding site for dissociative anesthetics such as phencyclidine (PCP) and ketamine. hallucinations. It is postulated that γ-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 NMDA receptor for glutamate has a number of modulatory sites that affect its activity (i. There is also a strychnine-insensitive binding site for the co-agonist glycine.e. However. When ketamine is administered to patients with schizophrenia stabilized with antipsychotic medication. chronic PCP administration also increases subcortical dopamine release. D-serine. The suppressed GABAergic neurons do not secrete as much GABA as they should. emphasizing the reciprocal modulation of the glutamate and dopamine neuronal systems in schizophrenia. When these agents were added to ongoing antipsychotic treatment. The GABAB receptors are inhibitory in nature.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. cognitive function. and D-cycloserine) that indirectly or directly activate the NMDA receptor.3 . which serve as non-competitive antagonists. Moreover. The exact mechanisms responsible for such changes in dopaminergic transmissions are not yet fully understood. and it produces the characteristic cognitive deficits of schizophrenia.g. 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. thereby acting as a non-competitive antagonist. Ketamine is an anesthetic that has approximately a 10. consistent with the patient's typical pattern of psychotic relapse. particularly in the nucleus accumbens. There are also data from postmortem studies suggesting alterations in pre.e.

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in the mesocortical pathway might induce negative symptoms (e. Decreased dopaminergic transmission. sulpiride is often considered by clinicians as 'atypical' in nature. and intramuscular administration. 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. Moreover. by blocking D2 receptors. The D2 blockade induces a subsequent improvement of 'positive' psychotic symptoms (delusions. It occurs in up to 90% of patients during the first 10 weeks of treatment. Although the antagonism of the D2 receptors takes place almost immediately. Risk factors are male sex. other receptors (e. and globus pallidus). This usually occurs during the first 3 months of treatment. particularly dopaminergic. Notes about the scheme All typical APDs block (at least to some extent) D2 dopaminergic receptors and are not selective. Most of the neurological and endocrinological adverse effects associated with APDs are related to their antagonistic effects on those receptors. and the olfactory tubercle (mesolimbic pathway). Furthermore.1 . and highpotency antipsychotic agents. Parkinsonism. Prolactin secretion is enhanced following this blockade. since it is quite selective as a D2 blocker (although non-selective in its brain distribution). and alogia). As mentioned. especially the following:1 . • • . It is characterized by rigidity. These are dopaminergic neurons that project from the substantia nigra to the basal ganglia (caudate nucleus.and secondgeneration) are equally efficacious. all typical APDs have a high affinity for D2 receptors. there is increased dopaminergic neurotransmission in the mesolimbic pathway and decreased transmission in the mesocortical region (see Section 4. Hence.4 • • Nigrostriatal. tremor. their clinical potency is closely related to their specific affinity for D2 dopamine receptors. In that respect. and dysphoria. disorganized behavior. Sulpiride is a relative exception. since dopamine inhibits prolactin secretion. it takes a few weeks for amelioration of psychotic symptoms to occur. hallucinations. and catatonia). implying a secondary mechanism (presently unknown). Virtually all APDs are non-selective. and postural instability. and histaminergic. Tuberoinfundibular. It is assumed that in schizophrenia. serotoninergic. typical APDs often cause extrapyramidal sideeffects. typical APDs decrease dopaminergic transmission in the nigrostriatal pathway. 5-HT and D4). At the mesolimbic pathway. adrenergic.4'5 • Dystonia. whereas atypical APDs block. This is a subjective feeling of muscular discomfort. more dominantly. and affects up to 10% of treated patients. although they exert their maximal antipsychotic effects in various doses (different potency). typical APDs block mainly the D2 component. the amygdala. These are dopaminergic projections from the posterior hypothalamus to the medial eminence and the posterior and intermediate lobes of the pituitary. high-potency antipsychotic agents. age less than 40 years. meaning that they do not target specific brain regions. with a therapeutic effect being evident if more than 70% of D2 receptors are occupied by APDs. affective flattening. which leads to restless pacing. might further decrease these suppressed dopaminergic activities and worsen these 'negative' symptoms.The common pathway of all typical/ firstgeneration as well as 'atypical'/ secondgeneration antipsychotic drugs (APDs) is their capacity for antagonizing dopamine receptors. Extrapyramidal side-effects are mostly related to the antagonistic effect of APDs on these dopaminergic pathways. agitation. bradykinesia. This occurs usually during the first few hours/days of treatment in about 10% of patients. disorganized speech. The major dopaminergic pathways that are most relevant to schizophrenia are: • Mesolimhic and mesocortical.1 for details). putamen.g. Risk factors are age over 40 years. Practically all APDs (both first. avolition. They possess a wide range of antagonizing capacities. Typical APDs.g. Akathisia. cholinergic.

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while most exert a mild-moderate capacity to antagonize D2 dopaminergic receptors. (c) SGAs block 5-HT2A receptors located on nigrostriatal dopaminergic neurons. except risperidone in relatively high doses. There is no one specific receptor interaction responsible for a drug's atypical propensities. it could be that there is a basal overstimulation of 5-HT2A receptors. However. this phenomenon may 'over-ride' the decrease in dopaminergic transmission due to the blockade of D2 receptors (by the SGAs). and especially the 'positive' symptoms in specific subjects (e. This could explain the potential beneficial effects of SGAs in alleviating 'negative' symptoms. dopaminergic transmission in these neurons. 4 . 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).1. treatment-resistant patients). Especially relevant for schizophrenia might be upregulation of 5-HT2A receptors located on dopaminergic neurons of the mesolimbic pathway. sertindole. although several main mechanisms have been suggested: (a) SGAs bind less to D2 receptors in the striatum they are more selective (b) They have comparable affinity for these striatal D2 receptors but they bind much more loosely ('loose binding'). Besides the mesocortical dopaminergic pathway). Hence. presumably. with a consequent increase in dopaminergic transmission. risperidone. olanzapine. this latter concept is quite hypothetical and further research is needed to establish its role in schizophrenia. and stimulation of these receptors decrease physiologically. aripiprazole. 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). in suppression of the dopaminergic neurons of the mesocortical pathway. Hence. the increased serotonergic transmission (ca used by the up regulated receptors) in the mesolimbic region may explain their potential superior efficacy in improving some aspects of schizophrenia. In schizophrenia. 5-HT3A receptors are located on dopaminergic neurons of the mesocortical pathway (see Section 4. olanzapine.5 and 4.12 .g. and ziprasidone) have also shown some capacity to improve 'negative' symptoms. Some researchers believe that alleviating. at least to some extent. Other SGAs (amisulpiride. 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 criterion is controversial because only clozapine has shown a consistent and significant capacity to improve negative symptoms in.7 • • Notes about the scheme Amisulpiride. quetiapine. resulting. and ziprasidone are termed second-generation APDs (SGAs.7 8 SGAs. with consequent induction of the 'negative' symptoms of the disorder.1) (as well as in other regions that are less relevant to schizophrenia). Schematically. although such results are usually inconsistent.Second-generation ('atypical') antipsychotic drugs (SGAs. often designated as 'atypical'). SGAs are potent inhibitors of postsynaptic 5-HT2A serotonergic receptors. although a few have been postulated (see also Sections 4. do not usually cause marked extrapyramidal side-effects. This may result in a decreased firing rate of these neurons. large and well-established studies of schizophrenia patients. The reason for this is not fully established.6 . some of the 'negative' symptoms of schizophrenia should also be a necessary criterion for defining a drug as an 'atypical' APD. clozapine. However. allowing nearly normal dopaminergic transmission. Upregulation of 5-HT2A receptors in other brain regions (i. risperidone. '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. at present.6). quetiapine.e.

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Chapter 5 Drugs affecting sexual function .

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Increased sexual desire and arousal were noted among patients receiving L-dopa (Sevodopa). and treatment of sexual dysfunction. in part by activation of central 5-HT2 receptors. 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. centrally and peripherally. such as mirtazapine and trazodone. while activation of the 5-HT1B/ID and 5-HTlc receptors inhibits it. and by the increasing number of new treatment regimens for sexual dysfunction. 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. including penile tissue. among these are progesterone and prolactin (which inhibit centrally mediated arousal) and testosterone (which stimulates centrally mediated arousal). Cocaine potently enhances dopaminergic activity and may produce intense sexual pleasure. central cholinergic transmission may also play a role in modulating sexual function. these may not be the only brain regions involved in the complex regulation of desire. . However.1 Moreover. Intact dopaminergic function is necessary for both female and male sexual arousal and orgasm/ejaculation.1-2 Adrenergic system Stimulation of α1-adrenoreceptors will likely lead to detumescense. presumably by their dopaminergic blockade. cause delayed or inhibited orgasm/ejaculation. apomorphine.2 Serotonergic system Most prominent among the psychotropics that enhance serotonergic transmission are the selective serotonin reuptake inhibitors (SSRSs). Dopaminergic system There is strong evidence from animal and human data that dopamine plays a major role in human sexual response. whereas blockade of these receptors. but the overall data concerning the role of various neurotransmitters in female sexual function are still scanty. The dopaminergic system is diffusely distributed in the central and peripheral nervous system. Antidepressants that antagonize the 5-HT2 receptor. Hence. arousal. of which the best known are the phosphodiesterase-5 (PDE5) inhibitors for the treatment of male erectile dysfunction.2 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. including the sex organs. This has been fostered by growing awareness of the potentially deleterious effects of psychopharmacological agents on sexual function and behavior. Stimulation of the 5-HT1A receptor facilitates sexual functioning. and orgasmic phases of the sexual response cycle. as well as various hormones. and it is suspected that central muscarinic receptors may mediate arousal. Two dopamine reuptake blocking agents. may produce erection. have been shown to modulate sexual function. nomifensine (withdrawn from the market) and bupropion.Increasing research attention has been paid to the neurobiology of sexual function. However. Dopaminergic stimulation of the ventral portion of the striatum enhances desire. Female sexual arousal has been associated with an active sympathetic nervous system. it is estimated that 20-85% of non-adherence to psychopharmacology is due to adverse sexual side-effects of the drugs. notably tricyclic antidepressants (TCAs). whereas the dorsal portion of the striatum controls intromission and ejaculation. Erectile difficulties and orgasmic inhibition are the main side-effects attributable to antagonism of the cholinergic system. cause fewer sexual side-effects compared with the SSRIs. antipsychotic drugs. exert sexual facilitatory effects in the desire and arousal phases. which may induce sexual dysfunction in as many as 50-75% of patients. Other compounds Other neurotransmitter systems. and bromocriptine (dopamine agonists). understanding.

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allowing more blood to enter the corpus cavernosa and induce erection. as well as their quality of life. which is present in the tissue of the corpora cavernosa. it is estimated that as many as 1560% of neuroleptic-medicated subjects (especially with first-generation drugs such as thioridazine) suffer from sexual adverse effects. and sertraline) can delay ejaculation. Another approach to the treatment of erectile dysfunction has been the use of dopaminergic agents. At the cellular level. . with consequent accumulation of cGMP. and phentolasnine. major depression. It is assumed that dopaminergic neurons impinge on oxytocinergic cell bodies in the paraventricular nucleus. fluvoxamine and citalopram appear to have the least effect on ejaculation [3]. treatment with SSRIs can be considered for patients with premature ejaculation. Effective treatments for sexual dysfunction. with consequent activation of these oxytocinergic neurons. which increase intracellular cAMP in the smooth muscle of the corpora cavernosa and induce subsequent erection. and especially for erectile dysfunction. have progressed enormously. Some data suggest that. a drug with a relaxant effect on smooth muscle. nitric oxide (NO) activates guanylate cyclase (GC). Such treatments may increase patients' adherence to psychiatric pharmacotherapy. breaks down cGMP. Sildenafil works by inhibiting PDE5. allowing the penis to return to a flaccid state. The latter acts as a second messenger of NO and provide a signal for smooth muscle relaxation by a decrease in intracellular calcium. For example. inhibitory) activity in the nucleus paragigantocellularis of the medulla. enhances noradrenergic neurotransmission and may improve erectile dysfunction via adrenergic system activation. it is important to be acquainted with psychotropic-induced sexual dysfunction and with the rapid evolving treatments available for such adverse effects (e. Hence. paroxetine. The serotonergic drugs have been hypothesized to delay ejaculation by increasing serotonergic (i. which produces cGMP. The resultant reduction in intracellular calcium leads to vasodilatation and penile erection. This nucleus sends inhibitory serotonergic fibers to sexual centers in the spinal cord. During sexual excitement. Apomorphine is a nonselective dopaminergic agonist that presumably works at the level of the spinal cord and centrally at the paraventricular nucleus of the hypothalamus. The enzyme PDE5. an α2-adrenoreceptor antagonist. The relaxed musculature causes vasodilatation. Two other marketed PDE5 inhibitors are tadalafil and vardenafil. including hypertension. phosphodiesterase-5 (PDE5) inhibitors).g.e.3 P r e ma t u r e e ja c u l a t i o n Controlled double-blind studies have consistently demonstrated that a number of serotonin enhancers (confirmed with clomipramine. smooth muscle is mediated by the cyclic adenosine monophosphate (cAMP) or the cyclic guanosine monophosphate (cGMP) pathway. an a-adrenergic receptor blocker.3 Other agents used to treat erectile dysfunction include intracavernosal and transurethral alprostadil (prostaglandin E1).3 Hence. Other intracorporal agents used to induce penile erections include papaverine. 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. these neurons mediate apomorphine-induced penile erections. Current data suggest that among the selective serotonin reuptake inhibitors (SSRIs). including erectile dysfunction. Yohimbine. and after prostatectomy. Both primary and secondary sexual dysfunctions are common in clinical practice and are frequent side-effects of psychopharmacological treatment. The efficacy of sildenafil has been demonstrated in erectile dysfunction associated with numerous conditions.Understanding the treatment options for sexual disorders is of importance to most psychiatrists as well as other professionals in clinical practice. causing the smooth muscle to contract. fluoxetine. spinal cord injury. diabetes.

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Retrograde ejaculation can appear as complete (no antegrade fraction) or incomplete (only minimal antegrade emission). Diagnostic evidence of retrograde ejaculation includes absent or intermittent emission of ejaculate. Pharmacotherapy is also used to delay ejaculation. nausea. the squeeze technique. Drugs frequently used are imipramine. but later case reports and open trials described the beneficial effects of monoamine oxidase inhibitors (MAOEs). However. it seems that the beneficial effect of SSRI treatment in premature ejaculation results from 5-HT2C receptor stimulation. Diagnostic clues to anejaculation are complete absence of antegrade ejaculation combined with non-viscous.4 . midodrine. Failures in the initial step can lead to anejaculation. or shortly after penetration and before the person wishes it. To date. and sperm-negative postorgasmic urinalysis. paroxetine. it has been suggested that long-term SSRI administration is much more efficient than short-term treatment. sleep disturbances. and midodrine (with 50-80% success rates). and other psychotherapeutic interventions. retrograde ejaculation is the most common cause of ejaculatory dysfunction and accounts for 0. and the absence of spermatozoa and fructose in postcoital specimens of urine. In the absence of antegrade ejaculation. The involvement of central serotonergic neurotransmission in human ejaculation has been investigated mainly in animal studies. Moreover. benzodiazepines. Spinal cord injury is the most common diagnosis in patients with anejaculation. imipramine. The most effective pharmacological treatments of retrograde ejaculation include chlorpheniramine plus phenylpropylamine.6 . weakness. dry mouth. together with parasympathetically (originating from S2-S4) induced contraction of the bulbocavernosus and ischiocavernosus muscles and pelvic floor activity. Behavioral therapies include the stop-start technique. Premature ejaculation is defined as persistent or recurrent ejaculation with minimal sexual stimulation before. and brompheniramine. and sweating. chlorpheniramine plus phenylpropylamine. restlessness. leads to antegrade ejaculation through the urethral meatus. which is defined as total failure of seminal emission into the posterior urethra. ability to empty the bladder during erection.Notes about the scheme Initial stimulation of the sympathetic nerves from sympathetic motor neurons emerging in segments T12(11)-L3. on. and idiopathic retrograde ejaculation (no identifiable cause for ejaculatory dysfunction). which is defined as substantial propulsion of seminal fluid from the posterior urethra into the bladder. it has been shown that the initial positive effects of behavioral techniques disappear after 3 years. and sertraline. The most common reasons for retrograde ejaculation in patients attending infertility clinics are a history of retroperitoneal lymph node dissection. Among the SSRIs. Drugs used in the medical treatment of retrograde ejaculation include a-adrenergic agonists or anticholinergic and antihistaminic drugs. sympathetic contraction of the posterior urethra and closure of the bladder neck. orgasm without ejaculation. bladder neck surgery. paroxetine has been demonstrated to be more effective than clomipramine and the other SSRIs. Frequent side-effects at the doses given are various degrees of dizziness. diabetes mellitus. which together account for more than 80% of patients with retrograde ejaculation. Following the initial emission of semen into the posterior urethra. Failures in the latter two steps lead to retrograde ejaculation. initially.3-2% of cases of male infertility. and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine. local anesthetic ointments were recommended. produces emission of semen from the ampulla of the vas deferens into the posterior urethra. transurethral resection of the prostate. which either increase the sympathetic or decrease the parasympathetic tone of the bladder. Various medical treatments have been proposed for the treatment of anejaculation or retrograde ejaculation. clomipramine. fructose-negative.

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

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independent of dopamine. functional activity of the cAMP pathway gradually recovers and increases far above control levels upon removal of the opiate (e. The locus ceruleus (LC). while chronic treatment aims at reducing the craving for opiates by replacing the prohibited drug with legal substitutes such as opioid receptor agonists (e. This cause acute 'down regulation' of intracellular components such as cAMP and AC. and agitation). which are members of the G-protein-coupled receptor family. cramps. the major noradrenergic nucleus in the brain. vigilance. These drugs appear to produce both reward and reinforcement by means of activation by disinhibition . methadone and L-α-acetylmethadol (LAAM)) and the partial agonist buprenorphine1 . headache. and inhibition of the sodium current. naloxone). Κ and δ. aches. Opioid receptors thus typically mediate inhibitor responses that reduce membrane excitability and reduce the likelihood of cell firing. Upregulation of the cAMP pathway in LC neurons contributes to the dramatic activation of these neurons upon induction of opiate withdrawal.e. denoted μ. by administration of the opioid receptor antagonist. This brain region provides most of the noradrenergic innervation of the cerebrum and is thought to be important for regulation of alertness.The opiates and their synthetic analogs are the most effective analgesics known. and attention state. with continued and chronic opiate exposure. CREB binds specific DNA sequences. Repeated administration of opiates increases the level of expression of AC and PKA. Some of the adaptation to chronic opiate administration is mediated by the transcription factor cAMP-response elementbinding protein (CREB). with a consequent increases in the excitability of LC neurons by activating a Na+ current. are both analgesic and addictive. including heroin (diamorphine). Opiates acutely inhibit LC neurons.i. Opiate drugs bind to three subtypes of opioid receptors. Notes about the scheme Opiates acutely inhibit the functional activity of cyclic adenosine monophosphate (cAMP)dependent protein phosyphorylation. as they inhibit the noradrenergic firing rate. has served as a useful model system for understanding the molecular details that underlie upregulation of the cAMP pathway.g. they inhibit inhibitory neurons affecting dopaminergic transmission of the ventral tegmental area. probably via opening of inwardly rectifying K+ channels (mediated by direct G-protein gating) and via closing of sodium (Na+) current (mediated via inhibition of the cAMP pathway). Treatment options for acute opiate intoxication are based mainly on drugs that antagonize the opioid receptors (naloxone and naitrexone).5. Morphine-like opiates. 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. However. activation of inwardly rectifying potassium (K+) channels. a widely abused substance. which in turn leads to many of the signs and symptoms of physical opiate withdrawal (mostly diarrhea. termed cAMP-response elements (CREs) that are present within the regulatory regions of certain genes to regulate transcription. nausea. Chronic opiate use increases the expression of CREB in the LC. and addiction. This coupling result in inhibition of adenylate cyclase (AC).g. 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). but at the same time can produce tolerance. releasing dopamine in the nucleus accumbens -and by direct binding to opioid receptors in the nucleus accumbens. which may explain in part the beneficial attenuating effect of the a2 presynaptic agonists clonidine and fofexidine in the treatment of opiate withdrawal. dependence. . and interact with greatest affinity with the μ receptor. with consequent decreased firing rate of various neurons.

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stroke. where leaves of the shrub are chewed by the population to obtain antifatigue effects. pemoline. and venlafaxine have shown good tolerability and a reduction in cocaine use. Current research strategies that involve blocking cocaine euphoria or reversing cocaine-induced neuroadaptations may actually have fundamental limitations. dopaminergic neuron burst firing habituates to predictable rewards and occurs instead when the organism perceives environmental cues that are associated with the rewarding activity.16 . these effects are relatively minor compared with the capacity to block dopamine reuptake. and current data suggest that such dopaminergic agents (e. with resulting reductions in dopaminergic neurotransmission within the prefrontal cortex and extended amygdala. During novel rewarding activity. Complex brain reward circuitry. resulting in stimulation of the D1 and D2 dopaminergic receptors. dextroamphetamine. Psychiatric effects can mimic the positive and negative symptoms of schizophrenia. where extracellular dopamine is acutely increased by most addictive drugs. Pharmacological treatment of cocaine intoxication is non-specific and includes general medical support and administration of psychotropics for specific symptoms. Blocking reward is unlikely to address craving and the low hedonic function reported by many cocaine-addicted patients. After a period of time. Although a medication with robust efficacy for cocaine dependence has yet to be identified. bupropion. Cocaine toxicity has both somatic and psychiatric manifestations. uncontrolled 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. it also has some capacity to stimulate the postsynaptic dopaminergic receptors. the baseline pacemaker firing of these dopaminergic neurons transforms to burst firing.11 . Among the non-dopaminergic enhancers. currently a barrier to cocaine research. Agents that increase dopaminergic activity have the theoretical capacity to decrease withdrawal symptoms. modafinil. The restoration of normal hedonic function after protracted cocaine exposure might instead require the passage of time and innovative biological approaches. Midbrain dopaminergic neurons in the ventral tegmentum that project to the NAc form a 'reward circuit' that is activated by cocaine. bromocriptine. several trials have yielded some success. partially due to cocaine-related myocardial sodium channel blockade and coronary and cerebral vasoconstriction. However. malignant dysrhythmias.Cocaine is an alkaloid derived from the shrub Erythroxylon coca. dopaminergic neuron firing plunges below basal level. which is indigenous to South America. related. reward does not materialize (in animal models of craving). However. and selegiline) can be beneficial in some cocaine abusers. Somatic effects include myocardial depression. and sudden death. However. The main mechanism of action of cocaine is related to blockade of dopamine reuptake by the dopamine transporter. to its activities at the mesolimbic dopaminergic pathway. presumably. cocaine also blocks the reuptake of norepinephrine and serotonin into the presynaptic nerves. the exact mechanism underlying their beneficial effects is unclear and their potential to alleviate cocaine-induced symptoms is currently quite questionable. amantadine. should ultimately provide new insights in the search for abstinence-promoting agents. Cocaine has powerful addictive qualities. Such life-threatening conditions occur mainly when cocaine is combined with other abused drugs. 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. Moreover. This capacity of dopaminergic neurons to fire upon exposure to conditioned cues involves learning and is an essential feature of the addictive process.g. When anticipated trials of divalproex (semisodium valproate). gabapentin.

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Hence.27 . bruxism. neuromuscular symptoms may develop. The cytochrome P450 enzyme CYP2D6 is the primary metabolizer of MDMA. shivering. quinidine.Notes about the scheme The illicit drug used most commonly by young people at parties and 'raves' is 3. rhabdomyolysis. paranoia. delirium. depression. methadone. More importantly. and seizure precautions. and nystagmus. tremor. a new antibacterial with mild MAOI properties. and urinary retention. diaphoresis. haloperidol. cardiac monitoring. and cyproheptadine (an antihistaminergic and 5HT2A blocker) or chlorpromazine should be considered. Lirtezolid. The most serious cases of central serotonin syndrome can develop with the irreversible monoamine oxidase inhibitors (MAOEs). Moderate symptoms manifest as sweating. myoclonus. and include tachycardia. Induction of emesis is not recommended. pulse oximetry. hyperreflexia. chemical panel. Psychiatric and neurological manifestations include confusion. and to a lesser extent enhance dopamine and norepinephrine release from presynaptic nerve terminals. sweating. Rhabdomyolysis should be treated with alkaline intravenous fluids (D5W with sodium bicarbonate). elation. toxicology screen. A florid central serotonin syndrome involving autonomic. urinanalysis. fluoxetine. may also interact dangerously with MDMA. disseminated intravascular coagulation. Anxiety can be treated with benzodiazepines. 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. clomipramine. The serotonin boost can produce a sense of emotional closeness. pimozide. lithium. Severe hypertension may be treated with labetalol (an α1. These drugs (e. or nitroprusside. The plasma concentration of MDMA increases 9-15% when the drug is taken with alcohol. autonomic instability. and sensory delight.4methylenedioxymethamphetamine (MDMA) or 'ecstasy'. but it is believed to inhibit the reuptake of serotonin. The mechanism of action of MDMA is not completely understood.and β2-adrenergic receptor antagonist). diarrhea. parkinsonism. tremor. various amphetamines) may be ingested inadvertently as contaminants of MDMA. St John's wort. and. irritability. Cases of death have been reported from MDMA interactions with the irreversible MAOI phenelzine and the reversible MAOI moclobemide. paroxetine. severe symptoms include myoclonus. Treatment includes primary supportive measures such as cardiorespiratory maintenance. fluoxetine. The most dangerous effects of MDMA ingestion is hyperthermia and the associated serotonin syndrome. Serotonin syndrome should be treated with primary supportive measures. Hyperthermia should be treated by rapid cooling. resulting in rigidity. potential outcome adverse effects of MDMA ingestion result from sympathetic overload. tramadol. it might be associated with the addictive properties of the drug. hypertension. arrhythmias. The proserotonergic effects of MDMA can be augmented by the ingestion of other proserotonergic drugs. and agitation. and fever. phentolamine (a potent α1-antagonist. along with the potential of MDMA to increase dopamine transmission in the 'reward' pathway. 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. mydriasis. potent CYP2D6 inhibitors (bupropion. and acute renal failure. Proserotonergic drugs such as amphetamines. 17 . and ritonavir) potentially slow the metabolism of MDMA and may further stimulate its toxic effects.g. cocaine. and venlafaxine prescribed for medical disorders may increase the likelihood and severity of the serotonergic effect of MDMA. and life-threatening hyperthermia that may be further complicated by rhabdomyolysis. cognitive. and acute renal failure. to facilitate serotonin release. The acute adverse effects of MDMA may include increased heart rate and blood pressure. The most troublesome. esophoria (a tendency for the eyes to turn inward).

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If APDs are employed.g. The substance was originally developed as a general anesthetic. 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. to date. which is one of the various receptors in the brain though which the neurotransmitter glutamate exerts its effect. longterm. and death can follow. Acute exposure to PCP may cause intense psychosis. it is preferred to use high-potency drugs (e. visual hallucinations. PCP stands as the current best model of schizophrenia in humans and animals.2).g. the use of APDs should be limited to severe psychotic/agitated patients. social incompetence. However. persistent impaired cognition. for PCP intoxication. Benzodiazepines are usually used to treat autonomic instability. and thioridazine) or some of the relative newly introduced secondgeneration APDs (SGAs: clozapine. the medical use of PCP is presently contraindicated due to its potential severe adverse side-effects mainly delirium (in about 33% of abusers). akathisia and dystonia). the first and most common stage. and decreased frontal blood flow. it is probably second to marijuana in frequency of use among drugs of abuse. poor social judgment. In the second stage. and quetiapine). Treatment is symptomatic. anxious. and rhabdomyolysis (in about 2%). delusions and euphoric or flattened affect. However. patients can often become stuporous and comatose. The ability of PCP to produce schizophrenia-like symptoms in healthy people is related to its ability to block the N-methyl-D-aspartate (NMDA) receptor (see Section 4.g. poor interpersonal relationships. PCP intoxication may be viewed as occurring in three stages. muscle spasms. for more severe intoxication. Hence. since these agents can lower the seizure threshold and induce convulsions. Mild intoxication. olanzapine. delusions with religious content. In the third stage. labile. No antidote has been found beneficial. agitation.Phencyclidine (PCP) is a synthetic drug that is often abused. PCP-induced symptoms in humans (especially its capacity to induce 'positive'. Thus. in the USA. thought disorder. and PCPinduced seizures. chlorpromazine. patients tend not to respond to deep pain stimuli. is manifested primarily by psychiatric signs and symptoms. Activated charcoal is indicated if the patient reaches the hospital soon enough. auditory hallucinations. PCP exposure models the behavioral and metabolic dysfunction of schizophrenia. hallucinations. and increased frontal blood flow. 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. and may also aid in controlling some of the aggressive/agitated behavior. and includes careful monitoring of the patient's level of consciousness and their cardiovascular and respiratory functioning. levomepromazine.and 'negative'-like symptoms) appear to offer a more complete model of schizophrenia than that offered by amphetamine-induced symptoms. poor attention span and concentration. It alters sensory perception and may produce peculiar experiences and even psychotic behavior. but not acute. 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. or paranoid affect. haloperidol).28 . but they still have intact deep pain responses. impaired cognition.30 . Repeated exposure to PCP may cause intense psychosis. overt impulsiveness. treatment in an intensive care unit is mandatory. Clinical studies have consistently shown that a single exposure to PCP may produce behavioral disruption in healthy individuals that mimic schizophrenic symptoms. since these have a relatively reduced capacity to induce seizures compared with the low-potency phenothiazines (e. Treatment of PCP intoxication includes APDs and benzodiazepines. Although amphetamines may also produce symptoms that closely mimic those of schizophrenia. or they may cause adverse side-effects that can aggravate patients' problems (e.

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31 . The effect of acamprosate appears to be most effective in decreasing alcohol consumption and prolonging abstinence. The brain's main inhibitory neurotransmitter is y-aminobutyric acid (GABA). controlled clinical trials have yielded inconsistent results. The objective of disulfiram treatment is to create an aversion to alcohol. Pharmacological treatment of alcohol withdrawal involves the use of medication that is cross-tolerant with alcohol. resulting in decreased overall excitability.e. leading to accumulation of acetaldehyde and subsequent unpleasant intoxication. The following are among the best studied treatments. and amisulpiride) have been tried in alcohol-dependent patients. the treatment effects seemed to wane after discontinuation of treatment. has demonstrated some efficacy with regard to measures of drinking frequency and intake. Hence. Carbamazepine is an effective alternative to benzodiazepines in the treatment of alcohol withdrawal syndrome in patients with mild to moderate symptoms. Treatment options for alcohol abuse have focused on all of the above-mentioned neurotransmitter systems. As with naltrexone. Disulfiram is the first-line therapy for alcohol abuse. and opioid systems.Notes about the scheme The brain maintains neurochemical balance through inhibitory and excitatory neurotransmitters. Ondansetron. Haloperidol or medium. Dopamine antagonists (tiapride. Acute alcohol intoxication also downregulates NMDA receptors. and are the preferred agents for treating the symptoms of alcohol withdrawal syndrome. Naltrexone is an opioid antagonist that is thought to reduce the positive reinforcing pleasurable effects of alcohol and to reduce craving. However. 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. Brain excitability manifests clinically as anxiety. Acamprosate has effects on drinking behavior that are related to modulation of glutamatergic transmission. flupenthixol. while lithium has no effect on drinking behavior. and its use has demonstrated a reduction in frequency of heavy drinking. because receptors inhibited by alcohol are no longer inhibited and excitatory receptors (i. Acute alcohol (ethanol) intoxication enhances the effect of GABA.to high-potency antipsychotics can be used to treat agitation and hallucinations. particularly for preventing or treating seizures and delirium. with negative results.45 . while the major excitatory neurotransmitter is glutamate. This drug remains the most widely validated treatment medication for the treatment of alcoholism. Treatment with β-blockers should be considered in patients with coronary artery disease. which have shown at least some established efficacy. while chronic alcohol exposure results in upregulation of these receptors. Nalmefene is also an opioid antagonist. NMDA) are upregulated. there is not sufficient evidence that carbamazepine prevents seizure and delirium due to alcohol withdrawal. Benzodiazepines have been shown to be safe and effective. Disulfiram (and calcium carbamide) prevent the metabolism of alcohol by inhibiting the enzyme aldehyde dehydrogenase. rather than modulating its neurochemical effects. a 5-HT3 serotonergic receptor antagonist. Carbamazepine has shown some efficacy with regard to alcohol consumption. In particular. alcohol also interacts with several other brain neurotransmitter systems. It is not sedating and has little potential for abuse. the largest study performed to date produced negative findings. and delirium tremens. However. however. which usually acts through GABAA receptors. seizures. including the dopaminergic. abrupt cessation of alcohol exposure results in brain hyperexcitability. agitation. From a neurochemical perspective. acamprosate depresses the elevated glutamatergic transmission and NMDA receptor activation that occur in alcohol dependence and withdrawal. which acts through the N-methyl-D-aspartate (NMDA) receptor. irritability. serotonergic. It has been demonstrated to reduce both alcohol consumption and craving.

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for example.46 . is expressed only in the peripheral immune system. Both cannabinoid receptors are members of the Gprotein-coupled class. is contained in marijuana at a concentration of over 5%. and their activation is linked to inhibition of adenylate cyclase activity. but these are much less than amphetamines. and the limbic forebrain (particularly in the hypothalamus and in the anterior cingulated cortex). Moreover. Smoking remains the most efficient means of delivering the drug. the CB1 antagonist rimonabant has been demonstrated to suppress appetite and to induce weight loss. sometimes with synesthesia (where sounds take on visual qualities). and appear to be synthesized and released locally on demand. It is particularly distributed in the frontal regions. There are a series of arachidonic acid derivatives (endogenous cannabinoids) with potent action at cannabinoid receptors. particularly for sweet foods. Cannabis has some addictive properties. Anandamide and other endogenous cannabinoids are rapidly inactivated by a combination of a transporter mechanism and by the enzyme fatty acid amide hydrolase. Many subjective reports suggest that cannabis intoxication is associated with increased appetite. Among the well-established effects of acute intoxication with cannabis is an impairment of short-term memory. These are anandamide (N-arachidonylethanolamine) and 2-arachidonylgiyceryI ether. To date. 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. the basal ganglia. 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.The active compound in herbal cannabis. and this is one of the medical indications for which the drug has official approval in the USA. almost half of all 18-years-olds in the USA and most European countries admit to having tried it at least once. The addictive properties. depending on the dose of the drug. Apart from being an abused substance. The relative scarcity of cannabinoid receptors in the brainstem nuclei may account for the low toxicity of cannabis when given in overdose. of cannabis are due. One subjective effect that has been confirmed is the sensation that cannabis users experience time as passing more quickly relative to real time. Despite being illegal. interesting and important cannabis-induced effects are emerging as potential future treatments for psychiatric and neurological conditions. 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. probably. A temporary form of drug-induced psychosis can occur in some cannabis users as a result of taking large doses. The endogenous cannabinoids known as endocannabinoids are present in only small amounts in the brain or other tissues. cannabis is one of the most widely used intoxicants. This suggests that cannabinoids may play a role in the regulation of food intake an d body weight. but absorption is delayed. experienced users can titrate the dose by adjusting the frequency and depth of inhalation.e. A second cannabinoid receptor. although they are assumed to play a role in the regulation of food intake and body weight.48 . and about 10% of that age group are regular users. the cerebellum. there are no well-established data regarding the physiological role of the endocannabinoids. Notes about the scheme Cannabis acts as an agonist at the CB1 cannabinoid receptor. CB2. to its indirect capacity to enhance dopaminergic transmission in the 'reward' pathway (i. Δ9tetrahydrocannabinol (THC). Cannabis can also be taken orally in fat-containing foods or dissolved in suitable pharmaceutical oil. The experience of cannabis use is highly variable. Some users often report a subjective enhancement of visual and auditory perception. which is the only one known to date to be expressed in the brain. by suppressing GABAergic neurons that modulate the dopaminergic pathway).

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11). although animal studies have demonstrated that such compounds can antagonize some of the effects of LSD. years. Reassurance. Low-potency APDs such as chlorpromazine have been shown to induce seizures and to cause cardiovascular collapse when co-administered with hallucinogens. and supportive care are the hallmarks in the treatment of hallucinogen intoxication. That is. or dependence. In contrast to other abused drugs (heroin and cocaine). psychotic. There are some animal data implying that chronic LSD abuse causes depletion of serotonin from presynaptic nerve terminals. in the complete absence of the drug. They usually do so at doses that are not toxic to mammalian organ systems. and there appears to be no relationship between frequency of hallucinogen use and rate of occurrence. hallucinogens are powerful in producing altered states of consciousness as their primary effect. usually as a consequence of fatal accidents such as during LSD intoxication. It enhances the activities of postsynaptic 5-HT2 serotonergic receptors and it causes a decrease in the firing rate of serotonergic neurons. and it reverses in about a week following complete abstinence. Anxiety states can be treated with hertzodiazepines. Serotonergic antagonists prevent animals from identifying LSD in drug discrimination tests. It can also stimulate (probably indirectly) dopaminergic transmission. in some cases. reduction of sensory input. To date.Notes about the scheme Hallucinogens are generally considered to be physiologically safe molecules whose principal effects are on consciousness.50 . no antidote has been found to be beneficial in reducing or eliminating hallucinogen-induced clinical symptoms. Many natural and synthetic hallucinogens are abused by humans.Ndimethyltryptamine (DMT). The net effect of these changes is tolerance to the drug effects and decreased serotonergic transmission in the affected regions. or possibly aggressive. It is relatively well established that LSD acts at two main sites. but if the patient is severely agitated. including the mesolimbic and mesocortical pathways.49 . originating from the ventral tegmental area (VTA) and projecting to major limbic structures (the nucleus accumbens and olfactory tubercle) and to the frontal cortex. The most studied and the 'first' abused (prototypic) synthetic hallucinogen is lysergic acid diethylamide (LSD). These are dopaminergic neurons. Hallucinogens or LSD do not induce physical dependence and no clinically significant withdrawal syndrome is apparent. hallucinations (usually visual). which have been termed the 'reward' system. mescaline. due possibly to degenerative processes at these neuron endings. and heightening of consciousness.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). and psilocybin (see Section 6. The natural substances most commonly abused are N.49 There is no evidence that any of the hallucinogens cause damage to any human body organ. The use of antipsychotics is usually not indicated. low doses of high-potency antipsychotic drugs (APDs) might be administered. probably due to the decreased serotonergic transmission mentioned above. Controlled studies of the use of 5-HT2 antagonists as possible antidotes for hallucinogens have not been performed. Repeated administration of LSD to rats was also found to downregulate the 5-HT2 receptors. Among the adverse consequences of hallucinogen use are so-called 'flashbacks'. perceptual distortions (depersonalization. Tolerance to the psychological and behavioral effects of LSD develops quite rapidly (2-4 days of repeated use). the stimulation of these reward mechanisms is relatively slight and LSD does not produce the classic reinforcing effects. and synesthesias). Flashbacks most often appear as visual symptoms and can persist for months or. Hallucinogen abuse can lead to death. derealization. LSD binds with high affinity either to the serotonin binding site itself or to an adjacent site on the serotonergic receptor. 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.

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When benzodiazepines are withdrawn. a short-acting benzodiazepine can be replaced by a longer-acting one. and at the same time.g. The increased influx hyperpolarizes the neuron and further enhances the inhibitory effects of the GABAergic neuron. The tapering schedule should include a reduction of about 20-25% of the consumed dosage per week. alprazolam should be tapered at a maximum rate of 0. anxiety. when they are suppressed. Buspirone has been found to be beneficial in reducing the craving for benzodiazepines. non-impaired psychomotor performance. benzodiazepines act as neuromodulators that enhance the inhibitory effects of GABA. Since GABAergic nerves exert inhibitory effects on major brain regions. and no anterograde amnesia. and lorazepam). alprazolam). they suppress the expression of the specific messenger ribonucleic acid (mRNA) coding for the production of the on subunit of the GABAA receptor. Benzodiazepine abuse is different from other substance abuse disorders (opiates. 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). leading eventually to their downregulation and to a decrease in chloride influx.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. 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. the GABAA receptors are still downregulated and their activities are relatively suppressed compared with their baseline status.Notes about the scheme Benzodiazepines exert their therapeutic effects by increasing the affinity of γaminobutyric acid (GABA) to the GABAA receptor and thus increasing chloride influx into the intracellular space. insomnia. Because of the decreased chloride influx into the intracellular GABAergic nerves that follows chronic benzodiazepine abuse.51 . Thus.g. with tapering-off starting only afterwards.53 . This is the physiological basis for the development of tolerance. Both are used primarily as anxiolytic agents. Several treatment options are relevant in the case of benzodiazepine abuse. and when they are chronically abused. Benzodiazepines enhance the activities of GABA at its receptor site. Therefore. In fact. 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). 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. the affected brain regions are in a relatively hyperexcitable state.5 mg every 3 days). Gradual tapering of benzodiazepines is probably the hallmark and the most effective approach. Detoxification can be accomplished within 7-21 days. chronic benzodiazepine abuse impairs the effectiveness of the GABAA receptors. Alternatively. and their main advantages are diminished abuse potential. For short-acting benzodiazepines (e. and tremor). As potential drugs of abuse. flunitrazepam. larger doses of benzodiazepines are needed to exert the same clinical effects.51 . This subunit is one of the major components responsible for the effective coupling between the GABAA receptor and the adjacent chloride channel. The gradual tapering enables the downregulated GABAA receptors to recover in parallel with the decrease in benzodiazepine dose. amphetamines. the absence of withdrawal syndromes during acute abstinence. This excitability causes increased noradrenergic neurotransmission and it might play a major role in the induction of characteristic withdrawal symptoms (agitation. a more conservative detoxification plan should be taken (e. short-acting benzodiazepines seem to be preferred among addicts because of the rapidity of their onset of action (alprazolam. most people do not find the subjective effects of benzodiazepines pleasant beyond their therapeutic anxiolytic or sleep-inducing effects.

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cardiac arrhythmia.and heteroreceptors (with consequent decreased secretion of norepinephrine and serotonin from presynaptic nerve terminals). It motivates smoking by about 1.56 Treatment of tobacco dependence involves a combination of behavioral therapies and pharmacological treatment. dependence on cigarette smoke represents a particularly potent form of nicotine addiction. only nicotine-replacement therapy and bupropion are approved by the US FDA for the treatment of tobacco dependence. Most attempts to quit smoking fail. which perhaps explains the difficulty many smokers experience when they try to quit the habit. is a non-selective norepinephrine reuptake inhibitor. and for nicotine in particular. and the prefrontal cortex. and serious toxicity with overdose. and that elevation reinforces tobacco use. Blocking dopamine release in the nucleus accumbens with antagonists or lesions attenuates the rewarding effects of nicotine. representing approximately one-third of the global population aged 15 and over. from which it reaches the brain very rapidly as series of boli each time the smoker takes a puff of cigarette smoke.In developed countries. This area of the brain is believed to mediate reward for nicotine use and for other drugs of dependence. Some anecdotal data suggest that it may have similar beneficial effects as bupropion. the efficacy of which is attributed to blockade of dopamine reuptake in the mesolimbic dopaminergic system. innervating the striatum. Thus. since it delivers the drug directly to the lungs. Cigarette smoke provides an ideal vehicle for the administration of nicotine. including 'antidepressants'. at least in longterm abstinence outcomes. The addictive power of tobacco is exemplified by the difficulty in quitting. as indicated by reduced self-administration in animals. which is attenuated by preventing dopaminergic signaling in the nucleus accumbens. However.55 The strongest evidence for the reinforcing influence of nicotine is that it supports self-administration.59 . data concerning its efficacy are limited and not wellestablished. 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. Nortriptyline.1 billion people all over the world. a central α2agonist that enhances the inhibitory effects of α2adrenergic auto. The mesocorticolimbic pathway originates in the ventral tegmental area. Pharmacological treatments include nicotine-replacement therapy and non-nicotine medications. may also be effective in prevention of smoking relapse. the accumulation of evidence supports the hypothesis that mesocorticolimbic dopaminergic systems mediate the reinforcement for continued drug use despite the harmful consequences. Nicotine is the primary psychoactive component of tobacco. the most efficacious 'antidepressant' for the treatment of tobacco dependence is bupropion. To date.54 Notes about the scheme For nicotine and other psychostimulant drugs of abuse. to date. making it the largest single cause of preventable death. a tricyclic antidepressant. However. and success is achieved only after repeated attempts in the minority of smokers. may be summarized as follows: nicotine elevates dopamine in the nucleus accumbens.58 Clonidine.57 Nortriptyline carries the risk of postural hypotension. smoking is presently estimated to cause 20% of all deaths. the amygdala. An oversimplification of the standard hypothesis of addiction.

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63"65 However. it is essential to understand basic pharmacological data about psilocybin and to know what kind of symptoms to anticipate. Their abuse potential produces partially harmful effects in a growing population of psychedelic drug users. where it binds with higher affinity to the 5-HT2A and to a lesser extent the 5-HT1A receptors. It does not cause alteration in electrolyte levels. altered psychological functioning. 5-HT2A. and alteration of thought and time sense. has been demonstrated to be superior to haloperidol (a first-generation 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). and 5-HT2C serotonergic receptor subtypes). in contrast to the indoleamine lysergic acid diethylamide (LSD). Concerning the use of antipsychotic drugs (APDs) in cases of psilocybin-induced hallucinations. enhanced ability for introspection.66 .60 Notes about the scheme Psilocybin is a substituted indolealkylamine that belongs to the group of hallucinogenic tryptamines. Therefore. affective activation. although it has been found in many species of mushrooms worldwide. The latter. represents a major center for the integration of sensory input.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'.61 Psilocybin interaction with serotonergic receptors has inhibiting effects on the dorsal raphe nuclei. hallucinations produced by psiiocybin intake may be treated with 5-HT2A antagonists such as ritanserin and ketanserin. risperidone. 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. besides its role as a major site for noradrenergic projections to various brain regions. perceptual changes such as illusions and synesthesias. it should be stressed that its psychotomimetic effects in vulnerable individuals may lead to unexpected dangerous behavior. Psilocybin was isolated from Central American mushrooms (Psilocybe mexicana). or liver toxicity. These mushrooms represent a growing problem regarding hallucinogenic drug abuse throughout the world. no affinity for dopaminergic D2 receptors. The serotonergic neurons arising from the raphe physiologically inhibit the adjacent locus ceruleus.62 The evidence reviewed suggests that psilocybin exhibits low toxicity and may be physiologically well tolerated. psilocybin-induced inhibition of these raphe neurons causes a net activation of the nearby locus ceruleus. or alterations in blood sugar. Its main psychic effects produce a well-controlled altered state of consciousness manifested by marked stimulation of affect.Psilocybin (4-phosphoryloxy-W. 5-HT1D. To date.60 Psilocybin interacts mainly with serotonergic neurotransmission (5HT1A. no physical damage has been well documented. but many psychiatric complications have been reported. Since it seems that psilocybin has agonistic activity at 5-HT2A receptors. Hence. This may explain some forms of perceptual alterations such as synesthesias. It should be noted that psilocybin and its active metabolite psilocin have. a second-generation antipsychotic (SGA) with 5-HT2A/D2 antagonistic properties. and it is assumed that psilocybin-containing mushrooms are among the major hallucinogenic drugs of abuse today.67 .60 with consequent perceptual alterations. Wdimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms with a worldwide distribution. The effects usually last from 3 to 6 hours. Based on the capacity of SGAs to antagonize the 5-HT2A receptor compared with the first-generation APDs.

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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 γaminobutyric 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, orfibrosis, 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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Chapter 7
Miscellaneous drugs/treatment modalities

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 acetykholinesterase (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 noncompetitive 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

mentioned overactivated neurotransmitter systems (dopaminergic. Thus. leading in some individuals to dystonic reactions. metoprolol. albeit non-selective. Dopaminergic receptors. Possible compensatory cholinergic receptor hypersensitivity occurs. Thus. noradrenergic. mirtazapine. a somewhat schematic conceptualization of EPS involves the following cascade of reactions: 1. a noradrenergic and probably serotonergic compensatory hyperactivity occurs. When APD serum levels are temporarily decreased (and while the dopaminergic receptors are steadily hypersensitive). with a consequent improvement in akathisia. mianserin. caudate. and trazodone) in treating akathisia. although it is presumed to act as a dopamine reuptake inhibitor and/or dopamine releaser. centrally and peripherally. Specifically. These. thus reducing its concentration. cholinergic. and trihexphenidyl. β-adrenergk antagonists These (atenolol. As a parallel reaction to the relative dopaminergic hypersensitivity. This is a selective α2-adrenergic agonist that suppresses the release of norepinephrine from presynaptic vesicles into the synaptic cleft. and propranolol) are beneficial in the treatment of akathisia (with about a 75% response rate) by blocking the presumed hyperadrenergic activity. This relative 'hypodopaminergic' and 'hypercholinergic' state is believed to be a major factor in drug-induced parkinsonism. all current available treatments for EPS focus on suppressing one or more of the above- . putamen. have an inhibitory effect on most brain areas. the drugs antagonize dopaminergic neurotransmission in the nigrostriatal pathway (from the substantia nigra to the basal ganglia). The main drugs used for this purpose are benztropine. They are regarded as first-line agents for this problem. and as long as the subject does not receive APD treatment. altered manipulation of the dopaminergic system. although it is apparent that it involves. ritanserin. 5. a relative hyperdopaminergic state exists. procyclidine. 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. 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 (SCAs). 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. Normally. This phenomenon is partially effective in recovering the baseline balanced dopaminergic-cholinergic activity. 6. 3. nadolol. via enhancing CABAA receptors. Bromocriptine acts as a postsynaptic dopamine agonist. and globus pallidus receive balanced cholinergic versus dopaminergic neural inputs. Zolmitriptan This is a selective 5-HTiD agonist that suppresses the release of serotonin from presynaptic neurons. selegiline. and are considered to be superior to all other anti-akathisia modalities. serotonergic. including on the hyperexcitability of the noradrenergic. at least in part. anecdotal data suggest that it is quite beneficial in alleviating akathisic symptoms. However. 4. However. and/or serotonergic). are upregulated and become hypersensitive. causing imbalanced dopaminergic-cholinergic neurotransmission.8-11 Benzodiazepines Clonidine 2.Notes about the scheme Extrapyramidal side-effects (EPS) can be caused by practically all antipsychotic drugs (APDs). The exact mechanism underlying the evolution of EPS is not fully understood. This notion is further supported by accumulated data about the beneficial effects of other. Its exact mechanism is unknown. serotonergic antagonists (cyproheptadine. It is usually used for treating migraine headaches. biperidone. Anticholinergic drugs These agents block the acetylcholine muscarinic receptors. and cholinergic systems. Dopaminergic agents These exert their effects by enhancing dopaminergic transmission. thereby decreasing cholinergic activity and alleviating adverse effects such as acute dystonia and parkinsonism. following chronic APD treatment (probably as a compensatory mechanism). Among these are monoamine oxidase inhibitors (MAOIs) (type B). leading to akathisia. Following administration of APDs. the basal ganglia. Normal administration of APDs is characterized by fluctuating serum drug levels.

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Unfortunately. 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. β3-adrenergic agonists.18 Bupropion (an antidepressant licensed as an aid for smoking withdrawal) inhibits the reuptake of norepinephrine and dopamine and has appetitesuppressant properties (demonstrated to be more effective than placebo for weight reduction).20 Leptin. an inhibitor of serotonin and norepinephrine reuptake. Orlistat inhibits pancreatic lipase and can block 30% of triglyceride hydrolysis in subjects eating a 30% fat diet. obesity is considered an epidemic. Sibutramine.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. is a potential therapeutic agent for the treatment of obesity. and glucagon-Iike peptide-1 agonists. All in all. these recommendations have proven to be ineffective in adequately addressing the broad. Several orlistat and sibutramine weightloss studies have been performed to date. Orlistat causes gastrointestinal side-effects (e. an antiepileptic agent that suppresses appetite in some patients. dyslipidemia.19 . and analogs are currently being developed. accumulating data suggest that it may increase the concentration of anorexogenic substances (i. 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. neuropeptide Y antagonists. All in all. As some redundancy exists in the central regulatory system controlling body weight. Its mode of action is far from being established. Obesity is associated with an increased risk of coronary artery disease as well as a metabolic syndrome comprising abdominal obesity.16 Other substances are currently being evaluated for treating obesity. Other agents include amylin. One of these is: zonisamide. it may act at the level of the hypothalamus by interfering with neuropeptide Y activities. resulting in accelerated morbidity and mortality. Topiramate. Compared with placebo. melanocortin-4 receptor agonists. an antiepileptic agent that has serotonergic and dopaminergic activity in addition to blockade of sodium and calcium channels. increased fasting blood glucose levels.14 . norepinephrine and serotonin). all of which are recognized cardiovascular risk factors.g.12 . a gut lipase inhibitor. although they are effective in some individuals. However. have been approved by the US FDA for body weight loss. a hormone produced by adipocytes that inhibits food intake. CB1 antagonists.17 It has been demonstrated to induce more weight loss than placebo when combined with a hypocaloric diet. and hypertension. some agents might need to be used in combination in order to exert more beneficial responses. 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. orlistat-treated patients lose about 3 kg and patients on sibutramine lose about 4 kg. and lifestyle changes constitute important recommendations for treatment. and frequent and fatty stools) and sibutramine is usually associated with small increases in blood pressure and pulse rate.In many industrialized nations. has undergone clinical trials. Diet. Ongoing studies are continuing to evaluate other drug treatments that may result in body weight reduction through a number of different mechanisms. and orlistat.e. diarrhea. It induces weight loss by affecting the physiological process of satiety and stimulating thermogenesis. exercise. enlarging scope of this public problem.

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as with most of the various antidepressant modalities. catatonic states. The most consistent alterations in intracellular functions are certain modulations of receptor functioning. and certain cases of schizophrenia. and American Society of Anesthesiology risk level 4 or 5. while ECT has been shown to normalize these functions. Additionally. Animal studies support the observation that ECT stimulates the release of various cathecholamines (especially norepinephrine and serotonin) into the synaptic cleft. is associated with increased and continuous expression of certain neurotrophic factors. leading to increased secretion of norepinephrine. Alterations in global brain functioning or in interneural transmission are also evident during ECT. Moreover. with average response rates of 7090%. with a consequent increase in their availability for neuronal transmission.Electroconvulsive therapy (ECT) is probably the most effective treatment for major depressive disorder (MDD) with psychotic features. Seizure induction is the most relevant and necessary event that has to take place in order to achieve the therapeutic effects of ECT.22 . ECT is also suggested to suppress both presynaptic a2-adrenergic and postsynaptic 5-HT1A serotonergic receptors. long-term ECT treatment.23 In contrast to the rarity of medical complications associated with ECT. such as tardive dyskinesia and neuroleptic malignant syndrome (NMS). Furthermore. ECT may be considered the firstline option for specific severe cases such as suicidal patients. Moreover. increased intracranial pressure. serotonin. It has also been proposed that ECT induces the production of an endogenous anticonvulsant that.21 Notes about the scheme ECT affects both intracellular and intercellular functioning. it has been reported to ameliorate the motor symptoms of Parkinson's disease and various other movement disorders. and upregulation of postsynaptic 5HT2A serotonergic receptors. Although ECT has no absolute contraindications. However. Furthermore. such as the '24-hour biological clock'. Other and less consistent evidence suggests that ECT is associated with increased cerebral blood flow and increased permeability of the blood-brain barrier. thus serving as an exogenous zeitgeber. is unclear as yet. among them stimulation of the N-methyl-D-aspartate (NMDA) receptor for glutamate. memory disturbances of varying severity are common and are by far the most bothersome adverse effects.1 and 2. It is a very safe procedure (the death rate due to treatment is approximately 1 in 10 000 patients). when released into the synaptic cleft might increase the seizure threshold and/or suppress limbic kindling.3. downregulation of postsynaptic (3-adrenergic and acetycholine muscarinic receptors. . with a consequent decrease in phospholipase C and adenylate cyclase activities. such as brain-derived neurotrophic factor (BDNF). The response rates for MDD without psychosis are comparable between 'regular' medications and ECT (about 70-75%). The mechanism underlying the clinical efficacy of ECT in several syndromes. ECT is highly effective for mania. catatonically stuporous patients. the reduced slow-wave sleep. especially the short rapid eye movement sleep latency. Several abnormal sleep parameters are also normalized following ECT. or those refusing food and fluids. and dopamine. relative contraindications include the presence of a brain tumor. compared with only about 40% for 'regular' antidepressant medications. certain mood disorders are associated with desynchronization of certain circadian rhythms. Some data. ECT inhibits the coupling of various neurotransmitters to their corresponding Gproteins. suggest that MDD might be associated with right-hemispheric dysfunction. and ECT has been shown to normalize such dysregularities. The role of these factors in depression is discussed in detail in Sections 2. based mainly on neuropsychological testing. and especially in affective disorders. and the high nocturnal temperature associated with depressive disorders. ECT is usually given to patients whose condition is refractory to or who are intolerant of antidepressant medication. unstable myocardial infarction. Moreover.

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Chapter 8 Drug interactions .

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For haloperidol. cardiac collapse. This is most evident with amitriptyline. Antihypertensive agents The antihypertensive effects of clonidine are reduced by about 50% when it is coadministered with clomipramine or desipramine. Carbamazepine also induces liver enzymes. No significant interactions were found with amitriptyline or desipramine and moclobemide. although rare cases of serotonin syndrome are documented. Morphine Amitriptyline. clomipramine. An increase in serum levels of nortriptyline and trazodone has also been reported. Antipsychotic drugs (APOs) Most APDs. leading to a decrease in TCA serum levels (up to 50% reduction in serum levels of amitriptyline. Thiothixene levels are usually increased by TCAs such as doxepin. or desipramine). Anticonvulsants Phenytoin. clomipramine. with a consequent reduction in serum levels of TCAs (observed with amitriptyline. Monoamine oxidase inhibitors (MAOIs) Co-administration is usually safe and effective. or desipramine. while thioridazine has been reported to increase desipramine serum levels. Anecdotal reports suggest that alprazolam might increase the serum levels of imipramine by up to 30%. More modest increases are found when fluoxetine is combined with trazodone.Alcohol (ethanol) Chronic abuse of alcohol can lead to enhanced activity of cytochrome P450 enzymes and a consequent decrease in tricyclic antidepressant (TCA) serum levels. convulsions. doxepin. clomipramine. and nortriptyline. desipramine. clomipramine. Amitriptyline and nortriptyline are safer than clomipramine. probably due to decreased gastrointestinal absorption of TCAs. amitriptyline. TCA levels could increase by up to 5-fold via inhibition of cytochrome P450 enzymes. These effects of carbamazepine have not been observed with clomipramine. Clonazepam can decrease desipramine levels. and trazodone can raise warfarin serum levels up to 30%. 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). a liver enzyme inducer. the net effect of enzyme induction (by phenytoin) and enzyme inhibition (by TCAs) seem to be in 'favor' of the inhibitory effects. but not by maprotiline. clomipramine. This is evident with amitriptyline. Methylphenidate This can increase TCA serum levels (clomipramine and nortriptyline). while diazepam can increase amitriptyline serum levels in a few cases. are inhibitors of the cytochrome P450 enzymes. thus potentially increasing each other's serum levels. with the doxepin-fluoxetine regimen. With paroxetine. Clomipramine should be avoided. Barbiturates These can induce cytochrome P450 enzymes. but have been reported with selective serotonin reuptake inhibitors (SSRIs). desipramine. and nortriptyline). doxepin. The antihypertensive effects of guanethidine can be reduced by doxepin. even though tested. leading to potential increases in TCA serum levels by 1-2-fold. Perphenazine has been found to increase serum levels of amitriptyline. desipramine. with a consequent reduction in serum levels of TCAs (amitriptyline. Fiber-rich diet This lowers serum levels of TCAs (desipramine and doxepin). Smoking Components of cigarettes/tobacco are hepatic enzyme inducers. Anticoagulants There are anecdotal reports of trazodone decreasing heparin serum levels by about 20%. and could be evidenced by hyperpyrexia. and nortriptyline. and death. desipramine or imipramine. and tachycardia). Benzodiazepines Most studies have revealed no significant interactions with TCAs. nortriptyline. as well as TCAs. Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine inhibits cytochrome P450 liver catabolic enzymes. Such changes were not found. Desipramine levels were not found to be impaired. desipramine. and nortriptyline). Central receptor interactions between alcohol and TCAs can cause impaired motor abilities (evident with amitriptyline. desipramine. Clomipramine. and nortriptyline). and nortriptyline. clomipramine. tremor. decreases serum levels of TCAs (especially desipramine and domipramine). Additive toxicity is rare. and doxepin can enhance the analgesic and respiratory effects of morphine (mediated by serotonergic stimulation). and clomipramine (the latter combination increases the risk for tardive dyskinesia). although this is not evident with . In these cases. although an additive adverse effect profile is evident (nausea. nortriptyline. desipramine. Levomepromazine can significantly increase clomipramine serum levels. Fluvoxamine also inhibits cytochrome P450 liver catabolic enzymes. leading to increased TCA serum levels by 2-4-fold.

12 .nortriptyline.

or imipramine. Anecdotal data suggest that citalopram may increase the serum levels of levomepromazine. Other SSKSs There are no published data about pharmacokinetic interactions between citalopram and any of the other SSRBs. or zuclopenthixol. APDs Escitalopram does not interfere with the metabolism of APDs. Sumatriptan There is an increased risk of central nervous system toxicity when escitalopram is combined with sumatriptan. 6 . citalopram may increase desipramine plasma concentrations by up to 50% Antipsychotic drugs (APDs) Citalopram does not interfere with the metabolism of APDs. 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. β -adrenergic antagonists Escitalopram may increase plasma levels of metoprolol.g. and there appears to be no evidence for acute kinetic or dynamic interactions between alcohol and citalopram. haloperidol. and this is reflected in their drug interaction profile. CYP2C19. This probably has minor or no clinical significance. Other SSRIs (e. There have been no case reports or controlled studies investigating the pharmacokinetic interaction between citalopram and alcohol (ethanol). partially by the cytochrome P450 enzyme CYP2C19 and partially by CYP3A4. who may be more sensitive to alterations in drug concentrations. Lithium No pharmacokinetic interaction has been noted when escitalopram is combined with lithium. for example patients on polypharmacotherapy and particularly elderly patients. citalopram has been used in several studies as an adjunct treatment of alcohol dependence. Sumatriptan There is an increased risk of central nervous system toxicity when citalopram is combined with sumatriptan. This was explained by a weak inhibitory effect of desmethylcitalopram on CYP2D6. Miscellaneous Neither citalopram nor selegiline appear to be affected by one another. and Ndesmethylcitalopram is further Ndemethylated by CYP2D6 to the likewise inactive metabolite desmethylcitalopram. Benzodiazepines There are no data of the effects of citalopram on the pharmacokinetics of benzodiazepines. Sibutramine A case of hypomania has been reported when cltalopram/escitalopram were combined with sibutramine. Lithium Citalopram does not appear to alter the kinetics of lithium when the two are co-administered.3-4 Antidepressants Addition of citalopram does not significantly affect the plasma concentration of tricyclic antidepressants (TCAs) such as amitriptyline. clomipramine. Antidepressants Escitalopram may increase desipramine plasma concentrations by up to 50%. fluvoxamine. Warfarin Co-administration of warfarin and citalopram produces a small increase in mean prothrombin time. Moclobemide There have been a few documented cases of serotonin syndrome when citalopram was combined with moclobemide. β-adrenergic blockers Citalopram may increase plasma levels of various β -blockers (mainly evident with metoprolol). Escitalopram This may be considered one of the safest SSRIs with respect to pharmacokinetic drug interactions. perphenazine. where it seems to have clinical efficacy. and paroxetine) display greater in vitro inhibition of CYP3A4. Citalopram does not have any significant effect on serum levels of digoxin. Buspirone There is one documented case report of serotonin syndrome when citalopram was combined with buspirone. clozapine. However. However. thioridazine. the isoform responsible for the 2-hydroxylation of desipramine. At a dose of 40 mg/day. fluoxetine. CYP2D6. Current data suggest that citalopram is neither the source nor the cause of any clinically important pharmacokinetic drugdrug interactions. citalopram caused no significant changes in plasma concentrations of chlorpromazine. and CYP1A2 than citalopram.5.Citalopram This selective serotonin reuptake inhibitor (SSRI) is N-demethylated to Ndesmethylcitalopram.

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including decreased energy. Antipsychotic drugs In a few cases. Bupropion A few cases have been reported suggesting that bupropion metabolism might be inhibited by fluoxetine. probably via the antiserotonergic properties of cyproheptadine. Lithium Evidence is not conclusive. potentially increasing their serum levels. in addition to increases in their plasma concentration. or by additive effects. resulting in phenytoin intoxication. delirious state. and serotonin syndrome with the combined Lithium-fluoxetine regimen. thus raising their serum levels. nausea and flushing. a few isolated reports have described the emergence of lithium toxicity. The combined Lithium-fluoxetine regimen is generally considered as safe.7 Benzodiazepines Fluoxetine may impair the elimination of some benzodiazepines such as diazepam and alprazolam. possibly associated with signs of toxicity. dry mouth. Morphine Fluoxetine may increase the serum levels of morphine. Buspirone Fluoxetine can antagonize the anxiolytic effects of buspirone. Concomitant treatment with fluoxetine and risperidone is associated with a mean 4-fold increase in the plasma concentration of risperidone. seizure induction. and memory loss. and parkinsonism) have been reported with fluphenazine. Methadone Fluoxetine may increase the serum levels of methadone. Even so. fluoxetine was found to produce a significant elevation in plasma levels of both trazodone and its metabolite m-chlorophenylpiperazine (mCPP). including fatal serotonin syndrome. 8 . sulpiride. The inhibitory effect of fluoxetine on carbamazepine metabolism might occur only at doses higher than 20 mg/day. 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). Fluoxetine can increase the risk of seizure induction when added to clozapine due to an increase in clozapine serum levels. pindolol. may cause a 2-4-fold increase in plasma concentration of tricyclic antidepressants (TCAs). The mechanism of this interaction may be attributed to the potent inhibitory effect of fluoxetine and norfluoxetine on the CYP2D6-mediated hydroxylation of TCAs. Calcium-channel blockers The combination of fluoxetine with the calciumchannel blockers nifedipine and verapamil has been reported to be associated with signs of toxicity such as edema. Antidepressants Fluoxetine at a dose of 20-60 mg/day. marked extrapyramidal sideeffects (akathisia. and propranolol). Fluoxetine may impair phenytoin metabolism. This can antagonize the antidepressant effects of fluoxetine.Alcohol (ethanol) The pharmacokinetics of alcohol are not significantly affected by fluoxetine. presumably via inhibition of cytochrome P450 enzymes. This might explain the occurrence of severe bradycardia or heart block. sedation. β-adrenergic blockers Fluoxetine has some capacity to inhibit the oxidative metabolism of β -adrenergic blockers (especially the lipophilic ones: metoprolol. Fluoxetine has been shown to increase haloperidol serum levels by about 20%.4. and thiothixene when fluoxetine is added to the regimen. Warfarin There may be a marked elevation of the International Normalized Ratio (INR) and prolongation of prothrombin time when fluoxetine is combined with warfarin. perphenazine. Antidiabetic drugs There are anecdotal data indicating enhanced hypoglycemia capacity when fluoxetine is added to hypoglycemic agents or given to insulin-dependent patients. 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. the major cytochrome P450 enzyme involved in the metabolism of carbamazepine. dystonia. which could eventually lead to abrupt emergence of psychosis and seizure disorder. Serotonin syndrome and seizure disorder have also been reported with this combination. psychomotor retardation. When given in combination with the heterocyclic antidepressant trazodone. Anticonvulsants Fluoxetine and its metabolite norfluoxetine are mild to moderate inhibitors of CYP3A4.

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Plasma levels of several antidepressant drugs (e. and warfarin. leading to an increase in tricyclic antidepressant (TCA) serum levels. and this effect is potentiated by the concurrent use of non-steroidal antiinflammatory drugs (NSAIDs) or lowdose aspirin. fluvoxamine inhibits the metabolism of caffeine. maprotiline. including fatal serotonin syndrome. ibuprofen. fluvoxamine but not fluoxetine was found to increase the plasma concentration of methadone by about 30-50%. possibly resulting in toxic effects. CYP3A4 is not significantly affected by fluvoxamine. Lithium Established data are lacking. even though they might be comparable to those of fluoxetine. and a few cases of hyperpyrexia and/or induction of seizure disorder were reported with a combined lithiumfluvoxamine regimen. anorexia. Fluvoxamine may increase the plasma clozapine concentration by about 5-10-fold.g. 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. most of the current data suggest that there are no clinically significant pharmacokinetic interactions between fluvoxamine and benzodiazepines. and seizures. Reversible inhibitors of monoam ine oxidase type A (RIMAs) To date. Lithium may enhance the serotonergic effects of fluvoxamine. Antidepressants Fluvoxamine inhibits the cytochrome P450 liver catabolic enzymes (predominantly this is inhibition of N-demethylation). sometimes fatal. Fluvoxamine can increase the risk of seizure induction when combined with levomepromazine. clomipramine. since carbamazepine is metabolized mainly by the cytochrome P450 enzyme CYP3A4 while fluvoxamine is metabolized by CYP1A2. to the fact that both theophylline and fluvoxamine are metabolized (at least to some extent) by hepatic CYP1A2. However. clinically significant or severe interactions between fluvoxamine and moclobemide have not been found in several relatively well-controlled studies.2-fold increase in serum haloperidol concentration. As theophylline toxicity is a serious. Even at low daily doses (10-20 mg). Monoamine oxidase inhibitors (MAOIs) Few data are available about fluvoxamine interactions with MAOIs. to the fact that both propranolol and fluvoxamine are metabolized by hepatic CYP1A2. Anticonvulsants Co-administration with fluvoxamine may result in increases in carbamazepine serum levels by up to 60%. imipramine. The selective serotonin reuptake inhibitors (SSRIs) increase the risk of upper gastrointestinal bleeding. Fluvoxamine has also been found to increase olanzapine plasma concentration by approximately 2fold.4-7'8 . desipramine. This is due.8-4. another methylxanthine. amitriptyline. Fluvoxamine at a daily dose of 50-100 mg causes a 3-4-fold increase in the plasma concentration of mirtazapine. Anticoagulants A potentially dangerous interaction may occur between fluvoxamine and warfarin. probably. Methadone In addicts on maintenance treatment with methadone. nausea. There are anecdotal reports of bleeding disorder with the concomitant use of nicoumalone (a coumarin derivate). β-adrenergic blockers Co-administration of fluvoxamine 100 mg/day with propranolol 160 mg/day can result in up to a 5-foid increase in plasma propranolol concentrations (without major impairments in blood pressure or cardiac transmission). probably. condition. The mechanism is not totally understood. This is due. Theophylline Concomitant treatment with fluvoxamine may cause a marked elevation in plasma theophylline levels associated with signs of theophylline toxicity. and nortriptyline) have been reported to increase by up to 4-fold during coadministration with fluvoxamine.Alcohol (ethanol) The pharmacokinetics of alcohol are not significantly affected by fluvoxamine. A n t i ps y c h ot i c dr u g s Addition of fluvoxamine 50-300 mg to haloperidol results in a 1. including ventricular tachycardia. Benzodiazepines Fluvoxamine may decrease the metabolism of alprazolam and diazepam. fluvoxamine should be avoided in patients taking theophylline. There is a 65% increase in plasma warfarin concentration and a significant prolongation of prothrombin time.

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Methadone Oral contraceptives No significant pharmacokinetic interactions have been found up to date between oral contraceptives and paroxetine. moclobemide and paroxetine orfluoxetine appeared to produce adverse effects indicative of potentiated serotonergic activity. Alcohol (ethanol) and sedative drugs Paroxetine does not appear to potentiate the sedative effects of psychomotor retardation induced by amylobarbital. Steady-state plasma methadone levels may rise with paroxetine. Clinically significant bleeding was observed in approximately 25% of healthy volunteers receiving paroxetine 30 mg/day and warfarin 5 mg/day for 14 days. Clinically significant or severe interactions have not been found to date. Benzodiazepines Paroxetine has not been found to alter the pharmacokinetics of diazepam or oxazepam. with associated extrapyramidal side-effects. Anticonvulsants Serum levels of paroxetine can decrease when it is co-administered with anticonvulsants (some of which are enzyme inducers). but it seems that phenytoin may cause the greatest decrease. anecdotal reports suggest that bleeding tendency may be increased by the co-administration of the two drugs. If paroxetine is administered with clozapine. In addition to being metabolized by CYP2D6. However. Antidiabetic drugs Paroxetine is highly protein-bound. desipramine. it is susceptible to pharmacokinetic interaction with drugs that either induce or inhibit this enzyme. mean plasma concentrations of clozapine and norclozapine may increase significantly (by about 30%). Antipsychotic drugs A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are combined.Paroxetine is metabolized by the hepatic cytochrome P450 enzyme CYP2D6. With respect to the second-generation antipsychotic drugs (SGAs). the combined use of paroxetine and benzodiazepines is considered relatively safe. Administered together in patients with depression. but only in poor CYP2D6 metabolizers. Cimetidine This can increase paroxetine serum levels by up to 50% (due to its inhibitory effects on hepatic microsomal enzymes). Note that TCA levels could also increase. Antidepressants Paroxetine levels might be increased (tricyclic antidepressants (TCAs) inhibit its metabolism). These adverse effects are not necessarily associated with hepatic drug-drug interactions. Valproate serum levels are unchanged by paroxetine co-administration. Sumatriptan When combined with paroxetine. Hence. this may lead to weakness. Raised paroxetine levels after the addition of pindolol have also been reported. Studies so far have confirmed this with desipramine and imipramine (whose half-life can increase by 5-fold). followed by carbamazepine. CYP2D6 by paroxetine may lead to accumulation of another β-blocker metoprolol. Paroxetine has also been shown to increase haloperidol and perphenazine serum levels. imipramine. and in vitro studies have shown that it does not significantly alter the protein binding of glibenclamide. and nortriptyline. Lithium No significant pharmacokinetic interactions have been found to date between lithium and paroxetine. or oxazepam. Warfarin No significant pharmacokinetic interactions between paroxetine and warfarin have been found to date. hyperreflexia and incoordination. paroxetine did not affect the pharmacokinetics of propranolol. However. alcohol. even though they might be similar to those of other selective serotonin reuptake inhibitors (SSRIs). since paroxetine concomitantly inhibits their metabolism. although the clinical significance is questionable. From a pharmacokinetic perspective. The mechanism is presumably via inhibition of hepatic enzymes.4-7-8 β-adrenergic blockers In a number of interaction studies. the inhibition of . Monoamine oxidase inhibitors (MAOIs) Few data are available about paroxetine interactions with MAOIs. paroxetine inhibits this enzyme. probably via CYP2D6 inhibition. The data are limited. This may lead to enhanced plasma concentrations of any co-administered drugs that are metabolized by CYP2D6. this is evident mainly with amitriptyline. paroxetine at a dose of 20 mg/daily produces a 3-9-fold elevation in plasma risperidone.

since inhibition of the hepatic enzyme CYP2D6 is dosedependent. current data suggest that the co-administration of sertraline with hypoglycemic agents is generally safe. in healthy volunteers. CPY2E1 rarely metabolizes any of the other regularly used 'psychiatric' drugs. However. However. fluvoxamine. Even so. This is due. Anticonvulsants Sertraline at a dose of 200 mg/day does not alter the pharmacokinetic parameters of carbamazepine (metabolized by CYP3A4) and phenytoin (metabolized by CYP2C9). 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. coadministration of sertraline 50-200 mg/day with diazepam or alprazolam caused no significant modifications in their pharmacokinetic Alcohol (ethanol) Current data suggest no clinically significant pharmacokinetic interaction between sertraline and . Such findings are to be expected since both clozapine and olanzapine are metabolized mainly by CYP1A2. Antidiabetic drugs In most studies. With regard to this. no clinically significant pharmacokinetic interactions were found with the combined use of tolbutamide and sertraline. at its usual effective dose of 50 mg/day. while sertraline is metabolized by other isoenzymes. to the fact that alcohol is metabolized by the hepatic cytochrome P450 enzyme CYP2E1. Antipsychotic drugs Anecdotal reports have documented a moderate increase in the plasma concentration of clozapine after co-administration of sertraline. probably. some anecdotal data suggest clinically insignificant increases in serum tolbutamide levels when combined with sertraline. and paroxetine). Antidepressants Sertraline. Moreover. formal kinetic studies have indicated that sertraline does not significantly affect plasma concentrations of clozapine or olanzapine. Acute liver damage possibly related to sertraline and venlafaxine ingestion has been reported. The latter does not metabolize sertraline. No pharmacokinetic interactions have been found with the combination of glibenclamide and sertraline. Benzodiazepines There is no evidence of a metabolic interaction between sertraline and benzodiazepines. significant increase in plasma concentration of TCAs may occur when higher doses of sertraline are administered.alcohol. Thus.

even though they are expected to be similar to those of the other SSRIs.4. sertraline is assumed to exert the least effect on warfarin. Dolasetron A serotonin syndrome has been reported with the combined use of both drugs. 8 . Of the SSRIs. there is an increased risk of central nervous system toxicity. Warfarin Sertraline has been found to produce small increases in the free fraction of warfarin and a modest (-9%) increase in prothrombin time. Lithium Most studies have found that sertraline does not decrease lithium serum levels (or does so only negligibly). Monoamine oxidase inhibitors (MAOIs) Few data are available about sertraline interactions with MAOIs. serotonin syndrome has been reported with the combined tranylcyprominesertraline-clonazepam regimen. β-adrenergic blockers No pharmacokinetic interactions have been found with the combined sertraline-atenolol regimen. Thus. At present. However. However. has been reported with the combined tranylcypromine-sertraline (and clonazepam also) regimen. the combined use of sertraline and sumatriptan is not usually recommended. only this specific combination should be avoided. Hence. the most serious reported adverse effect of the combined regimen was the enhancement of lithium-induced tremor. Hence. To date.parameters. Cimetidine This can increase sertraline serum levels by about 25%. Tramadol Serotonin syndrome has been reported when tramadol was combined with sertraline. 7. Oxycodone Visual hallucinations and tremor induced by sertraline and oxycodone in a bone marrow transplant patient have been reported. the co-administration of these two agents is considered relatively safe (with regard to pharmacokinetic interactions). serotonin syndrome Sumatriptan This is a 5-HT1D agonist (inhibiting the release of serotonin from presynaptic nerve terminals). The data are limited and the clinical significance of such findings is currently questionable. which are considered clinically insignificant. even though it suppresses central serotonergic transmission (opposite to the effect of sertraline).

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respectively. Benzodiazepines Caffeine Single-dose venlafaxine does not alter the single-dose pharmacokinetic profile of caffeine (metabolized by CYP1A2). SNRIs To date. Formation of the Odesmethyl metabolite is mediated by the cytochrome P450 CYP2D6 isoenzyme. with only limited protein binding (<30% for both parent drug and metabolite). whereas the majority of Ndemethylation seems to be via CYP3A4. venlafaxine undergoes extensive first-pass metabolism to a major metabolite (O-desmethylvenlafaxine). serotonin-norepinephrine reuptake inhibitors (SNRIs) and antidepressant drugs. Hence. there are no other reported interactions between any of the other SNRIs (i. O-didesmethylvenlafaxine). when switching from fluoxetine to venlafaxine. The oral clearance of diphenhydramine. Therefore.4. 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. duloxetine and milnacipran) and MAOIs. there are no other reported interactions between any of the Diphenhydramine This drug significantly increases the plasma concentration of venlafaxine. It is widely distributed in the body. To date. if at all. leading to a higher concentration of venlafaxine in the blood. and the way in which venlafaxine and its major metabolite Odesmethylvenlafaxine are metabolized in the liver by these enzymes may reduce the clearance of both the parent drug and its active metabolite. Monoamine oxidase inhibitors (MAOIs) Combinations of venlafaxine and MAOEs have been reported to cause or be associated with serotonin syndrome. however. However. caution is advised with the use of cimetidine and venlafaxine in elderly patients. such combinations must be considered carefully.e. Paroxetine has been shown to moderately increase duloxetine concentrations. The reason for titrating the venlafaxine dose is that fluoxetine inhibits both CYP2D6 and CYP3A4. there are no reported interactions between the SNRIs. Upon absorption.Venlafaxine is rapidly absorbed after oral administration. Venlafaxine is extensively metabolized by CYP2D6. this interaction is unlikely to be of clinical significance. Cimetidine The steady-state plasma concentration of venlafaxine increases by 61% when it is combined with cimetidine. and in patients with hepatic or renal dysfunction. 7. 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. in patients with pre-existing hypertension. the potential for drug interactions is reduced compared with drugs that are metabolized by this system. To date. When milnacipran was administered with lithium in healthy volunteers. Coadministration of milnacipran and levomepromazine increases the milnacipran plasma concentration because of a modification of the apparent total clearance of the drug. is reduced by 6% and 18%. Because milnacipran has low and non-saturable protein binding and is not metabolized by the hepatic cytochrome P450 system. 10 . When milnacipran was administered with lorazepam in healthy volunteers. Alcohol (ethanol) Antidepressants Venlafaxine does not alter the pharmacokinetic disposition of alcohol in healthy volunteers. in both extensive and reduced metabolizers. and to two minor metabolites (N-desmethylvenlafaxine and N. no changes in the pharmacokinetics of any drug were detected. with food or fasting dietary conditions minimally affecting the rate and extent of absorption. venlafaxine weakly inhibits the metabolism of risperidone. no changes in the pharmacokinetics of any drug were detected. Antipsychotic drugs At steady state. 9. Single-dose venlafaxine does not alter the singledose pharmacokinetic profile of drugs metabolized by CYP3A4 (alprazolam and diazepam). which is equal in antidepressant activity to the parent compound.

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O-dealkylation. In vitro hepatic experiments have indicated that CYP3A4 is the major enzyme responsible for the metabolism of reboxetine. Benzodiazepines Studies in healthy subjects have shown that reboxetine does not significantly interfere with the pharmacokinetics of alprazolam or lorazepam. clozapine. and -3A4. it should be administered cautiously to patients taking medications (e. Cimetidine General enzyme inducers co-administered with bupropion could theoretically induce the metabolism of bupropion. Antidepressants Desipramine is metabolized by CYP2D6 and when co-administered with bupropion. including hydroxylation. Long-term administration of valproate (a weak inhibitor of hepatic metabolism) has no effect on bupropion plasma concentration. Cyclophosphamide Potential interactions between bupropion and cyclophosphamide (affected by CYP2B6) may be expected. Orphenadrine Potential interactions between bupropion and orphenadrine (affected by CYP2B6) may be expected. and theophylline. 2E1. For example. co-administration of reboxetine 8 mg/day did not affect the plasma levels of either clozapine or risperidone. 12 L-Dopa (levodopa) . 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. Antidepressants Reboxetine does not affect the pharmacokinetic parameters of fluoxetine. 11. Alcohol (ethanol) Bupropion administered as a single dose of 100 mg did not exhibit clinically significant pharmacokinetic interactions with alcohol. Nicotine It has been observed that the incidence of treatmentemergent hypertension is elevated among patients treated concurrently with bupropion and nicotine patches compared with patients treated with bupropion alone. results of clinical studies have been inconsistent regarding this possibility. Reboxetine Reboxetine has a complex hepatic biotransformation in humans. antipsychotics. increases the incidence of adverse experiences such as gastrointestinal effects. cimetidine has not been found to affect the pharmacokinetics of bupropion. its plasma half-life is prolonged by approximately 2-fold. Seizure-inducing agents Bupropion should be administered cautiously to patients taking medications or undergoing treatment regimens that may lower the seizure threshold (e. Antipsychotic drugs Bupropion can considerably lower the seizure threshold. However. 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. systemic corticosteroids. and oxidation. or olanzapine) or undergoing treatment regimens that may also lower the seizure threshold. 8. The administration of bupropion and L-dopa Dextromethorphan Studies in healthy volunteers have shown that reboxetine 8 mg/day does not interfere with the pharmacokinetics of dextromethorphan:4.g. Bupropion and hydroxybupropion inhibit CYP2D6 in vitro. Antipsychotic drugs In a study of patients with schizophrenia or schizoaffective disorder. followed by glucuronidation and sulfoconjugation.g. antidepressants. In addition. reboxetine was found to be a weak in vitro inhibitor of the activity of CYP2D6 and CYP3A4. -2A6. It has been shown that bupropion does not cause clinically relevant changes in the pharmacokinetics of a single dose of 100 mg of lamotrigine.Bupropion Bupropion is metabolized to hydroxybupropion primary by the cytochrome P450 CYP2B6 isoenzyme and to a much lesser extent by CYP1A2. Anticonvulsants Carbamazepine decreases the plasma concentration of bupropion to about 90% even after a single dose of 150 mg of carbamazepine. -2C9. Hence. and restlessness compared with the use of L-dopa alone. excitement. low-potency neuroleptics.

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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. and oxyphenbutazone.14'19 Marked electroencephalogram changes and tonic-clonic seizures have been observed when lithium has been combined with clozaplne. withdrawal from caffeine can result in increased serum lithium concentration. Pharmacokinetic interactions between lithium and newer antidepressants seem to be of no clinical importance. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations. can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis.24 In contrast.Alcohol (ethanol) and sedative-hypnotics The effects of alcohol do not appear to be potentiated by the simultaneous administration of lithium. Therefore.31 Electroconvulsive therapy (ECT) A lithium-free interval of 24-48 hours is recommended before surgical intervention or narcosis.14 Anticonvulsants Some anecdotal reports have suggested that phenytoin or carbamazepine can possibly increase the frequency and intensity of lithium-induced adverse events..24 Special caution is advised when long-term thiazides are combined with lithium. some clinicians consider the combination of lithium and calcium-channel blockers potentially hazardous. as well as an increased risk of extrapyramidal side-effects and seizures. Non-steroidal anti-inflammatory drugs (NSAIDs) Various NSAIDs.14 Regarding the selective serotonin reuptake inhibitors (SSRSs) and venlafaxine. piroxicam. especially in polyuric patients.14 The action of muscle relaxants that are used during general anesthesia or ECT (pancuronium bromide.14 Verapamil usually increases lithium clearance. metronidazole.17'18 There is a risk of bradycardia when fluoxetine and lithium are combined.34 . and ticarcillin.25 Nevertheless.22 Caffeine Heavy caffeine consumption may increase the renal clearance of lithium. an angiotensin II antagonist. succinykholine bromide. whereas methyldopa has been reported to induce neurotoxic symptoms in some lithium-treated patients.15 Regular monitoring of lithium plasma levels is advised when it is combined with cisplatin in cancer patients.26~29 There is a risk of lithium intoxication with simultaneous administration of angiotensin-converting enzyme inhibitors (ACEIs). there are anecdotal reports of serotonin syndrome when they are combined with lithium. was anecdotally reported to induce lithium intoxication. indomethacin. No apparent interactions have been observed with moclobemide or phenelzine.14 Antibacterials and antineoplastics Increases in serum lithium concentration have been reported in patients receiving antibacterials (e.35 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. spectinomycin.g. a worsening of lithiuminduced tremor may occur. phenylbutazone. such as ibuprofen. tetracyclines. lithium clearance may be reduced by up to 25%. and vancuronium bromide) can be prolonged by lithium.13 There are no clinically relevant interactions between lithium and benzodiazepines or other sedatives. furosemide and possibly xanthine derivatives such as caffeine do not possess such action and may even increase lithium excretion.30 Losartan.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. ketoprofen. No adverse interactions have been reported in patients treated with lithium and P-adrenoreceptor antagonists.20-21 Monoamine oxidase inhibitors (MAOEs) Few cases of tardive dyskinesia have been reported with the combined used of tranylcypromine and lithium.16 Antidepressants When tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) are combined with lithium.14 The potassium-sparing diuretics such as spironolactone can also increase plasma Theophylline Serum levels of lithium can be decreased by as much as 20-30% when theophylline is combined with lithium. since the lithiumtreated patient is generally endangered by the necessary restriction of water intake prior to such interventions.14 lithium concentrations. .

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Acetazolamide This can increase the serum levels of carbamazepine by up to 50%. No significant interaction has yet been found between paroxetine and carbamazepine or valproate. Carbamazepine has been reported to reduce valproate serum levels by about 60%. Higher doses of estrogen are vital to secure safety. These effects were not observed with clomipramine. and is partially associated with pre-existing brain abnormalities. and so can increase serum levels of carbamazepine. while it increases olanzapine clearance by 44% and reduces its half-life by 20%. Erythromycin produces a rapid 100-200% rise in carbamazepine levels. tranylcypromine. and nortriptyline). and when co-administered with carbamazepine it can increase the serum levels and effects of the latter. The diuretic effect of lithium outweighs the antidiuretic effect of carbamazepine. the aripiprazole dose should be doubled. Danazol Anticonvulsants Valproate has some inhibitory effects on hepatic metabolism. desipramine. Mefloquine may antagonize the anticonvulsant effect of carbamazepine. Loxapine may induce carbamazepine metabolism. with the possible development of toxicity (mechanism unclear). H 2 blockers Transient elevation of carbamazepine plasma levels is evident with cimetidine (due to the latter's cytochrome P450 inhibition capacity). doxepin. Carbamazepine does not protect against lithiuminduced diabetes insipidus. These have complex interactions with anticonvulsants. 36 . with a consequent reduction in serum levels of antidepressants (mainly described with amitriptyline. Carbamazepine induces hepatic catabolic enzymes. The co-administration of carbamazepine can (infrequently) cause significant (up to 50%) decreases in serum levels of clonazepam or Benzodiazepines Warfarin Serum levels and anticoagulant effects may be decreased due to the effect of carbamazepine on the hepatic metabolism of warfarin. Calcium-channel blockers Diltiazem and verapamil have inhibitory effects on hepatic microsomal enzymes. Carbamazepine has been shown to reduce the plasma levels of risperidone by as much as 50%. Ritonavir. A decrease in bupropion serum levels was also reported with carbamazepine. This inhibits the hepatic microsomal enzymes. Toxicity is possible while blood levels are within the normal range. Thus.1. may cause toxicity by raising carbamazepine plasma levels. respectively). Lithium Antipsychotic drugs Carbamazepine was found to decrease the plasma levels of phenothiazines by as much as 50% (described with chlorpromazine. and fluphenazine). afprazolam. Lithium can enhance carbamazepine-induced hyponatremia. Nifedipine has not been studied as well as the other calcium-channel blockers. Theophylline Isolated data suggest that theophylline might decrease carbamazepine serum levels. Carbamazepine and lithium can elevate each other's serum levels (the mechanism is unknown). and leads to the possible emergence of toxicity (disorientation and aggression). perphenazine. carbamazepine serum levels can increase by up to 2fold. imipramine. Monoamine oxidase inhibitors (MAOIs) Phenelzine. Oral contraceptives Carbamazepine has been shown to increase the hepatic metabolism and to decrease the effects and safety of oral contraceptives. Cyclosporine The metabolism of cyclosporine is accelerated by carbamazepine to give reduced plasma levels. Fluoxetine and fluvoxamine inhibit the metabolism of carbamazepine and valproate (up to 30% and 50% increases in serum levels. a protease inhibitor. mianserin. thus. moclobemide have no clinically significant interactions with carbamazepine. 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. Carbamazepine increases aripiprazole metabolism through CYP3A4 induction. but present data suggest that it probably does not interact significantly with carbamazepine. Digoxin Antidepressants Carbamazepine increases the risk of cardiac conduction disturbances (digoxin serum levels can decrease). Isoniazid increases carbamazepine serum levels. There is a possibility of reduced plasma levels of the protease inhibitors indinavir and saquinavir with carbamazepine. and Ranitidine This has little/no interaction with carbamazepine. Anti-infective drugs Ciprofloxacin can greatly increase the risk of seizure induction in patients taking anticonvulsants.

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Special caution should be used in patients who receive valproate and lamotrigine. and mitochondrial beta oxidation . Thus. phenobarbital. although this clinical outcome is rare.37-38 Benzodiazepines Lithium Methylphenidate Ranitidine/cimetidine . Valproate inhibits glucuronidation of zidovudine and increased events from zidovudine are possible. an effect of valproate on inhibiting the glucuronidation of olanzapine might be anticipated. Antiepileptic drugs The most extensive investigation of drug interactions with valproate has been with regard to its combination with antiepileptic drugs. Valproate has an insignificant effect on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. Valproate increases lamotrigine plasma concentrations. Combined use of valproate and haloperidol or chlorpromazine has not been found to result in any significant drug-drug interaction. although the combination of valproate and clozapine is considered relatively safe. contributing to the potential of valproate to cause hepatotoxicity. Combinations of valproate and ranitidine or cimetidine have not been found to result in any significant interaction that is likely to be clinically important. it should not interfere with the normal metabolism of steroid contraceptives. Phenobarbital or carbamazepine co-administration leads to higher clearance of valproate. including children. to increased lamotrigine concentration. resulting in increased clearance of valproate. probably. with corresponding reductions in plasma valproate concentrations ranging from 30% to 40% in adults.glucuronide conjugation. Of the three metabolic pathways of valproate elimination . Antipsychotic drugs The combination of antipsychotics and valproate is frequently used in patients. The combined use of valproate and lithium was not found to result in any significant drug-drug interaction. Valproate in combination with clonazepam was reported to result in increased absence seizures in children. Two patients aged 4 and 6 years old experienced tics and dyskinetic movements after starting on methylphenidate added to pre-existing treatment with valproate. Valproate inhibits diazepam metabolism and alters its plasma protein binding. Both patients improved when methylphenidate was no longer administered. This induction of microsomal enzymes by rifampin is thought to increase the production of toxic metabolites. Oral contraceptives There is no substantial evidence for enzymeinducing properties of valproate. The common use of aspirin should alert to the need for caution if these drugs are co-administered. While limited data appear to document interactions between valproate and benzodiazepines. Therefore. nor should it decrease the effective plasma concentrations of other drugs. Valproate has been reported to cause thrombocytopenia. Aspirin An interaction involving protein binding displacement may occur with aspirin.the first two have been shown to be inducible by other drugs (carbamazepine. and phenytoin). Antidepressants The combined use of valproate and paroxetine has not been found to result in any significant drug-drug interaction. with mood disorders and aggressive behavior. 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. Interaction with other non-steroidal anti-inflammatory drugs (NSAIDs) may not be so prominent. The interaction between valproate and lorazepam is marginal.Antibiotics Rifampin is a prototype inducer of the cytochrome P450 enzyme CYP3A4. because a severe rash reaction has been reported to occur due. Among the second-generation ('atypical') antipsychotic drugs (SCAs). cytochrome P450 oxidation. careful attention should be given to a potential increased risk of valproate and clozapine. the addition of valproate to pre-existing pharmacotherapy that includes a benzodiazepine should be accompanied by increased monitoring for effects such as sedation. especially as the use of combination pharmacotherapy for treatment of epilepsy is common.

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Anticonvulsants Topiramate interacts with other antiepileptic agents. teniposide. The mechanism is not clear. The concomitant use of topiramate with carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide may increase the risk of renal calculi. including carbamazepine. resulting in more rapid metabolism and elimination and reduced plasma concentration of topiramate. patients with moderate or several renal impairment show 42% and 52% reductions. topiramate has a Oral contraceptives Topiramate may compromise the efficacy of oral contraceptive drugs.41 . fluoxetine. tolbutamide. Lamotrigine enhances the metabolism of valproate. fluconazole. predominantly via /V-glucuronidation.39. Lamotrigine has not been found to alter the pharmacokinetics of lithium. phenytoin. Because of the depressant effects of topiramate on the central nervous system. with peak plasma concentrations being achieved approximately 2 hours after administration of a 400 mg dose. omeprazole. CYP2C19 inhibitors Drugs such as cimetidine.40 Alcohol (ethanol) Acetaminophen (paracetamol) This may reduce serum concentrations of lamotrigine. with approximately 70% of an administered dose being eliminated unchanged by the kidneys. felbamate. Carbonic anhydrase inhibitors Lithium Selective serotonin reuptake inhibitors (SSRIs) Toxicity has been anecdotally reported with the combined use of lamotrigine and sertraline. and valproate. Hepatic impairment may also decrease clearance. while enzyme-inducing drugs such as carbamazepine. while topiramate has been shown to increase phenytoin serum levels by about 50%. Lamotrigine is extensively metabolized in the liver. The phenomenon is relevant only in long-term use. Phenytoin can lower topiramate serum levels by up to 25%. Metabolism of topiramate is not extensive and its oral plasma clearance is slow. or race. Absorption of lamotrigine is unaffected by food. although the clinical relevance is unclear. and troglitazone that inhibit the cytochrome P450 enzyme CYP2C19 thereby inhibit the metabolism of topiramate and can increase its serum levels. Anticonvulsants Enzyme-inhibiting drugs such as valproate increase the plasma concentration of lamotrigine. in creatinine clearance. Carbamazepine can reduce topiramate serum levels by up to 25%. respectively. extreme caution is advised when administering the combination of topiramate and alcohol. Lamotrigine pharmacokinetics appear not to be significantly altered by many commonly used psychotropic agents. phenobarbital. Clearance in adults is not affected by age. Data about potential interactions with other SSRIs are currently not available.39 long elimination half-life of 19-25 hours. and undergoes minimal first-pass metabolism. Topiramate Absorption of topiramate is rapid and unaffected by food intake. 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%. When used as monotherapy. however. and phenytoin may decrease it. fluvoxamine. Linear pharmacokinetics show the peak lamotrigine concentration to occur 1-3 hours after a dose.Lamotrigine Oral lamotrigine is readily bioavailable (98%). sex. Lamotrigine may increase the serum concentration of the epoxide metabolite of carbamazepine.

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Anecdotal data describe marked hypotension and impaired consciousness when morphine is added to tranylcypromine. tranylcypromine is known to inhibit CYP2C19 and some potential for such an interaction exists. SRIs) should. Antipsychotic drugs Many reports. tranylcypromine. However. then the tricyclic antidepressants (TCAs) are conceived as relatively safer (especially amitriptyline and nortriptyline). Hyperpyrexia. which does not detoxify the ingested phenylephrine. with up to 50% of patients having toxic reactions (including serotonin syndrome). including some that became fatal when selective serotonin reuptake inhibitors (SSRIs: paroxetine and sertraline) were combined with MAOIs. Many studies have shown no clinically significant interactions with isocarboxazid. This is due to the inhibited gut monoamine oxidase. edema. Meperidine (pethidine) Many cases of serious (some fatal) adverse effects have been reported when meperidine is added to an MAOI (phenelzine or tranylcypromine). probably by inhibition of microsomal enzymes. Isolated cases of non-fatal hypertensive reactions (with phenelzine or tranylcypromine) have been reported. Hence. there are many reported cases of serotonin syndrome. present data suggest that antidepressants (at least the serotonergic drugs) should not be combined with MAOIs. Few data are available about potential interactions between the newly introduced antidepressant drugs and MAOIs (due. P-adrenergic blockers Propranolol used with MAOIs may cause severe hypertension and slight bradycardia. respiratory failure. they do not directly act on postsynaptic receptors). All in all. in isolated reports. and impaired consciousness (including coma and death). tremor. to the relative avoidance in clinical practice of such regimens). to enhance the activities of barbiturates (mainly amybarbital).Antidepressants Antidepressant drugs with dominant serotonergic enhancement capacity (i. including in patients with known adverse reactions to meperidine. especially in the elderly. except rare reports of fatal adverse effects when an MAOI (pargyline or tranylcypromine) was given with methotrimeprazine. including well-controlled studies. ephedrine. The combination should be monitored carefully. and morphine. be avoided as adjuvants to monoamine oxidase inhibitors (MAOIs) due to the potential induction of the serotonin syndrome. eventually leading to death (in some cases). Sympathomimetics (indirectly acting) Combining MAOIs with agents such as amphetamines. and others (including many cold and allergy medications) can cause a potentially fatal hypertensive crisis. cocaine. The concurrent use of fluoxetine and MAOIs (phenelzine and tranylcypromine) is considered highly dangerous. If an antidepressant is to be given with a MAO1. Dextromethorphan A few fatal cases and a couple of severe adverse effects have been reported with the combination of phenelzine and dextromethorphan. pseudoephedrine. most likely. phenylpropanolamine. methylphenidate. cardiovascular collapse/arrhythmias. this is normally considered a safe combination. combined therapy is relatively contraindicated. where possible. pemoline. have found no averse interaction with phenothiazines. Even so. Barbiturates MAOIs (mainly tranylcypromine) have been shown. but higher doses should be avoided. there are many published cases and studies that have not revealed any interaction between MAOIs and meperidine. and impaired consciousness/coma developed within minutes to a few hours of ingesting agents containing dextromethorphan. phenelzine. as should L-dopa as sole agent. Benzodiazepines Although there are isolated cases of MAOI toxicity. nausea. L-dopa (levodopa) Low-dose L-dopa with carbidopa or benserazide seems safe. and hepatotoxicity. muscle spasm. The mechanism of the potentially fata I reactions is unknown. Buspirone Warfarin No interactions have been reported to date. serotonin reuptake inhibitors. Morphine Phenylephrine Life-threatening hypertensive crisis has been reported with combinations of phenelzine or tranylcypromine and phenylephrine.7 . Sympathomimetics (directly acting) Combining MAOIs with agents such as epinephrine or norepinephrine is relatively safe since MAOIs cause them to accumulate in the nerve terminal (thus. Even so. The most commonly encountered adverse and serious symptoms are hyperpyrexia. Clinicians should monitor patients closely when using this combination.e.

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clozapine. no clinically significant interactions have been reported concerning the combined use of moclobemide and calcium-channel blockers (mostly examined with nifedipine). L-dopa (levodopa) Moclobemide has a negligible capacity to increase dopaminergic neurotransmission. Unlike the combined monoamine oxidase inhibitor (MAOI) and dextromethorphan regimen (where fatal interactions are well documented). Meperidine (pethidine) Many cases of serious (some fatal) adverse effects have been reported when pethidine is added to a RIMA. Benzodiazepines Morphine Oral contraceptives Co-administration of moclobemide with several types of oral contraceptives has not shown any significant interaction. but other studies suggest a greater risk (incidence increasing by up to 100%) of developing adverse effects. This effect was not confirmed in other studies. especially if they have pre-existing hypertension. 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. usually related to moclobemide (mainly sedation). clopenthixol. Digoxin No interaction has been reported. β-adrenergic blockers Moclobemide can further enhance the hypotensive properties of metoprolol. Hypoglycemic agents Numerous hypoglycemic agents (including chlorpropramide. and no clinically significant interactions have been observed. and no clinically significant interactions have been noticed. A ma n t a d i n e There has been an isolated report of a hypertensive reaction when amantadine was combined with moclobemide and other agents. and moclobemide. Diuretics Only a few published cases concerning the combined use of diuretics and moclobemide have been reported. fluvoxamine.Alcohol (ethanol) To date. Dietary restrictions are generally not required. but studies so far have revealed no significant interactions or major adverse side-effects when moclobemide is co-administered with L-dopa. and dose reduction of morphine and fentanyl should be considered. Ibuprofen This has no clinically significant interactions with moclobemide. Antipsychotic drugs Many reports have found no adverse pharmacokinetic interactions with most of the butyrophenones. Antidepressants A few cases of fatal and rapidly developing serotonin syndrome have been reported with the combined use of citalopram and moclobemide. due to its inhibitory effects on hepatic microsomal enzymes. and there does not appear to be any alteration in the efficacy of either agent. no clinically significant interactions have been reported concerning the combined use of moclobemide and alcohol. glibenclamide.7 Dextromethorphan . The mechanism is unknown and the clinical significance questionable. Clinically significant or severe interactions have not been found to date (in several well-controlled trials) with the combined use of fluoxetine. phenothiazines. Anticonvulsants Only a few published cases concerning the combined use of carbamazepine and moclobemide have reported to date. but the effect is usually mild and clinically insignificant. Calcium-channel blockers To date. and metformin) have been co-administered with moclobemide. but patients should avoid eating excessive amounts of tyramine-containing foods. 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. Tyramine Cimetidine Moclobemide does not appear to significantly potentate the pressor effects of tyramine. Hydrochlorothiazide was shown to have no significant interactions with moclobemide and there are no significant changes in the efficacy of either regimen. even though some inconsistent interactions were evident in animal studies. and sulpiride. nor with amitriptyline or desipramine when given with moclobemide. Lithium Preliminary data suggest that there are no significant pharmacokinetic interactions between moclobemide and lithium. there is only limited evidence from animal studies supporting potentially dangerous interactions between dextromethorphan and moclobemide. This can increase moclobemide serum levels by 40100%. Moclobemide is alleged to potentate the effect of opiates.

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Alcohol (ethanol) combined. Marked extra pyramidal side-effects have been reported in a few cases with fluphenazine or perphenazine when fluoxetine was added to the regimen. to alter alcohol metabolism (in contrast to haloperidol. Hydroxyzine The antipsychotic effect of phenothiazines may be decreased. to date. 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). Chlorpromazine and thioridazine have not been found. Propranolol Isolated data suggest that propranolol might reduce the elimination of chlorpromazine and thioridazine. fluphenazine. desipramine. There are anecdotal reports of fatal cardiac arrhythmia (ventricular fibrillation) with a combined phenylpropanolamine and thioridazine regimen. Phenylpropanolatnine Pimozide Pimozide and both chlorpromazine and thioridazine can prolong the QTc interval. Anticonvulsants Carbamazepine induces hepatic microsomal enzymes that can decrease the steady-state plasma levels of phenothiazines (reported mainly with chlorpromazine. Antacids Chlorpromazine serum levels can be rapidly decreased by about 50% (due to its absorption onto gel) when coadministered with antacids. Chlorpromazine increases imipramine serum levels. imipramine. and perphenazine). A mutual! increase in serum levels of both thioridazine and paroxetine is evident when these agents are Naltrexone There are anecdotal reports of prolonged and severe lethargy when naltrexone was co-administered with thioridazine. thioridazine.An increased risk of emergence of acute dystonic reactions has been described. which can increase alcohol levels). Anticholinergic drugs The combined use of phenothiazines (reported mainly with chlorpromazine) that have marked anticholinergic properties with other anticholinergic drugs can induce heat stroke. Some of these events were apparent while lithium serum levels were within the normal range.7 . and nortriptyline. Severe hypotension was evident in few cases when trazodone was added to chlorpromazine or trifluoperazine. mainly with fluphenazine and trifluoperazine. especially in hot and humid conditions. Thioridazine has also been shown to increase TCA serum levels (mainly desipramine). 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 flupenthixol. Disulfiram There is an anecdotal report of a more than 50% decrease in perphenazine serum levels when disulfiram was added to the regimen. fluphenazine. Perphenazine has been reported to increase the serum levels of amitriptyline. Orphenadrine This induces hepatic oxidizing enzymes and has been reported to lower chlorpromazine serum levels. The mechanism is not known. haloperidol. The rise in body temperature might be the result of suppressed sweat gland activity regulated by parasympathetic cholinergic innervation. with a consequent increase in their serum levels/therapeutic effects. 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. thus potentially increasing each other's serum levels. Chlorpromazine serum levels are reduced in the presence of lithium. Levomepromazine can cause a significant increase in clomipramine serum levels. or thiothixene. Barbiturates The serum levels of both barbiturates and phenothiazines (chlorpromazine and thioridazine) can be reduced by about 30%. Other serious adverse and additive effects of such combined regimens are the induction of paralytic ileus and atropine-like psychosis. Antidepressants Most antipsychotic drugs as well as tricyclic antidepressants (TCAs) are inhibitors of the chytochrome P450 liver catabolic enzymes. presumably because barbiturates are potent hepatic catabolic enzyme inducers. Chlorpromazine and thioridazine may increase the serum levels of phenytoin due to its inhibition of hepatic mono-oxygenase activities.

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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. Smoking Components of cigarettes/tobacco are hepatic enzyme inducers (mainly CYP1A2). Alcohol (ethanol) Numerous reports suggest that combined antipsychotic drug (APD)-alcohol consumption further impairs driving abilities and cognitive or neuromotor functioning. 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. and some permanent brain damage). Such serum level abnormalities are not observed with desipramine. However. there is opposing and substantial evidence that the concurrent use of these agents is safe. Additive adverse effects have also been reported when co-administered with clomipramine (rapid development of tardive dyskinesia). due probably to additive anticholinergic effects. Rifampin This can increase haloperidol elimination.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). Antacids Aluminum hydroxide can reduce the absorption of sulpiride and lower its serum levels. Indomethacin Isolated cases of severe drowsiness and fatigue have been reported when indomethacin was coadministered with haloperidol. side-effects. hyperthermia. Some data suggest that old age and administration during the acute phase of a manic episode hold a greater risk for developing these effects. Benzotropine Lithium There are anecdotal and rare reports of severe adverse effects induced by the combined haloperidol-lithium regimen (extrapyramidal There is an isolated case of reversible esophageal atonia and dilatation with thiothixene. There is another isolated report of impaired esophageal contractility with increased upper esophageal sphincter pressure with molindone. and haloperidol. no apparent interaction is evident to date between flupenthixol and imipramine or any other TCA. Antidepressants Thiothixene levels are usually increased by TCAs (doxepin and nortriptyline). Fluoxetine and paroxetine have been shown to increase haloperidol serum levels (by about 20%). and (to a lesser extent) sulpiride.7 . Unlike the established interactions between most phenothiazines and TCAs. Preliminary data suggest that haloperidol can lower valproate serum levels. Guanethidine Benzodiazepines Most data are consistent with relatively safe use of combined APDs and benzodiazepines (with respect to pharmacokinetic interactions). and this effect is noted mostly with chlorpromazine and flupenthixol. Marked extrapyramidal side-effects have been reported (a few cases only) with sulpiride or thiothixene when fluoxetine is added to the regimen. probably via inhibition of the cytochrome P450 enzyme CYP2D6. with a concomitant decrease in serum levels by about onethird. Alcohol serum levels could be elevated by concurrent use of haloperidol. Marked extrapyramidal side-effects have been reported (a few cases only) with haloperidol when fluoxetine is added to the regimen. Chlorpromazine This may significantly increase haloperidol levels. dyskinesia. Barbiturates Phenobarbital can lower haloperidol serum levels via inhibition of hepatic enzymes. delirium. The antihypertensive effects of guanethidine can be opposed by the concurrent use of haloperidol. Miscellaneous APDs (not haloperidol) Buspirone A few uncontrolled studies have shown an increase of about 50% in haloperidol serum levels. thioridazine. 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. in which serum levels of both agents could increase.

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Cigarette components also accelerate the metabolism of olanzapin. result in a moderate elevation (about 30%) of clozapine plasma levels. Benzodiazepines Caffeine There is a potential interaction between clozapine and caffeine. Ritonavir Administration of ritonavir. and so the aripiprazole dose should also be halved. Quinidine decreases aripiprazole metabolism. may decrease olanzapine plasma levels by about 50%. the combined olanzapine-warfarin regimen has not revealed any pharmacokinetic interactions. Anti-inflammatory drugs Ketoconazole decreases aripiprazole metabolism. in vivo studies with a combined olanzapine-imipramine regimen have not revealed any pharmacokinetic interactions. so this combination should be avoided. between clozapine and caffeine at the CYP1A2 enzyme. resulting in an increased concentration of one or both drugs. especially if smoking is stopped. The combined regimen is safe and effective. due probably to a competitive pharmacokinetic interaction . leading to a decrease in clozapine serum levels or therapeutic/side-effects. No interactions have been reported to date between aripiprazole and warfarin. Antidepressants Lithium To date. amisulpiride is unlikely to be involved in clinically relevant pharmacokinetic drug interactions. Smoking Components of cigarettes are hepatic enzyme inducers (especially of CYP1A2). To date. no pharmacokinetic interactions have been reported between aripiprazole and valproate. There are anecdotal data suggesting that the addition of ciprofloxacin 250 mg twice daily almost doubles the plasma concentration of olanzapine. There are no reports of pharmacokinetic interactions between olanzapine and benzodiazepines (studied mainly with diazepam). and so the aripiprazole dose should be decreased by about half during coadministration. a potent inhibitor of the cytochrome P450 enzymes CYP1A2 and CYP2C19 and a moderate inhibitor of CYP3A4. increasing its renal clearance and reducing its plasma half-life by as much as 40%.147 Amisulpiride Biotransformation in humans involves /V-dealkylation and oxidation. Erythromycin Anecdotal data suggest that erythromycin can increase clozapine serum levels (via CYP1A2 blockade). Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. Plasma concentrations of clozapine and its metabolites have been reported to be either slightly decreased or increased when combined with valproate. To date. Warfarin To date. Thus. while citalopram and sertraline have been reported to cause minimal or no elevation of plasma levels of clozapine. an HIV-1 protease inhibitor known to inhibit CYP3A4 and to reduce CYP1A2 at a dose of 300-500 mg twice daily. As a consequence of its limited metabolic elimination. with toxic effects. a potent inhibitor of CYP1A2. Ciprofloxacin Anecdotal data suggest that low doses (250 mg twice daily) of ciprofloxacin. no pharmacokinetic interactions have been reported between aripiprazole and lithium.Anticonvulsants These can decrease clozapine serum levels by about 60% (carbamazepine) and 85% (phenytoin) due to hepatic cytochrome P450-inducing properties. since each agent alone has the capacity to induce this sideeffect. 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. has been reported to cause a 5-10-fold elevation of plasma clozapine concentration. Diuretics There is an increased risk of bone marrow suppression with a combined captopril-clozapine regimen. Fluoxetine and paroxetine may also increase plasma clozapine concentrations.4 Antipsychotic drugs Anecdotal cases have been described of a substantial (about 2-fold) increase in clozapine serum levels following the co-administration of risperidone. Close monitoring is suggested. Fluvoxamine. although severe cardiovascular or respiratory adverse effects may occur with high closes of clozapine when combined with diazepam and lorazepam. but the isoenzymes involved in these reactions are as yet unidentified.

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It is contraindicated in patients receiving antipsychotic drugs known to prolong the QTc interval (e. Other antidepressants with a weaker inhibitory effect on CYP2D6. has been reported to decrease the plasma concentrations of risperidone and its metabolite (9-hydroxyrisperidone) by 5080%. Sertindole is extensively metabolized by CYP2D6 and 3A4 and is a weak CYP2D6 and -3A4 inhibitor. including amitriptyline. Anti-infective agents Rifampin induces CYP3A4. mirtazapine. Carbamazepine. Fluoxetine. 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). Anticonvulsants Carbamazepine. with possible occurrence or worsening of extrapyramidal symptoms. there have been no reports on the effects of other CYP3A4 inducers. Antidepressants Imipramine is a substrate of hepatic CYP2D6. quinidine. To date. sotalol. 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. but present data suggest that it has no significant effect on the pharmacokinetics of quetiapine. astemizole. Hence. in whom the addition of carbamazepine to pre-existing risperidone therapy resulted in a marked decrease in the plasma concentration of both risperidone and 9hydroxyrisperidone and in an acute exacerbation of psychotic symptoms. plasma levels of sertindole are reported to increase by about 2-3-fold. 7 . 4. 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. On the other hand. erythromycin. probably via CYP2D6 inhibition. Ketoconazole also causes a modest increase in ziprasidone plasma levels. have been found not to modify significantly the total plasma risperidone concentration. dexamethasone. and itraconazole. caution may be required when it is co-administered with other potent CYP3A4 inhibitors such as clarithromycin. When administered with fluoxetine/paroxetine. Since ziprasidone is associated with slight prolongation of the QTc interval. It is contraindicated in patients receiving drugs affected by the same enzymes or known to prolong the QTc interval. phenytoin. a potent CYP2D6 inhibitor and moderate CYP3A4 inhibitor. citalopram. QTc-prolonging drugs Sertindole is contraindicated in patients receiving drugs known to prolong the QTc interval.1. the serum levels of haloperidol 15 mg/day or risperidone 6 mg/day are not altered by the addition of quetiapine. Lovastatin A prolonged QTc interval has been reported with the combination of quetiapine and lovastatin (both of which undergo hepatic metabolism by CYP3A4). consequently accelerating quetiapine metabolism and decreasing its plasma concentration. The clinical relevance of this interaction was documented in a case study concerning a patient with chronic schizophrenia. such as amiodarone. such as amiodarone. Ketoconazole is a potent inhibitor of CYP3A4 and may increase quetiapine plasma blood levels by 235-522%.g. Since ziprasidone is associated with slight prolongation of the QTc interval. causes a minimal or statistically insignificant increase in quetiapine plasma levels. reboxetine. QTc prolongation by sertindole makes the combination of sertindole and macrolides a contraindication. an inducer of drugmetabolizing enzymes. decreasing its plasma concentrations and potentially leading to reduced efficacy. and barbiturates are all inducers of CYP3A4 and may accelerate the metabolism of quetiapine. and venlafaxine. thioridazine. on risperidone disposition. lower maintenance doses might be needed. Antipsychotic drugs Thioridazine at a dose of 400 mg/day significantly decreases quetiapine (given at 600 mg/day) serum levels by about 70%.Amiodarone Since ziprasidone is associated with slight prolongation of the QTc interval. and ziprasidone. fluconazole. such as phenytoin and phenobarbital. thioridazine and ziprasidone).

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Opiates There is an increased risk of death from respiratory failure. flurazepam. diazepam). including benzodiazepines. chlordiazepoxide. Diazepam was noted. The mechanism is unknown. the halflives of benzodiazepines such as alprazolam. nitrazepam.7 . which consequently alter benzodiazepine pharmacokinetics. with a possible enhancement of their therapeutic or adverse effects. Alcohol (ethanol) Alcohol and benzodiazepines produce synergistic central depression. A few studies have suggested that chlordiazepoxide. The effects of lorazepam and oxazepam are practically unchanged. Ranitidine probably has no significant interaction with most benzodiazepines. there is an isolated report of about 40% reduction in the clearance of chlordiazepoxide. leading to increased serum levels. probably via direct excitant action. diazepam. The mechanism is probably via induction by heparin of concomitant free fatty acid changes. Rifampin is a potent catabolic enzyme inducer. Tricyclic antidepressants Alprazolam has been found to increase imipramine and desipramine serum levels by about 25%. there are no reports suggesting clinically relevant interactions between lithium and benzodiazepines. Benzodiazepines metabolized by glucuronide conjugation (lorazepam. As a result. lorazepam. Consequently. diazepam. The clinical significance of this interaction merits further investigation. chlordiazepoxide. 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). probably via separate activity on the yaminobutyric acid (GABA) type A receptor. Isolated data suggest that disulfiram does not affect the metabolism of alprazolam.Acetazolamide This improves oxygenation at high altitudes. anecdotally. oxazepam. and triazolam were found to be increased. Lithium To date. Isoniazid reduces the clearance of diazepam and triazolam. thus enhancing the elimination of many agents. Anticonvulsants The co-administration of carbamazepine can infrequently cause significant decreases in serum levels of some benzodiazepines (described with alprazolam and clonazepam). diazepam. leading to enhancement of their therapeutic and/or adverse effects. and diazepam may elevate serum levels of phenytoin. and temazepam) are not affected by cimetidine. Oral contraceptives These inhibit oxidative metabolism and at the same time enhance glucuronidation. clonazepam. including benzodiazepines such as diazepam and nitrazepam (whose half-lives decrease to about 15-35% of baseline). Cimetidine inhibits the liver enzymes associated with oxidative metabolism. For ketoconazole. Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine can raise the serum levels of alprazolam and diazepam.g. and triazolam) were found to be increased when cimetidine was co-administered. and oxazepam. The cytochrome P450 enzyme CYP3A4 is speculated to be inhibited by erythromycin. Probenecid This inhibits the hepatic glucuronidation metabolism and the renal excretion of many drugs. Disulfiram This can antagonize the sedative or anxiolytic effects of benzodiazepines (e. the serum levels of most benzodiazepines affected by this metabolic pathway (alprazolam. Valproate displaces diazepam from plasma protein binding and possibly inhibits its metabolism. A n t i b i o t i c s / a n t i f u n g a l d r a g s There are many cases of increased serum levels of midazolam ortriazolam when co-administered with erythromycin. elimination half-lives of agents such as lorazepam have been reported to increase (up to 2-fold). Concomitant use should be avoided at high altitudes. can be significantly reduced. Benzodiazepines antagonize this effect due to an impaired respiratory response to hypoxia. Hence. Temazepam (an agent that undergoes metabolism via hepatic glucuronidation) was found not to be affected. but has no apparent effect on the pharmacokinetics of clonazepam or triazolam. and the half-life of lorazepam. Digoxin Theophylline This inhibits the metabolism of diazepam and chlordiazepoxide. to increase digoxin serum levels. H2 blockers Heparin This increases the free fraction of chlordiazepoxide. and to a lesser extent that of oxazepam.

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and tachycardia). Heavy drinkers. but not all. The risk of gastrointestinal bleeding is enhanced by concomitant use of alcohol and NSAIDs (and aspirin). leading to accumulation of acetaldehyde with a consequent anti-abuse reaction (flushing. a few studies have found alcohol to increase the serum levels of amitriptyline by up to 2-fold (due. N o n-s t e ro id a l a nt i. with a consequent decrease in TCA serum levels. Haloperidol can increase alcohol serum levels. Zolpidem and zopiclone To date. Mianserin and trazodone can aggravate impaired driving skills caused by alcohol. attention. Lithium Impaired driving skills have been reported. to a lesser extent. Amphetamines These can reduce some of the impairments attributed to alcohol abuse (memory. Some data suggest that alcohol might also inhibit the metabolism of nifedipine. clomipramine. Buspirone A minimal interaction and slightly increased sedation have been reported. hypotension. Some data suggest central receptor interactions between alcohol and TCAs that can cause impaired motor abilities (evident with amitriptyline. sulpiride. this effect being noted mostly with chlorpromazine and flupenthixol and. thereby worsening hepatic damage. while chronic alcohol abuse can decrease them complementary action on the y-aminobutyric acid (CABA) type A receptor. The mechanism is speculated to be via inhibition of hepatic alcohol metabolism. Zolpidem enhances alcohol performance impairment (the effect appears to be short-lived). dyspnea. headaches. reaction time. are at a greater risk. and alcohol have been observed. attention and functioning impairments caused by alcohol. while no clinically significant interactions between mirtazapine. vertigo. nefazodone.inf la m m at o ry drugs (NSAIDs) Ibuprofen has not been found to interact significantly with alcohol. Alcohol may produce a slight (12%) increase in peak lithium levels. and 10-30 minutes following the ingestion of alcohol. Antipsychotic drugs Numerous reports suggest that a combined antipsychotic-alcohol regiment further impairs driving abilities and cognitive or neuromotor functioning. vomiting. Disulfiram This antagonizes aldehyde dehydrogenase (which metabolizes acetylaldehyde. no clinically significant pharmacokinetic interactions between alcohol and zopiclone have been reported. although there are anecdotal data about the emergence of acute renal failure with combined alcohol-ibuprofen use. and thioridazine. there are no established data suggesting clinically significant pharmacokinetic interactions between alcohol and reboxetine or venlafaxine. fluvoxamine. thus raising its serum levels with consequent effects. the first metabolite of alcohol). recognition. and nortriptyline). H 2 blockers Some. nausea.7 Benzodiazepines . Raised heart rate and increased postural hypotension have been reported with quetiapine. doxepin. possibly. and decision making). acetaminophen (paracetamol) to Calcium-channel blockers Nifedipine and verapamil can increase alcohol serum levels by about 15-50%. especially. Fluoxetine. 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.Acetaminophen Alcohol can stimulate the conversion of hepatotoxic derivatives. Isolated reports suggest that fluvoxamine and paroxetine can slightly augment the motor. To date. Anticonvulsants Acute alcohol consumption increases serum phenytoin levels. although no clinically significantly adverse interactions have actually been reported. However. and paroxetine do not interact significantly with alcohol. Enhanced central nervous system sedation would be expected with olanzapine and quetiapine. chronic use of alcohol can enhance activity of the cytochrome P450 liver catabolic enzymes. Antidepressants With tricyclic antidepressants (TCAs). An increased incidence of acute dystonic reactions has been suggested with the combined use of alcohol and fluphenazine or trifluoperazine. to inhibition of amitriptyline metabolism). Alcohol and benzodiazepines produce synergistic central nervous depression due to Propranolol Alcohol may slightly reduce propranolol absorption and increase excretion. The mechanism involves the damaging effects of both agents on gastric mucosal cells. with haloperidol. leading to enhanced alcohol absorption). weakness.

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The presence of benzodiazepines and pblockers can reduce seizure duration. Among the selective serotonin reuptake inhibitors (SSRIs). 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. thiopental sodium) rapidly induce hypnosis. 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. then there is an increased risk that the ECT may stimulate epileptic foci. the combination of lithium and ECT is relatively contraindicated. methylphenidate. with methohexital probably being the most preferred agent. without significantly shortening seizure activity or causing hemodynamic instability. Small to moderate doses of these drugs have all been used successfully for this purpose. Therefore.51 Verapamil This is a calcium-channel antagonist. Most drug interactions with benzodiazepines are predictable and reflect the effects of two (or Benzodiazepines . Dopaminergic drugs To date. and pemoline pose a potential risk for potentiating seizure activity. methohexital. and topiramate. lamotrigine. to inhibit neuromuscular transmission and acts at the muscle membrane to inhibit muscle contraction. Buspirone To date. and short in duration. Some antidepressant drugs (e. there are no established data about such interactions between other calcium-channel blockers and ECT 4 β-adrenergic blockers The presence of p-blocker$ can reduce seizure duration. which can produce potentiation of suxamethonium and nondepolarizing neuromuscular blockers at doses within the therapeutic range. This is also a theoretical/practical concern with carbamazepine. and they may therefore cause dysrhythmias and heart block. no clinically significant interactions have been reported with the combination of ECT and buspirone. more) drugs with sedative properties (benzodiazepines in combination with thiopental sodium or propofol).g. Verapamil also exacerbates the increase in serum potassium levels after the administration of suxamethonium. propofol. Antidepressants Lithium This acts presynaptically. Succinylcholine is the only muscle relaxant that meets all of these requirements. If its use is contraindicated. profound in intensity. which can further progress into 'status epiiepticus'. and thus allow for rapid emergence from anesthesia. The anticonvulsant action of valproate may prevent ECT treatment from being effective by preventing seizure activity. As a rule of thumb. thereby leading to prolonged seizures or the risk of status epilepticus. Muscle relaxants These should be rapid in onset. gabapentin. Antipsychotic drugs These may enhance the effects of central nervous system depressants. mivacurium is currently the preferred short-acting alternative. routine administration of these agents during ECT is not advisable. via activation of ATP-sensitive potassium channels. no clinically significant interactions have been reported with the combination of ECT and estrogen compounds. Therefore. no clinically significant interactions have been reported with the combination of ECT and various dopaminergic drugs (e. Excessive seizure activity causes a higher incidence of unwanted adverse effects such as confusion and memory impairment.g.g. amantadine). fluoxetine may prolong seizure duration. Prolongation of neuromuscular block has been reported in patients receiving lithium and depolarizing and non-depolarizing neuromuscular blockers. To date. the doses of anesthetics drugs need to be titrated (usually reduced) to the effect required. Hence. Anticonvulsants CNS stimulants Central nervous system stimulants such as dextroamphetamine. tricyclics) inhibit the sodium/potassium adenosine triphosphatase (ATPase)-dependent pump that is important for membrane stabilization. Estrogen To date.Anesthetic induction agents These (e. Bupropion and trazodone can prolong seizure duration.

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Chapter 9 Treatment strategies (evidence based) .

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It may be necessary to add. If there is no response to the first trial. It is important to consider pharmacokinetic/pharmacodynamic factors (this may require an evaluation of serum levels of the antidepressant medication).g. moclobemide. and comorbid psychiatric disorders. trazodone.7). a previous episode of major depression. Olanzapine plus an antidepressant is second-line treatment. and tranylcypromine are third-line treatments. psychostimulants. The mean age of onset of MDD is approximately 30 years. medication should be switched to another non-MAOl. Amitriptyline and clomipramine are second-line treatments. and a first-degree family history of depression are the most consistently described risk factors for a depressive episode. If the second trial. For MDD with psychotic features. The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are usually considered as first-line treatments.2 The gross treatment options should follow the strategies listed in Scheme 9. paroxetine and venlafaxine are the first-line treatments. fluoxetine).3. medication should be switched to an MAOI. the trial should be extended by 2-4 weeks. most patients return to normal functioning with pharmacologic treatment). The following are only suggestions. paroxetine. including substance abuse and significant psychosocial problems. and benzodiazepines should be considered as adjunctive therapy. or increase the frequency of psychotherapy. preferably from a different class. Fluoxetine and moclobemide are second-line treatments. or hypomanic episode. Citalopram and fluoxetine are third-line treatments. the treatment regimen should be reappraised. MDD is a severe mood disorder. If only a partial response is achieved. Bupropion. Compliance should be checked.3 The treatment of MDD corresponds to three stages: acute phase. the minimum period is 5 weeks. treatment should be augmented with a non-MAOl antidepressant from a different class or another adjuvant medication (anticonvulsants. Phenelzine is the second-line treatment. and maintenance phase. lithium. ECT should be instituted. Untreated MDD has decreasing episode cycles with increasing episode number. Imipramine is the third-line treatment. TCAs. brightlight therapy is the first-line treatment.3 . with women being at a higher risk than men (the ratio is approximately 2 : 1 ) . pindolol. The disorder has a median life prevalence of 4. TCAs and moclobemide are the second-line treatments. Female gender. For partial responders. general medical comorbidities. mixed. For MDD with melancholic features. up to 20-30% of patients suffer chronically from at least some of their symptoms.5-18%. citalopram. change. continuation phase.1 Notes about Schemes 9.3 If the patient is not at least moderately improved after 4-8 weeks. Although the prognosis of MDD is generally considered quite favorable (e.Unipolar depressive disorder or major depressive disorder (MDD) is characterized by depressive symptoms without any history of a manic. fails. fluvoxamine. pindolol (see Section 2. the minimum period should be 2 weeks. For MDD with severe anxiety.g. and venlafaxine). For non-responders on moderate doses or those with low serum levels. associated with significant morbidity and mortality that affects individuals of all ages and races. or thyroid hormone). the dose should be increased and the patient monitored for increased side-effects.1-9. For MDD with seasonal pattern (MDDSP). Other tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs) are third-line treatments. The initial therapeutic treatment dose should be gradually maximized. For MDD with atypical features. mirtazapine. fluoxetine. which are based mainly on specific data from accumulated research. TCAs.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. electroconvulsive therapy (ECT) or an antipsychotic plus an antidepressant are first-line treatments. or thyroid hormone should be considered. augmentation with lithium. when switching from/to an MAOI to/from other antidepressants (e. If this fails.g. and sertraline are the first-line treatments. It occurs in about 5-10% of the adult population. If the second trial fails even with augmentation therapy.

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this has given mixed results. and positive effects may appear more rapidly. from the perspective of clinicians and patients. reduced medication costs.g. Switching from an SSRI to an SNRI (e. Combination strategies include the combination of noradrenergic tricyclic agents (e. These strategies allow the patient to maintain the improvement already achieved. e. wellcontrolled studies have not found consistent evidence for its beneficial effects. Other augmentation strategies include the addition of buspirone or bupropion to SSRIs.e. Electroconvulsive therapy (ECT) remains one of the most effective treatments for treatment-resistant depression. Adding an a2-adrenergic antagonist such as yohimbine is another approach to managing treatment-resistant depression. With this treatment approach in mind. The evidence about switching from an SSRI (or any other antidepressant) to bupropion is more limited. switching. augmenting. as residual symptoms are associated with poorer outcome and increased relapse risk. lithium has been best researched. and combining various pharmaceutical agents can be effective management strategies. switching to another SSRI may be beneficial but such a strategy has not been studies as yet in a well-controlled trial. Although the more traditional view of treatment resistance has focused on nonresponse. i. response without remission has a potentially poor outcome. bromocriptine.g. Mirtazapine is a safe and effective alternative when other antidepressant treatments fail. even in very resistant patients (failing to respond to at least three adequate trials of antidepressants). although it has also demonstrated its efficacy as augmentation to SSRIs.g. or a serotonin-norepinephrine reuptake inhibitor (SNRI. Augmentation and combination strategies are particularly helpful in managing treatment-resistant patients.5 . Combining risperidone or olanzapine and an SSRI has shown some promise. with up to 50-60% of patients not achieving an adequate response following antidepressant treatment. patients with non-psychotic unipolar major depressive disorder start treatment with antidepressant monotherapy.7). when their symptoms fail to achieve full remission during an adequate course of treatment. reboxetine). The combination of an SSRI and mirtazapine may also be an effective strategy. and it is considered the preferred augmentation to TCAs. Switching to an irreversible monoamine oxidase inhibitor (MAOI) requires a 2-week washout period (a 5-week washout period switching from fluoxetine). pramipexole. Another possibility is to switch to a selective noradrenaline (norepinephrine) reuptake inhibitor (NARI. However. Treatment-resistant depression is a relatively common occurrence in clinical practice.4 Notes about the scheme Generally. from the clinician's and patient's perspective. venlafaxine). Advantages of switching include improved compliance. However. Of all the augmentation strategies. Pindolol augmentation of SSRIs is another option (see Section 2. In addition. and pergolide) or methylphenidate. and maintenance of initial improvement. a tricyclic antidepressant (TCA). Some data suggest that it might be more beneficial in patients with a family history of thyroid disorder. not achieving remission despite adequate treatment represents a significant challenge.g. inadequate response implies that the treatment has failed to achieve remission. Thyroid hormone is another possibility. Other anecdotal augmentations include dopaminergic receptor agonists (e. The combination of yohimbine and mianserin may be useful in some cases.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. and fewer drug interactions. Most patients are started on a selective serotonin reuptake inhibitor (SSRI). venlafaxine) may be a very effective strategy. However. ropirinole. 6-12 weeks).g. Advantages of augmentation or combination include rapid response. no necessity for titration. there are limited data indicating that a switch from an SSRI to reboxetine/TCA can be useful. desipramine or nortriptyfine) or bupropion with SSRIs.4 . remission typically implies achieving a relatively asymptomatic state.

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However. macular degeneration. ileus. in order to eliminate. and cognitive decline. Most regularly used drugs ('psychiatric' and 'non-psychiatric') are metabolized by the hepatic cytochrome P450 enzymes CYP2D6 or CYP3A4. papillary dilatation increases the risk of developing closed angle glaucoma. The antidepressants that have been shown. for the most part. Dry mouth promotes dental decay and denture problems. Enlarged prostates are at risk of urinary retention. Venlafaxine may also be considered. Given that most antidepressants are effective in the elderly. A second option is to take drugs that are metabolized by other hepatic enzymes in addition to CYP2D6/3A4. an increasing problem with age. diabetes. the choice of drug is based on its side-effect profile and its potential to interact with other medications. in controlled studies. Mirtazapine may be used in patients with insomnia and decreased appetite due to its sedative side-effects and its promotion of increased appetite. stroke. desipramine and nortriptyline are the most recommended. Among the TCAs. 'nonpsychiatric'). Huntington's disease. reboxetine. numerous medical conditions. it should be used with caution since in 3-5% of patients it increases blood pressure. Higher prevalence rates are reported in the hospitalized elderly population (3646%) and about 10-22% in patients hospitalized in long-term facilities. and may result in delirium or other cognitive decline. multiple sclerosis. Taking this into account. and sertraline. to be effective in geriatric major depression are the SSRIs fluoxetine. 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. fluoxetine. since it has no negative impact on cardiac measures. cancer. Constipation. In the evaluation of a first or recurrent episode of depression. Many of the geriatric population receive numerous concomitant medications (i. use of β-blockers.Depression is often overlooked as a clinical diagnosis in older patients because it is mistakenly assumed to be a 'normal' response to aging. interferon-α. and venlafaxine. myocardial infarction. medications. the best drugs with respect to drug-drug interactions are probably citalopram. and other factors associated with age should be considered. or other life-events. paroxetine. the TCAs clomipramine and nortriptyline.6 . or intestinal obstruction. Compared with tricyclic antidepressants (TCAs).e. as much as possible. fluvoxamine. Sedation and increased appetite due to histamine blockade and hypotension from adrenergic blockade are also causes for concern. or many anticancer drugs.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. so that the influence of CYP2D6/3A4 is less dominant. their side-effects are better tolerated. parkinsonism. they are much safer in overdose and. physical deterioration.6 Notes about the scheme The selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment of depression in the elderly. since they have few anticholinergic side-effects. and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine. however. escitalopram. medical intervention for depression is appropriate in this population. may lead to laxative abuse. drug-drug interaction. especially in those patients with severe chronic disease. Therefore. Among these are hypothyroidism. Anticholinergic side-effects are particularly troublesome to elderly patients. microvascular disease.7 A number of placebocontrolled studies of post-stroke depression have shown efficacy for citalopram at doses of 10 mg and for nortriptyline (but not for fluoxetine). Anticholinergic effects on cognition can be significant and additive from multiple drugs. the best drugs to give a geriatric patient are those that are not metabolized by either CYP2D6 or CYP3A4. Alzheimer's disease.

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For patients with severe PMDD with comorbid psychiatric disorders such as depressive or anxiety disorder. relaxation and stress reduction techniques. and sleep deprivation. and carbohydrate craving . magnesium 200 or 360 mg/day. PMDD starts in the early to mid 20s. treatment of PMDD is usually based on selective serotonin reuptake inhibitors (SSRIs). The combination of the estrogen and progestin may produce symptoms similar to PMDD. impulse dyscontrol. In addition.most notably irritability. such as water retention and irritability. chocolate. Many of the typical symptoms of PMDD . light therapy (bright. increased exercise. and alcohol. Even though the symptoms of PMDD vary from woman to woman. Fluoxetine and sertraline are considered first-line treatment at 20 mg/day and 50-100 mg/day. intermittent premenstrual dosing is highly effective and very well tolerated. miscellaneous agents should be tried. The current predominant hypothesis is that those women who develop PMDD have an underlying vulnerability in the central nervous system. cognitive therapy. limited evidence does not support efficacy for oral contraceptive agents containing progestins derived from 19-nortestosterone. and progesterone. However. 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. non-pharmacological strategies are usually warranted. depressed mood. gonadotrophin-releasing hormone (GnRH) agonists. The benefit of SSRIs appears usually within 2-3 days. Venlafaxine has also been reported to exert significant efficacy at doses of 50-200 mg/day. such as vitamin B6 100-200 mg/day. 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).have been linked to serotonergic dysfunction.5 mg three times a day during the luteal phase or buspirone at continuous dosing are considered second-line treatment. refined sugars. Eeuprolide.Premenstrual dysphoric disorder (PMDD) occurs in 29% of women of reproductive age and requires clear impairment of functioning in order to be diagnosed. vitamin E 400-800 ILJ/day. the fact that chronically low estrogen levels increase the risks of both cardiovascular illness and osteoporosis makes these regimens less advised.8 Notes about the scheme In patients with less severe PMDD. However. It is characterized by mood symptoms that are sufficiently severe that they result in significant disruption of a women's normal level of functioning. martial counseling. among them reduction of caffeine. calcium 1000-1200 mg/day. continuous dosing (daily dose) is recommended. fluvoxamine. respectively. For patients with PMDD without comorbid psychiatric disorders. The various treatments that have been employed to achieve an anovulatory state include danazol.g. Symptoms of PMDD may remit if ovulation is suppressed. and over-thecounter analgesics such as naproxen and mefenamic acid. full-spectrum lights). citalopram. Hence. There is preliminary evidence that oral contraceptive pills containing low-dose estrogen and the progestin drospirenone (a spironolactone analog) instead of a 19nortestosterone derivative can reduce symptoms of water retention and other side-effects related to estrogen excess. Alprazolam at a daily dose of 0.8 .25 mg twice a day up to 0. salt. Effectiveness for PMDD has also been reported with other SSRIs (e. and paroxetine). the symptoms experienced by each individual have been shown to be relatively consistent from cycle to cycle. biofeedback. Oral contraceptives prevent ovulation and should be effective for the treatment of PMDD. although it may begin at menarche.

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citalopram. mirtazapine. In that case. bupropion. It has an early and insidious onset as well as a chronic course (the disorder may last up to 20 years.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 tricyclic antidepressants (TCAs) amitriptyline. All in all. Of these.11 Among the antidepressants found to be superior to placebo are the selective serotonin reuptake inhibitors (SSRIs. Some other data suggest the efficacy of olanzapine in dysthymia. Moreover. amineptine. Currently. the TCAs amitriptyline. Some data suggest that only 20-25% of patients attain complete remission a year following diagnosis. The lifetime prevalence of dysthymic disorder is approximately 6%. and the reversible and irreversible monoamine oxidase inhibitors (MAOIs) moclobemide and phenelzine. are currently considered the first-line treatment for the long-term treatment of dysthymic disorder.g. to date. and imipramine (with a 40-60% favorable response). Recommended doses for dysthymia are similar to those given for acute treatment of a major depressive episode. up to 20-25% of patients suffer from a chronic. respectively. small case series studies. In the case of failure or intolerance to SSRIs. given its chronicity and the presumed non-biological personality variables associated with it. the prognosis of the disorder worsens considerably. The thirdline options are usually second-generation antipsychotics (SGAs) and combination therapies. The SSRIs. there are no wellestablished or consistent data about its efficacy for this condition. amisulpiride is believed to block mainly the presynaptic dopaminergic autoreceptors. with results being evident so far with fluoxetine and sertraline). the prognosis of treated dysthymic disorder is variable. an entity known as 'doubledepression'. reboxetine. with consequent enhanced secretion of dopamine. especially when given in low doses (e. Other antidepressants (e. with females being affected almost twice as much as males. although these treatment modalities have not been well studied in controlled trials. most of the suggested treatment algorithms do not include ECT as an option. Although the optimal length of pharmacotherapy in dysthymia has not been studied in a controlled trial. the recently introduced amisulpiride has shown the most consistent beneficial effects in dysthymic disorder. desipramine. particularly if there is comorbidity with borderline personality disorder. dysthymic disorder has not been the focus of pharmacotherapeutic interventions. and venlafaxine) have also been reported in case reports. as a result of a series of placebocontrolled medical trials. with a median duration of about 5 years).10 However. non-remitting course of the disorder.10-11 . a course of treatment with an antidepressant for at least 2-3 years is recommended. and imipramine or the reversible SV1AOI moclobemide should be tried. Among the SGAs. due to their superior tolerability and side-effect profile. The reversible IVSAQJ phenelzine has shown superior effectiveness to imipramine in one double-blind study. However.12 However. Electroconvulsive therapy (ECT) has been suggested by some clinicians as the third-line option in dysthymic disorder.g. Psychotherapy and psychoanalysis were generally considered the firstchoice treatment options.9 Patients may suffer from 'superimposed' major depressive disorder. it should be reserved as third-line therapy due to its less-favorable side-effect profile and dietary restrictions. and open-label trials to exert some beneficial effects in dysthymia. nefazodone. Notes about the scheme Traditionally. this attitude has been changed. At these dosages. 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). desipramine. 50 mg/day).

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antidepressant monotherapy is probably recommended and efficient. Most patients with bipolar I disorder may also benefit from psychological treatments in addition to any pharmacological treatment. the next step is to switch to another antidepressant from a different class or to combine two first-line treatments. olanzapine. and they should be left for incapacitating symptoms in patients who have received practically all other possibilities. suicidality. for bipolar I disorder they have generally been studied only as add-ons to medications such as lithium or valproate. since it may cause Stevens-Johnson or other severe rash). as with unipolar depression.14 Systematic studies of bipolar I disorder. For patients who do not respond to optimal maintenance treatment. and the patient does not suffer from rapid cycling. Thus.g. trazodone. many of the treatment strategies concerning major depressive disorder (unipolar) are applicable. to some extent. if the patient is not receiving a mood stabilizer. While standard antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have shown good efficacy in the treatment of unipolar depression. or ziprasidone). or olanzapine plus fluoxetine. An additional focus of treatment is to avoid precipitation of a manic or hypomanic episode. treatment-resistant depressive episodes. quetiapine. to administer an antidepressant drug as a sole agent. 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. in bipolar I disorder. as might one of the secondgeneration antipsychotic drugs (e.13 . If there is no response to a combination of first-line treatments. Besides antidepressants. 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. the efficacy of these regimens in bipolar I disorder has not been studied in well-controlled trials. electroconvulsive therapy (ECT) represents a reasonable alternative. as they may increase the risk of switching to mania). or psychosis. In addition. is remission of the symptoms of major depression with return to normal levels of psychosocial functioning. 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. olanzapine or valproate should be added. lithium. ECT is a potential treatment for severe depression during pregnancy. However. an antidepressant such as bupropion or an SSRI could be added (tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) should be avoided. Other options include the administration of non-TCAs such as reboxetine.13 . For patients who. To date.14 . If the administration of an antidepressant drug is not relevant. the first-line intervention should be to optimize the dose of the maintenance medication. olanzapine. suffer a breakthrough depressive episode. given the risk of precipitating a switch to mania. and especially of the role of pharmacotherapy while on lithium maintenance therapy. or an MAOI. If the patient suffers from rapid cycling bipolar I disorder and the combination of two first-line treatments fails. aripiprazole. one of the following treatments might be appropriate: lamotrigine. or those episodes with catatonic or psychotic features. the best supported of the above treatment options is lithium. are quite limited. risperidone. despite receiving maintenance medication. In patients with life-threatening inanition.The primary goal of treatment of major depressive disorder (MDD) as part of bipolar I disorder. The addition of valproate should also be considered (the combination of lamotrigine with valproate should be avoided.

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15 . For patients experiencing a manic or mixed episode. although data are not well established. or agitated patients.16 Hence. while among patients with dysphoric mania only about 20% will respond favorably). antipsychotics may be needed. or valproate compared with lithium in the treatment of mixed states. manic episode as part of schizoaffective disorder. good prognostic signs for lithium may include: • • • • first-degree relatives with mood disorders. SGAs are favored because of their more benign side-effect profile. Moreover. and psychotic symptoms). As mentioned before.e. Carbamazepine may also be effective in specific cases of acute manic episode. risperidone. aggression. and grandiose ideas. clozapine may be particularly effective for treatment of refractory illness. or rapid cycling). olanzapine. Alternatives with less supporting evidence for treatment of manic or mixed states include other second-generation antipsychotics (SGAs) such as quetiapine or ziprasidone. but still with psychotic features. Good prognostic signs for valproate may include: • • rapid cycling or dysphoric mania. or changing from one antipsychotic to another. Short-term adjunctive benzodiazepines may be also helpful in managing symptom relief. various factors may lead the clinician to choose a particular medication. adding an antipsychotic if not already prescribed. flight of ideas. dysphoric. comorbid substance abuse. less than three lifetime manic episodes. ECT is a potential treatment for patients with mixed episodes or for severe mania experienced during pregnancy. among them the type of mania (i.16 For patients who experience a 'breakthrough' episode.Patients experiencing a manic episode show elevated mood. and generally should be tapered and discontinued if possible. Electroconvulsive therapy (ECT) may also be considered for patients with severe or treatmentresistant illness. Good prognostic signs for carbamazepine are: • • • • • secondary mania (due to brain disorder or pharmacotherapy). Lithium is most effective in euphoric mania and valproate is probably more effective in mixed states. When first-line medications at optimal dose fail to control symptoms. olanzapine. olanzapine. Alternative treatment options include adding carbamazepine or oxcarbazepine in lieu of an additional first-line medication. lithium. or a combination of quetiapine and carbamazepine. risperidone. For less severe mania. 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.15 Notes about the scheme Lithium and valproate are usually considered the first-line treatment options for acute exacerbation of non-psychotic mania. Of the antipsychotics. mixed. good responses to lithium in previous exacerbations. agitation. decreased sleep. expansiveness. and impulsiveness is particularly important to ensure the safety of patients and those around them. rapid cycling (for which carbamazepine is probably better than lithium but less effective than valproate). mixed or dysphoric mania. stable or decreasing frequency of manic exacerbations. euphoric mania (60-80% will respond favorably to lithium. The time of onset of action of lithium may be somewhat slower than that of valproate . Rapid control of agitation. the primary goal of treatment is the control of symptoms to allow a return to normal levels of psychosocial functioning.15. or valproate may be sufficient.16 For severely ill. Antidepressants may precipitate or exacerbate manic or mixed episodes. In addition. heightened self-esteem. psychotic. some evidence suggests a greater efficacy of carbamazepine. the medication dose should first be optimized. recommended treatment options include the addition of another firstline medication. impulsiveness. euphoric.

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17 For treatment-resistant patients who do not respond to SSRIs or TCAs. However.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. the side-effect burden of TCAs is a major hindrance to treatment in many patients. among studies examining the long-term efficacy of pharmacotherapy for PD. or increasing the dose of the SSRI. despite their abuse potential and the fact that wellcontrolled data suggest that patients taking SSRIs have a comparable clinical course to those taking benzodiazepines.17 For example. 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.g. and venlafaxine). they will be able to serve as their own therapists in the event that symptoms emerge with continuation of medication. mirtazapine.g.30 In order to optimize treatment.19. Since then. suggest that the selective serotonin reuptake inhibitors (SSRIs) are efficacious and well-tolerated for PD (studied mainly with paroxetine and sertraline).31 .18 Notes about the scheme Accumulating data. pindolol. or to the combination of TCAs/SSRIs with benzodiazepines. despite the current guidelines recommending the use of SSRIs for PD. moclobemide. a significant number of patients do not fully respond to initial treatment. and they are now considered second-line treatment for PD. 23 Tricyclic antidepressants (TCAs) such as imipramine and clomipramine were regularly used for the treatment of PD up to the early 1990s. especially when combined with SSRIs/TCAs (lithium.23 The benefit of combined therapy is associated with acceleration of response rather than ultimate outcome. CBT offers the hope that once patients learn its principles and applications. patients should avoid or reduce the consumption of compounds that could potentially induce/exacerbate panic attacks (e. However.21 many clinicians use benzodiazepines as first-line therapy. data on combined treatment do not suggest evidence of better ultimate outcome compared with monotherapy. phenelzine. caffeine. For maximizing the chances of remission in long-term treatment. Although a variety of pharmacological and cognitive-behavioral treatments appear to be effective for the acute treatment of PD. as yet.g. and propranolol). and others relapse when treatment is discontinued. there are few systemic data addressing the relative benefit of partial responders or non-responders to initial therapy. the three most common interventions are the addition of cognitive-behavioral therapy (CBT).22. about one-third of patients achieved continuous remission during the 4year follow-up period. alprazolam and clonazepam) have been more commonly used. and nicotine) and should exercise regularly. 50% continued to have mild to moderate symptoms or intermittent periods of remission.g.22 . severe symptoms. nefazodone. reboxetine. and frequent). and 19% suffered from persistent. however.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. Up to 20% of panic attacks appear without any sense of anxiety. and disabling condition that often appears to require ongoing treatment in clinical practice. alcohol.Panic disorder (PD) is a chronic. other antidepressants have shown at least some beneficial effects in alleviating PD symptoms (e.25 . adding a benzodiazepine (either alprazolam or clonazepam) to an SSRI. valproate or olanzapine should be considered. Other agents have also been reported to exert beneficial effects in PD. In cases where all treatments have failed. distressing. including well-controlled studies. incapacitating. patients whose symptoms are very severe. the SSRIs as sole agents or in combination with benzodiazepines (e. 20 However.

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may produce a rapid anxiolytic effect within 1 week of commencing treatment. it remains unclear whether a combination of cognitive behavioral therapy (CBT) and drug therapy is advantageous over each of the modalities alone. Hence. have an accident. interacting with alcohol.36 A limited number of studies have evaluated the efficacy of other agents in the treatment of GAD. pregabalin is not yet available for routine clinical use.32 Notes about the scheme Currently accepted (US FDA-approved) first-line treatments for CAD are the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine (75-225 mg/day).the problem is that they are excessive. These have included partial benzodiazepine receptor agonists such as abecarnil and suriclone. and a number of studies have indicated.5-75 mg/day) may also exert some beneficial effects in GAD.32 .36 However.35 However. sleep disturbances. Among patients responding to treatment. In treatment-resistant cases. all of which are non-delusional and non-bizarre in nature. Due to the lack of studies. rather than the psychological symptoms.36 Pregabalin interacts with the same binding site and has a similar pharmacological profile as its predecessor gabapentin. this drug might be the second choice in treating GAD. etc.37 In general. current data are not well established. Benzodiazepines as monotherapy may not be as robust as assumed.38 However. they can be combined with SNRIs/SSRIs in the first weeks of treatment before the onset of the therapeutic effects of the latter. muscle tension. Other anxiolytics may be useful. Moreover. imipramine (75200 mg/day) has been the most widely studied and has shown beneficial results. clonazepam. either long-acting (diazepam. Opipramol. that the effect of benzodiazepines may not be different from placebo after 4-6 weeks of treatment. has been shown to be superior to placebo and equally effective as alprazolam in the treatment of GAD. The most extensively studied of these agents. The efficacy of buspirone (a 5-HT1A partial agonist. with the exception of venlafaxine. irritability. Also. become ill. Patients suffer from somatic symptoms as well as from restlessness. it seems that the other SNRIs/SSRIs may prove to be as efficient. less than two-thirds will go into remission. and lorazepam) may be used when the patient does not have a history of addictive behavior. If first-line drugs such as venlafaxine. oxazepam. and thus it may be useful for the short-term treatment of GAD. However. the benefit of benzodiazepines extends primary to the relief of somatic symptoms. or inducing dependence. due to its relatively unfavorable side-effect profile compared with venlafaxine and the SSRIs. which are speculated to retain the anxiolytic efficacy of benzodiazepines but to be devoid of the potential for causing sedation. Among the tricyclic antidepressants (TCAs). a trial with second-line drugs such as buspirone and hydroxyzine is warranted. and being easily fatigued. and imipramine fail.33-34 or the selective serotonin reuptake inhibitor (SSRI) paroxetine (20-50 mg/day). even compared with buspirone. despite early improvements in anxiety symptoms. see Section 3. a key feature of GAD. which include worry. abecarnil. Such a worry can be that a patient's relative may suffer. difficulty in concentrating. Patients who suffer from CAD may express various worries. However. worries are realistic in nature . an antagonist of sigma receptors. benzodiazepines. and chlordiazepoxide) or short-acting (alprazolam.8) for GAD at doses of 1560 mg/day has been shown in a number of relatively small studies.36 The antihistaminergic drug hydroxyzine (37. these data have not been established via large and wellcontrolled studies. paroxetine. such as trazodone and nefazodone. long-term studies in GAD patients are lacking.The main features of generalized anxiety disorder (GAD) are excessive anxiety and worry.

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and venlafaxine have been reported. has led to a significant improvement in the prognosis of patients suffering from OCD. olanzapine. this combination may lead to a substantial increase in the level of tricyclics in the blood and/or increase the risk of serotonin syndrome. but as many as 30-60% of long-term treated patients complain of some residual symptoms).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 firstline pharmacological therapies for patients with OCD. trazodone. Hence. Over the past decades. Data are not well established concerning the efficacy of such combinations. up to 6570% of patients with OCD have a clinically meaningful response to their first SSRI therapy. however. Clinical experience with the SSRIs suggests that they alleviate the symptoms of OCD. although most do not reach full remission. Neurosurgery is the last resort. lithium. About 40% of patients with OCD do not completely respond to adequate trials of SSRIs. Moreover. Phenelzine may be helpful in symmetry-related or other atypical obsessions. with limited benefit. but they do not 'cure' the illness. a longer therapeutic lag occurs. and limbic leucotomy. in order to assess the family dynamics. clonidine. to date there are no well-established data to support/favor such combination.43 Augmentation of SSRIs with clomipramine (or vice versa) is a common practice in non-responders. Combinations of SSRIs with buspirone. risperidone. as many as 90% of patients will respond favorably (improvement varies.40 As mentioned above. inositol. anterior capsulotomy.41 To date. 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. For most patients. and as with the combination of SRIs and CBT. The treatment of OCD patients with SSRIs is unique in that a selective efficacy exists (other non-SRI antidepressants are ineffective in OCD). subcaudate tractotomy. only two augmenting agents have been found to be effective in double-blind studies: risperidone42 and pindolol. OCD is chronic and lifelong. Data from epidemiological and clinical studies suggest that OCD typically begins during late adolescence or early adulthood.40 In cases of partial or nonresponse. and higher doses are often required than in treating patients with major depression or other anxiety disorders. family therapy should also be suggested. along with the presence of effective behavioral treatments using exposure-response prevention techniques. the availability of the serotonin reuptake inhibitors (SRIs) and the introduction of selective serotonin reuptake inhibitors (SSRIs). No one SSRI has been demonstrated to be superior to the others in head-to-head trials. However.Obsessive-compulsive disorder (OCD) is an intriguing and often debilitating syndrome characterized by obsessions and compulsions. . pindolol. current operations include anterior cingulotomy. with sequential trials. Electroconvulsive therapy (ECT) should be reserved for severely depressed and suicidal OCD patients. an attempt should be made to combine cognitive-behavioral therapy (CBT) with pharmacological treatments. In cases of non-response. clonazepam. tryptophan. augmentation strategies are necessary for SSRI partial and non-responders. Augmentation is called for when there is partial or non-response to the above approaches.41 The outcome of such operations is questionable. The SSRIs provide clinically significant relief in up to 70% of OCD patients. 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. with fluctuations in the severity of symptoms over time. However.

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44 . in addition to its public health significance as a prevalent psychiatric disorder. This notion is based on a neurobiological model that assumes sensitization of regions related to anxious behavior following exposure to traumatic events and.48 The magnitude of effect achieved by the various pharmacological options for PTSD is often limited. especially in view of the great success of cognitive-behavioral therapy (CBT). CBT has shown beneficial effects in relatively wellcontrolled studies. other drugs can be tried. quetiapine. and poor compliance. paroxetine. which have been shown to reduce re-experiencing. irritability. Medication may be a good choice when patient acceptability of such an approach is high. while valproate seems to be more effective for reducing avoidance/numbing symptoms. anecdotal data suggest that carbamazepine may reduce reexperiencing and aggressive behavior. evidence continues to accumulate indicating that.45 . there are no well-controlled studies about anticonvulsants and their potential beneficial effect in PTSD. Even so. aggressive behavior. and sertraline has been demonstrated in well-designed double-blind placebocontrolled studies to reduce all symptom domains (intrusive recollection. risk of overdose. avoidance/numbness. however. regular use of benzodiazepines is not recommended.49 Anticonvulsants might prove to play a role in alleviating some symptoms of PTSD. However. PTSD is a risk factor for many medical illnesses. and the presynaptic α2-agonists clonidine and guanfacine (which decrease secretion of norepinephrine from presynaptic neurons). postsynaptically. at present. densensitization following anticonvulsant therapy. thus. However. lithium cannot be recommended as treatment for PTSD. the activities of norepinephrine. or when CBT is not applicable. Furthermore. 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). sleep disturbances). with a much higher prevalence in countries affected by civil war. post-traumatic stress disorder (PTSD) has been shown to have a lifetime prevalence of about 8% in the USA. while the results with exposure therapy are inconsistent. and risperidone. TCAs and phenelzine are associated with a higher incidence of side-effects.47 Other treatment options include the tricyclic antidepressants (TCAs) amitriptyline and imipramine and the irreversible monoamine oxidase inhibitor (MAOI) phenelzine. social phobia. panic disorder.44 . and remission is rarely achieved. which is presumed to be overly secreted in anxious states of PTSD). which has produced marked reduction in traumatic nightmares and improved sleep. forced migration.49 Benzodiazepines can be used on an 'as-needed' basis for specific symptoms (e. genocide. such as lamotrigine and venlafaxine. and terrorism.44 There are no systematic data about lithium in respect to PTSD. In cases of non-response to the above medications. when comorbid conditions are present that are responsive to pharmacotherapy (e.44 Other options include antiadrenergic agents such as the postsynaptic padrenergic antagonist propranolol.Since its introduction as a formal diagnosis in 1980. to date.g. vice versa. the postsynaptic a!-antagonist prazosin (both of which block. Efficacy for fluoxetine. Pharmacotherapy is only one of several treatment options for PTSD.48 Alprazolam has demonstrated anecdotal efficacy.44 Notes about the scheme Selective serotonin reuptake inhibitors (SSRIs) are the first-line therapy for PTSD.especially for reducing intrusive recollection. and hyperarousal).g.48 as well as the second-generation antipsychotics (SGAs) olanzapine. depression. The best research on this class of agents has focused on prazosin. in comparison with SSRIs. avoidance/numbness behavior. and obsessive-compulsive disorder). which have shown some effectiveness at low doses .

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Before prescribing β-adrenergic antagonists. severe bradycardia. Exposure to the phobic stimulus is associated with an acute and severe anxiety reaction. Although there is a variation according to subtype. and unreasonable fear of a particular object or situation. but have little effect on autonomic symptoms. and lorazepam) reduce fear avoidance. Selective serotonin reuptake inhibitors (SSRIs: fluoxetine and paroxetine) have shown some benefit in preliminary reports.A specific phobia is a circumscribed. and atrioventricular block. blood injury. with women being two to three times as likely to be affected as men. 55 . They have been demonstrated to have some efficacy in performance anxiety. prescription of these drugs should be done with caution due to the cardiopulmonary sideeffects. situational. a baseline ECC should be performed.g. the non-associative model. The use of these agents in specific phobia is usually aimed at helping patients to engage in an exposure program and. The population prevalence of specific phobias is approximately 10%. the behaviorists suggested that this disorder might result from a similar process. Following the conditioning sessions. β-adrenergic antagonists that are lipidsoluble (e. Therefore. the rat would become frightened on hearing the buzzing. In the case of a depressed patient with performance anxiety. and nature re-e n vi ro n m e n t. a rat could be taught to be afraid of a soft buzzing noise if that noise were repeatedly followed by an electric shock. to date. most adjust their lifestyle so that they can completely avoid or at least minimize this contact. 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. Observing that specific phobics are also unrealistically afraid of situations that others deem harmless.54. such at atenolol. there is no definitive established treatment of specific phobia.51 . 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). DSM-IV has defined four subtypes on the basis of phobic stimulus: animal. They are contraindicated in asthma and chronic pulmonary disease. however. persistent. in the case of a specific phobic condition. even if the shock did not follow.53 β-adrenergic antagonists have not been found to be efficacious in augmentation behavioral treatments. and that specific phobias are conditioned fear. lonazepam. and relatively contraindicated in diabetes mellitus. which includes principally antidepressants.50 Notes about the scheme A few regimens have been studied with various degrees of success in specific phobia. therefore it is preferable to prescribe a βadrenergic antagonist that is water-soluble with a low central nervous system side-effect profile. less than 20% of affected individuals seek help. There are currently three main etiological approaches to specific phobias: modified conditioning. propranolol) may cause depressive states. and the psychoanalytical model. Benzodiazepines (alprazolam. most cases are characterized by early onset and a chronic course. however. There is considerable evidence of a variety of 'innate' (or unlearned) fears in both humans and animals. diazepam. 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. Even though effective treatments are available. For example. despite the fact that individuals with specific phobias recognize that their fear is unrealistic. The classic conditioning model of specific phobias was developed in the 1920s.

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with the mean age at onset being between 14 and 16 years. moclobemide. and is associated with somatic and cognitive symptoms.56 Fluvoxamine. and a tendency by clinicians to dismiss reported SAD as normal shyness. The combination of pharmacological treatment and cognitive-behavioral therapy (CBT) may be advantageous. and unreasonable fear of being observed or evaluated negatively by others in social performance or interaction situations.g. This may result from a trend for SAD patients to present for help for comorbid disorders. speaking to unfamiliar people. its efficacy in improving some of the cognitive aspects associated with SAD. The term 'social anxiety disorder' may have a number of advantages over 'social phobia'. including sedation and postural hypotension. While there is overlap between SAD and excessive shyness. Notes about the scheme As with most other Axis I psychiatric disorders. there is a more even gender distribution. and especially with the anxiety disorders. venlafaxine. Results with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide are inconsistent. they may play a role as adjunctive agents or for patients refractory to other treatments. a developmental period in which social relationships become more important. SAD patients who are refractory to treatment with SSRIs may benefit from second-line treatment such as clonazepam. Selective serotonin reuptake inhibitors (SSRIs) are regarded as first-line treatment in social phobia. among these are gabapentin. 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. or being exposed to possible scrutiny by other people. Prior to this. of writing in front of others) but not be shy in other situations. However. 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.5-2: 1 female-to-male. The onset of SAD most commonly occurs before the age of 25 years. Benzodiazepines are not recommended as firstline agents in treating social phobia.57 59 The irreversible monoamine oxidase inhibitor (IVSAO1) phenelzine shows robust results in terms of efficacy60 and has demonstrated (at least anecdotally).56 . and the MAOI tranylcypromine. and sertraline have been shown to be effective in double-blind placebo-controlled studies.56 SAD only entered the DSM nosology in 1980 with the publication of DSM-III. SAD should therefore not be dismissed as normal shyness. and phenelzine. The feared situations are avoided or else are endured with intense anxiety or distress. These situations include fear of speaking in public. persistent. phenelzine is usually less well tolerated than alternative treatments due to its associated dietary restrictions and adverse side-effect profile. but in clinical samples. Although SAD is a severely disabling disorder. because they are associated with abuse and long-term dependence. paroxetine. such as depression or other anxiety disorders. SAD had been recognized in DSM as a form of general phobia or anxiety neurosis rather than as a qualitatively distinct disorder. for example paruresis or shy bladder syndrome. 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. the gender ratio is approximately 1. rather than SAD per se. SAD). including a less pejorative sound. it is typically underdiagnosed and undertreated in healthcare settings.Social anxiety disorder (SAD) is characterized by marked. 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. In the general population. Certain forms of SAD are particularly poorly recognized. However.g. Other agents may be used in cases of failure or intolerance of second-line treatment.

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or with hyperlipidemia. and to reduce the severity of psychosis and associated symptoms (e. Among the SGAs. promoting and maintaining recovery from the debilitating effects of illness to the maximum extent possible. SGAs (aripiprazole. as well as its favorable cost/benefit ratio.62 Electroconvulsive therapy (ECT) in combination with APDs may be considered for treatment of resistant and/or suicidal schizophrenia patients. and may respond to antidepressants (OCD-like symptoms may respond to serotonin reuptake inhibitors (SRIs)). risperidone is most widely preferred as firstline drug due to its relatively tolerable side-effect profile. in treatment-resistant patients. Notes about the scheme The goals of treatment during an acute psychotic exacerbation of the disorder are to prevent harm. lorazepam has the advantage of reliable absorption when it is administered either orally or parenterally. treatment planning should have several main goals: • • • reduction or elimination of symptoms. and often require lower doses than patients with chronic schizophrenia. ziprasidone or aripiprazole may be the preferred agent. aggression. negative symptoms. Therefore. aggression. and. In patients with significant weight gain and/or sensitivity to hyperglycemia.Schizophrenia is a chronic illness that can influence many aspects of life in affected persons. maximizing quality of life and adaptive functioning. one of the SGAs (except risperidone at high doses) should be administered. Sleep disturbances are common in acute psychotic exacerbations. there is anecdotal evidence that a sedating antidepressant (e. to control disturbed behavior. mirtazapine or trazodone) or a sedative-hypnotic benzodiazepine may be helpful. and affective symptoms).61 With the widespread use of second-generation antipsychotics (SGAs) as first-line treatment. Benzodiazepines may be used to treat catatonia as well as to manage both anxiety and agitation until the APDs achieve therapeutic goals. and patients with persistent hostility and aggressive behavior. patients with predominant negative symptoms or persistent suicidal ideation or behavior. the management of schizophrenia has improved with regard to side-effects.61 . efficacy in comparison with the firstgeneration antipsychotics. risperidone. in many cases. and while controlled studies are lacking. Accurate diagnosis has enormous implications for shortand long-term treatment planning.63 There is some evidence that divalproex (semisodium valproate) and βadrenergic blockers (pindolol and nadolol) may be effective in reducing the severity of recurrent hostility and aggression. olanzapine. and ziprasidone) are the first-line treatment for a psychotic exacerbation. adherence with medication. clozapine might be recommended.g. and it is essential to note that diagnosis is a process rather than a one-time event. In patients with a history of repeated non-adherence to pharmacological treatment.61 Other psychoactive medications are commonly added to APDs in the acute phase to treat comorbid conditions or associated symptoms such as agitation.66 Major depression and obsessivecompulsive disorder (OCD) are common comorbid conditions in patients with schizophrenia. it is recommended that every patient have a thorough physical and laboratory evaluation as first screen in order to exclude an 'organic' etiology. In patients with a history of sensitivity to extrapyramidal side-effects or hyperprolactinemia.64 . long-acting injectable antipsychotic drugs (APDs) are recommended. and side-effects.g. agitation. The most agitated patients may benefit from an oral or parenteral benzodiazepine.62 First-episode patients are generally more sensitive to the therapeutic effects and side-effects of medication. quetiapine. In first-episode psychosis. In most cases.

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For patients who develop a major depressive episode after remission of acute psychosis. It is almost always advisable to administer one regimen at a time (for side-effect evaluation and treatment response). In schizophrenia patients.71 and it may also be used in subsequent prophylaxis. Lamotrigine seems to be more effective than lithium in such cases.67. to date. more effective in preventing relapse or improving prognosis in any other way. are often treated with an antipsychotic drug (APD) plus an antidepressant. the abovementioned doses were found to lengthen the time between exacerbations and to lower the risk for relapse. In such instances. probably. Therefore. due. and a switch to one of the SGAs (aripiprazole. an attempt to optimize APD doses and/or add an antiparkinsonian regimen should be made. to their mood-stabilizing effect. This is true especially with the combined use of first-generation ('typical') APDs (FGAs) and antidepressants versus FGAs/antidepressants alone. the situation is somewhat different. depressed type. For major depressive disorder as part of schizoaffective disorder. olanzapine. also seems to be superior to lithium in schizoaffective disorder. psychotic mania.67. 68 . A logical practice. These estimates were tested in maintenance treatment following acute schizophrenic exacerbation. Before administering an antidepressant. and their validity for schizoaffective disorder should be challenged. As in the maintenance treatment of other chronic psychotic disorders. quetiapine. the addition of an antidepressant drug should be considered (following a few days of evaluating potential adverse effects). However. although not proven in well-controlled trials. but should be considered. there are some accumulating data suggesting the superior efficacy of second-generation ('atypical') antipsychotic drugs (SCAs) over FGAs. depressed type (especially with concomitant psychotic features). Therefore.Notes about the scheme Patients with schizoaffective disorder.g. This side-effect can mimic some depressive symptoms. depressed type is almost as effective as the combined F/SGAantidepressant regimen.70 Carbamazepine. the clinician should consider the possibility of neuroleptic-induced parkinsonism. depressed type. the long-term use of highdose APDs should be questioned due to the increased risk of developing severe adverse side-effects (e. especially taking into consideration the proven greater efficacy of lamotrigine in the treatment of bipolar depression. is to continue with the same regimen that improved the acute depressive exacerbation. Another probable assumption is the emergence of socalled 'negative symptoms'. ECT has a proven efficacy in the treatment of affective disorders and is also beneficial in some of the psychotic disorders.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. Therefore. depressed type is not well established. APDs given as sole agents appear to be as effective as APDs plus antidepressants. If so. the expected response rate (of one regimen alone) is only about 40%. ECT might prove to be a beneficial tool for the treatment of depressive episodes as part of schizoaffective disorder. lowering the neuroleptic dose might not be sufficient. or major depressive disorder with psychotic features). depressed type. especially if affective components are present (catatonia. Consequently. some data suggest that the use of SGAs as sole regimens in schizoaffective disorder. or risperidone) should be considered if the patient has already been treated with FGAs. There are too few sufficiently well-established data concerning the maintenance treatment of schizoaffective disorder. For acute psychotic exacerbations of schizoaffective disorder. 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. 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). tardive dyskinesia) and the fact that long-term high-dose APD treatment has not been proven. 68 The role of electroconvulsive therapy (ECT) in schizoaffective disorder. an anticonvulsant with known moodstabilizing capacity.

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Short-term adjunctive benzodiazepines may also be helpful in managing symptoms relief. especially when the following factors exists: • • • • predominant mood symptoms. if possible. although data are not well established. or changing from one APD to another. better efficacy (as a prophylactic agent) in schizoaffective disorder. impulsiveness. olanzapine. clozapine may be particularly effective for the treatment of refractory illness. agitation. serum levels above 0. During remissions. when a family history of mood disorders is evident. Carbamazepine is contraindicated as augmentation therapy to clozapine. lithium is probably less effective than carbamazepine in improving depressive episodes as part of schizoaffective disorder. Antidepressants may precipitate or exacerbate manic or mixed episodes and generally should be tapered and discontinued if possible. manic type as compared with depressed type. the second-generation antipsychotics (SGAs) clozapine.g. Electroconvulsive therapy (ECT) may also be considered for patients with severe or treatmentresistant illness. Of the APDs. clozapine should be reserved only for specific patients (e. manic type. however. oxcarbazepine and valproate have been shown to exert similar efficacy in controlling mood symptoms in schizoaffective disorder. When the acute episode has been controlled and the clinical state stabilized.76 . and ziprasidone are considered first-line treatment. For patients who experience a 'breakthrough' when first-line medications at optimal doses fail to control symptoms. among these. the combination of SGAs and lithium or carbamazepine seems a reasonable approach. adding an APD if not already prescribed. lithium has been found to be an efficient modality for schizoaffective disorder. and psychotic symptoms). an attempt should be made to taper down the mood stabilizer regimen to the minimum effective dose. lithium and valproate are the firstline treatment of acute non-psychotic mania. to a 'lower effective' dose (equivalent to chlorpromazine 300 mg/day or haloperidol 2-4 mg/day). In addition. In non-psychotic patients. maintenance treatment should be continued with the antipsychotic drug (APD). Doses should be gradually decreased.Notes about the scheme In patients with acute psychotic (including manic psychosis) exacerbation of schizoaffective disorder. In resistant patients. If the patient cannot tolerate lithium. resistant ones) due to its potential severe adverse side-effects (hematological or seizure-inducing properties). Lithium is most effective in euphoric mania and valproate is probably more effective in mixed states. All in all. ECT is a potential treatment for patients with mixed episodes or for severe mania experienced during pregnancy.6 mmol/l. Alternative treatment options include adding carbamazepine or oxcarbazepine in lieu of an additional first-line medication. However. risperidone. due to their synergistic effects on bone marrow suppression.72 . Carbamazepine seems to be equipotent to lithium in controlling mood symptoms. 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. It is reasonable (although not tested) to use them in combination with SGAs in iller patients. recommended treatment options include the addition of another first-line medication. The time to onset of action of lithium may be somewhat slower than that of valproate.

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 firstline 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 placebocontrolled 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.

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 1 3-14 and 1 7-18 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, placebocontrolled 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 wellcontrolled 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

Even so. although very costly. 93 Both desipramine and imipramine have been found to be effective in short-term. since chaotic bingeing and purging preclude the necessary dietary restrictions accompanying the use of these agents. as often happens in BN. Ondansetron.92. is the use of mirtazapine. There are various axis I and II disorders associated with BN. and may be used as second-line treatment. and mainly due to compensatory measures taken by patients in order to reduce weight. 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. Notes about the scheme Cognitive-behavioral therapy (CBT) is the most empirically validated treatment for BN.95 Therefore. and the disorder is often chronic with a waxing and waning course. especially those with comorbid alcoholism and/or self-injurious behavior. The anticonvulsant topiramate has also been reported to be effective in reducing binge and purge frequencies in comparison with placebo. Estimates of the prevalence of BN among young women range from 3% in adolescents to 10% in young adults. probably due to its relative narrow therapeutic window and particularly because its serum levels can shift markedly with rapid volume changes. impaired cognition.8591 There are a few other classes of drugs that have been found. it is worth considering in refractory or severe cases. randomized controlled trials. mostly anecdotally. The prognosis is variable. the risk of seizures far outweighs its potential benefits. an antidepressant drug with marked 5-HT3 antagonistic capacity (like ondansetron) that enhances appetite. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment of BN.84 However. Naltrexone is a possible adjunct in patients who are refractory to SSRIs. 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. Another option.94 Although bupropion has been found anecdotally to be effective in reducing bingeing and purging frequency. has been found to be effective in reducing bingeing and purging when compared with placebo. Tricyclic antidepressants (TCAs) should be used with caution for patients at high risk of suicide. The antibulimic effects of antidepressants have been shown in several studies to be independent of the drugs' antidepressant effects per se. several antidepressant agents have shown some beneficial results in BN. However. More than 95% of patients with BN are females. and renal calculi may lessen its usefulness. Lithium has shown its capacity as an augmenter in various axis I disorders.Bulimia nervosa (BN) is more common than anorexia nervosa and usually begins early in adolescence.96 Hence. Even so.98 . about 70% of BN patients display moderate-good relief of symptoms during longterm follow-up. a potent 5-HT3 antagonist and an antiemetic indicated for the treatment of chemotherapy-induced nausea and vomiting in patients with cancer.97 However. about 70% of affected patients remain within the normal range of body weight. its use in BN (as well as in anorexia nervosa) is relatively contraindicated.91 those studied in BN using randomized controlled trials are fluoxetine (FDA-approved) and fluvoxamine. its use in BN has not been properly examined. bothersome sideeffects such as paresthesias. theoretically relevant but not examined as yet. to improve some aspects of BN. Monoamine oxidase inhibitors (MAOIs) should also be avoided.84 The core feature of the disorder is recurrent episodes of binge eating accompanied by the feeling of being out of control.

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and its once-daily dosing provides full coverage even into the evening. daydreaming. Stimulant drugs used to treat adults with ADHD are considered safe and effective. and nortriptyline have been shown to exert some beneficial effects in ADHD. Anecdotal reports suggest that modafinil. which facilitates compliance by eliminating frequent dosing. 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. intrusiveness. imipramine. and pemoline) and atomoxetine (a non-stimulant selective norepinephrine reuptake inhibitor.100-101 . nervousness. just as in children. guanfacine (also an α2-adrenergic agonist) may be an alternative due to its better sideeffect profile compared with clonidine. impulsivity. 99 Non-stimulant medications (except atomoxetine) are second-line treatment for adult ADHD. 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. low frustration tolerance. High divorce rates and poor academic or occupational functioning are also commonly observed. Bupropion. Since clonidine is often quite sedative. Pemoline is not recommended as firstline treatment due to the risk of hepatoxicity. and rebound worsening of symptoms. Patients with a past history of substance abuse. approved by the FDA for adult ADHD) are the first-line treatments of adult ADHD. distractibility. a mild increase in pulse and blood pressure. unresponsive patients. insomnia. and frequent shifts in activities.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. 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. the TCAs may still take priority in a subgroup of ADHD patients with tics and/or Tourette's syndrome. due to its low risk of inducing mania. Potential side-effects of stimulant medication in adults with ADHD include appetite loss. and have been well studied. irritability. it is important to start with a low dose of medication and keep increasing it slowly until the optimal risk-to-benefit ratio has been determined. which causes less rebound. and those with intolerable side-effects (dysphoria. which has been used for many years for the treatment of ADHD despite debate regarding its efficacy and safety (rebound hypertension). the difficulties related to ADHD become increasingly prominent over the lifetime. Prevalence is estimated at about 5% of the adult population. dysphoria. Controversy exists as to whether it exerts its therapeutic effect via improvement in cognition or whether it simply has a non-specific sedative effect. Males are affected 3-5 times more than females. Moreover. is also beneficial in adult ADHD. As with all medication trials. mixed amphetamine salts. especially ADHD patients who have experienced tic exacerbation with stimulants. There are several new long-acting formulations of stimulant medication. an antidepressant that inhibits the reuptake of dopamine and norepinephrine. anxiety. a stimulant used for the treatment of narcolepsy. Stimulant medication (methylphenidate. is an effective alternative in the relatively small subgroup of ADHD patients who suffer from bipolar disorder. The most common clinical symptoms in adult ADHD are inattention. and severe rebound) may react better to atomoxetine. impatience. Venlafaxine has also shown some benefit in adult ADHD. Tricyclic antidepressants (TCAs) such as desipramine. As the demands for planning increase with age. In adults. forgetfulness. as well as the a2adrenergic agonist clonidine. lasting 6-12 hours. the symptoms of ADHD are described by the deficits associated with the core syndrome.

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and flushing. pallor. autonomic instability. tachycardia diaphoresis.Neuroleptic malignant syndrome (NMS) continues to be an unpredictable and rare .105 Other non-pharmacological interventions should begin as soon as possible.102 Management of the post-NMS patient demands judicious use of medications. and altered consciousness. albeit less frequently. an indirect dopamine enhancer.102 . If dysphagia or dyspnea secondary to dystonia of throat and chest musculature is present. such as mechanical cooling. If either rigidity or temperature elevation is mild or absent. since withdrawal of amantadine may exacerbate NMS and amantadine itself may be used for the treatment of NMS. causing excessive skeletal muscle contraction coupling. It is most prudent to discontinue potentially contributing medications even before the diagnosis is definite. However. incontinence. a diagnosis of NMS is questionable. tremor. it is most recommended when other treatments have failed or when severe or 'lethal' catatonia is in the differential diagnosis. including clozapine. The most effective pharmacological interventions include bromocriptine and other dopaminergic agents (amantadine and L-dopa (levodopa) in combination with carbidopa) and dantrolene sodium. Benzodiazepines are best used in prominent catatonic symptoms.07% and 0. Electroconvulsive therapy (ECT) might be effective in the treatment of NMS. Antipyretics are not useful/ since the temperature elevation is not associated with the action of pyrogens.104 Anecdotal data suggest the efficacy of the relatively newly introduced aripiprazole or the vesicular monoamine transporter inhibitor tetrabenazine in NMS. dyspnea. with white blood cell counts commonly ranging from 10 000 to 20 000/mm3. a complete medical and neurological work-up is necessary. The same goes for amantadine in patients who receive the drug for the management of extrapyramidal side-effects (EPS). however. Leukocytosis may occur. It reduces heat production and begins taking effect within minutes. clinicians are advised to use low-potency APDs or APDs with marked anticholinergic properties. Stopping anticholinergic medication abruptly is not advised. it nonetheless also occurs in patients receiving second-generation antipsychotics (SGAs). Abrupt discontinuation of antipsychotic drugs (APDs) is warranted despite the potential for precipitating psychotic relapse. or discontinuation of anticholinergic agents (cholinergic rebound induces relative dopamine deficit) have also been associated with triggering NMS. dysphagia. its mechanism of action is blockade of intracellular calcium efflux. and more common with first-generation antipsychotics (FGAs). fluctuating blood pressure. Dantrolene sodium is a directly acting skeletal muscle relaxant. although their mechanism of action here is unclear. sialorrhea.102 Presumably linked to dopamine blockade. The incidence rates of NMS are between 0. Early and aggressive supportive interventions are the cornerstone of managing NMS. In such cases.102 . Discontinuation of amantadine. Notes about the scheme The most enduring theory about the pathophysiology of NMS is that the central and peripheral manifestations of NMS are the often-noted consequences of dopamine blockade. oral intake should be avoided. It usually appears early in the course of neuroleptic treatment (about 80% of cases are evident within the first 2 weeks of treatment). rigidity. they are anecdotally reported to exert beneficial effects in NMS. The associated features of NMS include akinesia. intravenous fluid replacement should be given.9%.but potentially fatal complication associated with the use of antipsychotic drugs (APDs). dystonias. and intubation and ventilatory support should be considered. since cholinergic rebound resulting from withdrawal of anticholinergics may contribute to the syndrome itself. since recurrent NMS has been reported with FGAs and SGAs. The cardinal features of NMS are hyperthermia. When the syndrome is suspected.

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calcium-channel blockers such as diltiazem. However. and those with comorbid mood disorder. depression is well recognized during treatment with tetrabenazine and especially with reserpine. nimodipine. clinicians should carefully weigh up the possible benefits against their potential adverse effects. however. essential fatty acids. The prevalence of TD is about 5-20% of chronic APDtreated patients.109 . There is no strong evidence to support the use of any of these agents in TD. concurrent brain injury. but it is as high as 70% in populations at risk (the elderly. naloxone. females. stepholidine. produce less blockade of dopaminergic receptors. but also with second-generation antipsychotics (SCAs). diabetes. The mean time for appearance is about 7 years.112 . The main goal in treating TD is to desensitize the hyperactive dopaminergic receptors or to counterbalance their activities. There is a growing interest in using nondopaminergic agents in an attempt to reduce the severity of TD. before evaluation of these drugs in larger randomized controlled trials. mostly of the face. and electroconvulsive therapy (ECT) have been tried for TD. the results must be considered inconclusive. or concomitant anticholinergic medications). or that SGAs have reduced affinity to the nigrostriatal pathway.106 Cholinergic drugs are of interest to researchers. It is assumed that SGAs. Notes about the scheme Once TD has developed. tryptophan. Another possible step is to increase the APD dose. estrogens. although this has the consequence of an unpleasant feeling of entering a vicious cycle. therefore causing less hypersensitization of the dopaminergic receptors (see Section 4.107 Small trials with uncertain quality of randomization indicate that vitamin E protects against deterioration of TD. especially clozapine.111 Different treatments such as botufinum toxin. caused by long-use of antipsychotic drugs (APDs). repetitive. total or partial substitution with SGAs (especially clozapine) is proposed as the first-line strategy for patients who have to continue APDs. ganglioside. Another option is to administer 'dopaminergic depletors' such as tetrabenazine and reserpine. there is no debate about the role played by neuroleptics in inducing certain movement disorders. it was considered to be a new syndrome and quite rare. cyproheptadine. neurosurgery. TD can appear at any time following APD treatment (between weeks and a few years). but there is no evidence that it improves TD. phenylalanine. 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. because of the small sample sizes. nifedipine. When TD was first described in the middle of the 20th century. It is most commonly observed with first-generation antipsychotics (FGAs). However.108 Based on anecdotal data. Because prolonged and complete drug withdrawal is often difficult. spontaneous improvement occurs in 30-50% of cases within 2 years after discontinuation of the APD. but this strategy is less effective in controlling the disorder.4). which have been found to reduce the severity of TD.Tardive dyskinesia (TD) is a hyperkinetic. but at present their use should be considered experimental. purposeless. lithium. persistent drug-induced movement disorder. piracetam. The most widely accepted theory focuses on dopamine receptor hypersensitivity. Benzodiazepines may have something to contribute to patients with TD. and verapamil are beneficial for treating TD. albeit less frequently. Although there are unanswered questions concerning the role of antipsychotic drugs in TD. but currently have little place in routine clinical work.

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g. or trazodone (50-100 mg/day). . Among the p-adrenergic blockers. by reducing the dose of the APD. It is a major extrapyramidal sideeffect that is mostly associated with the use of firstgeneration antipsychotic drugs (FGAs) and to a lesser extent second-generation antipsychotics (SGAs). and trihexyphenidyl (2-10 mg/day). usually indicated for the treatment of migraine) act on the presynaptic serotonergic receptor and inhibit the secretion of serotonin to the synaptic cleft. Accumulating data suggest that the combined benzodiazepine-anticholinergic drug regimen is more effective than either of the drugs alone. a benzodiazepine such as clonazepam (0. namely acute.113 Notes about the scheme The diagnosis of NIA may be difficult owing to the existence of various forms of NIA. Second-line treatment usually includes the anticholinergic benzotropine (1. pindolol. it may be a contributing factor in the suicidal and violent behavior of patients with schizophrenia. If there is a partial response (mainly in patients with marked distress) to first. chronic. switching to a low-potency FGA such as thioridazine.Neuroleptic-induced akathisia (NIA) is characterized by a subjective sense of inner restlessness and objective fidgety movements. to be effective in alleviating symptoms of NIA. or • risperidone. or switching to an SGA such as mianserin (15-30 mg/day). it may be predictive of more severe psychopathology.113 . If there is no response a change to clozapine can be considered. as much as possible.5-8 mg/day). in patients with diabetes/glucose intolerance and in the hypotensive population. biperiden (4-12 mg/day). olanzapine. Since passage through the blood-brain barrier is probably directly correlated with drug lipophilicity. withdrawal. although it seems to be associated with hypemoradrenergic and/or serotonergic transmission in the central nervous system. The (3-adrenergic blockers should be avoided. the underlying mechanisms have not yet been adequately explained. Akathisia is thought to be a risk factor for the development of tardive dyskinesia. such as agitation and restlessness.116 ritanserin (5-20 mg/day).and/or second-line treatment.5-1 mg/day). Moreover. and propranolol) have been found. The anxiolytic buspirone has shown conflicting effects in NIA and is currently not a recommended treatment. Such drugs (e. and they might be considered as fourth-line therapy. quetiapine. Thereby. 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. and it seems to herald a poor response and non-adherence to treatment. along with diurnal variations in its expression and its common association with other symptoms. only the more lipophilic drugs (betaxolol.116 aripiprazole.15 mg/day) may also exert some beneficial response in selective patients. Amantadine (100 mg/day) and clonidine (up to 0. this implies that a central mechanism is a predominant factor in inducing NIA. and tardive. or lorazepam (12 mg/day) can be added. These are mainly advised in patients with concurrent parkinsonism. mirtazapine (15 mg/day). Early detection and adequate treatment of NIA are important because of its negative clinical consequences and serious adverse effects. zolmitriptan. to date. Addition of anti-akathisia agents: either propranoloi (usually up to 40-120 mg/day) or a postsynaptic 5-HT2A serotonergic antagonist such as cyproheptadine (8-16 mg/day). diazepam (5-15 mg/day). When NIA is diagnosed. Despite its high incidence (20-45%). The more hydrophilic fl-adrenergic blockers (metoprolol and nadolol) are practically inefficient. they decrease the presumed enhanced serotonergic transmission that is thought to be associated with NIA. Recent data also suggest the substantial efficacy of presynaptic inhibitory 5-HT1Dβ receptor agonists.

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perceptual abnormalities. Risk factors in delirium can be categorized according to whether they are predisposing factors or more immediate precipitating factors. Benzodiazepines with rapid onset and short duration of action. reassurance. and. and prompt attention to obvious precipitating factors should be the first aim of management. hypnotic withdrawal. Second-generation antipsychotics (SGAs: olanzapine. Delirium can be caused by numerous etiologies.5 mg/day are recommended. infections. The clinical picture is so characteristic that a confident diagnosis of delirium can be made even if the underlying cause is not firmly established. fluctuating course with rapid onset.from 0. maintaining behavioral control.6% in those over 85. especially in the dorsal tegmental area of the brainstem's reticular formation (believed to be a major site for regulation of attention and arousal). In practice. art acetylcholinesterase inhibitor (which thus enhances cholinergic transmission).5-10 mg/day (intramuscularly or intravenously) improves most symptoms of delirium and is especially effective in the control of more severely disturbing and aggressive patients. at some stage. l-our key steps have been described: addressing the underlying cause. and supporting functional needs. and fecal impaction (especially in people with pre-existing dementia). urinary retention. sensory deprivation. oral drug treatment is accepted and obviously preferred to a parenteral route. decreased cholinergic activity. these manipulations are still recommended as an integral part of the management of delirium. except in cases of delirium caused by alcohol or sedative. Haloperidol in doses of 0. 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. such as an abnormal electroencephalogram (EEG). While there are no randomized controlled trials of interventions such as noise control. if the patient's clinical condition allows. cerebral hypoxia.4% in those over the age of 18 to 13.118 Donepezil and rivastigmine.121 .117 Benzodiazepines may be particularly helpful if the delirium is caused by withdrawal of alcohol or sedatives. light intensity. such as lorazepam. The adage in psychopharmacology in older patients is 'start low. In many older patients.119.5 mg/day of haloperidol or risperidone and olanzapine at 2. The prevalence of delirium increases with age . but particularly psychotropic drugs with strong anticholinergic effects such as tricyclic antidepressants (TCAs). Many drugs may cause delirium.Delirium is a clinical syndrome manifested by altered consciousness. global disturbances of cognition. risperidone. with a recommended upper limit of 2 mg intravenously every 4 hours. Haloperidol is the preferred drug when the parenteral route is necessary. evidence of cerebral dysfunction. quetiapine. go slow'. The mechanism is unclear but it involves. the commonest causes are drugs. starting doses of 0. and stimulus modification. about 85% of which are extracranial. and evidence of a physical cause. are preferred and may be given orally or intravenously. may be helpful in delirium superimposed on dementia or parkinsonism. In addition to a history of an underlying physical or brain disease. 120 while serotonin antagonists such as trazodone have also been found helpful anecdotally. preventing complications. For example. pain. fluid balance and metabolic disorders. usually but not invariably shows a slowing of background activity. Antipsychotic drugs (APDs) are the mainstay of treatment and are effective in all types of delirium.117 Notes about the scheme Delirium is a medical emergency. 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).

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 sideeffects 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 make 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 ct2-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

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.128129

properties. For disinhibited anger coexisting with other affective symptoms, SSRIs are the treatment of choice. For severe behavioral dyscontrol, the addition of a lowdose SCA should be considered. Monoamine oxidase inhibitors (MAOIs) are effective but are not considered first-line treatment because of their sideeffects 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 IVIAOI after an appropriate washout period. Carbamazepine, valproate, or an SGA could also be considered. Clozapine may be warranted after other treatments have failed.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

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

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

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