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sigma-aldrich.com/cellsignaling disease. second leadingcauseofdisability, surpassedonlybyheart mood-elevating effect inpatientsreceiving thedrug. that iproniazid, adrugusedtotreat tuberculosis, induceda hypothesis ofschizophrenia. Ithadbeennotedinthe1950s serendipitous observationsthatleadtothedopamine “monoamine theoryofdepression” parallelhistoricallythe serotonin, incriticalbrainareas. Theoriginsofthis monoamine neurotransmitters, mainlynorepinephrine and order stemsfrom decreases insynapticconcentrationsof conclusively identified,itisgenerallybelievedthatthedis- Although theunderlyingcausesofdepression havenotbeen experiential andenvironmental factors. predisposing geneswithvariablecontributionsfrom prior phrenia, susceptibilityisprobably determinedbymultiple Major Depression indisputable antidepressant efficacy. ensuing decades.Drugsfrom bothclasseshaveshown synthesized andevaluatedasantidepressants overthe tional MAOinhibitorsandtricyclic antidepressants were brain synapsesmightrelieve depression. Anumber ofaddi- and thatdrugswhichcouldrestore theirlevelsatcritical epinephrine and/orserotonin wasresponsible fordepression, to theproposal inthemid-1960sthat adeficiencyofnor- trations. Knowledgeofthesebiochemicalactionswascritical these monoaminesthereby increasing theirsynapticconcen- depressant, wasshowntoinhibitthe neuronal reuptake of terminals. Incontrast,imipramine,thefirsttricyclicanti- mitters andsubsequentlygreater levels ofrelease from nerve This causesincreases inintraneuronal stores ofthesetrans- oxidatively deaminatesbothnorepinephrine andserotonin. to inhibitmonoamineoxidase(MAO),theenzymethat transmitters atcentralsynapses.Thus,iproniazid wasfound have actionsthatresult inanelevationofmonoamineneuro- effect indepressed patients.Bothdrugswere laterfoundto phenothiazines, wasobservedtoexertanantidepressant Similarly, imipramine,adibenzapinestructurallysimilartothe ed onanannualbasis. approximately 18millionadultsintheUSpopulationafflict- cold” ofmentalillness.Itisaprevalent disorder with Major depression hasbeenreferred toasthe“common to lifecrises. from bereavement, substanceabuseornormal responses fest. Thesefeelingsare persistentandcanbedistinguished agitation. Recurrent thoughtsofdeathmayalsobemani- mild tosevere, andare oftenassociatedwithanxietyand decisions orconcentrate.Thesymptomscanrangefrom mental slowing,alossofenergyandaninabilitytomake Most individualssuffering from depression alsoexperience worthlessness, despairandlossofinterest inallpleasures. mood. Symptomsincludefeelingsofprofound sadness, Major depression isanaffective disorder, ordisorder of suggesting ageneticpredisposition. common infirst-degree relatives ofdepressed persons, 13% inmen.Itsoccurrence istwoto three timesmore 41 Worldwide, itsprevalence is21%inwomenand 5 40 It hasbeenestimatedtobethe 42 As withschizo- 25 to thedelayedonsetofantidepressant drugaction. over thesametimecourseandmayinsomewaycontribute β further elevationofsynaptictransmitterlevels.Postsynaptic may permitincreases inrelease from theseterminals,causing onset ofantidepressant activity. Autoreceptor subsensitivity nerve terminalsisknowntooccurwithadelaysimilarthe regulating autoreceptors onnorepinephrine andserotonin changes remains speculative,butsubsensitivityofrelease- the increases inneurotransmitter levels.Thenature ofthese suggests theinvolvementofadaptivechangessecondaryto occur almostimmediately. Thisdelayedonsetofaction are apparent, despitethefactthattheirbiochemicalactions several weeksofadministrationbefore theirclinicaleffects antidepressant drugaction.Allantidepressants require ephrine orserotonin mayconstituteonlyaninitialstepin effects revealed thatelevatingsynapticlevelsofnorepin- Intensive studyoftheiracuteandchronic neurochemical they are used,dietaryrestrictions mustbefollowed. unresponsive tootherclassesofantidepressants, andwhen and tranylcypromine are nowusedonlyinpatients of thisinteraction,termedthe“cheeseeffect”, phenelzine ensuing hypertensivecrisiscanbelife-threatening. Because due toblockadeofitsintraneuronal metabolism.The which ispresent inelevatedquantitiesnerveterminals gic neurons andevokesmassiverelease ofnorepinephrine, such cases,tyramineenterscentralandperipheraladrener- ing tyramine(suchasagedcheeses,wine,beer, etc).In taking MAOinhibitorsingestfoodsorbeveragescontain- omimetic amine.Seriousside-effects canoccurifpatients lism oftyramine,afood-derived,indirectly-acting sympath- as wellbrain,itsinactivationinterferes withthemetabo- MAO isanimportantamine-oxidizingenzymeintheliver, irreversibly andtherefore permanentlyinactivateit.Since second drawbackwastheirabilitytobindtheenzyme hydrazine derivativesthatare nownolongeravailable.A problem washepatotoxicityassociatedwithsomeofthe cypromine remain availableintheUnitedStates.One secondary status,andtoday, onlyphenelzineandtranyl- drawbacks havenowrelegated theolderMAOinhibitorsto Despite theirefficacy asantidepressants, severalserious dietary restrictions. likely tointeractwithtyramine and thusdonotrequire large intraneuronal stores ofnorepinephrine, sothey are less apparently donotresult ininactivationofliver metabolismor depressants. Theirreversibility andshortduration ofaction have generatedsomeresurgence ofinterest asanti- Agents thatcanselectivelyandreversibly inhibitMAO-A while MAO-Bhasspecificityfordopamine. has substratespecificityfornorepinephrine andserotonin, (e.g. iproniazid, nialamide,phenelzine). TheMAO-Atype to irreversibly inhibitboththeAandBisoformsofMAO cally, anumberremain usefulresearch toolsfortheirability Although theseolderMAOinhibitorsare rarely usedclini- brofaramine, moclobemide, toloxatone,andbefloxatone), are underevaluationor inuseasantidepressants (e.g., -adrenoceptors and5-HT 43 Several short-actingMAO-Ainhibitors 2A receptors alsodown-regulate 27 25 Major Depression levels increase inthesynapticcleftthereby enhancingneurotransmission. When amonoaminergicreuptake inhibitorispresent (B),itbindstothemonoaminetransporterandblocksreuptake ofthene via theirreuptake intothepre-synaptic viaspecifictransporterproteins followingwhichtheneurotransmitter istakenupint ters thenbindtotheirrespective receptors onthepost-synapticneuron, thereby transferringthe signal.Theactionsofthen serotonin, dopamineornorepinephrine, are released intothesynapticcleftfrom storagevesiclespresent inthepre-synaptic n ReuptakeInhibitors. SelectiveMonoaminergic Figure 2.MechanismofAction Vesicles Vesicles A B Pre-synaptic Neuron Pre-synaptic Neuron Transporter Transporter Transporter Transporter Reuptake Inhibitor Monoaminergic During neurotransmission, monoamineneurotransmitters suchas Post-synaptic Neuron Post-synaptic Neuron Receptors Receptors o thevesiclesforre-release. eurotransmitters are terminated euron (A).Theneurotransmit- Signal Signal Signal Signal urotransmitter, whose

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sigma-aldrich.com/cellsignaling a numberoftroublesome side-effects. Peripheral cholinergic receptors, andtheseactionsare responsible for disorders. effective inobsessive-compulsive,anxietyandpanic The atypicalantidepressants havealsobeenshowntobe antimuscarinic, hypotensiveandcardiac stimulatingeffects. over theearliertricyclicsinsofarastheylackprominent older antidepressants, buttheyrepresent animprovement These agentsare notnecessarilymore effective thanthe nefazadone andtrazadoneare members ofthisgroup. blocking theirreuptake. Bupropion, mianserin,mirtazapine, ability toelevatesynapticmonoamines,inmostcasesby tional tricyclicringstructure, butdogenerallyshare an The “atypical”antidepressants donot possessthetradi- serotonin reuptake inhibitors. antidepressants, aswellthedevelopmentofselective duction ofagroup of“secondgeneration”or“atypical” tolerated antidepressants, andeventuallyleadtotheintro- effects prompted asearch forsafer, faster-acting and better dry mouth,urinaryretention andconstipation.Theseside- antimuscarinic side-effects are alsoprominent, including to treat andpotentiallylife-threatening. Otherperipheral Cardiac arrhythmiasthatoccuruponover-dose are difficult reuptake contributetocardiac stimulationandtachycardia. muscarinic blockadeandinhibitionofnorepinephrine ceptor blockadecausesposturalhypotension,whereas Major Depression 1960 to1990. became themostwidelyusedantidepressant drugsfrom non-selective MAOinhibitors,thetricyclicantidepressants Because oftheproblems associatedwiththeuseof and Ro16-6491. research tools,includingpargyline,clorgyline,Ro41-1049 activity. OtherselectiveMAO-Binhibitorsare usefulas investigated asananitdepressant, althoughitmayexertsuch dopamine metabolism.Deprenyl hasnotbeenthoroughly the treatment ofParkinson’s diseaseduetoitsprevention of is availableintheUnitedStates,butusedexclusivelyfor selective MAO-Binhibitor, deprenyl (alsoknownasselegiline) but noneare availableclinicallyintheUnitedStates.One moderate affinity for take. Inaddition,thetricyclicantidepressants alsopossessa and clomipraminepredominantly inhibitserotonin reup- whereas imipramine,amitriptyline,doxepin,trimipramine all relatively selectivenorepinephreine reuptake inhibitors, nortriptyline, protriptyline, amoxapineandmaprotiline are these transporters antidepressants basedontheirrelative abilitiestoinhibit Important differences existbetweenthevarioustricyclic located onpre-synaptic nerveterminals(seeFigure 2). released aminesbytheirrespective membranetransporters and/or serotonin, butdosobyblockingreuptake ofthe increase insynapticconcentrationsofnorepinephrine 44 As withthetricyclicantidepressants andMAO 25 25 Like theMAOinhibitors,theycausean 25 (see Table 2).Thus,desipramine, α 1 -adrenoceptors andmuscarinic α 1 -adreno- sexual side-effects. agitation andrestlessness, alongwithgastrointestinal and tion of5-HT levels atcentralandperipheralsynapsesleadstostimula- tachyarrhythmias. However, theelevationofserotonin and free ofserioustoxicity. Theylackappreciable muscarinic antidepressant drugsofchoicelargelybecausetheyare increased transmitterrelease. TheSSRIshavebecomethe down-regulation ofrelease-regulating autoreceptors and longed administrationoftricyclicantidepressants, i.e. similar tothoseoccurringatadrenergic synapsesafterpro- ary adaptivechangesmustoccuratserotonergic synapses, blockade ofserotonin reuptake. Itispresumed thatsecond- onset ofthemood-elevatingeffect, despitetherapid antidepressants, there isalagofseveralweeksbefore agents acttorelieve depression. Aswithotherclassesof gy ofdepression. However, itisnotclearexactly howthese deficiency isacommonneurochemical basisfortheetiolo- pressants, strongly supportthehypothesisthataserotonin uptake bythesedrugs,andtheirclinicalefficacy asantide- tiomer, escitalopram.Theselectiveinhibitionofserotonin tine, sertraline,fluvoxamine,citalopram,anditsS-enan- prototype ofthisgroup. Othermembersincludeparoxe- decades. Fluoxetine,thefirstSSRItobeintroduced, isthe dominate thetreatment ofdepression overthelasttwo tive serotonin reuptake inhibitors(SSRIs)havecometo Even more sothantheatypicalantidepressants, theselec- depressant effect, orside-effects, isunclear. although thecontributionoftheseactionstotheiranti- transporter. cyclic antidepressant withselectivity for thenorepinephrine but otherwisedisplaysactionssimilartodesipramine,atri- sants andthesexualdysfunctionassociatedwithSSRIs, It lacksthecardiotoxicity oftheolder tricyclicantidepres- and hasbeenshowntobeeffective in severe depression. tomoxetine andreboxetine. Reboxetine isavailableclinically have beensynthesized,includingnisoxetine,maprotiline, as potentialantidepressants. Anumber ofsuchcompounds ment ofselectivenorepinephrine reuptake inhibitors(SNRIs) The successoftheSSRIsrekindled interest inthedevelop- tonin receptors, i.e.5-HT Mirtazepine andmianserinalsoblockpostsynapticsero- terminals thereby increasing norepinephrine release. appears toblock serotonin transporter. Mirtazapineisuniqueinthatit nefazadone andtrazadonedisplayrelative selectivityforthe some extent,norepinephrine transporters.Incontrast, diverse profiles. Bupropion inhibitsthedopamine and,to effects becomeapparent. Mechanistically, thesedrugshave inhibitors, ittakesseveralweeksbefore theirantidepressant α -adrenoceptor blockingproperties, anddonotcause 2C and 5-HT α 25 2 -adrenergic autoreceptors onnerve 3 2A receptors, whichcontributesto , 5-HT 2C and 5-HT 3 receptors, 25,45 25