43 - Antidepressants

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43 AntidepressantsMaurizio Fava, MD, and George I. Papakostas, MD

KEY POINTS

• Theimmediatemechanismofactionofmodernantidepressants(“immediateeffects”)involvesinfluencingthefunctionofoneormoremonoamineneurotransmittersystems(serotonin,norepinephrine[noradrenaline],ordopamine).

• Influencingmonoaminergicfunctionhasbeenshowntoresultinseveralchangesinsecond-messengersystemsandgeneexpression/regulation(“downstreameffects”).

• “Downstreameffects”mayexplainthedelayedonsetofantidepressantresponseseenwithallcontemporaryagents(mostpatientsimprovefollowingatleast3weeksoftreatment).

• Forthemostpart,allcontemporaryantidepressantsareequallyeffectivewhentreatingmajordepressivedisorder.

• Therearesignificantdifferencesintherelativetolerabilityandsafetyofcontemporaryantidepressants.

OVERVIEWAlargenumberofcompoundshavebeendevelopedtotreatdepression.Traditionally,thesecompoundshavebeencalled“antidepressants,” even though most of these drugs are alsoeffectiveinthetreatmentofanumberofanxietydisorders(suchas panic and obsessive-compulsive disorder [OCD]) and avarietyofotherconditions(Box43-1).Theprecursorsoftwoofthemajorcontemporaryantidepressantfamilies,themonoam-ine oxidase inhibitors (MAOIs) and the tricyclic antidepres-sants(TCAs),werediscoveredbyserendipityinthe1950s.

Specifically, the administration of iproniazid, an anti-mycobacterialagent,wasfirstnotedtopossessantidepressanteffects in depressed patients suffering from tuberculosis.1Shortly thereafter, iproniazid was found to inhibit MAO,which is involved in the catabolism of serotonin, norepine-phrine(noradrenaline),anddopamine.

Inparallel,imipraminewasinitiallydevelopedasananti-histamine,butKuhn2discoveredthatofsome500imipramine-treatedpatientswithvariouspsychiatricdisorders,onlythosewithendogenousdepressionwithmentalandmotorretarda-tionshowedaremarkableimprovementduring1to6weeksofdailyimipraminetherapy.Thesamecompoundwasalsofoundto inhibit the re-uptake of serotonin and norepinephrine.3,4Thus,itwasthediscoveryoftheantidepressanteffectsofipro-niazid and imipramine that led to the development of theMAOIsandTCAs,andthisdiscoverywasinstrumentalintheformulationofthemonoaminetheoryofdepression.Inturn,guidedby this theory, the subsequentdevelopmentof com-poundsselectiveforthere-uptakeofeitherserotoninornore-pinephrineorbothwasdesigned,ratherthanaccidental.Asaresult,overthelastfewdecades,chemicalalterationsofthesefirst antidepressants have resulted in the creation of a widevariety of monoamine-based antidepressants with a varietyof mechanisms of action. The antidepressant drugs are a

heterogeneousgroupofcompoundsthathavebeentradition-allysubdividedintomajorgroupsaccordingtotheirchemicalstructure or, more commonly, according to their effects onmonoamine neurotransmitter systems: selective serotoninre-uptake inhibitors (SSRIs); TCAs and the related cyclicantidepressants (i.e., amoxapine and maprotiline); MAOIs;serotoninnorepinephrinere-uptakeinhibitors(SNRIs);nore-pinephrine re-uptake inhibitors (NRIs); norepinephrine/dopamine re-uptake inhibitors (NDRIs); serotonin receptorantagonists/agonists; and alpha2-adrenergic receptor antago-nists. Because they overlap, the mechanisms of action andthe indications for use for the antidepressants are discussedtogether,butseparatesectionsareprovidedfortheirmethodofadministrationandtheirsideeffects.

MECHANISM OF ACTIONThe precise mechanisms by which the antidepressant drugsexert their therapeutic effects remain unknown, althoughmuch is known about their immediate actions within thenervoussystem.Allofthecurrentlymarketedantidepressantsinteractwiththemonoamineneurotransmittersystemsinthebrain,particularlythenorepinephrineandserotoninsystems,and to a lesser extent the dopamine system. Essentially allcurrently marketed antidepressants have as their moleculartargets components of monoamine synapses, including there-uptaketransporters(thatterminatetheactionofnorepine-phrine, serotonin, or dopamine in synapses), monoaminereceptors,orenzymesthatservetometabolizemonoamines.What remains unknown is how these initial interactionsproduceatherapeuticresponse.5Thesearchforthemoleculareventsthatconvertalteredmonoamineneurotransmitterfunc-tionintotheliftingofdepressivesymptomsremainsamatterofveryactiveresearch.

SinceTCAsandMAOIswerethefirstantidepressantstobediscoveredandintroduced,thiswasinitiallyinterpretedassug-gestingthatantidepressantsworkbyincreasingnoradrenergicor serotonergic neurotransmission, thus compensating for apostulatedstateofrelativemonoamine“deficiency.”However,thissimpletheorycouldnotfullyexplaintheactionofantide-pressantdrugsforanumberofreasons.Themostimportantoftheseincludethelackofconvincingevidencethatdepressionischaracterizedbyastateofinadequateor“deficient”mono-amineneurotransmission.Infact,theresultsofstudiestestingthe monoamine depletion hypothesis in depression haveyielded inconsistent results.5 Moreover, blockade of mono-amine re-uptake or inhibition of monoamine degradationoccursrapidly(withinhours)followingmonoaminere-uptakeinhibitor or MAOI administration, respectively. However,treatmentwithantidepressantsforlessthan2weeksisunlikelytoresultinasignificantliftingofdepression;ithasbeencon-sistentlyobservedandreportedthatremissionofdepressionoftenrequires4weeksoftreatmentormore.Theseconsidera-tions have led to the idea that inhibition of monoaminere-uptakeorinhibitionofMAObyantidepressantsrepresentsan initiatingevent.Theactual therapeutic actionsof antide-pressants, however, result from slower adaptive responseswithin neurons to these initial biochemical perturbations(“downstream events”).6 Although research geared towardunderstanding the therapeutic actions of antidepressantshas been challenging, receptor studies have been useful in

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490 PARTX Treatment Approaches

understandingandpredictingsomeofthesideeffectsofcon-temporaryantidepressants.Forexample,thebindingaffinityofantidepressantsatmuscarinic cholinergic receptorsgenerallyparallelstheprevalenceofcertainsideeffectsduringtreatment(e.g.,drymouth,constipation,urinaryhesitancy,poorconcen-tration).Similarly,treatmentwithagentsthathavehighaffini-tiesforhistamineH1receptors(e.g.,doxepinandamitriptyline)appearstobemorelikelytoresultinsedation,andincreasedappetite. Such information is very useful to clinicians andpatients when making treatment decisions or to researcherswhenattemptingtodevelopnewantidepressants.

The architecture of the monoamine neurotransmittersystemsinthecentralnervoussystem(CNS)isbasedonthesynthesisof theneurotransmitterwithinarestrictednumberofnucleiwithinthebrainstem,withneuronsprojectingwidelythroughoutthebrainand,fornorepinephrineandserotonin,thespinalcordaswell.5Norepinephrineissynthesizedwithinaseriesofnucleiinthemedullaandpons,ofwhichthelargestisthenucleuslocuscoeruleus.Serotoninissynthesizedinthebrainstemraphenuclei.Dopamineissynthesizedinthesub-stantianigraandtheventraltegmentalareaofthemidbrain.Throughextensiveprojectionnetworks,theseneurotransmit-tersinfluencealargenumberoftargetneuronsinthecerebralcortex, basal forebrain, striatum, limbic system, and brain-stem,wheretheyinteractwithmultiplereceptortypestoregu-latearousal,vigilance,attention,sensoryprocessing,emotion,andcognition(includingmemory).7

Norepinephrine, serotonin, and dopamine are removedfrom synapses after release by re-uptake, mostly into pre-synapticneurons.5Thismechanismofterminatingneurotrans-mitteractionismediatedbyspecificnorepinephrine,serotonin,anddopaminere-uptaketransporterproteins.Afterre-uptake,norepinephrine,serotonin,anddopamineareeitherre-loadedintovesiclesforsubsequentreleaseorbrokendownbyMAO.MAOispresentintwoforms(MAOAandMAOB),whichdifferin their substrate preferences, inhibitor specificities, tissueexpression,andcelldistribution.MAOApreferentiallyoxidizesserotoninandisirreversiblyinactivatedbylowconcentrationsoftheacetylenicinhibitorclorgyline.MAOBpreferentiallyoxi-dizes phenylethylamine (PEA) and benzylamine and is irre-versibly inactivated by low concentrations of pargyline anddeprenyl.5Dopamine,tyramine,andtryptaminearesubstratesforbothformsofMAO.Catecholaminesarealsobrokendown

bycatecholO-methyltransferase(COMT),anenzymethatactsextracellularly.

The classification of antidepressant drugs has perhapsfocusedtoonarrowlyonsynapticpharmacology(i.e.,“imme-diate effects”), and has certainly failed to take into accountmolecular and cellular changes in neural function that arebroughtaboutbythechronicadministrationoftheseagents.5For example, it has been postulated that changes in post-receptor signal transduction may account for the aforemen-tioned characteristic lag-time between the time a drug isadministeredandthedrug-inducedresolutionofadepressiveepisode.Infact,studieshaveshownthathippocampalneuro-genesis occurs following chronic antidepressant treatmentin animal models.8 In parallel, rapid activation of the TrkBneurotrophin receptor and PLC gamma-1 signaling hasbeendescribedwithalmostallantidepressantdrugs,apossiblemechanism by which the process of neuronal neurogenesisobservedfollowingchronicadministrationofantidepressantsmay occur.9 Alternatively, one could postulate that thislag phase in antidepressant action may be related to are-organizationofneuronalnetworks,postulatedasapotential“finalcommonpathway”forantidepressanteffectstooccur.5Nevertheless, further research isurgentlyneeded inorder tohelpusunderstandthespecificeffectsoftheantidepressantsandwhatconstitutesillnessandrecoveryindepression.

Mechanism of Action of Selective Serotonin Re-uptake InhibitorsAttherapeuticallyrelevantdoses,theSSRIsexhibitsignificanteffectsprimarilyonserotoninre-uptakeinthehumanbrain.10SomeSSRIsalsoappeartohaveeffectsonothermonoaminetransporters,withsertralinedemonstratingmodestdopaminere-uptake inhibition, and paroxetine and fluoxetine demon-strating modest norepinephrine re-uptake inhibition.10 Inaddition,fluoxetine,particularlytheR-isomer,hasmild5-HT2Aand 5-HT2C antagonist activity. Non-monoaminergic effectshave also been described for some of the SSRIs, includingmoderateand selectiveeffectsonglutamate receptorexpres-sion and editing.11 The SSRIs have minimal or no affinityfor muscarinic cholinergic, histaminergic, and adrenergicreceptors,withtheexceptionofparoxetine(whichisaweakcholinergicreceptorantagonist),citalopram(whichisaweakantagonistofthehistamineH1receptor),andsertraline(whichhasweakaffinityforthealpha1receptors).10Overall,theaffin-ity of these agents for these specific receptors is lower thanthose of the TCAs, resulting in a milder side-effect profile.Similarly,thelackofsignificantactionfortheremainingSSRIsonthesereceptorsisalsothoughttocontributetothemilderside-effectprofileoftheseagentscomparedwiththeTCAs.

Mechanism of Action of Serotonin Norepinephrine Re-uptake InhibitorsUnlike the TCAs, SNRIs inhibit the re-uptake of serotoninmorepotentlythanthere-uptakeofnorepinephrine.10Similarto most SSRIs, the SNRIs have minimal or no affinity formuscarinic cholinergic, histaminergic, and adrenergic recep-tors.10Interestinglyenough,administrationofthesedrugshasbeen shown to prevent a decrease in cell proliferation andBDNFexpressioninrathippocampusobservedwithchronicstress, inastudythatoffers further insights into the“down-stream effects” of these agents.12 In parallel, studies suggestthat chronic treatment with the SNRI duloxetine not onlyproducesamarkedup-regulationofBDNFmRNAandproteinbutmayalsoaffect thesub-cellularre-distributionofneuro-trophin,potentiallyimprovingsynapticplasticity.13

BOX43-1 Possible Indications for Antidepressants

• Major depressive disorder and other unipolar depressive disorders

• Bipolar depression• Panic disorder• Social anxiety disorder• Generalized anxiety disorder• Post-traumatic stress disorder• Obsessive-compulsive disorder (e.g., clomipramine and SSRIs)• Depression with psychotic features (in combination with an

antipsychotic drug)• Bulimia nervosa• Neuropathic pain (tricyclic drugs and SNRIs)• Insomnia (e.g., trazodone, amitriptyline)• Enuresis (imipramine best studied)• Atypical depression (e.g., monoamine oxidase inhibitors)• Attention-deficit/hyperactivity disorder (e.g., desipramine,

bupropion)

SNRIs, Serotonin norepinephrine re-uptake inhibitors; SSRIs, selective serotonin re-uptake inhibitors.


Antidepressants 491

43appearsthattheneteffectofvilazodoneatrelease-regulating5-HT1A autoreceptors is inhibitory, leading to markedlyincreasedserotoninoutput.

Vortioxetine is a recently-approved antidepressant withmulti-modalactivitythatfunctionsasaserotonin5-HT3,5-HT7and 5-HT1D receptor antagonist, serotonin 5-HT1B receptorpartialagonist,serotonin5-HT1Areceptoragonistandinhibi-tor of the serotonin transporter in vitro.37 Vortioxetine hasshowntobeabletoincreaseextracellularserotonin,dopamine,andnorepinephrineinthemedialprefrontalcortexandventralhippocampus,38andtosignificantlyincreasecellproliferationand cell survival and stimulate maturation of immaturegranulecellsinthesub-granularzoneofthedentategyrusofthehippocampusafter21daysoftreatment.37

Mechanism of Action of Norepinephrine/Dopamine Re-uptake InhibitorsThe NDRIs primarily block the re-uptake of dopamine andnorepinephrine and have minimal or no affinity for pre-synapticorpost-synapticmonoamine receptors.Themecha-nism of action of bupropion has not been fully elucidated,althoughitappearstoprimarilyblockthere-uptakeofbothdopamineandnorepinephrine.39Bupropionanditsmetabo-liteshavebeenshowntobeabletoinhibitstriataluptakeoftheselectivedopaminetransporter(DAT)-bindingradioligand(11)C-betaCIT-FE in vivo,40 and to have mild affinity for thenorepinephrinetransporter,41althoughsomeresearchershavearguedthattheeffectofbupropiononnorepinephrineispri-marily through an increase in pre-synaptic norepinephrinerelease.42 Whatever the exact mechanism may be, it appearsthat the overall effect of bupropion is a dose-dependentincreaseinbrainextracellulardopamineandnorepinephrineconcentrations.43 It also appears that bupropion acts as anantagonistatalpha3beta2andalpha3beta4nAChRsinratstria-tumandhippocampus,respectively,acrossthesameconcen-trationrangethatinhibitsDATandnorepinephrinetransporter(NET)function.44

Mechanism of Action of Alpha2-Adrenergic Receptor AntagonistsThealpha2-adrenergicreceptorantagonists(e.g.,mirtazapineandmianserin)appeartoenhancethereleaseofbothserot-oninandnorepinephrinebyblockingauto-andhetero-alpha2receptors.45Sincemirtazapineappearstobeablockerofsero-tonin 5-HT2 and 5-HT3 receptors as well, it is thought toenhance the release of norepinephrine and also enhance5-HT1A–mediated serotonergic transmission.46 Mirtazapinewas the first alpha2-adrenergic receptor antagonist to beapproved by the Food and Drug Administration (FDA) fordepression. Mirtazapine is also a potent histaminergic H1-receptorantagonist.10Mianserin,alsoanalpha2-noradrenergicreceptorantagonistandaserotonin5-HT2antagonist,isavail-ableinEuropeandisnotFDA-approved.

Mechanism of Action of Tricyclic AntidepressantsTCAs,referredtoassuchbecausetheyshareachemicalstruc-ture with two joined benzene rings, have been in use foralmost half a century for the treatment of depression. Withthe exception of clomipramine, and in contrast with theSNRIs,theTCAsinhibitthere-uptakeofnorepinephrinemorepotentlythanthere-uptakeofserotonin.RecentstudieshavealsoshownthatfiveoftheTCAsbindtotheS1S2domainoftheGluR2subunitoftheAMPAreceptor,suggestinganeffectof TCAs on the glutamergic system.47 In addition, doxepin,

Mechanism of Action of Norepinephrine Re-uptake InhibitorsAt therapeutically relevant doses, the NRIs have significanteffects primarily on norepinephrine re-uptake, although theNRIatomoxetineisalsoaweakinhibitorofserotoninuptake.14NRIsalsoappeartohaveseveralnon-monoaminergicproper-ties.Specifically,theNRIreboxetinealsoappearstofunction-allyinhibitnicotinicacetylcholinereceptors.15Inaddition,inrats,atomoxetinehasbeenshowntoincreasein vivoextracel-lular levels of acetylcholine (ACh) in cortical but not sub-cortical brain regions, with a mechanism dependent onnorepinephrine alpha1 and/or dopamine D1 receptor activa-tion.16Furthermore,themajorhumanmetaboliteofatomox-etine (4-hydroxyatomoxetine) is a partial agonist of thekappa-opioid receptor.17 Finally, reboxetine has also beenfoundtobetheantidepressantthataffectsglutamatereceptors(GluR)most,withadecreaseofGluR3expression.11

Mechanism of Action of Serotonin Receptor Agonist/AntagonistsBothtrazodoneandnefazodonearerelativelyweakinhibitorsofserotoninandnorepinephrineuptake,andtheyprimarilyblockserotonin5-HT2Areceptors(insomecases,demonstrat-ing partial agonist properties as well).18–21 They also share ametabolite,m-chlorophenylpiperazine(mCPP),whichactsasaserotonin5-HT2Cagonistandappearstobeabletoreleaseserotoninpre-synaptically.22Trazodonealsoappearstostimu-late the mu1- and mu2-opioid receptors23 and is a potentagonistof theserotonin5-HT2Creceptors,which,whenacti-vated,24,25may inhibitNMDA-inducedcyclicGMPelevation.Sincetrazodoneisalsoaweakinhibitorofserotoninre-uptakeaswell,theoveralleffectoftrazodoneappearstobeanincreasein extracellular levels of serotonin in the brain.26 This effectexplainsthefactthattrazodonetreatmenthasbeenassociatedwith the occurrence of a serotonin syndrome.27 Both trazo-doneand(althoughtoalesserdegree)nefazodonearepotentblockersofthealpha1-adrenergicreceptor.

Agomelatine,availableinEuropeasanantidepressant,isaselective5-HT2CantagonistandactsasamelatoninMT1andMT2 receptor agonist. The 5-HT2C antagonism properties ofagomelatinehavebeenthoughttoberesponsibleforincreasesin frontocortical dopaminergic and adrenergic activity inanimalsduringadministrationofagomelatine.28

Buspirone and gepirone act as full agonists at serotonin5-HT1A autoreceptors and are generally, but not exclusively,partialagonistsatpost-synapticserotonin5-HT1Areceptors.29Neither buspirone or gepirone are approved for depression,butbuspirone isFDA-approved for the treatmentofanxiety.Buspironeandgepironeshowweakalpha1-adrenoceptoraffin-ity,butsignificantandselectivealpha1-adrenoceptorintrinsicefficacy,whichwasexpressedinatissue-andspecies-dependentmanner.30BuspironealsoshowsbindingwithhighaffinitytorecombinanthumanD3andD4 receptors (~98and~29nmrespectively).31 Buspirone and gepirone are thought to leadto excitation of noradrenergic cell firing,32 antagonizingprimarilypre-synapticinhibitorydopamineD2autoreceptorsat dopaminergic neurons.33 Buspirone also has potentalpha2-adrenoceptor antagonist properties via its principalmetabolite,1-(2-pyrimidinyl)-piperazine.34,35Vilazodone isaserotonin5-HT1Areceptorpartialagonistandaselectivesero-tonin re-uptake inhibitor that induces maximal serotoninlevelsthataresimilarinthemedialandthelateralcortexandareuptosix-foldhigher thanthose inducedbySSRIs testedin parallel, when serotonin levels are measured in twosub-regionsof the ratprefrontal cortexbymicrodialysis.36 It



More recently, additional pharmacological properties forthe MAOIs have been revealed. MAOIs, for instance, alsoappeartoinhibitthebindingof[3H]quinpirole,adopamineagonist with high affinity for D2 and D3 dopamine recep-tors.58,59 To complicate the pharmacology of MAOIs further,twooftheMAOIs,selegilineandtranylcypromine,havemeth-amphetamine and amphetamine as metabolites.60,61 Inaddition,phenelzinealsoelevatesbraingamma-aminobutyricacid (GABA) levels, and as yet unidentified metabolites ofphenelzinemayberesponsibleforthiseffect.61R(−)-butnotS(+)- selegiline also appears to induce dopamine release bydirectly modulating ATP-sensitive potassium channels.62Finally, (+)-tranylcypromine (TCP) has been shown to bemore potent than (−)-TCP as an inhibitor of 5-HT uptake,whereas (−)-TCP has been shown to be more potent than(+)-TCP as an inhibitor of dopamine and norepinephrineuptake.63

Although the risk for serotonin syndromesmaybe lowerthanwiththeolderMAOIs,andanumberofstudiessuggestedthe safety of combining moclobemide with SSRIs,64–66 therehavebeenanumberofnon-fatal67,68andfatalserotoninsyn-dromes involving the co-administration of moclobemideand SSRIs.69–74 For these reasons, the concomitant use ofmoclobemideandserotonergicagentsshouldbeavoided.Inaddition,theco-ingestionofmoclobemideandSSRIsinover-dosemayresultindeath,whichneedstobetakenintoaccountforpatientsatriskforsuicide.70

CLINICAL USES OF ANTIDEPRESSANTSSincetheintroductionoffluoxetine,theSSRIsandtheSNRIshavebecomethemostoftenprescribedinitialpharmacologi-cal treatment for major depressive disorder (MDD). ThesuccessoftheseneweragentsindisplacingTCAsasfirst-choiceagentsisnotbasedonestablisheddifferencesinefficacy,butratheronagenerallymorefavorableside-effectprofile(suchasalackofanticholinergicandcardiacsideeffects,andahightherapeutic index, i.e., theratioof lethaldosetotherapeuticdose), combined with ease of administration. Furthermore,with certain co-morbidities of depression (such as OCD),SSRIsofferadvantagesinefficacyovertheTCAs.Nonetheless,theTCAsremainusefulalternativesforthetreatmentofsomepatientswithdepression.Incontrast,becauseoftheirinferiorsafety profile, the traditional MAOIs are a class of drugsreserved for patients in whom other treatments have failed.Clearly,thenewerantidepressants(SSRIs,SNRIs,NRIs,NDRIs,and serotonin receptorantagonists) allhavemajor safetyortolerabilityadvantagesovertheTCAsandMAOIs.Therecently-approvedserotoninreceptorantagonistvortioxetinemayhavetheadditionaladvantageofdistinctivepro-cognitiveeffects.

Continuation and Maintenance of Antidepressant TreatmentOriginally,basedonstudieswithTCAs,patientswithunipolardepressive disorders were observed to be at high risk forrelapsewhentreatmentwasdiscontinuedwithinthefirst16weeks of therapy. Therefore, in treatment-responders, mostexperts favor a continuation of antidepressant therapy for aminimumof6months followingtheachievementof remis-sion.Thevalueofcontinuationtherapyforseveralmonthstopreventrelapseintotheoriginalepisodehasalsobeenestab-lishedforvirtuallyalloftheneweragents.75Riskofrecurrenceafter this6- to8-monthcontinuationperiod(i.e., thedevel-opment of a new episode after recovery from the indexepisode) is particularly elevated in patients with a chroniccourse before recovery, residual symptoms, and multipleprior episodes (three or more).76 For these individuals, the

amitriptyline,andnortriptylinealsoinhibitglycineuptakebyblockingtheglycinetransporter1b(GLYT1b)andglycinetrans-porter2a(GLYT2a)toasimilarextent.48AmoxapinedisplaysaselectiveinhibitionofGLYT2abehavingasa10-foldmoreeffi-cientinhibitorofthisisoformthanofGLYT1b

48andisalsoadopamineD2receptorantagonist.49Interestingly,in vitrodatasuggest that trimipramineandclomipraminehavecompara-ble affinity for the dopamine D2 receptor.50 The TCAs, tovarying degrees, are also fairly potent blockers of histamineH1receptors,serotonin5-HT2receptors,muscarinicacetylcho-linereceptors,andalpha1-adrenergicreceptors.10,50

Mechanism of Action of Monoamine Oxidase InhibitorsMAOIsactbyinhibitingMAO,anenzymefoundontheoutermembraneofmitochondria,whereitcatabolizes(degrades)anumber of monoamines including dopamine, norepine-phrine, and serotonin.Specifically, following their re-uptakefrom the synapse into the pre-synaptic neuron, norepine-phrine,serotonin,anddopamineareeitherloadedintovesi-clesforsubsequentre-releaseorbrokendownbyMAO.MAOis present in two forms (MAOA and MAOB), which differ intheirsubstratepreferences,inhibitorspecificities,tissueexpres-sion,andcelldistribution.MAOApreferentiallyoxidizessero-toninandisirreversiblyinactivatedbylowconcentrationsofthe acetylenic inhibitor clorgyline. MAOB preferentially oxi-dizes phenylethylamine (PEA) and benzylamine and is irre-versibly inactivated by low concentrations of pargyline anddeprenyl. Dopamine and the dietary (exogenous) amines,tyramine and tryptamine, are substrates for both forms ofMAO.51 In thegastrointestinal (GI) tract and the liver,MAOcatabolizes a number of dietary pressor amines (such asdopamine, tyramine, tryptamine, and phenylethylamine).52For this reason, consumption of certain foods (that containhigh levels of dietary amines) while on an MAOI mayprecipitate a hypertensive crisis, characterized by hyperten-sion, hyperpyrexia, tachycardia, tremulousness, and cardiacarrhythmias.53 The same reaction may also occur duringco-administrationofdopaminergicagentsandMAOIs,whilethe co-administration of MAOIs with other antidepressantsthatpotentiateserotonincouldresultinserotoninsyndromesduetotoxicCNSserotoninlevels.Theserotoninsyndromeischaracterizedbyalterations incognition(e.g.,disorientationand confusion), behavior (e.g., agitation and restlessness),autonomicnervoussystemfunction(e.g.,fever,shivering,dia-phoresis, and diarrhea), and neuromuscular activity (e.g.,ataxia, hyperreflexia, and myoclonus).54–56 Since MAO enzy-matic activity requires approximately 14 days to be fullyrestored, such foodormedications shouldbeavoided for2weeksfollowingthediscontinuationofanirreversibleMAOI(“MAOI washout period”). Serotonergic and dopaminergicantidepressantsaretypicallydiscontinued2weeksbeforetheinitiationofanMAOI,withtheexceptionoffluoxetine,whichneeds tobediscontinued5weeks in advancebecauseof itsmuchlongerhalf-life.

OlderMAOIs,includingphenelzine,tranylcypromine,andisocarboxazid, irreversibly inhibit the enzymatic activity ofbothMAOAandMAOB,whileneweronesarerelativelyselec-tive (brofaromine and moclobemide preferentially inhibitMAOA; oral selegiline selectively inhibits MAOB). ReversibleMAOA-selective inhibitors aredesigned tominimize the riskof hypertensive crises, and patients on conventional dosesof moclobemide do not need to strictly adhere to the low-tyraminediet,although,atveryhighdoses(e.g.,900mg/dayof moclobemide), inhibition of MAOB also occurs.57 AllMAOIsavailableintheUSareirreversibleinhibitorsofMAOAandMAOBactivity.


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43tionofadultandpediatricpatientstreatedwiththesedrugsforworsening depression or the emergence of suicidality. Thiswarningwasbasedontheanalysesofclinicaltrialsdatathatcomparedtherelativeriskofemergenceofsuicidalideationonthesedrugscomparedtoplacebofollowinginitiationoftreat-ment. The difference was small, but statistically significant.This finding underscores the need for good practice, whichincludeseducationofpatients(andfamiliesifthepatientisachild)aboutsideeffectsofdrugs(includingthepossibleemer-genceof suicidal thoughtsandbehaviors), closemonitoring(especiallyearlyintreatment),andtheavailabilityofaclini-cianincasesuicidalityemergesorworsens.Ageneralconsen-susremains,however,thattherisksassociatedwithwithholdingantidepressant treatment from patients, including pediatricpatients, with serious depression vastly outweighs the risksassociatedwiththedrugsbymanyordersofmagnitude.

CHOICE OF AN ANTIDEPRESSANTAlargenumberofantidepressantsareavailable(Table43-1),including SSRIs, SNRIs, NRIs, NDRIs, serotonin receptorantagonists/agonists, the alpha2-adrenergic receptor antago-nists,TCAsandrelatedcompounds,andMAOIs.TheavailableformulationsandtheirtypicaldosagesarelistedinTable43-1,andaspectsoftheirsuccessfulusearelistedinBox43-2.

Selective Serotonin Re-uptake InhibitorsTheoverallefficacyoftheSSRIsinthetreatmentofdepressionisequivalenttothatofolderagents,includingtheTCAsandtheMAOIsmoclobemide80andphenelzine,81whileallSSRIsappeartobeequallyeffectiveinthetreatmentofdepression.82However,thereissomeevidencesuggestingthatthattheSSRIescitalopram may be more effective than the remaining fiveSSRIs in the treatment of MDD,83 although this evidenceremainscontroversial.

Becauseoftheirfavorableside-effectprofile,theSSRIsareusedasfirst-line treatment in theoverwhelmingmajorityofcases,withmorethan90%ofcliniciansinonesurveyindicat-ing that SSRIs were their first-line treatment.84 Despite thetolerabilityandthewidespreadefficacyoftheSSRIs,thereismounting evidence to suggest that depressed patients withcertain characteristics (including co-morbid anxiety disor-ders85 and a greater number of somatic symptoms [such aspain, headaches, and fatigue]86) respond less well to SSRIsthanthosewithoutsuchcharacteristics.

optimaldurationofmaintenancetreatmentisunknown,butis assumed to be much longer (measured in years). In fact,basedonresearchtodate,prophylacticefficacyofanantide-pressanthasbeenobserved foras longas5yearswithclearbenefit.77 In contrast to the initial expectation that mainte-nance therapywouldbeeffectiveatdosages lower than thatrequired for acute treatment, the current consensus is thatfull-dosetherapyisrequiredforeffectiveprophylaxis.78About20% to 30% of patients who are treated with each of theclassesofantidepressantswillexperiencea returnofdepres-sivesymptomsdespitecontinuedtreatment.Insuchpatients,adoseincreaseoftheantidepressantistypicallythefirst-lineapproach.79

Suicide RiskUnlike theSSRIsandotherneweragents, theMAOIs,TCAs,andrelatedcyclicantidepressants(maprotilineandamoxap-ine)arepotentiallylethalinoverdose.Thus,acarefulevalua-tionofimpulsivenessandsuicideriskinfluencesnotonlythedecisionastotheneedforhospitalizingapersonwithdepres-sionbutalsothechoiceofanantidepressant.Forpotentiallysuicidalorhighlyimpulsivepatients,theSSRIsandtheotherneweragentswouldbeabetterinitialchoicethanacycliccom-pound or an MAOI. Patients at elevated suicide risk whocannottoleratethesesafercompoundsorwhodonotrespondto themshouldnot receive largequantitiesor refillablepre-scriptionsforTCAsorMAOIs.Generally,patientswhoarenewtotreatmentorthoseatmorethanminimalriskforsuicideorwhose therapeutic relationship is unstable should receive alimitedsupplyofanymedication.Evaluationforsuicideriskmustcontinueevenaftertheinitiationoftreatment.Althoughsuicidal thoughts are often among the first symptoms toimprovewithantidepressanttreatment,theymayalsobeslowtorespondtotreatment,andpatientsmaybecomedemoral-izedbeforetherapeuticefficacyisevident.Sideeffects(suchasagitationandrestlessness)and,mostimportant,inter-currentlifeeventsmayexacerbatesuicidalthoughtsbeforeafullthera-peuticresponse.Thus,rarely,foravarietyofreasons,patientsmay temporarilybecomemore suicidal following the initia-tionoftreatment.Shouldsuchworseningoccur,appropriateinterventionsmayincludemanagementofsideeffects,morefrequentmonitoring,discontinuationoftheinitialtreatment,orhospitalization.In2004,theFDAaskedmanufacturersofalmostallthenewerantidepressantdrugstoincludeintheirlabelingawarningstatementthatrecommendscloseobserva-

TABLE43-1A Available Preparations of Antidepressants: Selective Serotonin Re-uptake Inhibitors (SSRIs)

Drug TherapeuticDosageFormsUsualDailyDose(mg/day)

ExtremeDosage(mg/day)

PlasmaLevels(ng/ml)

Fluoxetine (Prozac and generics) C: 10, 20, 40 mg 20–40 5–80LC: 20 mg/5 mlWeekly: 90 mg

Fluvoxamine (Luvox and generics)* T: 50, 100 mg 50–150 50–300

Paroxetine (Paxil and generics) T: 10, 20, 30, 40 mg 20–40 10–50LC: 10 mg/5 mlCR: 12.5, 25, 37.5 mg 25–50 12.5–50

Sertraline (Zoloft and generics) T: 25, 50, 100 mg 50–150 25–300LC: 20 mg/ml

Citalopram (Celexa and generics) T: 10, 20, 40 mg 20–40 10–60LC: 10 mg/5 ml

Escitalopram (Lexapro and generics) T: 10, 20 mg 10–20 10–30

*Not marketed for depression in the US.C, Capsules; CR, controlled release; LC, liquid concentrate or solution; T, tablets.



TABLE43-1B Available Preparations of Antidepressants: Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs)



PlasmaLevels(ng/ml)

Venlafaxine (Effexor and generics) T: 25, 37.5, 50, 75, 100 mg 75–300 75–450XR: 37.5, 75, 150 mg

Duloxetine (Cymbalta and generics) C: 20, 30, 60 mg 60–120 30–180

Desvenlafaxine (Pristiq) T: 50, 100 mg 50–100 25–200

Levomilnacipran ER (Fetzima) C: 20, 40, 80, 120 mg 40–120 20–240

C, Capsules; T, tablets; XR, extended-release.

TABLE43-1C Available Preparations of Antidepressants: Norepinephrine Re-uptake Inhibitors (NRIs)



PlasmaLevels(ng/ml)

Reboxetine* T: 4 mg 4–10 4–12

Atomoxetine (Strattera) T: 10, 18, 25, 40, 60 mg 40–80 40–120

*Not marketed for depression in the US.T, tablets.

TABLE43-1D Available Preparations of Antidepressants: Serotonin Receptor Antagonists / Agonists



PlasmaLevels(ng/ml)

Trazodone (Desyrel and generics) T: 50, 100, 150, 300 mg 200–400 100–600

Trazodone Extended Release (Oleptro) T: 150, 300 mg 150–300 75–600

Nefazodone (Serzone and generics) T: 50, 100, 150, 200, 250 mg 200–400 100–600

Vilazodone (Viibryd) T: 10, 20, 40 mg 40–80 20–160

Vortioxetine (Brintellix) T: 5, 10, 20 mg 10–20 5–40

T, tablets.

TABLE43-1E Available Preparations of Antidepressants: Norepinephrine Dopamine Re-uptake Inhibitors (NDRIs)



PlasmaLevels(ng/ml)

Bupropion (Wellbutrin and generics) T: 75, 100 mg 200–300 100–450XR: 100, 150, 200 mgXL: 150, 300 mgSoltabs: 15, 30, 45 mg

Soltabs, orally disintegrating tablet; T, tablets; XL, extended-release; XR, extended-release.

TABLE43-1F Available Preparations of Antidepressants: Alpha2-receptor Antagonists



PlasmaLevels(ng/ml)

Mirtazapine (Remeron and generics) T: 15, 30, 45 mg 15–45 7.5–90Soltabs: 15, 30, 45 mg

Soltabs, orally disintegrating tablet; T, tablets.

DosageBecauseoftheirrelativelylowside-effectburden,thestartingdose of SSRIs is often the minimally effective daily dose:10mg for escitalopram (Lexapro); 20mg for fluoxetine(Prozac),paroxetine(Paxil),andcitalopram(Celexa);50mgfor sertraline (Zoloft); 25mg for paroxetine CR (Paxil CR);

and100mgforfluvoxamine(Luvox).Startingatlowerdosesand increasing the dose shortly thereafter (i.e., after 1 to 2weeks)mayfurtherimprovetolerability.Maximumtherapeu-ticdoses forSSRIsare typicallyone-fold to four-foldgreaterthan the startingdose.Thedosagesand formulationsof theSSRIsmarketedintheUSarelistedinTable43-1.Onlyoneof theSSRIs,fluvoxamine, isnotapprovedfor thetreatment


43

BOX43-2 Requirements for Successful Use of Antidepressants

1. Good patient selection as determined by a thorough and comprehensive diagnostic evaluation. In particular, attention should be paid to co-morbid psychiatric and medical disorders.

2. Choice of a drug with an acceptable side-effect profile for the given patient.

3. Adequate dosage. In the absence of side effects and response, dose escalations within the recommended range should be pursued aggressively.

4. Use of the antidepressant for at least 6–12 weeks to determine whether it is helping or not.

5. Consideration of drug side effects. Although there are some differences in efficacy across the class of antidepressants for sutypes of depression, the major clinically significant differences among the antidepressants are in their side effects.

6. Use of a drug that was clearly effective in the past if it was well tolerated by the patient.

7. Selection of an appropriate agent for patients with initial insomnia, for example, a sedating secondary amine TCA (e.g., nortriptyline) given at bedtime (a strategy used by some clinicians), avoidance of agents with anticholinergic and cardiovascular side effects (therefore, the sleep-enhancing, alpha2-adrenergic receptor antagonist mirtazapine would be preferred, with the expectation that daytime sedation will abate over time with these medications). An alternative to prescribing a sedating antidepressant is the temporary use of a short-acting benzodiazepine or other hypnotic combined with an SSRI or another non-sedating newer antidepressant,

with the expectation of tapering and discontinuing the hypnotic when the depression has improved. Trazodone at lower doses (50–300 mg at bedtime) has been used in place of benzodiazepines or other hypnotics to treat insomnia, particularly middle to late insomnia, in patients treated for depression with an SSRI.

8. Consideration of effects on sexual function. In particular, decreased libido, delayed orgasm or anorgasmia, arousal difficulties, and erectile dysfunction have been reported with almost all of the classes of antidepressants.

9. Awareness of co-morbid conditions. The co-morbid disorder should influence initial treatment selection in choosing an agent thought to be efficacious for the co-morbid condition, as well as the depression, as with SSRIs and OCD or the NDRI bupropion and attention-deficit disorder.

10. Consideration of metabolic effects on drug levels and elimination half-life. The elderly may have alterations in hepatic metabolic pathways, especially so-called phase I reactions, which include demethylation and hydroxylation, which are involved in the metabolism of both SSRIs and cyclic antidepressants. In addition, renal function may be decreased, and there may be increased end-organ sensitivity to the effects of antidepressant compounds. Because the elimination half-life of antidepressants can be expected to be significantly greater than what it is in younger patients, accumulation of active drug will be greater and occur more slowly. Clinically this means that the elderly should be started on lower doses, that dosage increases should be slower, and that the ultimate therapeutic dose may be lower than in younger patients.

NDRI, Norepinephrine/dopamine re-uptake inhibitor; OCD, obsessive-compulsive disorder; SSRI, selective serotonin re-uptake inhibitor.

TABLE43-1G Available Preparations of Antidepressants:Tricyclic Antidepressants (TCAs) and Other Cyclic Compounds



PlasmaLevels(ng/ml)

Imipramine (Tofranil and generics) T: 10, 25, 50 mg 150–200 50–300 >225*C: 75, 100, 125, 150 mgINJ: 25 mg/2 ml

Desipramine (Norpramin and generics) T: 10, 25, 50, 75, 100, 150 mg 150–200 50–300 >125C: 25, 50 mg

Amitriptyline (Elavil and generics) T: 10, 25, 50, 75, 100, 150 mg 150–200 50–300 >120†INJ: 10 mg/ml

Nortriptyline (Pamelor and generics) C: 10, 25, 50, 75 mg 75–100 25–150 50–150LC: 10 mg/5 ml

Doxepin (Adapin, Sinequan, and generics) C: 10, 25, 50, 75, 100, 150 mg 150–200 25–300 100–250LC: 10 mg/ml

Trimipramine (Surmontil and generics) C: 25, 50, 100 mg 150–200 50–300

Protriptyline (Vivactil and generics) T: 5, 10 mg 10–40 10–60

Maprotiline (Ludiomil and generics) T: 25, 50, 75 mg 100–150 50–200

Amoxapine (Asendin and generics) T: 25, 50, 100, 150 mg 150–200 50–300

Clomipramine (Anafranil and generics) C: 25, 50, 75 mg 150–200 50–250

*Sum of imipramine plus desipramine.†Sum of amitriptyline plus nortriptyline.C, Capsules; INJ, injectable form; LC, liquid concentrate or solution; T, tablets.

TABLE43-1H Available Preparations of Antidepressants: Monoamine Oxidase Inhibitors (MAOIs)



PlasmaLevels(ng/ml)

Phenelzine (Nardil and generics) T: 15 mg 45–60 15–90

Tranylcypromine (Parnate and generics) T: 10 mg 30–50 10–90

Isocarboxazid (Marplan and generics) T: 10 mg 30–50 30–90

Selegiline Transdermal System (patch) (Emsam) P: 6, 9, 12/day 6–12 6–18

T, tablets.



dizziness, insomnia, nervousness, irritability, nausea, andagitation.115,116Theriskofsuchadverseeventsoccurringseemstobeinverselyrelatedtothehalf-lifeoftheSSRI,withfluoxe-tinereportedashavingasignificantlylowerriskthanparoxe-tineintwostudies.115,117Formoreseverediscontinuation-relatedadverseevents,re-institutionoftheSSRIandslowtapermaybenecessarytoalleviatethesesymptoms.118

Drug InteractionsWiththeexceptionperhapsofcitalopram,anditsstereoisomerescitalopram,119 SSRIs may inhibit cytochrome P (CYP) 450isoenzymes to varying degrees, potentially causing substratelevels to rise, or reducing conversion of a substrate into itsactiveform.Concernaboutdruginteractions,however,isper-tinent to patients who take medications with narrow thera-peuticmarginsthataremetabolizedbyisoenzymesinhibitedbyanSSRIandiftheprescriberisunfamiliarwithorunabletodeterminetheappropriatedoseadjustment.Giventheirvastavailability, reports of clinically significant interactions withtheSSRIsareremarkablyrare.AmongtheSSRIs,fluvoxamineisapotentCYP1A2andCYP2C19inhibitor,andamoderateCYP2C9,CYP2D6,andCYP3A4inhibitor,whilefluoxetineandparoxetinearepotentCYP2D6inhibitors,andfluoxetine’smain metabolite, norfluoxetine, has a moderate inhibitoryeffectonCYP3A4.119SertralineisamoderateCYP2D6inhibi-tor, while citalopram and escitalopram appear to have littleeffect on the major CYP isoforms.119 However, for all of theSSRIs,somevigilanceisreasonableconcerningthepossibilityofincreasedtherapeuticortoxiceffectsofotherco-prescribeddrugsmetabolizedbyP4502D6. Inparticular, ifcombininga TCA with an SSRI, the TCA should be initiated with lowdoses,andplasmalevelsshouldbemonitored.Giventhehighcapacity of the CYP 450 3A3/3A4 system, inhibition of thisisoenzyme is not a major concern for the SSRIs, althoughfluvoxamine, and less so fluoxetine, can inhibit it to someextent. Of little importance to drug interactions is the highrateofprotein-bindingoftheSSRIsbecause,ifotherdrugsaredisplacedfromcarrierproteins,theresultissimplyanincreasein therateandamountof freedrugbeingmetabolized.TheaugmentationandcombinationofSSRIswithotherseroton-ergicagents, tryptophan,5-HT,orMAOIsmayalso result intheserotoninsyndrome;SSRIsshouldneverbeusedconcomi-tantly with MAOIs, because there have been a number ofreportsoffatalcasesofserotoninsyndromeduetothesimul-taneous use of these classes of drugs or to the inadequatewashoutperiodbetweenthetwo.54–56

Use of Selective Serotonin Re-uptake Inhibitors in Pregnancy and the Post-partum PeriodThereisaccumulatinginformationabouttheuseofSSRIsinpregnancy, although the bulk of the available data are onfluoxetine. One prospective study of 128 pregnant womenwho took fluoxetine,120 10 to 80mg/day (mean 25.8mg),duringtheirfirsttrimesterdidnotfindelevatedratesofmajormalformations compared with matched groups of womentakingTCAsordrugsthoughtnottobeteratogenic.Therewasahigher,albeitnotstatisticallysignificant,rateofmiscarriagesinthefluoxetine(13.5%)andTCA(12.2%)groupscomparedwith the women exposed to known non-teratogenic drugs(6.8%).Whetherthisincreasedrateofmiscarriagesisbiologi-callysignificantand,ifso,whetheritrelatestothedrugsortothe depressive disorder could not be determined from thisstudy. Decisions on continuing antidepressant drugs duringpregnancymustbeindividualized,butitmustberecalledthatthe effects of severe untreated depression on maternal andfetalhealthmaybefarworsethantheunknownrisksoffluox-etineortricyclicdrugs.Alargeregistryoffluoxetineexposure

ofdepressionin theUS,as it isapprovedonly for the treat-mentofOCD,althoughseveralplacebo-controlledtrialshavedemonstratedtheefficacyoffluvoxamineinMDD.87,88

Side-effect ProfileThemostcommonsideeffectsoftheSSRIsarenausea,tremor,excessivesweating,flushing,headache,insomnia,activationorsedation,jitteriness,dizziness,rash,anddrymouth.89SedationdoesnotappeartooccurmoreoftenwithanyparticularSSRI,whiletheSSRIsappeartobeequallywelltoleratedandeffectiveinthetreatmentofdepressedpatients,regardlessofwhethertheycauseinsomnia,activation,orsedation.82TheuseofSSRIsis also associated with the emergence of sexual dysfunction(includingdecreased libido,delayedejaculation, impotence,and anorgasmia), or the worsening of pre-existing sexualdysfunction in depression.90 These side effects tendto improve rapidlyafter temporary(“drugholiday”)discon-tinuationoftheSSRIs,particularlythoseSSRIswithashorterhalf-life,91althoughprolongingsuchdrugholidayscarriesariskofwithdrawaleffectsandofdepressiverelapse.Somepatientstreated with SSRIs may also experience cognitive symptoms(suchasmentalslowingandworsenedattention),psychologi-calsymptoms(suchasapathyandemotionalblunting),92andmotorsymptoms(suchasbruxismandakathisia).93,94Other,lesscommon,adverseeventsassociatedwithSSRI treatmentinclude diarrhea, tremor, bruxism, rash, hyponatremia, hairloss,andthesyndromeofinappropriateantidiuretichormone(SIADH) secretion. There are also case reports of the SSRIsworsening motor symptoms in patients with Parkinson’sdisease,95–97aswellascreatingincreasedrequirementsforlevo-dopainParkinson’spatientsfollowinginitiationofanSSRIfordepression.98SSRIshavebeenassociatedwithabnormalbleed-ing(e.g.,bruisingandepistaxis) inchildrenandadultswhohaveunremarkableroutinehematological laboratoryresults,exceptforabnormalbleedingtimeorplateletcounts.99Asys-tematicstudyofthisissuehasfailedtorevealabnormalitiesinplateletaggregation,hematopoiesis,orcoagulationprofileinSSRI-treated patients.100 Although many patients may alsoexperiencereducedappetiteandweightlossduringtheacutephaseoftreatmentwithSSRIs,101,102anybeneficialeffectsoftheSSRIswithrespecttoweightlossdonotseemtobesustainedduring the continuation and maintenance phases of treat-ment,101,102whileonestudyrevealsagreaterriskforsignificantweightgainduringlong-termtreatmentwithparoxetine,butnot fluoxetine or sertraline.103 Although SSRI-induced sideeffects appear to be well tolerated by most patients,104 fordepressedpatientswhoareunabletotolerateoneSSRI,switch-ing to another SSRIhasbeeneffective andwell tolerated inmost cases.105–108 For patients complaining of GI side effectswithparoxetine,thecontinued-releaseformulation(PaxilCR),reportedtohavealowerincidenceofnausea,maybeusedinplaceofthestandardformulation.109Aswithotherantidepres-sants,thepotentialadverseneuroendocrineandskeletaleffectsoftheSSRIshaveyettobesystematicallyexplored.110However,astudyfromourgrouphasshownthat4.5%ofmenand22.2%ofwomenwithMDDdevelopednew-onsethyperprolactine-miafollowingSSRItreatment,111anddailySSRIuseinadults50yearsandolderwasassociatedwithatwo-foldincreasedriskof fractures after adjustment for potential co-variates.112 TheSSRIs also appear to possess extremely low toxicity in over-dose.113Finally,ofallantidepressants,fluoxetinehasthemostextensiveliteraturesupportingitsreproductivesafety.114

Selective Serotonin Re-uptake Inhibitors Discontinuation SyndromeAnumberof reportsalsodescribediscontinuation-emergentadverse events after abrupt cessation of SSRIs, including


Antidepressants 497

43discontinuation-related adverse events similar to thosedescribedfortheSSRIs.145Finally,inoneuncontrolledstudy,4of13patientstreatedwithvenlafaxineduringelectroconvul-sive therapy (ECT) experienced asystole.146 Although theauthorsnotedthatthisseriousadverseeventonlyoccurredinpatientsondailydosesofvenlafaxinegreaterthan300mgandin patients anesthetized with propofol, in the absence offurtherdatatheuseofvenlafaxineinpatientsrequiringECTandperhapsevengeneralanesthesiashouldbeavoided.

Desvenlafaxine (Pristiq) is a major active metabolite ofvenlafaxine and an SNRI with little affinity for muscarinic,histaminic,oradrenergicreceptors.Desvenlafaxineismetabo-lizedbyCYP4503A4anditisaveryweakinhibitorof2D6.Thehalf-lifeofdesvenlafaxineisabout10hours.Theaugmen-tationandcombinationofdesvenlafaxinewithotherseroton-ergicagents,tryptophan,5-HT,orMAOIsmayalsoresultintheserotonin syndrome. Desvenlafaxine was found to be moreeffectivethanplacebointhetreatmentofMDDintwoseparaterandomized,double-blindclinicaltrials.Sideeffectsreportedinthosestudiesincludednausea,drymouth,sweating,som-nolence, anorexia, constipation, asthenia, vomiting, tremor,nervousness,abnormalvision,andsexualdysfunction.Therehavebeenreportsofincreasesindiastolicbloodpressure,andtheabruptdiscontinuationofdesvenlafaxinealsocarriesariskof discontinuation-related adverse events similar to thosedescribedfortheSSRIs.Therearealsoreportsofanincreaseinliver enzymes among patients treated with desvenlafaxine.Desvenlafaxine is commonly used at doses between 50 and100mgdailyinasingleadministration.

DuloxetineDuloxetine (Cymbalta) also inhibits the re-uptake of bothserotoninandnorepinephrine.147Duloxetineappearstobeaseffectiveas theSSRIs in the treatmentofMDD,although inmoreseveredepressiontheremaybesomeadvantages.148

Duloxetinelackssignificantcholinergic,antihistaminergic,and alpha1-adrenergic blocking effects. Duloxetine is exten-sivelymetabolizedtonumerousmetabolitesthatareprimarilyexcreted into the urine in the conjugated form. The majormetabolitesinplasmaareglucuronideconjugatesof4-hydroxyduloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10),4,6-dihydroxy duloxetine (M9), and a sulfate conjugate of5-hydroxy-6-methoxyduloxetine(M7).Duloxetineismetabo-lizedbyCYP4502D6,ofwhichitisalsoamoderateinhibitor,intermediate between paroxetine and sertraline. Drugs thatinhibit thisenzymemay increaseduloxetineconcentrations.Thehalf-lifeofduloxetineisabout12.5hours.Abruptdiscon-tinuationofduloxetineisassociatedwithadiscontinuation-emergentadverseeventprofilesimilartothatseenwithSSRIsand SNRI antidepressants.149 Therefore, duloxetine’s discon-tinuationshouldbeaccomplishedwithagradualtaper(overatleast2weeks)toreducetheriskofdiscontinuation-emergentadverseevents.Duloxetine is commonlyusedatdailydosesof 60 to 120mg, often started at 30mg. Duloxetine alsoappearstobeeffectiveinthetreatmentofsomaticsymptomsofdepression,suchaspain.150,151Commonsideeffectsassoci-ated with duloxetine include dry mouth, headache, nausea,somnolence, sweating, insomnia, and fatigue.152 Duloxetinedoesnotappeartocausehypertension.152

Levomilnacipran and MilnacipranLevomilnacipran(Fetzima)isanSNRIandisthe1S-2Renan-tiomerofmilnacipram,anSRNIapproved fordepression inEurope (brand names: Dalcipran, Ixel). Levomilnacipran ismetabolizedbyCYP4503A4anditisnotaninhibitorofCYP450systems.Itshalf-lifeisabout12hours.Theaugmentationand combination of milnacipran or levomilnacipran with

duringpregnancyisconsistentwithgenerallyreassuringdatafromtheTCAerathatantidepressantagentsarenotevidentlyteratogens.

On the other hand, infants exposed to SSRIs during latepregnancy may be at increased risk for serotonergic CNSadverseeffects,althoughtheincidenceoftheseeventshasnotbeenwellestablished.Recently,theFDAhasissuedawarningforallSSRIs,reportinganincreasedriskforneonataltoxicityand recommending cessation of treatment before delivery.However, inclinicalpractice,theriskofpost-partumdepres-sionoftenwarrantscontinuedtreatmentandclosemonitoringofthenewborn.

Whenever possible, unnecessary exposure to any drugshould be minimized, and thoughtful pre-pregnancy treat-mentplanningandconsiderationofalternativeinterventions,such as psychotherapies (e.g., cognitive-behavioral therapy[CBT]),aretoberecommended.

SSRIsaresecreted inbreastmilk.Because theireffectsonnormalgrowthanddevelopmentareunknown,breast-feedingshouldbediscouragedformotherswhoareonSSRIs.

Serotonin Norepinephrine Re-uptake InhibitorsVenlafaxine,duloxetine,desvenlafaxine,andlevomilnacipransharethepropertyofbeingrelativelypotentre-uptakeinhibi-torsofserotoninandnorepinephrineandarethereforecon-sidered SNRIs. They are all approved for the treatment ofdepressionintheUS.

Venlafaxine and DesvenlafaxineVenlafaxine(Effexor)wasthefirstSNRItogainFDAapprovalfor the treatment of depression. At daily doses greater than150mg,121 venlafaxine inhibits the re-uptake of both sero-tonin and norepinephrine, while mostly inhibiting there-uptakeofserotoninatlowerdoses.122,123Theaugmentationand combination of venlafaxine with other serotonergicagents, tryptophan, 5-HT, or MAOIs may also result in theserotoninsyndrome.Venlafaxinelackssignificantcholinergic,antihistaminergic, and alpha1-adrenergic–blocking effects.Venlafaxine is metabolized by CYP 450 2D6, of which it isalsoaveryweakinhibitor.Thehalf-livesofvenlafaxineanditsactivemetaboliteO-desmethylvenlafaxineareabout5and11hours,respectively.Thedrugandthismetabolitereachsteadystateinplasmawithin3daysinhealthyadults.Venlafaxineisgenerallyeffectiveatdailydosesatorabove150mg,and isoften started at 75mg or even 37.5mg, typically in itsextended-release (XR) formulation.124 Several meta-analysessuggestvenlafaxinetobemoreeffectivethantheSSRIsinthetreatmentofMDD,125–127withtheexceptionofescitalopram,whoserelativeefficacyappearstobecomparable.83

Venlafaxine, alongwith theSSRIsandbupropion, is alsocommonly chosen as a first-line treatment for depression.84Venlafaxineisalsousedintreatment-refractorydepressionasa “next-step” strategy,128–135 reported as the most popularswitchstrategyforrefractorydepressioninonelargesurveyofclinicians.136

Commonsideeffectsofvenlafaxineincludenausea,insom-nia, sedation, sexual dysfunction, headache, tremor, palpi-tations, and dizziness,137 as well as excessive sweating,tachycardia, and palpitations. There are also reports ofbruxism.138,139 Venlafaxine’s potential for sexual dysfunctionappearstobecomparabletothatoftheSSRIs.140,141Theinci-denceofGIsideeffectsanddizzinessappearstobelowerwiththe use of the XR formulation than the immediate-releaseformulation.142Between2%and6%ofpatientsalsoexperi-enceanincreaseindiastolicbloodpressure,143whichappearsto be dose-related.144 The abrupt discontinuation of ven-lafaxine, given its short half-life, also carries a risk of



Atomoxetinehasalsobeenassociatedwithmildincreasesinbloodpressureandpulse thatplateauduring treatmentandresolveafterdiscontinuation.Therehavebeennoeffectsseenon the QT interval. It is a substrate of CYP 2D6 and itsbiotransformationinvolvesaromaticringhydroxylation,ben-zylic oxidation, and N-demethylation. At high therapeuticdoses, atomoxetine inhibits CYP 2D6 and CYP 3A activity,although in vivo studies clearly indicate that atomoxetineadministrationwithsubstratesofCYP2D6andCYP3Adoesnotresultinclinicallysignificantdruginteractions.

Norepinephrine/Dopamine Re-uptake InhibitorsBupropionTheNDRIbupropionappears tobeaseffectiveas theSSRIsinthetreatmentofdepressive177,178andanxietysymptomsindepression,179 and more effective than the SSRIs in thetreatmentofsleepinessandfatigueindepression.180Interest-ingly,bupropionhasbeenshowntobeaseffectiveastheSNRIvenlafaxineinthetreatmentofMDD.181

BupropionisaphenethylaminecompoundthatiseffectiveforthetreatmentofMDD.Bupropionisstructurallyrelatedtoamphetamineandthesympathomimeticdiethylpropion,anditprimarilyblocksthere-uptakeofdopamineandnorepine-phrineandhasminimalornoaffinityforpost-synapticrecep-tors. Although some researchers have argued that the NDRIbupropion’seffectonnorepinephrineisprimarilythroughanincrease in pre-synaptic release, there is still convincing evi-dence for binding of both norepinephrine and dopaminetransporters.Bupropionisrapidlyabsorbedafteroraladmin-istration and demonstrates biphasic elimination, with aneliminationhalf-lifeof11to14hours.Itisconvertedtothreeactivemetabolites,hydroxybupropion,threohydrobupropion,anderythrohydrobupropion,allofwhichhavebeendemon-strated to have antidepressant activity in animal models.Bupropionlacksanticholinergicpropertiesanddoesnotcausepostural hypotension or alter cardiac conduction in a clini-callysignificantmanner.ItisasubstrateofCYP4502B6andappears to have CYP 450 2D6 inhibition potential, whichsuggeststhat,whenitiscombinedwithfluoxetineorparoxet-ine,both2D6substrates,levelsoftheSSRImayincrease.OneadvantageoftreatmentwithbupropioncomparedtotheSSRIsis the lower risk of sexual dysfunction.140,141,182–187 Treatmentwithbupropion isalsoassociatedwitha lower incidenceofGI side effects (e.g., nausea and diarrhea)185,186 and seda-tion177,179,185thantheSSRIs.Althoughadifferenceintermsofweight changes in bupropion and SSRI-treated depressedpatientsisnotimmediatelyapparentduringtheacutephaseof treatment in randomized trials,183,185,186,188–190 there is evi-dencetosuggest thatanybeneficialeffectsofSSRIs intermsofweightreductionduringtheacutephasearenotsustainedduringthecontinuationandmaintenancephases.101,102Infact,long-termtreatmentwithsomeSSRIsmayalsoresultinlong-termweightgain.103Incontrast,long-term(44weeks)bupro-piontreatmentappearstoresultinweightchangesnodifferentthanthoseofplaceboinMDD.191Thus,long-termtreatmentwith bupropion may carry a lower risk of weight gain thanlong-termtreatmentwiththeSSRIs.

Thedoserangeforthesustained-release(SR)formulationofbupropion(WellbutrinSR)is150to450mgintwiceadayor three times a day dosing, with 100 or 150mg being acommonstartingdose.Aonce-dailydoseformulation(Well-butrin XL), available in 150 and 300mg doses, was subse-quently introduced. Common side effects include agitation,insomnia,weightloss,drymouth,headache,constipation,andtremor.189Themajormedicallyimportantadverseeventassoci-ated with bupropion is seizure. With the immediate-release

other serotonergic agents, tryptophan, 5-HT, or MAOIs mayalso result in the serotonin syndrome. A number of studieshaddemonstratedthattheSNRImilnacipran153isequivalenttotheSSRIs154–157andtheTCAs158–162andsuperiortoplacebointhetreatmentofdepression.163,164Similarly,severalstudieshaveshownthatthenorepinephrineandserotoninre-uptakeinhibitorlevomilnacipranissuperiortoplacebointhetreat-ment of depression.165–167 Because of the potent norepine-phrine re-uptake inhibition, levomilnacipran appears to beparticularlyeffectiveintreatingfatigueindepression.Commonside effects reported during treatment with milnacipraninclude headaches, dry mouth, dysuria, tremor, tachycardia,weightgain,andsedation,althoughthe incidenceofweightgain and sedation with milnacipran is lower than with theTCAs.162Levomilnacipran’sfrequentlyreportedadverseevents(≥5%inlevomilnacipranERandtwicetherateofplacebo)arenausea,dizziness,constipation,tachycardia,urinaryhesi-tation,hyperhidrosis,insomnia,vomiting,andelevatedbloodpressure.Dailydosesofmilnacipranrangefrom50to200mg,oftendividedintwice-dailydosing,whereastheusualdoseoflevomilnacipranERis40–120mgonce/daily

Norepinephrine Re-uptake InhibitorsReboxetineReboxetine168actsbyselectivelyinhibitingthenorepinephrinetransporter,therebyincreasingsynapticnorepinephrinelevels.Reboxetine,amorpholinecompound,ischemicallyunrelatedto the other antidepressants. It is highly protein-bound andhasaplasmahalf-lifeofabout13hours.Thedrugdoesnotappear tobeameaningful inhibitorof theCYP450 systemandismetabolizeditselfbyCYP4503A4isozymewithtwoinactive metabolites. Increased blood pressure has beenreportedtobeaproblemforsomepatients,particularlythosewith a genetic variant of the norepinephrine transporter(SCL6A2).ReboxetinehasnotreceivedFDAapprovalforthetreatment of depression, but is available in Europe for thetreatment of depression (brand name: Edronax). Double-blind,placebo-controlledtrialssuggestreboxetinetobemoreeffectivethanplacebo169–172andaseffectiveasfluoxetine170inthetreatmentofMDD.Thestartingdailydoseisusually8mgbutcanbeaslowas4mg,witheffectivedailydosesrangingfrom8to10mggivenindivideddoses(twiceaday).Commonsideeffectsincludeinsomnia,headache,drymouth,diaphore-sis,andconstipation,170aswellasurinaryhesitancy.Theinci-denceofnausea,headache,fatigue,170andsexualdysfunction173appearstobemorecommonduringtreatmentwiththeSSRIsthanwithreboxetine.Theurinaryhesitancyandconstipationdonotappeartoreflectanticholinergic,butrathernoradren-ergic,effects.

AtomoxetineAtomoxetine also selectively inhibits the re-uptake of nor-epinephrine.174In vitro,ex vivo,andin vivostudieshaveshownthat atomoxetine is a highly selective antagonist of the pre-synapticnorepinephrinetransporter,withlittleornoaffinityfor other noradrenergic receptors or other neurotransmittertransportersorreceptors,withtheexceptionofaweakaffinityfortheserotonintransporter.Atomoxetineisrapidlyabsorbed,withpeakplasmaconcentrationsoccurring1to2hoursafterdosing, and its half-life hovers around 3 to 4 hours. Whileatomoxetine is an FDA-approved treatment for attention-deficit/hyperactivity disorder (ADHD) (brand name: Strat-tera),thereisasingleopentrialofatomoxetineindepressioninvolving 10 patients, with daily doses ranging from 40 to70mg.175 Common side effects reported so far includedecreasedappetite,insomnia,andincreasedbloodpressure.176


Antidepressants 499

43effective antidepressant dosage in the 450 to 600mg/dayrangeindivideddoses.Slowerdosetitrationisrecommendedintheelderly.NefazodonehasbeenfoundtoinhibitCYP3A4and to result in serotonin syndrome when combined withSSRIs. Common side effects include somnolence, dizziness,drymouth,nausea, constipation,headache, amblyopia, andblurredvision.202Anunusualbutoccasionaladverseeffectisirritability (possibly related to its mCPP metabolite, whichmayoccurinhigherlevelsinthepresenceofaCYP4502D6inhibitor).Treatmentwithnefazodonehastheadvantageofalowerriskoflong-termweightgainthantheSSRIsorTCAs,97perhapsbecauseof theappetite-reducingeffectsofmCPP.203Nefazodonealsohas theadvantageofa lowerriskofsexualsideeffectsthantheSSRIs.140,141,204Ararebutserioussideeffectofnefazodoneispriapismofboththepenisandclitoris,205,206whichrequiresimmediatemedicalattention.Inaddition,anincreasing number of reports suggest that treatment withnefazodoneisassociatedwithanincreaseriskofhepatotoxic-ity(approximately29casesper100,000patientyears),207oftensevere(morethan80%ofcases),andoftenappearingduringthefirst6monthsoftreatment.208Todate,therehasevenbeenone reported death due to such hepatotoxicity.209 Therefore,this agent should be avoided in patients with current or ahistoryofliverabnormalities;liverenzymesshouldbecheckedperiodicallyinpatientsonnefazodone.Theminimaleffectivedosesfornefazodoneareusually300mgdaily,with600mgdailybeingtheoptimaldose.

VilazodoneVilazodone (Vibryd) is a serotonin 5-HT1A receptor partialagonistandaselectiveserotoninre-uptakeinhibitor.Studieshave shown its superiority over placebo in the treatment ofdepression.210Theaugmentationandcombinationofvilazo-done with other serotonergic agents, tryptophan, 5-HT, orMAOIsmayalsoresultintheserotoninsyndrome.Vilazodonelacks significant cholinergic, antihistaminergic, and alpha1-adrenergic–blockingeffects.Vilazodoneismetabolizedprim-arilybyCYP4503A4andisamoderateinhibitorof2C19and2D6.Theterminalhalf-lifeofvilazodoneisabout25hours.Vilazodonetherapyistypicallyinitiatedatadosageof10mgonce daily and incrementally adjusted over 14 days to therecommended target daily dose of 40mg; for optimal bio-availabilityandeffectiveness, it shouldbe takenaftera lightorhigh-fatmeal.Theadverseeffectsmostcommonlyreportedinclinical trialsofvilazodonewerediarrhea,nausea,vomit-ing, dizziness, insomnia and dry mouth. Treatment-relatedsexualsideeffectsmaybelesslikelythanwithSSRIs:inthreeplacebo-controlled studies, 8.0% of vilazodone-treatedpatients and 0.9% of placebo-treated patients reported ≥ 1sexual-function-relatedtreatment-emergentadverseevent(P<0.001)).211 Vilazodone was not associated with clinically-relevant weight change in the short-term trials. In an open-label 1-year study of vilazodone, mean weight increased by1.7kgamongtheobservedcases.212

VortioxetineVortioxetine(Brintellix)isarecently-approvedantidepressantwithmulti-modalactivitythatfunctionsasaserotonin5-HT3,5-HT7and5-HT1Dreceptorantagonist,serotonin5-HT1Brecep-tor partial agonist, serotonin 5-HT1A receptor agonist andinhibitoroftheserotonintransporterin vitro.Vortioxetinehasshowntobeabletoincreaseextracellularserotonin,dopamine,andnorepinephrinelevelsinthemedialprefrontalcortexandventralhippocampus.Theaugmentationandcombinationofvortioxetinewithotherserotonergicagents,tryptophan,5-HT,orMAOIsmayresultintheserotoninsyndrome.Vortioxetine

formulation the rate is 0.4% (4 per 1,000) at doses up to450mg/day,whereaswithbupropionSRtherate isof0.1%(1per1,000)atdosesuptothetargetantidepressantdoseof300mg/day(WellbutrinSRPrescribingInformation).192SSRIantidepressantsarealsoassociatedwithseizuresata similarrateofapproximately0.1%(WellbutrinSRPrescribingInfor-mation). Patients should only be administered bupropionwithextremecautionifapredispositiontoseizureispresent.For this reason, the maximum daily dose for bupropion SRand bupropion XL is 450mg, with no single dose above200mgfortheSRformulation.Inaddition,bupropionmaybe more likely to induce seizures in patients with bulimianervosa and histories of head trauma and it should not beusedinthesepatients.Sincetheriskofseizureappearstobedose-related and related to the peak plasma concentrations,theSRandXLformulationsarethoughttobeassociatedwitha somewhat lower seizure risk, estimated at 0.1% for dailydoseslowerthan450mg.192

Serotonin Receptor Antagonists/AgonistsTrazodoneAlthough the serotonin receptor antagonists trazodone(Desyrel)andnefazodone(Serzone)havebeenshowntobeaseffectiveastheSSRIsinthetreatmentofdepression,193theyareusedextremelyinfrequentlyasmonotherapyfordepression.84Trazodoneisrapidlyabsorbedfollowingoraladministration,achievingpeaklevelsin1to2hours.Ithasarelativelyshorteliminationhalf-lifeof3to9hoursandisexcretedmainlyinurine(75%);itsmetabolitemCPPhasasimilarpharmacoki-neticprofile.Despitetheshorthalf-life,once-dailydosingatbedtime is the usual route of administration because of itssedatingproperties.Whenusedasmonotherapyforthetreat-ment of depression, a patient is typically started on 100 to150mgdailyeitherindivideddosesorinasinglebedtimedoseandgraduallyincreasedto200to300mg/day.Anextended-release formulationof trazodone (Oleptro) is available. Thedoserangefortheextended-releaseisbetween150and300mgqHS.Foroptimalbenefit,dosesintherangeof400to600mgmaybeneededforeitherformulation.Low-dosetrazodone(25to150mgatbedtime)iscommonlyusedinthetreatmentofinsomnia secondary to antidepressant use,194 a strategy thatmayalsoresultinanimprovementindepressivesymptoms.195The most common side effects of trazodone are sedation,orthostatichypotension,andheadaches.Trazodonelacksthequinidine-likepropertiesofthecyclicantidepressantsbuthasbeenassociatedinrarecaseswithcardiacarrhythmias,whichmayberelatedtotrazodone’sabilitytoinhibitpotassiumchan-nels.Thus,trazodoneshouldbeusedwithcautioninpatientswithknowncardiacdisease.A rarebut serious sideeffectoftrazodoneispriapismofboththepenisandclitoris,196,197whichrequires immediate medical attention. Priapism has beenattributed to the alpha-adrenoceptor blocking properties oftrazodone by interference with the sympathetic control ofpeniledetumescence.198Rarecasesofhepatotoxicityhavebeenassociatedwiththeuseoftrazodone,199andfatalcasesoftra-zodone overdose have also been reported.200 In one review,trazodone was reported to carry one of the lowest risks forseizureofallantidepressantsexamined.201Theminimaleffec-tivedosefortrazodoneisusually300mgdaily.

NefazodoneNefazodonehaslessaffinityforthealpha1-adrenergicreceptorand is therefore less sedating.Thehalf-lifeofnefazodone isapproximately 5 hours. The usual starting dosage is 50mg/daygivenatbedtimeortwiceaday,titratedupintheabsenceofdaytimesedationasrapidlyastoleratedtoachieveausually



administereddrugsarehardlyaffectedbymirtazapine.Mirta-zapineisassociatedwithmoresedationandweightgainthantheSSRIs.233–236Thewidespreaduseofmirtazapineasafirst-line agent in depression has been primarily limited by itssedativeeffectsandweightgain.237Inadditiontosedationandweightgain,commonsideeffectsassociatedwithmirtazapineinclude dizziness, dry mouth, constipation, and orthostatichypotension.Duetoblockadeof5-HT2and5-HT3receptors,mirtazapine is associated with a lower risk of headaches233andnausea233–235,238,239 thantheSSRIs.Treatmentwithmirta-zapine is also associated with a lower incidence of sexualdysfunction than the SSRIs.141,234 In addition, switching tomirtazapinemayalleviateSSRIinducedsexualdysfunctioninSSRI-remitters.240Severeneutropeniahasbeenrarelyreported(1 in1,000)withanuncertainrelationship to thedrug,butaswithotherpsychotropics, theonsetof infectionandfevershouldpromptthepatienttocontacthisorherphysician.Thedrug is most efficacious at doses of 30 to 45mg (although60mg/dayhasbeenusedinrefractorycases)usuallygiveninasinglebedtimedose.Availablein15,30,and45mgscoredtabletsandinanorallysolubletabletformulation(Soltab)at15,30,and45mg,thelowerdosemaybesub-optimal,andcomparedwith15mg,the30mgdosealsomaybelessoratleast not more sedating, possibly as a consequence of thenoradrenergiceffectsbeingrecruitedatthatdose.Thestartingdailydosecanbeaslowas7.5mgintheelderly.

MianserinMianserinisapprovedfordepressioninEurope(brandname:Lantanon) and is not FDA-approved. Double-blind studiesreport theefficacyofmianserin inthetreatmentofMDDtobeequivalenttotheTCAs.241–243Themostcommonsideeffectsincludesomnolence,weightgain,drymouth,sleepproblems,tremor,andheadaches.244Effectivedailydosesformianserinrangefrom30to60mg,usuallygivenatbedtime.

Tricyclic and Related Cyclic AntidepressantsOralpreparationsofTCAsandrelateddrugsarerapidlyandcompletelyabsorbedfromtheGI tract;ahighpercentageofanoraldoseismetabolizedbytheliveras itpassesthroughtheportalcirculation(first-passeffect).TheTCAsaremetabo-lized by the microsomal enzymes of the liver; the tertiaryaminesarefirstmonodemethylatedtoyieldcompoundsthatarestillactive.Indeed,thedesmethylmetabolitesofamitriptyl-ineandimipraminearenortriptylineanddesipramine,respec-tively, and are marketed as antidepressants. Other majormetabolicpathwaysincludehydroxylation(whichmayyieldpartiallyactivecompounds)andconjugationwithglucuronicacid to produce inactive compounds. TCAs are highlylipophilic, meaning the free fraction passes easily into thebrainandothertissues.Theyarealsolargelyboundtoplasmaproteins. Given their lipophilicity and protein-binding, theyarenotremovedeffectivelybyhemodialysisincasesofover-dose. The time course of metabolism and elimination isbiphasic,withapproximatelyhalfofadoseremovedover48to72hoursandtheremainder,stronglyboundtotissuesandplasmaproteins,slowlyexcretedoverseveralweeks.There isconsiderablevariationamong individuals in theirmetabolicrate for cyclic antidepressants based on genetic factors, age,andconcomitantlytakendrugs. Infact,whenmetabolicdif-ferencesarecombinedwithvariationinthedegreeofprotein-binding, as much as a 300-fold difference in effective druglevelsmaybefoundamongindividuals.

Although TCAs’ overall efficacy in treating depression isequivalenttothatoftheSSRIs,245theytendtohaveconsiderablymore side effects and, due to their ability to block the

lacks significant cholinergic, anti-histaminergic, and alpha1-adrenergic–blockingeffects.Vortioxetineismetabolizedprim-arilybyCYP4502D6.Theterminalhalf-lifeofvortioxetineisabout66hours.Vortioxetinetherapyistypicallyinitiatedatadosageof10mgoncedailyandincrementallyadjusted20mgoncedaily,ifnecessary;thedosecanbeloweredto5mgdaily,ifnecessarybasedontolerability issues.Nausea,drymouth,diarrhea, nasopharyngitis, headache, dizziness, somnolence,vomiting, dyspepsia, constipation and fatigue were reportedin≥5%ofpatientsreceivingvortioxetine.213Ratesoftreatment-emergentsexualdysfunction(TESD)inthevortioxetinedosinggroups were similar to placebo.213 In a 52-week open-labelextension study, vortioxetine was associated with minimalweightgain.214Recentlypresenteddatasuggestthatvortioxet-ine may have the additional advantage of distinctive pro-cognitiveeffects.

RitanserinRitanserin,a serotonin5-HT2Aand5-HT2Cantagonist, isnotFDA-approved, but is available in Europe. One placebo-controlledstudyrevealedritanserintobeeffectiveinthetreat-mentofdysthymicdisorder,215whilea separate study foundritanserin tobeas effectiveas amitriptyline inpatientswithdepressionandchronicheadaches.216Ritanserinappearstobeeffectivefordepressionatdosesabove5mg.

AgomelatineAgomelatine, anewer agent, is a selective5-HT2C antagonistandactsasamelatoninMT1andMT2receptoragonist.Todate,atleasttwoplacebo-controlledtrialshavefoundagomelatine(25mg)tobemoreeffectivethanplaceboandaseffectiveastheSSRIs in the treatmentofMDD,217–219 andas effectiveastheSSRIparoxetineinMDD.217AgomelatineisapprovedforthetreatmentofdepressioninEurope,butnotintheUS.

Buspirone and GepironeBuspirone(BuSpar)andgepirone(Ariza)actasfullagonistsat serotonin5-HT1Aautoreceptorsandaregenerally,butnotexclusively,partialagonistsatpost-synapticserotonin5-HT1Areceptors.29 Buspirone is FDA-approved as a treatment foranxietyandnotfordepression,whilegepironehasnotbeenFDA-approved.Nevertheless,anumberofdouble-blindtrialsreportbuspirone220–223andgepirone224–228tobemoreeffectivethan placebo in the treatment of MDD. One advantage ofgepirone and perhaps buspirone is that their use does notappeartoberelatedtoagreater incidenceofweightgainorsexualsideeffectsthanplacebo,atleastduringtheacutephaseof treatment of depression.228 Effective doses for buspironeandgepironefordepressionrangebetween30and90mgand20and80mg, respectively. Sideeffects are similar for thesetwoagentsandincludeheadache,dizziness,light-headedness,nausea,andinsomnia.222,229

Alpha2-Adrenergic Receptor AntagonistsMirtazapineMirtazapineisaseffectiveastheSSRIs230andvenlafaxine231,232inthetreatmentofMDD.Mirtazapineshowslinearpharma-cokineticsoveradoserangeof15to80mganditselimina-tionhalf-liferangesfrom20to40hours,consistentwithitstimetoreachsteadystate(4to6days).BiotransformationismainlymediatedbytheCYP2D6andCYP3A4isoenzymes.Inhibitorsoftheseisoenzymes,suchasparoxetineandfluox-etine, causemodestly increasedmirtazapineplasmaconcen-trations, while mirtazapine has little inhibitory effects onCYP isoenzymes; therefore, the pharmacokinetics of co-


Antidepressants 501

43Amoxapine is the only TCA with documented, significantdopamine D2 receptor antagonism.49 Therefore, there havebeencasereportsoftardivedystoniaanddyskinesiaassociatedwith amoxapine treatment,257,258 and amoxapine should beavoided in patients with co-morbid depression and Parkin-son’sdisease.259

Anticholinergic-relatedsideeffectsresultfromtheaffinityof TCAs for muscarinic cholinergic receptors and typicallyincludedrymouth,blurredvision,constipation,urinaryhesi-tancy, tachycardia,memorydifficulties,andejaculatorydiffi-culties. Finally, due to their anticholinergic effects, TCAsshould be avoided in patients with narrow-angle glaucomaandprostatichypertrophy,assymptomsrelatedtothesecon-ditionsmayworsenbecauseofsuchanticholinergiceffects.

Antihistaminergic-relatedsideeffectsresultfromhistamin-ergic H1-receptor blockade and typically include increasedappetite,weightgain,sedation,andfatigue.WeightgainwithTCAs can be substantial, averaging 1 to 3lb per month oftreatment.260 As a result, TCAs may complicate the manage-mentofdiabetesandworsenglycemiccontrol,andshouldbeavoidedwheneverpossibleindiabetics.261TCAsmayalsohavehyperlipidemiceffects,thuscomplicatingtheirlong-termusein patients with hyperlipidemia.262 Xerostomia secondary toanticholinergicandantihistaminergiceffectsmayalsoincreasetheriskoforalpathology,particularlydentalcaries.263

Orthostatichypotensionandreflextachycardiamayresultfromalpha1-adrenergicreceptorantagonism.Nortriptylineisgenerallythoughttobelesslikelytocauseorthostatichypoten-sion than tertiary amine TCAs, such as imipramine264,265;however,nortriptyline’saffinityforthealpha1-adrenergicrecep-tor, although less than theaffinityofmostTCAs, is actuallymuch greater (e.g., by a factor of two) than the affinity ofdesipramineandprotriptyline.50Inaddition,homozygosityfor3435T alleles ofABCB1, the multi-drug resistance gene thatencodesaP-glycoprotein(P-gp)regulatingthepassageofmanysubstancesacrosstheblood–brainbarrier,appearstobeariskfactorforoccurrenceofnortriptyline-inducedposturalhypo-tension.266 Antidepressant-induced postural hypotension intheelderlymay,inturn,increasetheriskoffallsandfractures(e.g.,hip fractures).267Although less likely to suffera fallorfracture,thesedativepotentialofvariousTCAantidepressantsisalsoaseriousconsiderationinyoungerdepressedpatientsaswell, as this effect may increase the mortality risk from

aforementioned receptors, aswell as the sodiumchannel,246TCAs are often arrythmogenic247 and epileptogenic248 whentakeninverylarge(supra-therapeutic)quantities.Asaresult,theyarerarelychosenasfirst-lineagents inthetreatmentofdepression.84 Furthermore, several studies also suggest thatTCAsmaybemoreeffectivethantheSSRIsinthetreatmentofmelancholic depression, or in the treatment of depressedpatientswithcertainco-morbidmedical conditions.249–253 Inaddition,perhapsduetotheirabilitytoinhibitthere-uptakeofbothserotoninandnorepinephrine,aswellastheirabilitytoblocksodiumchannels,TCAsappeartobemoreeffectiveintreatingneuropathicpainthantheSSRIs.254Infact,theresultsofaseparatemeta-analysisrevealthattheTCAsaresuperiortotheSSRIsinthetreatmentofanumberofsomatic/paindisor-ders(includingheadaches,fibromyalgia,irritableboweldisor-der, idiopathic pain, tinnitus, and chronic fatigue) oftendiagnosed in patients with chronic depression.255 The TCAsmaybesub-dividedintotertiaryaminesandsecondaryamines(theirdemethylatedsecondaryaminederivatives).Inaddition,maprotiline(Ludiomil),whichisclassifiedasatetracyclicanti-depressant,iscommonlygroupedwiththeTCAs,duetosimi-laritiesindosing,mechanismofaction,andsideeffects.TertiaryamineTCAsincludeamitriptyline(Elavil,Adepril),imipramine(Tofranil,Antidepril),trimipramine(Surmontil,Herphonal),clomipramine(Anafranil,Clopress),anddoxepin(Sinequan,Deptran).SecondaryamineTCAsarenortriptyline(Pamelor,Aventyl), desipramine (Norpramin, Metylyl), protriptyline(Vivactil,Concordin),andamoxapine(Ascendin,Defanyl).

Side-effect ProfileIngeneral,thesideeffectsoftheTCAsandrelatedcyclicanti-depressantsaremoredifficultforpatientstotoleratethanarethesideeffectsofthenewerdrugs(Table43-2)andtheyprob-ablyaccountforhigherdrop-outratesthanareassociatedwiththe SSRIs.256 Thus, treatment is typically initiated at lowerdoses(e.g.,10mg/dayforimipramine)inordertominimizetheriskofadverseeventsandprematuretreatmentdiscontinu-ation.Theside-effectprofileoftheTCAscanbesub-categorizedintermsoftheirrelativeaffinityforanumberofmonoaminereceptors and transporters. Overall, secondary amine TCAstend to cause fewer anticholinergic, antihistaminergic, andanti-alpha1–related side effects than tertiary amine TCAs.

TABLE43-2 Tricyclic Antidepressants and Monoamine Oxidase Inhibitors Side-effect Profile

CategoryandDrugSedativePotency AnticholinergicPotency

OrthostaticHypotensivePotency

UsualAdultDailyDose(mg/day) Dosage(mg/day)

Tricyclic and Related Cyclic Compounds*

Amitriptyline High Very high High 150–200 75–300Amoxapine Low Moderate Moderate 150–200 75–300Clomipramine High High High 150–200 75–250Desipramine Low Moderate (lowest of the tricyclics) Moderate 150–200 75–300Doxepin High High Moderate 150–200 75–300Imipramine Moderate High High 150–200 75–300Maprotiline Moderate Low Moderate 150–200 75–225Nortriptyline Moderate Moderate Lowest of the tricyclics 75–100 40–150Protriptyline Low High Low 30 10–60Trimipramine High Moderate Moderate 150–200 75–300

Monoamine Oxidase Inhibitors

Isocarboxazid — Very low High 30 20–60Phenelzine Low Very low High 60–75 30–90Tranylcypromine — Very low High 30 20–90

*All of the tricyclic and related cyclic compounds have well-established cardiac arrhythmogenic potential.(From Rosenbaum JF, Arana GW, Hyman SE, et al., editors: Handbook of psychiatric drug therapy, ed 5, Philadelphia, 2005, Lippincott Williams &

Wilkins.)



remainingTCAsexhibitedacurvilinear(inverse“U”–shapedcurve)relationshipbetweenbloodlevelandclinicalresponse.The optimal ranges for nortriptyline, “total” imipramine(imipramine plus desipramine), and “total” amitriptyline(amitriptyline plus nortriptyline) (with their correspondingresponserateswithinversusoutsidethelevelrange)were58to148ng/ml(66%versus26%),175to350ng/ml(67%versus39%),and93to140ng/ml(50%versus30%),respectively.

Nortriptylinelevelshavebeenthebeststudiedoftheanti-depressants.Someresearchersbelievethatsuchstudiesrevealamorecomplexpatternthanwithimipramineordesipramine—an inverted U-shape correlation with clinical improvement,whichissometimesreferredtoasatherapeuticwindow.Clini-calimprovementcorrelateswithlevelsof50to150ng/ml.Thereasonforthepoorerresponsewithdosesabove150ng/mlisnotknown,butitdoesnotappeartorelatetoanymeasurabletoxicity.Ontheotherhand, thenumberofsubjects inwell-designed studies that indicate a window is small, so not allresearchers believe there is adequate evidence in favor of atherapeutic window. Studies of amitriptyline levels haveresultedindisagreementabouttheutilityoflevels,withlinear,curvilinear, and lack of relationship reported by differentinvestigators.Whenused,bloodlevelsshouldbedrawnwhenthedrughasachievedsteady-statelevels(atleast5daysafteradosagechangeinhealthyadults;longerintheelderly)and10to14hoursafterthelastoraldose.Abruptdiscontinuationsymptoms may emerge with TCAs and in part representcholinergicrebound,andincludeGIdistress,malaise,chills,coryza,andmuscleaches.

Use of Tricyclic and Related Cyclic Antidepressants during Pregnancy and the Post-partum PeriodTherearelimiteddataontheuseofTCAsduringpregnancy.Therehavebeenreportsofcongenitalmalformationsinasso-ciationwithTCAuse,butthereisnoconvincingcausalassoc-iation. Overall, the TCAs may be safe, but given the lack ofprovensafety,thedrugsshouldbeavoidedduringpregnancy,unlesstheindicationsarecompelling.PregnantwomenwhoareatriskforseriousdepressionmightbemaintainedonTCAtherapy. This decision should always be made very carefullyandwithextensivediscussionoftherisk–benefitfactors.Duetomoreclinicalexperience,olderagents,suchasimipramine,may be preferred to newer drugs during pregnancy. TCAsappeartobesecretedinbreastmilk.Becausetheireffectsonnormalgrowthanddevelopmentareunknown,breast-feedingshouldbediscouragedformotherswhoareontricyclics.

Overdoses with Tricyclic and Related Cyclic AntidepressantsAcutedosesofmorethan1gofTCAsareoftentoxicandmaybefatal.Deathmayresultfromcardiacarrhythmias,hypoten-sion, or uncontrollable seizures. Serum levels should beobtained when overdose is suspected, both because of dis-tortedinformationthatmaybegivenbypatientsorfamiliesandbecauseoralbioavailabilitywithverylargedosesofthesecompoundsispoorlyunderstood.Nonetheless,serumlevelsof the parent compound and its active metabolites provideless specific information about the severity of the overdosethanonemighthope.Serumlevelsofgreaterthan1,000ng/mlareassociatedwithseriousoverdose,asareincreasesintheQRSdurationoftheECGto0.10secondorgreater.However,seriousconsequencesofaTCAoverdosemayoccurwithserumlevelsunder1,000ng/mlandwithaQRSdurationoflessthan0.10second.Inacuteoverdose,almostallsymptomsdevelopwithin12hours.

automobile accidents. In fact, in a recent review,268 sedatingantidepressants (dothiepin, amitriptyline, imipramine,doxepin,andmianserin)werefoundtoresultindrivingimpair-mentsonastandardizedroadtestcomparabletoimpairmentsfound in drivers with a blood alcohol level of 0.8mg/ml,whereasnon-sedatingantidepressants(moclobemide,fluoxet-ine,paroxetine,venlafaxine,andnefazodone)werenotfoundtoadverselyaffectdrivingperformance.TCAsmayalsocausesexualdysfunctionandexcessivesweating.

TheabilityofTCAstoinhibitthesodiumchannelmayalsoresultinelectrocardiographicchangesinsusceptibleindividu-als(e.g.,inpost–myocardialinfarctionpatients,aswellasinpatients with bifascicular heart block, left bundle branchblock,oraprolongedQTinterval),evenattherapeuticdoses,269and, given that contemporary psychopharmacologists haveaccess toamultitudeof alternative treatmentoptions,TCAsshouldbeavoidedinthesepatients.Duetotheinhibitionofsodium channels and cholinergic receptors, the TCAs alsocarryariskofseizure.Maprotilineandclomipraminearecon-sidered the TCAs with the greatest risk of seizures.270 ThiscombinedriskofseizureandarrhythmiarenderstheTCAsastheleastsafeduringoverdose.271

Prescribing Tricyclic and Related Cyclic AntidepressantsAside from the electrocardiogram (ECG), no other tests aregenerally indicated in healthy adults before starting a TCA.TCAsarestartedatalowdosefollowedbygradualincreasesuntilthetherapeuticrangeisachieved.FindingtherightTCAdoseforapatientofteninvolvesaprocessoftrialanderror.Themostcommonerrorleadingtotreatmentfailureisinadequatedosage. In healthy adults, the typical starting dose is 25 to50mgof imipramineor itsTCAequivalent.Nortriptyline isabouttwiceaspotent;thus,itsstartingdoseis10to25mg.Insomeclinicalsituations,especiallyintheelderlyandpatientswith panic disorder, it may be necessary to start with lowerdoses (as low as 10mg of imipramine or the equivalent)because of intolerance to side effects. Generally, TCAs areadministeredonceadayatbedtimetohelpwithcomplianceand, when the sedating compounds are used, to help withsleep.Divideddosesareusedifpatientshavesideeffectsduetohighpeaklevels.Thedosagecanbeincreasedby50mgevery3to4days,assideeffectsallow,uptoadoseof150to200mgofimipramineoritsequivalentatbedtime(seeTable43-1).Ifthere isnotherapeuticresponse in3to4weeks, thedosageshould be slowly increased, again as side effects allow. ThemaximumdosageofmostTCAsistheequivalentof300mg/day of imipramine, although uncommonly, patients whometabolizethedrugrapidlymaydowellonhigherdosages.Ofthecurrentlyavailablecyclicantidepressants,onlyfourdrugs(imipramine, desipramine, amitriptyline, and nortriptyline)havebeenstudiedwellenoughtomakegeneralizationsaboutthe value of their blood levels in treatment of depression.Serumlevelsoftheothercyclicantidepressantshavenotbeeninvestigatedwellenoughtobeclinicallymeaningful,althoughtheycanconfirmpresenceofthedrugordocumentextremelyhighserumlevels.ThereisawiderangeofeffectivedosesforTCAs.Typicalantidepressantdosesare100to300mg/dayforimipramine.Thereisevidencetosuggestarelationshipbetweenserum levels of TCAs and clinical response. Perry and col-leagues272pooledandanalyzedallavailablestudiesexaminingtherelationshipbetweenTCAbloodlevelsandclinicalresponsewith the use of receiver operating-characteristics curves. Therelationship between clinical response and blood levels fordesipraminewas linear,with the threshold concentration inplasma for therapeutic responsebeinggreater thanor equalto 116ng/ml (response rates: 51% versus 15% for patientswith levelsaboveorbelowthat threshold, respectively).The


Antidepressants 503

43metabolites.Thereiscontroversyastowhetherphenelzineiscleavedandacetylatedintheliver.Itisknownthatasizablenumberofpeopleareslowacetylators(ahighpercentageofAsiansandabout50%ofwhitesandblacks),butthereislittleevidencethattherateofacetylationisclinicallysignificantforthisclassofdrugs.Ofclinical importance is theobservationthatmetabolismofMAOIsdoesnot seem tobe affectedbyuseofanticonvulsants.

AlthoughtheoverallefficacyofMAOIsdoesnotdifferfromthatofothercommonlyusedantidepressantsinthetreatmentofMDD,theiruseisconsiderablylimitedbytheriskofpoten-tially lethal adverse events, such as hypertensive crises andserotonin syndromes, and by the strict dietary restrictionsrequired to minimize such risks. As a result, they are rarelychosen as first-line agents in the treatment of depression84;their use is mainly limited to the treatment of treatment-refractorydepression,eitherasa“next-step”strategyinTCA-resistant depression,273–279 or even depression resistant to anumberofantidepressants.280–284HighdosesoftheMAOItra-nylcypromine (90 to170mgdaily)mayalsobeeffective indepressedpatientswhodonotexperiencesufficientimprove-ment during treatment with lower doses.285 In addition,perhaps due to their ability to inhibit the re-uptake ofdopamine in addition to serotonin and norepinephrine,MAOIsappeartobemoreeffectivethanTCAs286inthetreat-mentofatypicaldepression(characterizedbymoodreactivityinadditiontosymptomssuchashypersomnia,hyperphagia,extreme fatigue, and rejection sensitivity). In parallel, whiletheMAOIsalsoseemtobeeffectiveinthetreatmentoffatigueinfibromyalgiaorchronicfatiguesyndrome,287–291fouroffivestudiesdonotshowanyeffectof theSSRIson fatigue.292–296Although, to date, there are no double-blind studies thatcompare the relative efficacy of MAOIs versus the SSRIs orTCAsinthetreatmentoffatigueindepression,thesestudiessuggestapotentialadvantageforMAOIsoverSSRIs.

IntheGItractandtheliver,MAOcatabolizesanumberofdietary pressor amines (such as dopamine, tyramine, tryp-tamine,andphenylethylamine).52For thisreason,consump-tionof foodscontaininghighlevelsofdietaryamineswhileonanMAOImayprecipitateahypertensivecrisis,character-ized by hypertension, hyperpyrexia, tachycardia, tremulous-ness,andcardiacarrhythmias.53Thesamereactionmayalsooccur during co-administration of dopaminergic agents andMAOIs,whiletheco-administrationofMAOIswithotheranti-depressantsthatpotentiateserotonincouldresultinserotoninsyndromesdue to toxicCNSserotonin levels.Theserotoninsyndromeischaracterizedbyalterationsincognition(disori-entation,confusion),behavior(agitation,restlessness),auto-nomicnervoussystemfunction(fever,shivering,diaphoresis,diarrhea), and neuromuscular activity (ataxia, hyperreflexia,and myoclonus).54–56 Since MAO enzymatic activity requiresapproximately14days tobe restored, such foodormedica-tionsshouldbeavoidedfor2weeksafterthediscontinuationofanirreversibleMAOI(“MAOIwashoutperiod”).Seroton-ergicanddopaminergicantidepressantsare typicallydiscon-tinued 2 weeks before the initiation of an MAOI, with theexception of fluoxetine, which needs to be discontinued 5weeksinadvanceduetoitsrelativelylongerhalf-life.Inaddi-tion to its oral formulation, selegiline is also available in atransdermal form(patch),designed tominimize the inhibi-tionoftheMAOenzymesfoundintheliningoftheGItract.TreatingMDDwithtransdermalselegilineappearstobeeffec-tive297,298 and also safe, even in the absence of a tyramine-restricted diet.298 Although rare, serotonin syndrome mayoccur when oral selegiline is combined with serotonergicagents,particularlytheSSRIs.299Theriskofsuchdruginterac-tionswiththetransdermal formulationofselegilinehasnotbeenstudied.

Anti-muscarinic effects are prominent, including drymucousmembranes,warmdryskin,mydriasis,blurredvision,decreasedbowelmotility,and,often,urinaryretention.EitherCNS depression (ranging from drowsiness to coma) or anagitated delirium may occur. The CNS depressant effects ofcyclic antidepressants are potentiated by concomitantlyingested alcohol, benzodiazepines, and other sedative-hypnotics.Seizuresmayoccur,andinsevereoverdoses,respi-ratory arrest may occur. Cardiovascular toxicity presents aparticulardanger(Box43-3).Hypotensionoftenoccurs,evenwiththepatientsupine.

Avarietyofarrhythmiasmaydevelop,includingsupraven-triculartachycardia,ventriculartachycardia,orfibrillation,andvaryingdegreesofheartblock,includingcompleteheartblock.

Drug InteractionsThe cyclic antidepressants have a variety of important phar-macodynamic and pharmacokinetic drug–drug interactionsthatmayworsenthetoxicityofotherdrugs(seeBox43-3).

Monoamine Oxidase InhibitorsThe MAOIs are well absorbed after oral administration. Atransdermalformofselegiline(Emsam)isalsoavailableandapprovedby theFDA for the treatmentofdepression.SinceMAOIs irreversibly inhibit the enzymes, return of enzymefunctionafterdiscontinuationmayrequire2weeks(thetimeittakesforde novosynthesisoftheenzyme).Themetabolismof MAOIs is not well understood. Selegiline and tranylcy-promine have meta-amphetamine and amphetamine as

BOX43-3 Drug Interactions with Cyclic Antidepressants

WORSENSEDATION

AlcoholAntihistaminesAntipsychoticsBarbiturates, chloral hydrate, and other sedatives

WORSENHYPOTENSION

α-Methyldopa (Aldomet)β-Adrenergic blockers (e.g., propranolol)ClonidineDiureticsLow-potency antipsychotics

ADDITIVECARDIOTOXICITY

Quinidine and other type 1 antiarrhythmicsThioridazine, mesoridazine, pimozide, ziprasidone

ADDITIVEANTICHOLINERGICTOXICITY

Anti-histamines (diphenhydramine and others)Anti-parkinsonians (benztropine and others)Low-potency antipsychotics, especially thioridazineOver-the-counter sleeping medicationsGastrointestinal antispasmodics and anti-diarrheals (Lomotil and

others)

OTHER

Tricyclics may increase the effects of warfarinTricyclics may block the effects of guanethidine

(From Rosenbaum JF, Arana GW, Hyman SE, et al., editors: Handbook of psychiatric drug therapy, ed 5, Philadelphia, 2005, Lippincott Williams & Wilkins.)



syndrome.MAOIsmustbeusedwithcautioninpatientswithdiabetes(duetopossiblepotentiationoforalhypoglycemicsandworsenedhypoglycemia).

DosageThe optimal dosages for MAOIs vary from agent to agent.Initially,MAOIsareadministeredat lowdoses,withgradualincreasesassideeffectsallow.Sometolerancemaydeveloptoside effects, including postural hypotension. Phenelzine isusuallystartedat15mgtwicedaily(7.5to15mg/dayintheelderly), isocarboxazid at 10mg twice daily, and tranylcy-promineat10mgtwicedaily(5to10mg/dayintheelderly).Dosagescanbeincreasedby15mgweeklyforphenelzineand10mgweeklyforisocarboxazidandtranylcypromine(assideeffectsallow)to45to60mg/dayforphenelzine(30to60mg/dayintheelderly)and30to40mg/dayfortheothers.Dosagesashighas90mg/dayofthesedrugsmayberequired,althoughthese exceed the manufacturer’s recommendations. Oncedepressivesymptomsremit,fulltherapeuticdosesareprotec-tiveagainstrelapse,althoughinmanagingpatientsonMAOIs,doseadjustmentsovertimetomanagesideeffectsorclinicalresponsearecommon.Fortransdermalselegiline,theminimaleffective dose reported is 6mg/day. It is prudent to taperMAOIs over 2 weeks or more when discontinuing thembecause discontinuation reactions have been reported withabruptdiscontinuation.Thereislittleexperiencewiththeuseof MAOIs in pregnancy. For this reason, their use shouldbeavoided.

PatientshavereportedweightgainonallMAOIsandocca-sionally weight loss (more commonly on tranylcypromine).Anticholinergic-like sideeffectsoccur, although theyarenotduetomuscarinicantagonism.ThesesideeffectsarelessseverethanthoseseenwithTCAs,althoughpatientsonphenelzinemayexperiencedrymouth.Elderlypatientsmaydevelopcon-stipationorurinaryretention.Nauseaanddiarrheahavebeenreported by some patients. Sweating, flushing, or chills alsomayoccur.Rarely,hepatotoxicitymayoccurwithphenelzine,whichmaybeserious.Peripheraledemalikelyreflectingeffectsof the drug on small vessels may prove difficult to manage.Finally,somepatientscomplainofmuscletwitchingorelectricshock–likesensations.Thelattermayrespondtoclonazepam,althoughtheemergenceofneurologicalorneuropathicsymp-toms may reflect interference with absorption of vitamin B6thatshouldimprovewithdietarysupplementationofpyridox-ine(vitaminB6)50to100mg/day.

Side-effect ProfileThe most common side effects of MAOIs include posturalhypotension, insomnia, agitation, sedation, and sexual dys-function, although the incidence of sexual dysfunction islowerthanwiththeSSRIs.300Othersideeffectsincludeweightchange, dry mouth, constipation, and urinary hesitancy.51Peripheralneuropathieshavebeenreported,andmaybepre-vented by concomitant therapy with pyridoxine.301 A list ofside effects with MAOIs is reported in Table 43-2. Elderlypatients may develop constipation or urinary retention.Alternatively, nausea and diarrhea have been reported bysomepatients.Sweating,flushing,orchillsmayoccur.Rarely,hepatotoxicity (which may be serious) may occur withphenelzine. Peripheral edema likely reflecting effects of thedrugonsmallvesselsmayprovedifficulttomanage.Finally,some patients complain of muscle twitching or electricshock–likesensations.

Dietary Restrictions and Drug InteractionsAsdiscussedpreviously,treatmentwithMAOIscarriesariskofhypertensivecrisis.Tominimizethisrisk,patientsonMAOIsneedtoadheretoastrictdietaryregimenthatexcludesfoodsand beverages that have a high content of dietary amines,includingallagedcheeses;sourcream;yogurt; fermentedordriedmeats(sausages,basderma,pastrami,pepperoni,louza,lingiça,chorizo);offal(liver,sweetbread,kidney,tripe,brains);favaandbroadbeanpods(lima,lentils,snow-peas);marmiteyeastextract;sauerkraut;soysauceandothersoyproducts;over-ripebananasandavocado;eggplant;spinach;pickled,dried,orsalted fish; caviar; fish roe (tarama); and foods containingmonosodium glutamate (MSG). Patients should also avoidconsumptionofcaffeinateddrinks,andmostalcoholicbever-ages,especiallytapbeerandredwine,butalsocertainwhitewines,includingthosethatareresinated(retsina),botrytized(sauternes, cadillac, loupiac,monbazillac, coteauxdu layon,Alsacevendagetardive,tokajiaszú,trockenbeerenausle),aged(sherry),andothers(Riesling,vermouth).Sympathomimetics,bothprescribedandover-the-counter(pseudoephedrine,ephe-drine,oxymetazoline,dextroamphetamine,andmethylpheni-date),potentnoradrenergicanddopaminergicantidepressants,dextromethorphan,andmeperidine(Demerol)mayalsopre-cipitateahypertensivecrisis.Inaddition,asmentionedprevi-ously,combiningMAOIswithpotentserotonergicagents(suchas theTCAs,SSRIs,andothers)carriesa riskof serotonergic

TABLE43-3 Interactions of Monoamine Oxidase Inhibitors with Other Drugs*

Drug Effect

Sympathomimetics (e.g., amphetamines, dopamine, ephedrine, epinephrine [adrenaline], isoproterenol [Isuprel], metaraminol, methylphenidate, oxymetazoline [Afrin], norepinephrine, phenylephrine [Neo-Synephrine], phenylpropanolamine, pseudoephedrine [Sudafed])

Hypertensive crisis

Meperidine (Demerol and others) Fever, delirium, hypertension, hypotension, neuromuscular excitability, deathOral hypoglycemics Further lowering of serum glucoseL-dopa Hypertensive crisisTricyclic antidepressants,† duloxetine, venlafaxine, SSRIs,

clomipramine, tryptophanFever, seizures, deliriumNausea, confusion, anxiety, shivering, hyperthermia, rigidity, diaphoresis,

hyperreflexia, tachycardia, hypotension, coma, deathBupropion Hypertensive crisis

*This may include selegiline even at low doses.†Tricyclics and MAOIs are occasionally used together.SSRIs, Selective serotonin re-uptake inhibitors.(From Rosenbaum JF, Arana GW, Hyman SE, et al., editors: Handbook of psychiatric drug therapy, ed 5, Philadelphia, 2005, Lippincott Williams &

Wilkins.)


Antidepressants 505

43103. Fava M, Judge R, Hoog SL, etal. Fluoxetine versus sertraline

andparoxetineinmajordepressivedisorder:changesinweightwith long-term treatment. J Clin Psychiatry 61(11):863–867,2000.

106. ThaseME,FergusonJM,LydiardRB,etal.Citalopramtreatmentof paroxetine-intolerant depressed patients. Depress Anxiety16(3):128–133,2002.

107. ThaseME,BlomgrenSL,BirkettMA,etal.Fluoxetinetreatmentof patients with major depressive disorder who failed initialtreatmentwithsertraline.J Clin Psychiatry58(1):16–21,1997.

116. FavaM.Prospectivestudiesofadverseeventsrelatedtoantide-pressant discontinuation. J Clin Psychiatry 67(Suppl. 4):14–21,2006.

125. Thase ME, Entsuah AR, Rudolph RL. Remission rates duringtreatmentwithvenlafaxineorselectiveserotoninreuptakeinhib-itors.Br J Psychiatry178:234,2001.

140. Clayton AH, Pradko JF, Croft HA, etal. Prevalence of sexualdysfunction among newer antidepressants. J Clin Psychiatry63(4):357–366,2002.

144. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry59(10):502–508,1998.

145. FavaM,MulroyR,Alpert J, etal.Emergenceof adverseeventsfollowing discontinuation of treatment with extended-releasevenlafaxine.Am J Psychiatry154(12):1760–1762,1997.

157. PapakostasGI,FavaM.Ameta-analysisofclinicaltrialscompar-ingmilnacipran,aserotonin-norepinephrinereuptakeinhibitor,witha selective serotonin reuptake inhibitor for the treatmentof major depressive disorder. Eur Neuropsychopharmacol 17(1):32–36,2007.

178. Papakostas GI. Dopaminergic-based pharmacotherapies fordepression.Eur Neuropsychopharmacol16(6):391–402,2006.

179. TrivediMH,RushAJ,CarmodyTJ,etal.DobupropionSRandsertralinedifferintheireffectsonanxietyindepressedpatients?J Clin Psychiatry62(10):776–781,2001.

180. PapakostasGI,NuttDJ,HallettLA,etal.Resolutionof sleepi-nessandfatigueinmajordepressivedisorder:acomparisonofbupropionandtheselectiveserotoninreuptakeinhibitors.Biol Psychiatry60(12):1350–1355,2006.

193. PapakostasGI,FavaM.Ameta-analysisofclinicaltrialscompar-ing the serotonin (5HT)-2 receptor antagonists trazodoneandnefazodonewithaselectiveserotoninreuptakeinhibitorforthetreatmentofmajordepressivedisorder.Eur Psychiatry22(7):444–447,2007.

230. PapakostasGI,HombergerCH,FavaM.Ameta-analysisofclini-cal trials comparing mirtazapine with a selective serotoninreuptakeinhibitorforthetreatmentofmajordepressivedisor-der.J Psychopharmacol22(8):843–848,2008.

237. Schatzberg AF, Kremer C, Rodrigues HE, etal. Mirtazapine vs.Paroxetine Study Group: Double-blind, randomized compari-sonofmirtazapineandparoxetineinelderlydepressedpatients.Am J Geriatr Psychiatry10(5):541–550,2002.

260. Fava M. Weight gain and antidepressants. J Clin Psychiatry61(Suppl.11):37–41,2000.

274. McGrathPJ,StewartJW,NunesEV,etal.Adouble-blindcross-over trial of imipramine and phenelzine for outpatients withtreatment-refractorydepression.Am J Psychiatry150(1):118–123,1993.

279. McGrathPJ,StewartJW,HarrisonW,etal.Treatmentoftricyclicrefractorydepressionwithamonoamineoxidaseinhibitoranti-depressant.Psychopharmacol Bull23(1):169–172,1987.

286. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporarytreatment of depression. Neuropsychopharmacology 12(3):185–219,1995.

OverdoseMAOIs are extremely dangerous in overdose. Because theycirculateatverylowconcentrationsinserumandaredifficulttoassay,therearenogooddataontherapeuticortoxicserumlevels. Manifestations of toxicity may appear slowly, oftentakingupto12hourstoappearand24hourstoreachtheirpeak;thus,evenifpatientsappearclinicallywellintheemer-gency department, they should be admitted for observationafteranysignificantoverdose.Afteranasymptomaticperiod,aserotoninsyndromemayoccur,includinghyperpyrexiaandautonomic excitation. Neuromuscular excitability may besevereenoughtoproducerhabdomyolysis,whichmaycauserenalfailure.ThisphaseofexcitationmaybefollowedbyCNSdepressionandcardiovascularcollapse.Deathmayoccurearlyduetoseizuresorarrhythmias,orlaterduetoasystole,arrhyth-mias,hypotension,or renal failure.Hemolysis anda coagu-lopathy also may occur and contribute to morbidity andmortalityrisk.

Drug InteractionsImportant drug interactions with MAOIs are listed inTable43-3.

Access the complete reference list and multiple choice questions (MCQs) online at https://expertconsult.inkling.com

KEY REFERENCES5. Fava M, Kendler KS. Major depressive disorder. Neuron

28(2):335–341,2000.51. FavaM,RosenbaumJF.Pharmacotherapyandsomatictherapies.

InBeckhamEE,LeberWR,editors:Handbook of depression,NewYork,1995,Guilford.

76. Thase ME. Preventing relapse and recurrence of depression:abrief reviewof therapeuticoptions.CNS Spectr11(12Suppl.15):12–21,2006.

78. PapakostasGI,PerlisRH,SeifertC,etal.Antidepressantdose-reductionand the riskof relapse inmajordepressivedisorder.Psychother Psychosom76(5):266–270,2007.

79. Fava M, Detke MJ, Balestrieri M. Management of depressionrelapse: re-initiation of duloxetine treatment or dose increase.J Psychiatr Res40(4):328–336,2006.

80. PapakostasGI,FavaM.Ameta-analysisofclinicaltrialscompar-ing moclobemide with selective serotonin reuptake inhibitorsforthetreatmentofmajordepressivedisorder.Can J Psychiatry51(12):783–790,2006.

82. Fava M, Hoog SL, Judge RA, etal. Acute efficacy of fluoxetineversus sertraline and paroxetine in major depressive disorderincluding effects of baseline insomnia. J Clin Psychopharmacol22(2):137–147,2002.

85. Fava M, Uebelacker LA, Alpert JE, etal. Major depressive sub-types and treatment response. Biol Psychiatry 42(7):568–576,1997.

90. FavaM,RankinM.SexualfunctioningandSSRIs.J Clin Psychiatry63(Suppl.5):13–16,discussion23–25,2002.

92. FavaM,GravesLM,BenazziF, etal.A cross-sectional studyoftheprevalenceofcognitiveandphysicalsymptomsduringlong-term antidepressant treatment. J Clin Psychiatry 67(11):1754–1759,2006.


https://expertconsult.inkling.com

Antidepressants 505.e1

43REFERENCES1. Crane GE. The psychiatric side-effects of iproniazid. Am J Psy-

chiatry112:494–501,1956.2. KuhnR.The treatmentofdepressivestateswithG22355(imi-

praminehydrochloride).Am J Psychiatry115:459–464,1958.3. Gershon S, Homberg G, Mattson E, etal. Imipramine hydro-

chloride: its effects on clinical, autonomic, and psychologicalfunctions.Arch Gen Psychiatry6:96–101,1962.

4. Glowinski J, Axelrod J. Inhibition of uptake of tritiated-noradrenalineintheintactratbrainbyimipramineandstructur-allyrelatedcompounds.Nature204:1318–1319,1964.

5. Fava M, Kendler KS. Major depressive disorder. Neuron 28(2):335–341,2000.

6. HymanSE,NestlerEJ.Initiationandadaptation:aparadigmforunderstanding psychotropic drug action. Am J Psychiatry153(2):115–162,1996.

7. KaliaM.Neurobiologicalbasisofdepression:anupdate.Metabo-lism54(5Suppl.1):24–27,2005.

8. ChenH,PandeyGN,DwivediY.Hippocampalcellproliferationregulation by repeated stress and antidepressants. Neuroreport17(9):863–867,2006.

9. RantamakiT,HendolinP,KankaanpaaA, etal.Pharmacologi-callydiverseantidepressantsrapidlyactivatebrain-derivedneu-rotrophic factor receptor TrkB and induce phospholipase-cgammasignalingpathwaysinmousebrain.Neuropsychopharma-cology32(10):2152–2162,2007.

10. RichelsonE.Interactionsofantidepressantswithneurotransmit-tertransportersandreceptorsandtheirclinicalrelevance.J Clin Psychiatry64(Suppl.13):5–12,2003.

11. BarbonA,PopoliM,LaViaL,etal.Regulationofeditingandexpression of glutamate alpha-amino-propionic-acid (AMPA)/kainate receptors by antidepressant drugs. Biol Psychiatry59(8):713–720,2006.

12. XuH,ChenZ,He J,etal.Synergeticeffectsofquetiapineandvenlafaxine in preventing the chronic restraint stress-induceddecrease in cellproliferationandBDNFexpression in rathip-pocampus.Hippocampus16(6):551–559,2006.

13. CalabreseF,MolteniR,MajPF,etal.Chronicduloxetinetreat-mentinducesspecificchangesintheexpressionofBDNFtran-scripts and in the subcellular localizationof theneurotrophinprotein.Neuropsychopharmacology32(11):2351–2359,2007.

14. BymasterFP,KatnerJS,NelsonDL,etal.Atomoxetineincreasesextracellularlevelsofnorepinephrineanddopamineinprefron-talcortexofrat:apotentialmechanismforefficacyinattentiondeficit/hyperactivity disorder. Neuropsychopharmacology 27(5):699–711,2002.

15. MillerDK,WongEH,ChesnutMD,etal.Reboxetine:functionalinhibitionofmonoaminetransportersandnicotinicacetylcho-linereceptors.J Pharmacol Exp Ther302(2):687–695,2002.

16. Tzavara ET, Bymaster FP, Overshiner CD, etal. Procholinergicand memory enhancing properties of the selective norepine-phrineuptakeinhibitoratomoxetine.Mol Psychiatry11(2):187–195,2006.

17. CreightonCJ,RamabadranK,CicconePE,etal.Synthesisandbiological evaluation of the major metabolite of atomoxetine:elucidationofapartialkappa-opioidagonisteffect.Bioorg Med Chem Lett14(15):4083–4085,2004.

18. HariaM,FittonA,McTavishD.Trazodone.Areviewofitsphar-macology,therapeuticuseindepressionandtherapeuticpoten-tialinotherdisorders.Drugs Aging4(4):331–355,1994.

19. TaylorDP,CarterRB,EisonAS,etal.Pharmacologyandneuro-chemistry of nefazodone, a novel antidepressant drug. J Clin Psychiatry56(Suppl.6):3–11,1995.

20. Meyer JH, Cho R, Kennedy S, etal. The effects of single dosenefazodoneandparoxetineupon5-HT2Abindingpotentialinhumansusing [18F]-setoperonePET.Psychopharmacology (Berl)144(3):279–281,1999.

21. Hemrick-Luecke SK, Snoddy HD, Fuller RW. Evaluation ofnefazodone as a serotonin uptake inhibitor and a serotoninantagonistinvivo.Life Sci55(7):479–483,1994.

22. RothmanRB,BaumannMH.Serotoninreleasingagents.Neuro-chemical, therapeutic and adverse effects. Pharmacol Biochem Behav71(4):825–836,2002.

23. Schreiber S, Backer MM, Herman I, etal. The antinociceptiveeffectoftrazodoneinmiceismediatedthroughbothmu-opioid

andserotonergicmechanisms.Behav Brain Res114(1–2):51–56,2000.

24. MarcoliM,MauraG,TortaroloM,etal.Trazodoneisapotentagonist at 5-HT2C receptors mediating inhibition of theN-methyl-D-aspartate/nitric oxide/cyclic GMP pathway in ratcerebellum.J Pharmacol Exp Ther285(3):983–986,1998.

25. MauraG,MarcoliM,PepicelliO,etal.SerotonininhibitionoftheNMDAreceptor/nitricoxide/cyclicGMPpathwayinhumanneocortexslices:involvementof5-HT(2C)and5-HT(1A)recep-tors.Br J Pharmacol130(8):1853–1858,2000.

26. PazzagliM,GiovanniniMG,PepeuG.Trazodoneincreasesextra-cellularserotoninlevelsinthefrontalcortexofrats.Eur J Phar-macol383(3):249–257,1999.

27. Rao R. Serotonergic syndrome with trazodone. Hosp Med59(1):79,1998.

28. Millan MJ, Gobert A, Lejeune F, etal. The novel melatoninagonist agomelatine (S20098) is an antagonist at5-hydroxytryptamine2Creceptors,blockadeofwhichenhancestheactivityoffrontocorticaldopaminergicandadrenergicpath-ways.J Pharmacol Exp Ther306(3):954–964,2003.

29. Blier P, Ward NM. Is there a role for 5-HT1A agonists in thetreatmentofdepression?Biol Psychiatry53(3):193–203,2003.

30. Rimele TJ, Henry DE, Lee DK, etal. Tissue-dependent alphaadrenoceptor activity of buspirone and related compounds.J Pharmacol Exp Ther241(3):771–778,1987.

31. BergmanJ,RoofRA,FurmanCA,etal.Modificationofcocaineself-administration by buspirone (buspar®): potential involve-mentofD3andD4dopaminereceptors.Int J Neuropsychophar-macol16(2):445–458,2013.

32. PierceyMF,SmithMW,Lum-RaganJT.Excitationofnoradrener-giccellfiringby5-hydroxytryptamine1Aagonistscorrelateswithdopamine antagonist properties. J Pharmacol Exp Ther 268(3):1297–1303,1994.

33. LechinF, vanderDijsB, JaraH,etal.Effectsofbuspironeonplasma neurotransmitters in healthy subjects. J Neural Transm105(6–7):561–573,1998.

34. AstierB,LambasSenasL,SouliereF,etal. Invivocomparisonof two 5-HT1A receptors agonists alnespirone (S-20499) andbuspironeonlocuscoeruleusneuronalactivity.Eur J Pharmacol459(1):17–26,2003.

35. GobertA,RivetJM,CistarelliL,etal.Buspironemodulatesbasaland fluoxetine-stimulated dialysate levels of dopamine,noradrenaline and serotonin in the frontal cortex of freelymoving rats:activationof serotonin1Areceptorsandblockadeofalpha2-adrenergicreceptorsunderlie itsactions.Neuroscience93(4):1251–1262,1999.

36. van Amsterdam C, Seyfried CA. Mechanism of action of thebimodal antidepressant vilazodone: evidence for serotonin1A-receptor-mediatedauto-augmentationofextracellularserotoninoutput.Psychopharmacology (Berl)231(12):2547–2558,2014.

37. Guilloux JP, Mendez-David I, Pehrson A, etal. Antidepressantandanxiolyticpotentialofthemultimodalantidepressantvorti-oxetine(LuAA21004)assessedbybehaviouralandneurogenesisoutcomesinmice.Neuropharmacology73:147–159,2013.

38. MørkA,PehrsonA,BrennumLT,etal.PharmacologicaleffectsofLuAA21004:anovelmultimodalcompoundforthetreatmentofmajordepressivedisorder.J Pharmacol Exp Ther340(3):666–675,2010.

39. Ascher JA,Cole JO,Colin JN, etal.Bupropion:a reviewof itsmechanismofantidepressantactivity.J Clin Psychiatry56(9):395–401,1995.

40. Learned-CoughlinSM,BergstromM,SavitchevaI,etal.Invivoactivity of bupropion at the human dopamine transporter asmeasured by positron emission tomography. Biol Psychiatry54(8):800–805,2003.

41. Foley KF, Cozzi NV. Inhibition of transport function anddesipraminebindingatthehumannoradrenalinetransporterbyN-ethylmaleimideandprotectionbysubstrateanalogs.Naunyn Schmiedebergs Arch Pharmacol365(6):457–461,2002.

42. DongJ,BlierP.Modificationofnorepinephrineandserotonin,butnotdopamine,neuronfiringbysustainedbupropiontreat-ment.Psychopharmacology (Berl)155(1):52–57,2001.

43. LiSX,PerryKW,WongDT.Influenceoffluoxetineontheabilityof bupropion to modulate extracellular dopamine and nor-epinephrineconcentrationsinthreemesocorticolimbicareasofrats.Neuropharmacology42(2):181–190,2002.


505.e2 PARTX Treatment Approaches

44. Miller DK, Sumithran SP, Dwoskin LP. Bupropion inhibitsnicotine-evoked[(3)H]overflowfromratstriatalslicespreloadedwith[(3)H]dopamineandfromrathippocampalslicespreloadedwith[(3)H]norepinephrine.J Pharmacol Exp Ther302(3):1113–1122,2002.

45. HaddjeriN,BlierP,deMontignyC.Noradrenergicmodulationofcentralserotonergicneurotransmission:acuteandlong-termactionsofmirtazapine.Int Clin Psychopharmacol10(Suppl.4):11–17,1995.

46. AnttilaSA,LeinonenEV.A reviewof thepharmacologicalandclinical profile of mirtazapine. CNS Drug Rev 7(3):249–264,2001.

47. StollL,SeguinS,GentileL.Tricyclicantidepressants,butnottheselective serotonin reuptake inhibitor fluoxetine, bind to theS1S2domainofAMPAreceptors.Arch Biochem Biophys458(2):213–219,2007.

48. NunezE,Lopez-CorcueraB,VazquezJ,etal.Differentialeffectsof the tricyclic antidepressant amoxapine on glycine uptakemediatedbytherecombinantGLYT1andGLYT2glycinetrans-porters.Br J Pharmacol129(1):200–206,2000.

49. KapurS,ChoR, JonesC, etal. Is amoxapineanatypical anti-psychotic? Positron-emission tomography investigation of itsdopamine2andserotonin2occupancy.Biol Psychiatry45(9):1217–1220,1999.

50. RichelsonE,NelsonA.Antagonismbyantidepressantsofneu-rotransmitterreceptorsofnormalhumanbraininvitro.J Phar-macol Exp Ther230:94–102,1984.

51. FavaM,RosenbaumJF.Pharmacotherapyandsomatictherapies.InBeckhamEE,LeberWR,editors:Handbook of depression,NewYork,1995,Guilford.

52. HasanF,McCroddenJM,KennedyNP,etal.Theinvolvementofintestinalmonoamineoxidaseinthetransportandmetabolismoftyramine.J Neural Transm Suppl26:1–9,1988.

53. LavinMR,MendelowitzA,KronigMH.Spontaneoushyperten-sivereactionswithmonoamineoxidaseinhibitors.Biol Psychiatry34(3):146–151,1993.

54. Lane R, Baldwin D. Selective serotonin reuptake inhibitor–induced serotonin syndrome: review. J Clin Psychopharmacol17(3):208–221,1997.

55. FeighnerJP,BoyerWF,TylerDL,etal.Adverseconsequencesoffluoxetine-MAOI combination therapy. J Clin Psychiatry 51(6):222–225,1990.

56. Beasley CM Jr, Masica DN, Heiligenstein JH, etal. Possiblemonoamineoxidaseinhibitor–serotoninuptakeinhibitorinter-action: fluoxetine clinical data and preclinical findings. J Clin Psychopharmacol13(5):312–320,1993.

57. Bonnet U. Moclobemide: therapeutic use and clinical studies.CNS Drug Rev9(1):97–140,2003.

58. Levant B, Moehlenkamp JD, Morgan KA, etal. Modulation of[3H]quinpirolebindinginbrainbymonoamineoxidaseinhibi-tors:evidenceforapotentialnovelbindingsite.J Pharmacol Exp Ther278(1):145–153,1996.

59. LevantB,BancroftGN.Inhibitionof[3H]quinpirolebindingbya monoamine oxidase inhibitor in subcellular fractions of ratstriatum.Life Sci63(18):1643–1651,1998.

60. SlawsonMH,TaccognoJL,FoltzRL,etal.Quantitativeanalysisof selegiline and three metabolites (N-desmethylselegiline,methamphetamine, and amphetamine) in human plasma byhigh-performanceliquidchromatography–atmosphericpressurechemical ionization–tandem mass spectrometry. J Anal Toxicol26(7):430–437,2002.

61. Baker GB, Urichuk LJ, McKenna KF, etal. Metabolism ofmonoamine oxidase inhibitors. Cell Mol Neurobiol 19(3):411–426,1999.

62. Neusch C, Schnierle S, Moser A. Selegiline induces dopaminerelease through ATP-sensitive potassium channels in the ratcaudate-putameninvitro.Neurochem Int31(2):307–311,1997.

63. Tuomisto J, SmithDF.Effectsof tranylcypromineenantiomerson monoamine uptake and release and imipramine binding.J Neural Transm65(2):135–145,1986.

64. Dingemanse J, Wallnofer A, Gieschke R, etal. Pharmacoki-netic and pharmacodynamic interactions between fluoxetineand moclobemide in the investigation of development ofthe “serotonin syndrome. Clin Pharmacol Ther 63(4):403–413,1998.

65. EbertD,AlbertR,MayA,etal.CombinedSSRI-RIMAtreatmentinrefractorydepression.Safetydataandefficacy.Psychopharma-cology (Berl)119(3):342–344,1995.

66. JoffeRT,BakishD.CombinedSSRI-moclobemidetreatmentofpsychiatricillness.J Clin Psychiatry55(1):24–25,1994.

67. Chambost M, Liron L, Peillon D, etal. Serotonin syndromeduring fluoxetine poisoning in a patient taking moclobemide.Can J Anaesth47(3):246–250,2000.

68. Dardennes RM, Even C, Ballon N, etal. Serotonin syndromecausedbyaclomipramine-moclobemideinteraction.J Clin Psy-chiatry59(7):382–383,1998.

69. Hojer J, Personne M, Skagius AS, etal. Serotonin syndrome—several cases of this often overlooked diagnosis. Tidsskr Nor Laegeforen122(17):1660–1663,2002.

70. IsbisterGK,McGettiganP,DawsonA.Afatalcaseofmoclobemide-citalopramintoxication.J Anal Toxicol25(8):716–717,2001.

71. DamsR,BenijtsTH,LambertWE,etal.Afatalcaseofserotoninsyndrome after combined moclobemide-citalopram intoxica-tion.J Anal Toxicol25(2):147–151,2001.

72. Rogde S, Hilberg T, Teige B. Fatal combined intoxication withnew antidepressants. Human cases and an experimental studyof postmortem moclobemide redistribution. Forensic Sci Int100(1–2):109–116,1999.

73. Finge T, Malavialle C, Lambert J. Fatal form of serotonin syn-drome.Ann Fr Anesth Reanim16(1):80–81,1997.

74. SingerPP,JonesGR.Anuncommonfatalityduetomoclobemideandparoxetine.J Anal Toxicol21(6):518–520,1997.

75. GeddesJR,CarneySM,DaviesC,etal.Relapsepreventionwithantidepressantdrugtreatmentindepressivedisorders:asystem-aticreview.Lancet361(9358):653–661,2003.

76. Thase ME. Preventing relapse and recurrence of depression: abrief review of therapeutic options. CNS Spectr 11(12 Suppl.15):12–21,2006.

77. KupferDJ,FrankE,PerelJM,etal.Five-yearoutcomeformain-tenance therapies in recurrent depression. Arch Gen Psychiatry49(10):769–773,1992.

78. PapakostasGI,PerlisRH,SeifertC,etal.Antidepressantdose-reductionand the riskof relapse inmajordepressivedisorder.Psychother Psychosom76(5):266–270,2007.

79. Fava M, Detke MJ, Balestrieri M. Management of depressionrelapse: re-initiation of duloxetine treatment or dose increase.J Psychiatr Res40(4):328–336,2006.

80. PapakostasGI,FavaM.Ameta-analysisofclinicaltrialscompar-ing moclobemide with selective serotonin reuptake inhibitorsforthetreatmentofmajordepressivedisorder.Can J Psychiatry51(12):783–790,2006.

81. Pande AC, Birkett M, Fechner-Bates S, etal. Fluoxetine versusphenelzine inatypicaldepression.Biol Psychiatry40(10):1017–1020,1996.

82. Fava M, Hoog SL, Judge RA, etal. Acute efficacy of fluoxetineversus sertraline and paroxetine in major depressive disorderincluding effects of baseline insomnia. J Clin Psychopharmacol22(2):137–147,2002.

83. KennedySH,AndersenHF,LamRW.Efficacyofescitalopraminthetreatmentofmajordepressivedisordercomparedwithcon-ventionalselectiveserotoninreuptakeinhibitorsandvenlafaxineXR:ameta-analysis.J Psychiatry Neurosci31(2):122–131,2006.

84. PetersenT,DordingC,NeaultNB,etal.Asurveyofprescribingpractices in the treatmentofdepression.Prog Neuropsychophar-macol Biol Psychiatry26(1):177–187,2002.

85. Fava M, Uebelacker LA, Alpert JE, etal. Major depressive sub-types and treatment response. Biol Psychiatry 42(7):568–576,1997.

86. PapakostasGI,PetersenT,IosifescuDV,etal.Somaticsymptomsaspredictorsoftimetoonsetofresponsetofluoxetineinmajordepressivedisorder.J Clin Psychiatry65(4):543–546,2004.

87. MarchJS,KobakKA,JeffersonJW,etal.Adouble-blind,placebo-controlledtrialoffluvoxamineversusimipramineinoutpatientswithmajordepression.J Clin Psychiatry51(5):200–202,1990.

88. FeighnerJP,BoyerWF,MeredithCH,etal.Aplacebo-controlledinpatientcomparisonoffluvoxaminemaleateandimipraminein major depression. Int Clin Psychopharmacol 4(3):239–244,1989.

89. MasandPS,GuptaS.Selectiveserotonin-reuptakeinhibitors:anupdate.Harv Rev Psychiatry7(2):69–84,1999.



4390. FavaM,RankinM.SexualfunctioningandSSRIs.J Clin Psychiatry

63(Suppl.5):13–16,discussion23–25,2002.91. Rothschild AJ. Selective serotonin reuptake inhibitor-induced

sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry152(10):1514–1516,1995.

92. FavaM,GravesLM,BenazziF, etal.A cross-sectional studyoftheprevalenceofcognitiveandphysicalsymptomsduringlong-term antidepressant treatment. J Clin Psychiatry 67(11):1754–1759,2006.

93. Gerber PE, Lynd LD. Selective serotonin-reuptake inhibitor-inducedmovementdisorders.Ann Pharmacother32(6):692–698,1998.

94. GillHS,DeVaneCL,RischSC.Extrapyramidalsymptomsassoci-atedwithcyclicantidepressanttreatment:areviewofthelitera-ture and consolidating hypotheses. J Clin Psychopharmacol17(5):377–389,1997.

95. SteurEN.IncreaseofParkinsondisabilityafterfluoxetinemedi-cation.Neurology43(1):211–213,1993.

96. LeoRJ,LichterDG,HersheyLA.Parkinsonismassociatedwithfluoxetine and cimetidine: a case report. J Geriatr Psychiatry Neurol8(4):231–233,1995.

97. LeoRJ.Movementdisordersassociatedwiththeserotoninselec-tivereuptakeinhibitors.J Clin Psychiatry57(10):449–454,1996.

98. VandeVijverDA,RoosRA,JansenPA,etal.Startofaselectiveserotoninreuptakeinhibitor(SSRI)andincreaseofantiparkin-soniandrugtreatmentinpatientsonlevodopa.Br J Clin Phar-macol54(2):168–170,2002.

99. Lake MB, Birmaher B, Wassick S, etal. Bleeding and selectiveserotonin reuptake inhibitors in childhood and adolescence.J Child Adolesc Psychopharmacol10(1):35–38,2000.

100. Alderman CP, Seshadri P, Ben-Tovim DI. Effects of serotoninreuptake inhibitors on hemostasis. Ann Pharmacother30(11):1232–1234,1996.

101. Sussman N, Ginsberg DL, Bikoff J. Effects of nefazodone onbodyweight: apooledanalysisof selective serotonin reuptakeinhibitor- and imipramine-controlled trials. J Clin Psychiatry62(4):256–260,2001.

102. Michelson D, Amsterdam JD, Quitkin FM, etal. Changes inweight during a 1-year trial of fluoxetine. Am J Psychiatry156(8):1170–1176,1999.

103. FavaM,JudgeR,HoogSL,etal.Fluoxetineversussertralineandparoxetineinmajordepressivedisorder:changesinweightwithlong-termtreatment.J Clin Psychiatry61(11):863–867,2000.

104. PapakostasGI,PetersenT,MontoyaH,etal.Treatment-relatedadverseeventsandoutcomeinaclinical trialoffluoxetine fordepression.Ann Clin Psychiatry15(3–4):187–192,2003.

105. CalabreseJR,LondborgPD,SheltonMD,etal.Citalopramtreat-mentoffluoxetine-intolerantdepressedpatients.J Clin Psychiatry64(5):562–567,2003.

106. ThaseME,FergusonJM,LydiardRB,etal.Citalopramtreatmentof paroxetine-intolerant depressed patients. Depress Anxiety16(3):128–133,2002.

107. ThaseME,BlomgrenSL,BirkettMA,etal.Fluoxetinetreatmentof patients with major depressive disorder who failed initialtreatmentwithsertraline.J Clin Psychiatry58(1):16–21,1997.

108. BrownWA,HarrisonW.Arepatientswhoareintoleranttooneserotonin selective reuptake inhibitor intolerant to another?J Clin Psychiatry56(1):30–34,1995.

109. GoldenRN,NemeroffCB,McSorleyP,etal.Efficacyandtoler-abilityofcontrolled-releaseandimmediate-releaseparoxetineinthe treatment of depression. J Clin Psychiatry 63(7):577–584,2002.

110. MisraM,PapakostasGI,KlibanskiA.Effectsofpsychiatricdis-orders and psychotropic medications on prolactin and bonemetabolism.J Clin Psychiatry65(12):1607–1618,2004.

111. PapakostasGI,MillerKK,PetersenT,etal.Serumprolactinlevelsamong outpatients with major depressive disorder during theacute phase of treatment with fluoxetine. J Clin Psychiatry67(6):952–957,2006.

112. RichardsJB,PapaioannouA,AdachiJD,etal.CanadianMulti-centre Osteoporosis Study Research Group. Effect of selectiveserotoninreuptakeinhibitorsontheriskoffracture.Arch Intern Med167(2):188–194,2007.

113. HenryJA,AlexanderCA,SenerEK.Relativemortalityfromover-doseofantidepressants.BMJ310(6974):221–224,1995.

114. NonacsR,CohenLS.Assessmentand treatmentofdepressionduringpregnancy:anupdate.Psychiatr Clin North Am26(3):547–562,2003.

115. Rosenbaum JF, Fava M, Hoog SL, etal. Selective serotoninreuptake inhibitor discontinuation syndrome: a randomizedclinicaltrial.Biol Psychiatry44(2):77–87,1998.

116. FavaM.Prospectivestudiesofadverseeventsrelatedtoantide-pressant discontinuation. J Clin Psychiatry 67(Suppl. 4):14–21,2006.

117. Michelson D, Fava M, Amsterdam J, etal. Interruption ofselective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial. Br J Psychiatry 176:363–368,2000.

118. RosenbaumJF,ZajeckaJ.Clinicalmanagementofantidepressantdiscontinuation.J Clin Psychiatry58(Suppl.7):37–40,1997.

119. HemeryckA,BelpaireFM.Selective serotonin reuptake inhibi-torsandcytochromeP-450mediateddrug-druginteractions:anupdate.Curr Drug Metab3(1):13–37,2002.

120. Pastuszak A, Schick-Boschetto B, Zuber C, etal. Pregnancyoutcome following first-trimester exposure to fluoxetine(Prozac).JAMA269(17):2246–2248,1993.

121. SanchezC,HyttelJ.Comparisonoftheeffectsofantidepressantsand theirmetaboliteson reuptakeofbiogenic amines andonreceptorbinding.Cell Mol Neurobiol19(4):467–489,1999.

122. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dualmechanisms of action of venlafaxine. Arch Gen Psychiatry57(5):503–509,2000.

123. RoseboomPH,KalinNH.Neuropharmacologyof venlafaxine.Depress Anxiety12(Suppl.1):20–29,2000.

124. WellingtonK,PerryCM.Venlafaxineextended-release:areviewof itsuse in themanagementofmajordepression.CNS Drugs15(8):643–669,2001.

125. Thase ME, Entsuah AR, Rudolph RL. Remission rates duringtreatmentwithvenlafaxineorselectiveserotoninreuptakeinhib-itors.Br J Psychiatry178:234,2001.

126. RudolphRL.Achieving remission fromdepressionwithvenla-faxine and venlafaxine extended release: a literature review ofcomparativestudieswithselectiveserotoninreuptakeinhibitors.Acta Psychiatr Scand Suppl(415):24–30,2002.

127. SmithD,DempsterC,GlanvilleJ,etal.Efficacyandtolerabilityof venlafaxine compared with selective serotonin reuptakeinhibitorsandotherantidepressants:ameta-analysis.Br J Psy-chiatry180:396–404,2002.

128. Saiz-RuizJ,IbanezA,Diaz-MarsaM,etal.Efficacyofvenlafaxinein major depression resistant to selective serotonin reuptakeinhibitors.Prog Neuropsychopharmacol Biol Psychiatry26(6):1129–1134,2002.

129. MbayaP.SafetyandefficacyofhighdoseofvenlafaxineXL intreatment resistant major depression. Hum Psychopharmacol17(7):335–339,2002.

130. KaplanEM.Efficacyofvenlafaxineinpatientswithmajordepres-sivedisorderwhohaveunsustainedornoresponsetoselectiveserotonin reuptake inhibitors: an open-label, uncontrolledstudy.Clin Ther24(7):1194–1200,2002.

131. SchweitzerI,BurrowsG,TuckwellV,etal.Sustainedresponsetoopen-labelvenlafaxineindrug-resistantmajordepression.J Clin Psychopharmacol21(2):185–189,2001.

132. MitchellPB,SchweitzerI,BurrowsG,etal.Efficacyofvenlafax-ineandpredictorsofresponseinaprospectiveopen-labelstudyofpatientswithtreatment-resistantmajordepression.J Clin Psy-chopharmacol20(4):483–487,2000.

133. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison.Br J Psychiatry175:12–16,1999.

134. deMontignyC,SilverstonePH,DebonnelG,etal.Venlafaxineintreatment-resistantmajordepression:aCanadianmulticenter,open-labeltrial.J Clin Psychopharmacol19(5):401–406,1999.

135. Nierenberg AA, Feighner JP, Rudolph R, etal. Venlafaxine fortreatment-resistantunipolardepression. J Clin Psychopharmacol14(6):419–423,1994.

136. Kornbluh R, Papakostas GI, Petersen T, etal. A survey of pre-scribing preferences in the treatment of refractory depression:recenttrends.Psychopharmacol Bull35(3):150–156,2001.

137. Nelson JC. Safety and tolerability of the new antidepressants.J Clin Psychiatry58(Suppl.6):26–31,1997.



138. JaffeeMS,BostwickJM.Buspironeasanantidotetovenlafaxine-inducedbruxism.Psychosomatics41(6):535–536,2000.

139. Brown ES, Hong SC. Antidepressant-induced bruxism success-fully treated with gabapentin. J Am Dent Assoc 130(10):1467–1469,1999.

140. Clayton AH, Pradko JF, Croft HA, etal. Prevalence of sexualdysfunction among newer antidepressants. J Clin Psychiatry63(4):357–366,2002.

141. Montejo AL, Llorca G, Izquierdo JA, etal. Incidence of sexualdysfunctionassociatedwithantidepressantagents:aprospectivemulticenterstudyof1022outpatients.SpanishWorkingGroupfortheStudyofPsychotropic-RelatedSexualDysfunction.J Clin Psychiatry62(Suppl.3):10–21,2001.

142. EntsuahR,ChitraR.Abenefit-riskanalysisofonce-dailyvenla-faxineextendedrelease(XR)andvenlafaxineimmediaterelease(IR)inoutpatientswithmajordepression.Psychopharmacol Bull33(4):671–676,1997.

143. RudolphRL,DerivanAT.Thesafetyandtolerabilityofvenlafax-inehydrochloride:analysisoftheclinicaltrialsdatabase.J Clin Psychopharmacol16(3Suppl.2):54S–59S,1996.

144. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry59(10):502–508,1998.

145. FavaM,MulroyR,Alpert J, etal.Emergenceof adverseeventsfollowing discontinuation of treatment with extended-releasevenlafaxine.Am J Psychiatry154(12):1760–1762,1997.

146. Gonzalez-PintoA,GutierrezM,GonzalezN,etal.Efficacyandsafety of venlafaxine-ECT combination in treatment-resistantdepression.J Neuropsychiatry Clin Neurosci14(2):206–209,2002.

147. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, etal. Com-parativeaffinityofduloxetineandvenlafaxineforserotoninandnorepinephrinetransportersinvitroandinvivo,humanserot-oninreceptorsubtypes,andotherneuronalreceptors.Neuropsy-chopharmacology25(6):871–880,2001.

148. ThaseME,LuY,JoliatMJ,etal.Remissioninplacebo-controlledtrialsofduloxetinewithanSSRI comparator.Presentedat theAnnualMeetingoftheAmericanPsychiatricAssociation,2005.

149. PerahiaDG,KajdaszDK,DesaiahD,etal.Symptomsfollowingabruptdiscontinuationofduloxetinetreatmentinpatientswithmajor depressive disorder. J Affect Disord 89(1–3):207–212,2005.

150. DetkeMJ,LuY,GoldsteinDJ,etal.Duloxetine60mgoncedailydosingversusplacebo in theacute treatmentofmajordepres-sion.J Psychiatr Res36(6):383–390,2002.

151. Detke MJ, Lu Y, Goldstein DJ, etal. Duloxetine, 60mg oncedaily,formajordepressivedisorder:arandomizeddouble-blindplacebo-controlledtrial.J Clin Psychiatry63(4):308–315,2002.

152. Goldstein DJ, Mallinckrodt C, Lu Y, etal. Duloxetine in thetreatmentofmajordepressivedisorder:adouble-blindclinicaltrial.J Clin Psychiatry63(3):225–231,2002.

153. Mochizuki D, Tsujita R, Yamada S, etal. Neurochemical andbehavioural characterization of milnacipran, a serotonin andnoradrenaline reuptake inhibitor in rats. Psychopharmacology (Berl)162(3):323–332,2002.

154. ClercG,Milnacipran/FluvoxamineStudyGroup.Antidepressantefficacy and tolerability of milnacipran, a dual serotonin andnoradrenaline reuptake inhibitor: a comparison with fluvox-amine.Int Clin Psychopharmacol16(3):145–151,2001.

155. Guelfi JD, Ansseau M, Corruble E, etal. A double-blind com-parisonoftheefficacyandsafetyofmilnacipranandfluoxetineindepressedinpatients.Int Clin Psychopharmacol13(3):121–128,1998.

156. AnsseauM,PapartP,TroisfontainesB,etal.Controlledcompari-sonofmilnacipranandfluoxetineinmajordepression.Psychop-harmacology (Berl)114(1):131–137,1994.

157. PapakostasGI,FavaM.Ameta-analysisofclinicaltrialscompar-ingmilnacipran,aserotonin-norepinephrinereuptakeinhibitor,witha selective serotonin reuptake inhibitor for the treatmentof major depressive disorder. Eur Neuropsychopharmacol 17(1):32–36,2007.

158. van Amerongen AP, Ferrey G, Tournoux A. A randomised,double-blindcomparisonofmilnacipranandimipramineinthetreatmentofdepression.J Affect Disord72(1):21–31,2002.

159. Tignol J, Pujol-Domenech J, Chartres JP, etal. Double-blindstudyoftheefficacyandsafetyofmilnacipranandimipramine

inelderlypatientswithmajordepressiveepisode.Acta Psychiatr Scand97(2):157–165,1998.

160. SteenA,DenBoer JA.Adouble-blindsixmonthscomparativestudy of milnacipran and clomipramine in major depressivedisorder.Int Clin Psychopharmacol12(5):269–281,1997.

161. vonFrenckellR,AnsseauM,SerreC,etal.Poolingtwocontrol-led comparisons of milnacipran (F2207) and amitriptyline inendogenousinpatients.Anewapproachindoserangingstudies.Int Clin Psychopharmacol5(1):49–56,1990.

162. AnsseauM,vonFrenckellR,MertensC,etal.Controlledcom-parisonoftwodosesofmilnacipran(F2207)andamitriptylinein major depressive inpatients. Psychopharmacology (Berl)98(2):163–168,1998.

163. Macher JP, Sichel JP, Serre C, etal. Double-blind placebo-controlled study of milnacipran in hospitalized patients withmajor depressive disorders. Neuropsychobiology 22(2):77–82,1989.

164. LecrubierY,PletanY,SollesA,etal.Clinicalefficacyofmilnacip-ran:placebo-controlledtrials.Int Clin Psychopharmacol11(Suppl.4):29–33,1996.

165. SambunarisA,BoseA,GommollCP,etal.AphaseIII,double-blind, placebo-controlled, flexible-dose study of levomilnacip-ranextended-releaseinpatientswithmajordepressivedisorder.J Clin Psychopharmacol34(1):47–56,2014.

166. Montgomery SA, Mansuy L, Ruth AC, etal. The efficacy ofextended-release levomilnacipran in moderate to severe majordepressive disorder: secondary and post-hoc analyses from arandomized, double-blind, placebo-controlled study. Int Clin Psychopharmacol29(1):26–35,2014.

167. BakishD,BoseA,GommollC,etal.LevomilnacipranER40mgand80mginpatientswithmajordepressivedisorder:aphaseIII, randomized, double-blind, fixed-dose, placebo-controlledstudy.J Psychiatry Neurosci39(1):40–49,2014.

168. WongEH,SondersMS,AmaraSG,etal.Reboxetine:apharma-cologically potent, selective, and specific norepinephrinereuptakeinhibitor.Biol Psychiatry47(9):818–829,2000.

169. MontgomeryS,Ferguson JM,SchwartzGE.Theantidepressantefficacyofreboxetineinpatientswithseveredepression.J Clin Psychopharmacol23(1):45–50,2003.

170. AndreoliV,CaillardV,DeoRS,etal.Reboxetine,anewnoradren-alineselectiveantidepressant,isatleastaseffectiveasfluoxetineinthetreatmentofdepression.J Clin Psychopharmacol22(4):393–399,2002.

171. Versiani M, Amin M, Chouinard G. Double-blind, placebo-controlled study with reboxetine in inpatients with severemajordepressivedisorder. J Clin Psychopharmacol20(1):28–34,2000.

172. MassanaJ.Reboxetineversusfluoxetine:anoverviewofefficacyandtolerability.J Clin Psychiatry59(Suppl.14):8–10,1998.

173. ClaytonAH,ZajeckaJ,FergusonJM,etal.Lackofsexualdysfunc-tionwiththeselectivenoradrenalinereuptakeinhibitorreboxet-ine during treatment for major depressive disorder. Int Clin Psychopharmacol18(3):151–156,2003.

174. Preti A. Tomoxetine (Eli Lilly & Co). Curr Opin Investig Drugs3(2):272–277,2002.

175. ChouinardG,AnnableL,BradwejnJ.AnearlyphaseIIclinicaltrialoftomoxetine(LY139603)inthetreatmentofnewlyadmit-ted depressed patients. Psychopharmacology (Berl) 83(1):126–128,1984.

176. WernickeJF,KratochvilCJ.Safetyprofileofatomoxetineinthetreatmentof childrenandadolescentswithADHD. J Clin Psy-chiatry63(Suppl.12):50–55,2002.

177. ThaseME,HaightBR,RichardN,etal.Remissionratesfollowingantidepressant therapy with bupropion or selective serotoninreuptakeinhibitors:ameta-analysisoforiginaldatafrom7ran-domizedcontrolledtrials.J Clin Psychiatry66(8):974–981,2005.

178. Papakostas GI. Dopaminergic-based pharmacotherapies fordepression.Eur Neuropsychopharmacol16(6):391–402,2006.

179. TrivediMH,RushAJ,CarmodyTJ,etal.DobupropionSRandsertralinedifferintheireffectsonanxietyindepressedpatients?J Clin Psychiatry62(10):776–781,2001.

180. PapakostasGI,NuttDJ,HallettLA,etal.Resolutionof sleepi-nessandfatigueinmajordepressivedisorder:acomparisonofbupropionandtheselectiveserotoninreuptakeinhibitors.Biol Psychiatry60(12):1350–1355,2006.



43181. ThaseME,ClaytonAH,HaightBR,etal.Adouble-blindcom-

parisonbetweenbupropionXLandvenlafaxineXR:sexualfunc-tioning, antidepressant efficacy, and tolerability. J Clin Psychopharmacol26(5):482–488,2006.

182. Coleman CC, King BR, Bolden-Watson C, etal. A placebo-controlled comparison of the effects on sexual functioning ofbupropion sustained release and fluoxetine. Clin Ther23(7):1040–1058,2001.

183. ColemanCC,CunninghamLA,FosterVJ,etal.Sexualdysfunc-tion associated with the treatment of depression: a placebo-controlled comparison of bupropion sustained release andsertralinetreatment.Ann Clin Psychiatry11(4):205–215,1999.

184. SegravesRT,KavoussiR,HughesAR,etal.Evaluationofsexualfunctioning indepressedoutpatients:adouble-blindcompari-son of sustained-release bupropion and sertraline treatment.J Clin Psychopharmacol20(2):122–128,2000.

185. CroftH,SettleEJr,HouserT,etal.Aplacebo-controlledcom-parisonoftheantidepressantefficacyandeffectsonsexualfunc-tioningofsustained-releasebupropionandsertraline.Clin Ther21(4):643–658,1999.

186. KavoussiRJ,SegravesRT,HughesAR,etal.Double-blindcom-parison of bupropion sustained release and sertraline indepressedoutpatients.J Clin Psychiatry58(12):532–537,1997.

187. ModellJG,KatholiCR,ModellJD,etal.Comparativesexualsideeffectsofbupropion,fluoxetine,paroxetine,andsertraline.Clin Pharmacol Ther61(4):476–487,1997.

188. FeighnerJP,GardnerEA,JohnstonJA,etal.Double-blindcom-parisonofbupropionandfluoxetine indepressedoutpatients.J Clin Psychiatry52(8):329–335,1991.

189. SettleEC,StahlSM,BateySR,etal.Safetyprofileofsustained-releasebupropionindepression: resultsof threeclinical trials.Clin Ther21(3):454–463,1999.

190. Weihs KL, Settle EC Jr, Batey SR, etal. Bupropion sustainedreleaseversusparoxetineforthetreatmentofdepressionintheelderly.J Clin Psychiatry61(3):196–202,2000.

191. WeihsKL,HouserTL,BateySR,etal.Continuationphasetreat-mentwithbupropionSReffectivelydecreasestheriskforrelapseofdepression.Biol Psychiatry51(9):753–761,2002.

192. DunnerDL,ZisookS,BillowAA,etal.Aprospectivesafetysur-veillancestudyforbupropionsustained-releaseinthetreatmentofdepression.J Clin Psychiatry59(7):366–373,1998.

193. PapakostasGI,FavaM.Ameta-analysisofclinicaltrialscompar-ing the serotonin (5HT)-2 receptor antagonists trazodoneandnefazodonewithaselectiveserotoninreuptakeinhibitorforthetreatmentofmajordepressivedisorder.Eur Psychiatry22(7):444–447,2007.

194. Nierenberg AA, Adler LA, Peselow E, etal. Trazodone forantidepressant-associatedinsomnia.Am J Psychiatry151(7):1069–1072,1994.

195. NierenbergAA,Cole JO,GlassL.Possible trazodonepotentia-tion of fluoxetine: a case series. J Clin Psychiatry 53(3):83–85,1992.

196. ThompsonJWJr,WareMR,BlashfieldRK.Psychotropicmedica-tion and priapism: a comprehensive review. J Clin Psychiatry51(10):430–433,1990.

197. BardinED,Krieger JN.Pharmacologicalpriapism: comparisonoftrazodone-andpapaverine-associatedcases.Int Urol Nephrol22(2):147–152,2002.

198. SaenzdeTejadaI,WareJC,BlancoR,etal.Pathophysiologyofprolongedpenileerectionassociatedwithtrazodoneuse.J Urol145(1):60–64,1991.

199. FernandesNF,MartinRR,SchenkerS.Trazodone-inducedhepa-totoxicity:acasereportwithcommentsondrug-inducedhepa-totoxicity.Am J Gastroenterol95(2):532–535,2000.

200. deMeesterA,CarbuttiG,GabrielL, etal. Fataloverdosewithtrazodone: case report and literature review. Acta Clin Belg56(4):258–261,2001.

201. Pisani F, Spina E, Oteri G. Antidepressant drugs and seizuresusceptibility: from in vitro data to clinical practice. Epilepsia40(Suppl.10):S48–S56,1999.

202. CyrM,BrownCS.Nefazodone:itsplaceamongantidepressants.Ann Pharmacother30(9):1006–1012,1996.

203. Sargent PA, Sharpley AL, Williams C, etal. 5-HT2C receptoractivationdecreasesappetiteandbodyweightinobesesubjects.Psychopharmacology (Berl)133(3):309–312,1997.

204. Ferguson JM, Shrivastava RK, Stahl SM, etal. Reemergence ofsexual dysfunction in patients with major depressive disorder:double-blind comparison of nefazodone and sertraline. J Clin Psychiatry62(1):24–29,2001.

205. ToofannyN,MaddensME.Reversiblepenilepriapismassociatedwithnefazodone.J Am Geriatr Soc50(9):1610–1611,2002.

206. Brodie-MeijerCC,DiemontWL,BuijsPJ.Nefazodone-inducedclitoralpriapism.Int Clin Psychopharmacol14(4):257–258,1999.

207. CarvajalGP,GarciaD,SanchezSA,etal.Hepatotoxicityassoci-atedwiththenewantidepressants.J Clin Psychiatry63(2):135–137,2002.

208. Stewart DE. Hepatic adverse reactions associated with nefazo-done.Can J Psychiatry47(4):375–377,2002.

209. Ehrentraut S, Rothenhausler HB, Gerbes AL, etal. Acute liverfailure in nefazodone therapy? A case report. Nervenarzt73(7):686–689,2002.

210. KhanA,SambunarisA,EdwardsJ,etal.Vilazodoneinthetreat-mentofmajordepressivedisorder:efficacyacrosssymptomsandseverity of depression. Int Clin Psychopharmacol 29(2):86–92,2013.

211. ClaytonAH,KennedySH,Edwards JB,etal.Theeffectofvila-zodone on sexual function during the treatment of majordepressivedisorder.J Sex Med10(10):2465–2476,2013.

212. CitromeL.Vilazodoneformajordepressivedisorder:asystem-atic review of the efficacy and safety profile for this newlyapprovedantidepressant—whatis thenumberneededtotreat,numberneededtoharmandlikelihoodtobehelpedorharmed?Int J Clin Pract66(4):356–368,2012.

213. MahableshwarkarAR,JacobsenPL,ChenY,etal.Arandomised,double-blind, placebo-controlled, duloxetine-referenced studyoftheefficacyandtolerabilityofvortioxetineintheacutetreat-mentofadultswithgeneralisedanxietydisorder.Int J Clin Pract68(1):49–59,2014.

214. Alam MY, Jacobsen PL, Chen Y, etal. Safety, tolerability, andefficacyofvortioxetine(LuAA21004)inmajordepressivedisor-der: results of an open-label, flexible-dose, 52-week extensionstudy.Int Clin Psychopharmacol29(1):36–44,2014.

215. BersaniG,PozziF,MariniS,etal.5-HT2receptorantagonismindysthymicdisorder:adouble-blindplacebo-controlledstudywithritanserin.Acta Psychiatr Scand83(4):244–248,1991.

216. NappiG,SandriniG,GranellaF,etal.Anew5-HT2antagonist(ritanserin) in the treatmentofchronicheadachewithdepres-sion.Adouble-blindstudyvsamitriptyline.Headache30(7):439–444,1990.

217. LooH,HaleA,D’haenenH.Determinationofthedoseofago-melatine, a melatoninergic agonist and selective 5-HT(2C)antagonist, in the treatment of major depressive disorder: aplacebo-controlled dose range study. Int Clin Psychopharmacol17(5):239–247,2002.

218. KennedySH,EmsleyR.Placebo-controlledtrialofagomelatineinthetreatmentofmajordepressivedisorder.Eur Neuropsychop-harmacol16(2):93–100,2006.

219. MontgomerySA,OlieJP,AhokasA,etal.Antidepressant efficacy of agomelatine in MDD: a meta-analysis of three pivotal trials.Pre-sentedattheAnnualMeetingoftheEuropeanCollegeofNeu-ropsychopharmacology,2006.

220. RickelsK,AmsterdamJ,ClaryC,etal.Buspirone indepressedoutpatients:acontrolledstudy.Psychopharmacol Bull26(2):163–167,1990.

221. Rickels K, Amsterdam JD, Clary C, etal. Buspirone in majordepression: a controlled study. J Clin Psychiatry 52(1):34–38,1991.

222. RobinsonDS,RickelsK,FeighnerJ,etal.Clinicaleffectsofthe5-HT1Apartialagonists indepression:acompositeanalysisofbuspironeinthetreatmentofdepression.J Clin Psychopharmacol10(3Suppl.):67S–76S,1990.

223. FabreLF.Buspironeinthemanagementofmajordepression:aplacebo-controlledcomparison.J Clin Psychiatry51(Suppl.):55–61,1990.

224. Jenkins SW, Robinson DS, Fabre LF Jr, etal. Gepirone in thetreatment of major depression. J Clin Psychopharmacol 10(3Suppl.):77S–85S,1990.

225. McGrathPJ,StewartJW,QuitkinFM,etal.Gepironetreatmentof atypical depression: preliminary evidence of serotonergicinvolvement.J Clin Psychopharmacol14(5):347–352,1994.



226. WilcoxCS,FergusonJM,Dale JL,etal.Adouble-blindtrialoflow- and high-dose ranges of gepirone-ER compared withplacebo in the treatment of depressed outpatients. Psychophar-macol Bull32(3):335–342,1996.

227. Feiger AD. A double-blind comparison of gepirone extendedrelease,imipramine,andplacebointhetreatmentofoutpatientmajordepression.Psychopharmacol Bull32(4):659–665,1996.

228. FeigerAD,Heiser JF,ShrivastavaRK,etal.Gepironeextended-release: new evidence for efficacy in the treatment of majordepressivedisorder.J Clin Psychiatry64(3):243–249,2003.

229. Newton RE, Marunycz JD, Alderdice MT, etal. Review of theside-effectprofileofbuspirone.Am J Med80(3B):17–21,1986.

230. PapakostasGI,HombergerCH,FavaM.Ameta-analysisofclini-cal trials comparing mirtazapine with a selective serotoninreuptakeinhibitorforthetreatmentofmajordepressivedisor-der.J Psychopharmacol22(8):843–848,2008.

231. BenkertO,SzegediA,PhilippM,etal.Mirtazapineorallydisin-tegrating tabletsversusvenlafaxineextendedrelease:adouble-blind, randomized multicenter trial comparing the onset ofantidepressantresponseinpatientswithmajordepressivedisor-der.J Clin Psychopharmacol26(1):75–78,2006.

232. Guelfi JD, Ansseau M, Timmerman L, etal. Mirtazapine-VenlafaxineStudyGroup:mirtazapineversusvenlafaxineinhos-pitalizedseverelydepressedpatientswithmelancholicfeatures.J Clin Psychopharmacol21(4):425–431,2001.

233. HongCJ,HuWH,ChenCC,etal.Adouble-blind,randomized,group-comparative study of the tolerability and efficacy of 6weeks’ treatment with mirtazapine or fluoxetine in depressedChinesepatients.J Clin Psychiatry64(8):921–926,2003.

234. LeinonenE,SkarsteinJ,BehnkeK,etal.Efficacyandtolerabilityofmirtazapineversus citalopram:adouble-blind, randomizedstudyinpatientswithmajordepressivedisorder.NordicAntide-pressantStudyGroup.Int Clin Psychopharmacol14(6):329–337,1999.

235. Benkert O, Szegedi A, Kohnen R. Mirtazapine compared withparoxetineinmajordepression.J Clin Psychiatry61(9):656–663,2000.

236. WheatleyDP,vanMoffaertM,TimmermanL,etal.Mirtazapine:efficacy and tolerability in comparison with fluoxetine inpatients with moderate to severe major depressive disorder.Mirtazapine-FluoxetineStudyGroup.J Clin Psychiatry59(6):306–312,1998.

237. Schatzberg AF, Kremer C, Rodrigues HE, etal. Mirtazapine vs.Paroxetine Study Group: Double-blind, randomized compari-sonofmirtazapineandparoxetineinelderlydepressedpatients.Am J Geriatr Psychiatry10(5):541–550,2002.

238. WadeA,CrawfordGM,AngusM,etal.Arandomized,double-blind,24-weekstudycomparingtheefficacyandtolerabilityofmirtazapine and paroxetine in depressed patients in primarycare.Int Clin Psychopharmacol18(3):133–141,2003.

239. BehnkeK,SogaardJ,MartinS,etal.Mirtazapineorallydisinte-grating tablet versus sertraline: a prospective onset of actionstudy.J Clin Psychopharmacol23(4):358–364,2003.

240. GelenbergAJ,McGahueyC,LaukesC,etal.Mirtazapinesubsti-tution in SSRI-induced sexual dysfunction. J Clin Psychiatry61(5):356–360,2000.

241. MollerHJ,RiehlT,DietzfelbingerT,etal.Acontrolledstudyoftheefficacyandsafetyofmianserinandmaprotiline inoutpa-tientswithmajordepression.Int Clin Psychopharmacol6(3):179–192,1991.

242. MollerHJ,KasperS,MullerH,etal.Acontrolledstudyof theefficacyandsafetyofmianserinandamitriptylineindepressiveinpatients.Pharmacopsychiatry28(6):249–252,1995.

243. Wilcox CS, Cohn JB, Katz BB, etal. A double-blind, placebo-controlled study comparing mianserin and amitriptyline inmoderately depressed outpatients. Int Clin Psychopharmacol9(4):271–279,1994.

244. LichtRW,QvitzauS.Treatmentstrategiesinpatientswithmajordepression not responding to first-line sertraline treatment. Arandomised study of extended duration of treatment, doseincrease or mianserin augmentation. Psychopharmacology (Berl)161(2):143–151,2002.

245. AndersonIM.Selectiveserotoninreuptakeinhibitorsversustri-cyclicantidepressants:ameta-analysisofefficacyandtolerabil-ity.J Affect Disord58(1):19–36,2000.

246. PancrazioJJ,KamatchiGL,RoscoeAK,etal.Inhibitionofneu-ronalNa+channelsbyantidepressantdrugs.J Pharmacol Exp Ther284(1):208–214,1998.

247. Harrigan RA, Brady WJ. ECG abnormalities in tricyclic antide-pressantingestion.Am J Emerg Med17(4):387–393,1999.

248. WedinGP,OderdaGM,Klein-SchwartzW,etal.Relativetoxicityofcyclicantidepressants.Ann Emerg Med15(7):797–804,1986.

249. Danish University Antidepressant Group. Citalopram: clinicaleffect profile in comparison with clomipramine. A controlledmulticenter study. Psychopharmacology (Berl) 90(1):131–138,1986.

250. DanishUniversityAntidepressantGroup.Paroxetine:aselectiveserotonin reuptake inhibitor showing better tolerance, butweakerantidepressanteffectthanclomipramineinacontrolledmulticenterstudy.J Affect Disord18(4):289–299,1990.

251. RooseSP,GlassmanAH,AttiaE,etal.Comparativeefficacyofselective serotonin reuptake inhibitors and tricyclics in thetreatmentofmelancholia.Am J Psychiatry151(12):1735–1739,1994.

252. RobinsonRG,SchultzSK,CastilloC,etal.Nortriptylineversusfluoxetine in the treatment of depression and in short-termrecoveryafterstroke:aplacebo-controlled,double-blindstudy.Am J Psychiatry157(3):351–359,2000.

253. NavarroV,GastoC,TorresX,etal.Citalopramversusnortriptyl-ine in late-lifedepression: a12-week randomized single-blindstudy.Acta Psychiatr Scand103(6):435–440,2001.

254. SindrupSH, JensenTS.Efficacyofpharmacological treatmentsofneuropathicpain:anupdateandeffectrelatedtomechanismofdrugaction.Pain83(3):389–400,1999.

255. O’MalleyPG,JacksonJL,SantoroJ,etal.Antidepressanttherapyforunexplainedsymptomsandsymptomsyndromes.J Fam Pract48(12):980–990,1999.

256. Anderson IM, Tomenson BM. Treatment discontinuation withselective serotonin reuptake inhibitors comparedwith tricyclicantidepressants: a meta-analysis. BMJ 310(6992):1433–1438,1995.

257. HuangCC.Persistenttardivedyskinesiaassociatedwithamoxa-pinetherapy.Am J Psychiatry143(8):1069–1070,1986.

258. HayashiY,OhyagiY,InoueI,etal.Acaseofamoxapine-inducedtardive dystonia successfully treated with a low dose anti-cholinergicagent.Rinsho Shinkeigaku40(4):367–371,2000.

259. Okun MS, Watts RL. Depression associated with Parkinson’sdisease: clinical features and treatment. Neurology 58(4 Suppl.1):S63–S70,2002.

260. Fava M. Weight gain and antidepressants. J Clin Psychiatry61(Suppl.11):37–41,2000.

261. GoodnickPJ.Useofantidepressantsintreatmentofcomorbiddiabetesmellitusanddepressionaswellasindiabeticneuropa-thy.Ann Clin Psychiatry13(1):31–41,2001.

262. PollockBG,Perel JM,ParadisCF, etal.Metabolic andphysio-logicconsequencesofnortriptylinetreatmentintheelderly.Psy-chopharmacol Bull30(2):145–150,1994.

263. PeetersFP,deVriesMW,VissinkA.Risksfororalhealthwiththeuse of antidepressants. Gen Hosp Psychiatry 20(3):150–154,1998.

264. RooseSP,GlassmanAH,GiardinaEG,etal.Tricyclicantidepres-santsindepressedpatientswithcardiacconductiondisease.Arch Gen Psychiatry44(3):273–275,1987.

265. Thayssen P, Bjerre M, Kragh-Sorensen P, etal. Cardiovasculareffectof imipramineandnortriptyline in elderlypatients.Psy-chopharmacology (Berl)74(4):360–364,1981.

266. RobertsRL,JoycePR,MulderRT,etal.AcommonP-glycoproteinpolymorphismisassociatedwithnortriptyline-inducedposturalhypotension inpatients treated formajordepression.Pharma-cogenomics J2(3):191–196,2002.

267. RayWA,GriffinMR,MalcolmE.Cyclicantidepressantsandtheriskofhipfracture.Arch Intern Med151(4):754–756,1991.

268. RamaekersJG.Antidepressantsanddriverimpairment:empiricalevidence from a standard on-the-road test. J Clin Psychiatry64(1):20–29,2003.

269. Nelson JC, Kennedy JS, Pollock BG, etal. Treatment of majordepression with nortriptyline and paroxetine in patients withischemicheartdisease.Am J Psychiatry156(7):1024–1028,1999.

270. PisaniF,OteriG,CostaC,etal.Effectsofpsychotropicdrugsonseizurethreshold.Drug Saf25(2):91–110,2002.



43271. HenryJA,AlexanderCA,SenerEK.Relativemortalityfromover-

doseofantidepressants.BMJ310(6974):221–224,1995.272. PerryPJ,ZeilmannC,ArndtS.Tricyclicantidepressantconcen-

trationsinplasma:anestimateoftheirsensitivityandspecificityasapredictorofresponse.J Clin Psychopharmacol14(4):230–240,1994.

273. FlintAJ,RifatSL.Theeffectof sequentialantidepressant treat-ment on geriatric depression. J Affect Disord 36(3–4):95–105,1996.

274. McGrathPJ,StewartJW,NunesEV,etal.Adouble-blindcross-over trial of imipramine and phenelzine for outpatients withtreatment-refractorydepression.Am J Psychiatry150(1):118–123,1993.

275. NolenWA,HaffmansPM,BouvyPF,etal.Monoamineoxidaseinhibitors in resistant major depression. A double-blind com-parisonofbrofaromineandtranylcypromineinpatientsresist-ant to tricyclic antidepressants. J Affect Disord 28(3):189–197,1993.

276. ThaseME,FrankE,MallingerAG,etal.Treatmentofimipramine-resistant recurrent depression, III. Efficacy of monoamineoxidaseinhibitors.J Clin Psychiatry53(1):5–11,1992.

277. Nolen WA. Tranylcypromine in depression resistant to cyclicantidepressions.Prog Neuropsychopharmacol Biol Psychiatry13(1–2):155–158,1989.

278. NolenWA,vandePutteJJ,DijkenWA,etal.Treatmentstrategyindepression.II.MAOinhibitorsindepressionresistanttocyclicantidepressants:twocontrolledcrossoverstudieswithtranylcy-promine versus L-5-hydroxytryptophan and nomifensine. Acta Psychiatr Scand78(6):676–683,1988.

279. McGrathPJ,StewartJW,HarrisonW,etal.Treatmentoftricyclicrefractorydepressionwithamonoamineoxidaseinhibitoranti-depressant.Psychopharmacol Bull23(1):169–172,1987.

280. StablM,KasasA,BlajevB,etal.Adouble-blindcomparisonofmoclobemide and thioridazine versus moclobemide andplacebointhetreatmentofrefractory,severedepression.J Clin Psychopharmacol15(4Suppl.2):41S–45S,1995.

281. Hoencamp E, Haffmans PM, Dijken WA, etal. Brofaromineversuslithiumadditiontomaprotiline.Adouble-blindstudyinmaprotiline refractory depressed outpatients. J Affect Disord30(3):219–227,1994.

282. SunderlandT,CohenRM,MolchanS,etal.High-doseselegilineintreatment-resistantolderdepressivepatients.Arch Gen Psychia-try51(8):607–615,1994.

283. Volz HP, Faltus F, Magyar I, etal. Brofaromine in treatment-resistantdepressedpatients—acomparativetrialversustranylcy-promine.J Affect Disord30(3):209–217,1994.

284. GeorgotasA,FriedmanE,McCarthyM,etal.Resistantgeriatricdepressions and therapeutic response to monoamine oxidaseinhibitors.Biol Psychiatry18(2):195–205,1983.

285. AmsterdamJD,BerwishNJ.Highdosetranylcyprominetherapyforrefractorydepression.Pharmacopsychiatry22(1):21–25,1989.

286. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporarytreatment of depression. Neuropsychopharmacology 12(3):185–219,1995.

287. WhitePD,ClearyKJ.Anopenstudyoftheefficacyandadverseeffectsofmoclobemideinpatientswiththechronicfatiguesyn-drome.Int Clin Psychopharmacol12(1):47–52,1997.

288. NatelsonBH,CheuJ,ParejaJ,etal.Randomized,doubleblind,controlledplacebo-phaseintrialoflowdosephenelzineinthechronicfatiguesyndrome.Psychopharmacology (Berl)124(3):226–230,1996.

289. Hickie IB,WilsonAJ,Wright JM,etal.A randomized,double-blindplacebo-controlledtrialofmoclobemideinpatientswithchronic fatigue syndrome. J Clin Psychiatry 61(9):643–648,2000.

290. HannonenP,MalminiemiK,Yli-KerttulaU,etal.Arandomized,double-blind, placebo-controlled study of moclobemide andamitriptylineinthetreatmentoffibromyalgiainfemaleswithoutpsychiatricdisorder.Br J Rheumatol37:1279–1286,1998.

291. NatelsonBH,CheuJ,HillN,etal.Single-blind,placebophase-intrialoftwoescalatingdosesofselegilineinthechronicfatiguesyndrome.Neuropsychobiology37(3):150–154,1998.

292. Goldenberg D, Mayskiy M, Mossey C, etal. A randomized,double-blind,crossover trialoffluoxetineandamitriptyline inthe treatment of fibromyalgia. Arthitis Rheum 39:1852–1859,1996.

293. WolfeF,CatheyMA,HawleyDJ.Adouble-blindplacebocontrol-ledtrialoffluoxetineinfibromyalgia.Scand J Rheumatol23:255–259,1994.

294. CantiniF,BellandiF,NiccoliL,etal.Fluoxetineassociatedwithcyclobenzaprine in the treatment of primary fibromyalgia.Minerva Med85:97–100,1994.

295. Norregaard J, Volkmann H, Danneskiold-Samsoe B. A ran-domizedcontrolledtrialofcitalopraminthetreatmentoffibro-myalgia.Pain61:445–449,1995.

296. Vercoulen JH, Swanink CM, Zitman FG, etal. Randomizeddouble-blindplacebo-controlledstudyoffluoxetineinchronicfatiguesyndrome.Lancet347(9005):858–861,1996.

297. Bodkin JA, Amsterdam JD. Transdermal selegiline in majordepression: a double-blind, placebo-controlled, parallel-groupstudyinoutpatients.Am J Psychiatry159(11):1869–1875,2002.

298. AmsterdamJD.Adouble-blind,placebo-controlledtrialof thesafety and efficacy of selegiline transdermal system withoutdietary restrictions in patients with major depressive disorder.J Clin Psychiatry64(2):208–214,2003.

299. RichardIH,KurlanR,TannerC,etal.SerotoninsyndromeandthecombineduseofdeprenylandanantidepressantinParkin-son’s disease. Parkinson Study Group. Neurology 48(4):1070–1077,1997.

300. PhilippM,TillerJW,BaierD,etal.Comparisonofmoclobemidewith selective serotonin reuptake inhibitors (SSRIs) on sexualfunctionindepressedadults.TheAustralianandGermanStudyGroups.Eur Neuropsychopharmacol10(5):305–314,2000.

301. Harrison W, Stewart J, Lovelace R, etal. Case report of carpaltunnelsyndromeassociatedwithtranylcypromine.Am J Psychia-try140(9):1229–1230,1983.



MULTIPLE CHOICE QUESTIONS

Select the appropriate answer.Q1 Whichofthefollowingagentswasnotedinthe1950s

topossessantidepressantefficacyinpatientssufferingfromtuberculosis?

○ Chlorpromazine

○ Diphenhydramine

○ Iproniazid

○ Nortriptyline

○ Phenelzine

Q2 Whichofthefollowingsyndromesischaracterizedbyalterationsincognition(e.g.,disorientationandconfusion),behavior(e.g.,agitationandrestlessness),autonomicnervoussystemfunction(e.g.,fever,shivering,diaphoresis,anddiarrhea),andneuromuscularactivity(e.g.,ataxia,hyperreflexia,andmyoclonus)?

○ Catatonia

○ Delirium

○ Neurolepticmalignantsyndrome

○ Serotoninsyndrome

○ Wernicke’sencephalopathy

Q3 Whichofthefollowingisthetimethatmostexpertsfavorforacontinuationofantidepressanttherapyfollowingtheachievementofremissionafteranepisodeofmajordepression?

○ 2weeks

○ 4weeks

○ 8weeks

○ 16weeks

○ 26weeks

Q4 WhichofthefollowingSSRIsisnotFDA-approvedforthetreatmentofdepression?

○ Citalopram

○ Fluvoxamine

○ Fluoxetine

○ Paroxetine

○ Sertraline

Q5 WhichofthefollowingdrugsisBESTclassifiedasanorepinephrinedopaminereuptakeinhibitor?

○ Atomoxetine

○ Bupropion

○ Duloxetine

○ Trazodone

○ Venlafaxine

Q6 Whichofthefollowingisclassifiedasasecondaryaminetricyclicantidepressant?

○ Amitriptyline

○ Clomipramine

○ Desipramine

○ Doxepin

○ Imipramine

Q7 WhichofthefollowingagentsisLEASTlikelytocauseanticholinergicsymptoms?

○ Amitriptyline

○ Doxepin

○ Paroxetine

○ Phenelzine

○ Thioridazine

MULTIPLE CHOICE ANSWERSQ1 The answer is: Iproniazid.

Theprecursorsoftwoofthemajorcontemporaryantidepres-santfamilies,themonoamineoxidaseinhibitors(MAOIs)andthetricyclicantidepressants(TCAs),werediscoveredbyseren-dipityinthe1950s.

Specifically,theadministrationofiproniazid,anantimycobac-terialagent,wasfirstnotedtopossessantidepressanteffectsindepressedpatientssufferingfromtuberculosis.Shortlythere-after,iproniazidwasfoundtoinhibitMAO,andwasinvolvedinthecatabolismofserotonin,norepinephrine,anddopamine.

Inparallel,imipraminewasinitiallydevelopedasanantihis-tamine,butKuhnandcolleagues in1958discoveredthatofsome500imipramine-treatedpatientswithvariouspsychiat-ric disorders, only those with endogenous depression withmentalandmotorretardationshowedaremarkableimprove-mentduring1 to6weeksofdaily imipramine therapy.Thesame compound was also found to inhibit the reuptake ofserotoninandnorepinephrine.Thus, itwas thediscoveryoftheantidepressanteffectsof iproniazidandimipraminethatledtothedevelopmentoftheMAOIsandTCAs,butalsosuchdiscoverywasinstrumentalintheformulationofthemonoam-ine theoryofdepression. In turn,guidedby this theory, thesubsequent development of compounds selective for thereuptake of either serotonin or norepinephrine or both wasdesigned,ratherthanaccidental.Asaresult,overthelastfewdecades, chemical alterations of these first antidepressantshaveresultedinthecreationofawidevarietyofmonoamine-basedantidepressantswithavarietyofmechanismsofaction.

Q2 The answer is: Serotonin syndrome.

Monoamine oxidase inhibitors (MAOIs) act by inhibitingMAO,anenzymefoundontheoutermembraneofmitochon-dria,whereitcatabolizesanumberofmonoaminesincludingdopamine, norepinephrine, and serotonin. After reuptake,norepinephrine,serotonin,anddopamineareeitherreloadedinto vesicles for subsequent release or broken down by theenzymeMAO.

MAO is present in two forms (MAOA and MAOB), whichdiffer in their substrate preferences, inhibitor specificities,tissue expression, and cell distribution. MAOA preferentiallyoxidizesserotoninandisirreversiblyinactivatedbylowcon-centrationsoftheacetylenicinhibitorclorgyline.MAOBpref-erentiallyoxidizesphenylethylamine(PEA)andbenzylamineand is irreversibly inactivated by low concentrations of par-gyline and deprenyl. Dopamine, tyramine, and tryptaminearesubstratesforbothformsofMAO.Inthegastrointestinal(GI)tractandtheliver,MAOcatabolizesanumberofdietarypressoramines(suchasdopamine,tyramine,tryptamine,andphenylethylamine).



43For this reason, consumption of certain foods (that containhighlevelsofdietaryamines)whileonanMAOImayprecipi-tateahypertensivecrisis,characterizedbyhypertension,hyper-pyrexia,tachycardia,tremulousness,andcardiacarrhythmias.Thesamereactionmayalsooccurduringco-administrationofdopaminergicagentsandMAOIs,whiletheco-administrationofMAOIswithotherantidepressantsthatpotentiateserotonincouldresultinserotoninsyndromeduetotoxicCNSserotoninlevels.Theserotoninsyndromeischaracterizedbyalterationsin cognition (e.g., disorientation and confusion), behavior(e.g., agitation and restlessness), autonomic nervous systemfunction(e.g.,fever,shivering,diaphoresis,anddiarrhea),andneuromuscular activity (e.g., ataxia, hyperreflexia, and myo-clonus).SinceMAOenzymaticactivityrequiresapproximately14days tobe restored, such foodormedications shouldbeavoidedfor2weeksafterthediscontinuationofanirreversibleMAOI(“MAOIwashoutperiod”).Serotonergicanddopamin-ergicantidepressantsaretypicallydiscontinued2weeksbeforethe initiationof anMAOI,with the exceptionoffluoxetine,whichneedstobediscontinued5weeksinadvanceduetoitsrelativelylongerhalf-life.

Q3 The answer is: 26 weeks.

Originally, based on studies with tricyclic antidepressants(TCAs), patients with unipolar depressive disorders wereobserved to be at high risk for relapse when treatment wasdiscontinuedwithinthefirst16weeksof therapy.Therefore,intreatment-responders,mostexpertsfavoracontinuationofantidepressanttherapyforaminimumof6monthsfollowingthe achievement of remission. The value of continuationtherapyforseveralmonthstopreventrelapseintotheoriginalepisodehasalsobeenestablishedforvirtuallyalloftheneweragents.

Riskofrecurrenceafterthis6-to8-monthcontinuationperiod(thatis,thedevelopmentofanewepisodeafterrecoveryfromthe indexepisode) isparticularlyelevated inpatientswithachroniccoursebeforerecovery,residualsymptoms,andmul-tiplepriorepisodes(threeormore).Fortheseindividuals,theoptimaldurationofmaintenancetreatment isunknownbutitismeasuredinyears.Basedonresearchtodate,prophylacticefficacyofanantidepressanthasbeenobservedforaslongas5yearswithclearbenefit.

Incontrasttotheinitialexpectationthatmaintenancetherapywould be effective at dosages lower than that required foracutetreatment,thecurrentconsensusisthatfull-dosetherapyis required for effective prophylaxis. About 20% to 30% ofpatientswhoaretreatedwitheachoftheclassesofantidepres-santswillexperienceareturnofdepressivesymptomsdespitecontinuedtreatment.Insuchpatients,adoseincreaseoftheantidepressantistypicallythefirst-lineapproach.

Q4 The answer is: Fluvoxamine.

TheoverallefficacyoftheSSRIsinthetreatmentofdepressionisequivalenttotheotherantidepressants,whileallsixoftheSSRIsappeartobeequallyeffectiveinthetreatmentofdepres-sion.Due to their favorable side-effectprofile, theSSRIs areusedasfirst-line treatment in theoverwhelmingmajorityofcases,withmorethan90%ofcliniciansindicatingthatSSRIsweretheirfirstlineoftreatment.Despitethetolerabilityandthe widespread efficacy of the SSRIs, there is mounting evi-dencetosuggest thatdepressedpatientswithcertaincharac-teristics(includingco-morbidanxietydisordersandagreaternumberofsomaticsymptoms[suchaspain,headaches,andfatigue])respondlesswell toSSRIs thanthosewithoutsuchcharacteristics.

Onlyoneof theSSRIs,fluvoxamine, isnotapprovedfor thetreatmentofdepressionintheUnitedStates,asitisapproved

only for the treatment of obsessive-compulsive disorder(OCD).

Duetotheirrelativelylowside-effectburden,thestartingdoseofSSRIsisoftentheminimallyeffectivedailydose:10mgforescitalopram(Lexapro);20mgforfluoxetine(Prozac),parox-etine (Paxil), and citalopram (Celexa); 50mg for sertraline(Zoloft); and 100mg for fluvoxamine (Luvox). Starting atlower doses, and increasing the dose shortly thereafter (i.e.,after1to2weeks)mayfurtherimprovetolerability.MaximumtherapeuticdosesforSSRIsaretypicallyone-foldtotwo-foldgreaterthanthestartingdose.

Q5 The answer is: Bupropion.

The norepinephrine dopamine reuptake inhibitor (NDRI)bupropionappearstobeaseffectiveastheSSRIsinthetreat-mentofdepressiveaswellasanxietysymptomsindepression.Bupropionisaphenethylaminecompoundthatiseffectiveforthe treatment of major depressive disorder (MDD). Bupro-pion is structurally related to amphetamine and the sym-pathomimetic diethylpropion and it primarily blocks thereuptakeofdopamineandnorepinephrineandhasminimalor no affinity for postsynaptic receptors. Although someresearchershavearguedthattheNDRIbupropion’seffectonnorepinephrineisprimarilythroughanincreaseinpresynap-tic release, there is still convincing evidence for binding ofbothnorepinephrineanddopaminetransporters.

Venlafaxine, duloxetine, and milnacipran share the propertyofbeingrelativelypotentreuptakeinhibitorsofserotoninandnorepinephrine and are therefore considered selective nore-pinephrinereuptakeinhibitors(SNRIs).Ofthese,onlyvenla-faxine and duloxetine are approved for the treatment ofdepressionintheUnitedStates.

Reboxetine acts by selectively inhibiting the norepinephrinetransporter,therebyincreasingsynapticnorepinephrinelevels.Atomoxetine also selectively inhibits the reuptake of nore-pinephrine.Theseagentsarecallednorepinephrinereuptakeinhibitors(NRIs).

Trazodoneandnefazodoneareclassifiedasserotoninreceptorantagonists/agonists, while mirtazapine and mianserin arealpha2-adrenergicreceptorantagonists.

Q6 The answer is: Desipramine.

TheTCAsmaybesubdividedintotertiaryaminesandsecond-aryamines(theirdemethylatedsecondaryaminederivatives).Inaddition,maprotiline(Ludiomil),which is classifiedasatetracyclic antidepressant, is commonly grouped with theTCAs,duetosimilaritiesindosing,mechanismofaction,andsideeffects.

Tertiary amine TCAs include amitriptyline (Elavil, Adepril),imipramine (Tofranil, Antidepril), trimipramine (Surmontil,Herphonal),clomipramine(Anafranil,Clopress),anddoxepin(Sinequan,Deptran).

Secondary amine TCAs are nortriptyline (Pamelor, Aventyl),desipramine (Norpramin, Metylyl), protriptyline (Vivactil,Concordin),andamoxapine(Ascendin,Defanyl).

Q7 The answer is: Phenelzine

Anticholinergic-like side effects occur in MAOI-treatedpatients,althoughtheyarenotduetomuscarinicantagonism.These sideeffectsare less severe than those seenwithTCAs,althoughpatientsonphenelzinemayexperiencedrymouth.Elderly patients may develop constipation or urinary reten-tion.Alternatively,nauseaanddiarrheahavebeenreportedbysome patients. Sweating, flushing, or chills also may occurwiththeiruse.


43 - Antidepressants

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