SelectiveSerotoninReuptakeInhibitors: HowLongIsLongEnough?
Selectiveserotoninreuptakeinhibitors(SSRIs) areamongthemostcommonlyprescribed medications.Theyareamongthe first-linemedicationsforseveralchronicorrelapsingremittingpsychiatricconditions,including majordepressivedisorderandanxietydisorders.TheadvantagesofSSRIuseincludeease oftitrationandtheirtolerabilityandsafetyprofile.Guidelinesfortheshort-termuseofSSRIs arewidelyavailable,butthereisnowell-organizedguidanceonhowandwhethertomaintaina patientonSSRIsforthelong-term.Inthisarticle, wediscussthebenefitsandpossibleadverseconsequencesoflong-termSSRIuse,aswellasclinicalpracticeconsiderationswhenusingSSRIs chronically.Themajorbenefitoflong-termSSRI useisrelapseprevention.Thecurrentliterature suggeststhatthegeneralhealthrisksoflongtermSSRIusearelow;however,furtherresearch,particularlyinspecialpopulationsincluding youthandtheelderly,isneeded.Long-termSSRI useincreasestheriskoftachyphylaxisanddiscontinuationsyndrome.Recognizingthatmany patientsmayremainonSSRIsformanyyears, thereareseveralfactorsthatprescribersshould consideriftheychoosetouseanSSRIwheninitiatingtreatmentandduringlong-termmonitoring.Thedecisiontocontinueortodiscontinuean SSRIshouldbeanactiveone,involvingboththe patientandprescriber,andshouldberevisited periodically.PatientswhoremainonSSRIsfor thelong-termshouldalsohaveperiodicmonitoringtoreassesstherisk-benefitratioof remainingontheSSRI,aswellastoassessthe safety,tolerability,andefficacyofthemedication. (JournalofPsychiatricPractice2021;27;361–371)
KEYWORDS:antidepressant,selectiveserotonin reuptakeinhibitor(SSRI),psychopharmacology,depression,anxiety,discontinuationsyndrome,tachyphylaxis
Selectiveserotoninreuptakeinhibitors(SSRIs)are indicatedforthetreatmentofsomeofthemostdebilitatingandchronicpsychiatricdisorders.Although
ROBYNP.THOM,MD JEANNEL.ALEXANDER,MD DAVIDBARON,MSEd,DO
AMIRGARAKANI,MD LAWRENCEGROSS,MD JANETH.PINE,MD RAJIVRADHAKRISHNAN,MD ANDREWSLABY,MD✠ CALVINR.SUMNER,MD
SSRIsareintheclassofantidepressants,almostas manySSRIprescriptionsarewrittenforconditions otherthandepression.Manypatientswithchronic recurrentmoodoranxietydisordersmaybeonanSSRI foralifetime,althoughitshouldbenotedthat,in studiesofSSRIs,follow-upofparticipantsrarely extendsbeyond2to3years.Arecentnationalsurvey foundthatoveronefourthoftheindividualstakingan antidepressanthadbeenonthemedicationforlonger than10years.1 Whileguidelinesforthemanagement ofshort-termSSRIusearewidelyavailable,thereisno well-organizedguidanceforcliniciansonhowand whethertomaintainapatientonSSRIsforthelongterm.Thisarticleoffersaconsolidationofcurrent knowledgeaboutthelong-termuseofSSRIsandprovidesclinicianswithaframeworkforeffectivelymanagingextendedtreatmentwiththesemedications.The articlewilldiscussSSRIsprimarilyandmayusethe term “antidepressant” interchangeablywithSSRI, unlessreferringtoanotherclassofantidepressants.
THOM:MassachusettsGeneralHospital,LurieCenterfor Autism;DepartmentofPsychiatry,HarvardMedicalSchool, Lexington,MA;ALEXANDER:Privatepractice,Berkeley, CA;BARON:WesternUniversityofHealthSciences, Pomona,CA,andDepartmentofPsychiatry,KeckSchoolof MedicineofUniversityofSouthernCalifornia,LosAngeles, CA;GARAKANI:DepartmentofPsychiatryandBehavioral Health,GreenwichHospital,Greenwich,CT,andDepartment ofPsychiatry,YaleUniversitySchoolofMedicine,New Haven,CT;GROSSandPINE:DepartmentofPsychiatry, KeckSchoolofMedicineofUniversityofSouthernCalifornia, LosAngeles,CA;RADHAKRISHNAN:DepartmentofPsychiatry,YaleSchoolofMedicine,NewHaven,CT;SLABY: DepartmentofPsychiatry,YaleSchoolofMedicine,New Haven,CT,andPrivatepractice,NewYork,NY;SUMNER: DepartmentofPsychiatry,CharlesE.SchmidtCollegeof MedicineofFloridaAtlanticUniversity,BocaRaton,FL
Copyright©2021WoltersKluwerHealth,Inc.Allrights reserved. ✠Deceased. Theauthorsdeclarenoconflictsofinterest.
Pleasesendcorrespondenceto:DavidBaron,MSEd,DO, WesternUniversityofHealthSciences,OfficeoftheProvost, 309E.2ndStreet,Pomona,CA91766(e-mail:dbaron@westernu.edu).
DOI:10.1097/PRA.0000000000000578 JournalofPsychiatricPracticeVol.27,No.5September2021361
Copyright©2021WoltersKluwerHealth,Inc.Allrightsreserved.
SSRIsareaclassofmedicationsthatinclude fluoxetine,paroxetine,sertraline, fluvoxamine,citalopram,andescitalopram.Theyselectivelyblock thereuptakeofserotonin(5-HT)throughinhibition ofthesodium/potassiumadenosinetriphosphatasedependentserotonintransporterinpresynaptic neurons.SSRIshaveabroadspectrumofactivityin anumberofpsychiatricdisordersincludingmajor depressivedisorder(MDD),generalizedanxiety disorder,posttraumaticstressdisorder(PTSD), obsessive-compulsivedisorder(OCD),andthelongtermtreatmentofpremenstrualdysphoricdisorder (PMDD).2 Table1liststheSSRImedicationsand theirindications,pertheFoodandDrugAdministration(FDA),alongwithcommonstartingand therapeuticdoses.
ThedisordersforwhichSSRIsareusedhavehigh ratesofmorbidityandmortality.Depressionisthe leadingcauseofdisabilityworldwideandposesahigh riskfordeath,includingbysuicide,whichisthesecond leadingcauseofdeathgloballyinthose15to29years ofage.3 IndividualswithOCDmayalsobeatriskfor earlierdeathduetounnaturalcausessuchassuicide oraccidents,4 andthosewithPTSDhavegreaterlevels ofdisabilityandmayalsobeatriskforearlydeath.5 GiventhatindividualswithMDD,OCD,andPTSD oftenhaveachronic,relapsing-remittingdisease course,theirlong-termtreatmentwithSSRImedicationsisacommonclinicalpractice.Evenamong treatmentguidelines,however,thereisnoconsensus onhowlongtotreatpatientswithSSRImedications.
BENEFITSOFLONG-TERMSSRIUSE
RelapsePrevention
Themostcommonindicationsforinitiatingtreatment withanSSRIaremoodandanxietydisorders,6,7 which aretypicallychronic,relapsingandremittingconditions.Anepidemiologicalstudyfoundthat50%of adultswithMDDreportedthattheirdepressiveepisodesbeganinchildhood,and30%to70%ofyouth whoexperienceamajordepressiveepisodehavebeen reportedtolaterexperiencearelapse.8,9 Ina15-year observationalstudyof380adultswhorecoveredfroma majordepressiveepisode,Muelleretal10 founda cumulativerecurrencerateof85%.Thisstudyalso foundthat58%ofthosewhohadremainedwellforat least5yearsstillexperiencedarecurrenceinsubsequentyears.Factorsthatpredictedarecurrence
includedfemalesex,alongerdepressiveepisodebefore theintakeappointment,andmorepreviousepisodesof depression.Thepresenceofresidualdepressive symptomsisanotherimportantriskfactorfordepressiverecurrences.11 Longitudinalstudiesofthesymptomcourseofanxietydisorders,includingpanic disorder,socialphobia,andgeneralizedanxietydisorder,havesimilarlyreportedthatsymptomsareoften chronic.12,13
Duetothechronicnatureofmoodandanxiety disorders,multiplepractice guidelinescurrentlyrecommendlong-termSSRIusebeyondtheinitial remissionoftargetsymptomstopreventrelapse.The CanadianNetworkforMoodandAnxietyTreatments (CANMAT)2016clinicalguidelinesrecommendthat patientsmaintaintreatmentwithanantidepressant for6to9monthsafterachievingsymptomatic remissionandthatthosewithriskfactorsforrecurrencecontinuetreatmentforatleast2years.14 The AmericanPsychiatricAssociation(APA)Practice GuidelinefortheTreatmentofaMajorDepressive Disorderoutlines3phasesoftreatment:acute (achievingremissionofthedepressiveepisode,6to 12mo),continuation(preventingre-emergenceof symptoms,12to24mo),andmaintenance(preventingoccurrenceofanotherdepressiveepisode, > 24mo).15 Duringthecontinuationphase,theAPA PracticeGuidelinerecommendsthatantidepressants becontinuedfor4to9monthsafterremissionatthe dosethatestablishedremissionintheacutephase.15 Forpatientswhohaveexperienced3ormoreprior depressiveepisodes,theAPAPracticeGuidelinerecommendsmaintenanceantidepressanttherapy beyondthecontinuationphaseatthefulltherapeutic dose.Maintenancetherapyshouldalsobeconsidered forpatientswhohavemajorriskfactorsforrecurrence,includingresidualdepressivesymptoms,psychosocialstressors,earlyageofonsetofdepression, andafamilyhistoryofdepressivedisorders.15 Similarly,theAPAPracticeGuidelineforpanicdisorder recommendsthatpharmacotherapybecontinuedfor aminimumof1yearafteracuteresponseisachieved todecreasetheriskofrecurrence.16 Itisnotablethat these2APAPracticeGuidelinesdonotspecifythe durationofmaintenancepharmacotherapy.The TexasConsensusConferencePanelonMedication TreatmentofChildhoodMajorDepressiveDisorder, whichalsorecommendsmaintenanceSSRItherapy forallpatientsexperiencingtheirthirddepressive episodeandforpatientsexperiencingtheirsecond
TABLE1.SelectiveSerotoninReuptakeInhibitors(SSRIs):DosesandIndications
Medication Name(Brand)
FDA IndicatedUses Usual StartingDose TherapeuticDose Range(Adults)
Fluoxetine(Prozac)MDD20mg20-80mg OCD20mg20-80mg BN20mg20-60mg PD20mg20-60mg
Fluoxetine(Prozacweekly)MDD20mg/d90mg/wk
Fluoxetine(Sarafem)PMDD20mg20mg Olanzapine/fluoxetine(Symbyax)MDD,treatment-resistant6mg/25mgqpm*6mg/25-12mg/50mgqpm* BD,acutedepressive6mg/25mgqpm*6mg/25-12mg/50mgqpm*
Sertraline(Zoloft)MDD50mg50-200mg OCD50mg50-200mg PD50mg50-200mg PMDD50mg50-150mg PTSD25mg50-200mg SAD25mg50-200mg
Paroxetine(Paxil)MDD20mg20-50mg OCD20mg20-60mg PD10mg20-60mg SAD20mg20-60mg GAD20mg20-50mg PTSD20mg20-50mg
Paroxetine(Pexeva)MDD20mg20-50mg OCD20mg20-60mg PD10mg20-60mg GAD20mg20-50mg
ParoxetineCR(PaxilCR)MDD25mg25-62.5mg PD12.5mg25-75mg PMDD12.5mg12.5-25mg SAD12.5mg25-37.5mg
Citalopram(Celexa)MDD10-20mg20-40mg Escitalopram(Lexapro)MDD5-10mg10-40mg GAD5mg10-40mg
episodewithriskfactorsforrecurrence,notesthat whiletheoptimaldurationofSSRImaintenancehas notbeenestablished,itshouldrangefrom3yearsto lifetimemaintenance.17
Severaldouble-blind,placebo-controlledstudies haveassessedtheefficacyofSSRImaintenance treatmentforthepreventionofrecurrenceofdepression.Inthesecontrolledstudies,thedurationof
Fluvoxamine(Luvox)OCD100mg(split 50mgtwicedaily) 150-300mg FluvoxamineCR(LuvoxCR)OCD100mg150-300mg Vilazodone(Viibryd)† MDD10mg20-40mg *qpm = everyevening. †Medicationisbothaselectiveserotoninreuptakeinhibitoranda5-HT1A receptorpartialagonist. BDindicatesbipolarIdisorder;BN,bulimianervosa;GAD,generalizedanxietydisorder;MDD,major depressivedisorder;OCD,obsessive-compulsivedisorder;PD,panicdisorder;PMDD,premenstrualdysphoric disorder;PTSD,posttraumaticstressdisorder;SAD,socialanxietydisorder. JournalofPsychiatricPracticeVol.27,No.5September2021363
Copyright©2021WoltersKluwerHealth,Inc.Allrightsreserved.
maintenancetherapyhasrangedfrom4monthsto 2years.Inadouble-blind,placebo-controlledstudyof fluoxetinemaintenancetherapyforthepreventionof depressiverecurrences,patientswithrecurrentMDD whohadrespondedto32weeksofopen-label fluoxetinewererandomizedto fluoxetine20mgdaily (n = 70)orplacebo(n = 70)for48weeksofdoubleblindmaintenancetreatment.18 Twentypercentof thesubjectsinthe fluoxetinegroupexperienceda relapse,comparedwith40%intheplacebogroup (P = 0.01).Thesymptom-freeperiodwasalsolonger inthe fluoxetinegroup(295vs.192d, P = 0.002). Similarresultshavebeenreportedinotherrandomizedcontrolledtrialsthathaveassessedtheefficacyof maintenancetreatmentwithescitalopram, fluvoxamine,sertraline,citalopram,andparoxetinefor depressionrecurrence.19 23 Furthermore,arandomized,double-blindstudyassessingthedose-response efficacyofparoxetinefordepressionmaintenance therapyfoundthatmaintainingthefullacutedoseof paroxetinewasassociatedwithadecreasedriskfor recurrencecomparedwithdecreasingthedose.19
Datafromanaturalisticstudyoflong-termSSRI monotherapysuggestsbenefitfromlong-termSSRI maintenancebeyond5yearsafterremission.Ina sampleof87adultpatientswithMDDwhohad beenclinicallystablefor5years,60patientswho electedtocontinueSSRImonotherapywerecomparedwith27patientswhoelectedtodiscontinue SSRItreatment.24 ForpatientswhoelectedtodiscontinueSSRItreatment,themedicationwas graduallytaperedover2to5months.Thepatients whoremainedonanSSRIweretwiceaslikelyto remaininremission,withahazardratio(HR)of4.9 (P < 0.001).The1-yearrelapserateswere62%and 26%,respectively,amongthepatientswhodiscontinuedandthosewhocontinuedSSRItreatment.Furthermore,timetorelapsewasmorethan 3timeslonger(38vs.10mo)amongthepatients whocontinuedSSRImaintenancetreatment.
menstrualcycle.InpatientswithPMDDbutno comorbiddepressionoranxietydisorder,itispossible totaketheSSRIonlywhensymptomatic,duringthe latelutealphaseofthemenstrualcycle.29,30 However, patientswithalesswell-definedpatternofPMDDora comorbidmajordepressiveoranxietydisordermay choosetotaketheSSRIcontinuously.31 Patientswith depression,anxiety,orPMDDareadvisedtocontinue theirantidepressantduring perimenopause,sinceperimenopauseleadstounpredictablemenstrualcycles.32 Skippedcycles,particularlyanovulatorycycles,will resultinalowerfrequencyofPMDDduringthe perimenopause.33 Inaddition,aperimenopausal womanwhowasonpartial-monthSSRItreatmentmay opttostayontheSSRIfortheentiremonthsinceshe willnotbeabletopredictwhenherlutealphasewill occur.IntermsofdiscontinuingSSRIs,perimenopause isatimeofincreasedsusceptibilitytostress34,35 and depression.36,37 Therefore,perimenopauseisnotan advisabletimetodiscontinueanSSRI,33 particularlyin apatientwithcomorbidPMDD.38,39
ADVERSECONSEQUENCESOFLONG-TERM SSRIUSE
GeneralHealthRisks
MaintenancetreatmentwithSSRIs(treatmentlonger than24mo)issupportedbymedicalguidelines insituationsinvolvingmoreseveredisordersand/or comorbidityasdescribedabove.Factorssupporting thelong-termuseofSSRIsincludeahighriskof relapseifthemedicationisdiscontinued,achronicor persistentdisorderwithasignificanthistoryof recurrence,failuretorespondtononpharmacologic interventions,andrecurrenceofsignificantsymptoms whenapatientstopstakingSSRIs.WhenSSRI treatmentoccursforanextendedduration(> 24mo), theprescribingclinicianshouldconsiderseveral potentialadverseconsequencesanddiscussthemas appropriatewiththepatient.
Long-termSSRIsAreBeneficialinPMDD
Long-termSSRIuseisrecommendedforthetreatment ofPMDD25,26 andremainsthetreatmentwiththe strongestevidence-base.27 EvidencesuggeststhatpremenopausalwomenwithPMDDrequirelong-term SSRImaintenancetherapyuntiltheyhavecompleted menopause,28 definedas12consecutivemonthsofno
Therearesubtledifferencesinsideeffectsamong theSSRIsbutmostofthesesideeffectshavenot beenshowntoworsenwithdurationoftreatment. AlloftheSSRIsmaycausesideeffectsthatinclude headaches,gastrointestinaldisturbance,insomnia, sexualeffects,fatigue,andinitialanxiety,andallof theSSRIshavesomepotentialforadverseinteractionswithothermedicationsduetocompetitive metabolism.Paroxetinehasbeenreportedto
possiblybeassociatedwithmoreweightgainwith prolongedusage.DiscontinuationofanySSRIcan potentiallyresultinadiscontinuationsyndrome, whichismorecommonwithSSRIsthathaveashort half-lifesuchasparoxetine.40
Onthebasisofasystematicumbrellareviewof publishedmeta-analysesconcerningadversehealth outcomesdirectlyrelatedtothelong-termuseof antidepressantmedications,Dragiotietal41 concludedthat,ingeneral,highqualitystudieshave demonstratedfewadversehealthoutcomesdirectly associatedwithlong-termtreatmentwithantidepressantmedication.Furthermore,thestrength ofthoseassociationswasweakwhentheresults wereadjustedforconfoundingfactors.41 Individual studiesincludedinthesemeta-analysessuggested putativeassociationsbetweenlong-termSSRIuse andseveraladverseevents,includingincreasedrisk ofsuicidality;hip/osteoporoticfracturesinolder adults;autismspectrumdisorderintheoffspringof motherstakingSSRIs;andperinatalcomplications includingpre-termbirth,lowAPGARscores,and postpartumhemorrhage.However,aftercompleting theirumbrellareviewofmeta-analyses,theauthors concludedthatnoneoftheseassociationsremained supportedbyconvincingevidenceaftersensitivity analysisthatadjustedforconfounders.41 Nevertheless,onecannotconcludethatSSRIsarewithout riskinlong-termusejustbecauseanycausalrelationshipwithadversehealthoutcomesremainsto beproven.
Asurveyof180individualswhohadbeentaking antidepressantsfor3to15yearsfoundthatantidepressant-relatedsideeffectspersistedwithlongtermuse.42 Inadditiontotheexpectedsideeffectsof themedication,adverseeffectsmostdirectlyattributabletolong-termusewerewithdrawalsymptoms whentryingtostopthemedication(73.5%),concerns aboutbeing “addicted” tothemedication(43%),sexualproblems(71.8%),andweightgain(65.3%).42 Somerespondentsexpressedaneedformoreinformationaboutlong-termrisksandincreasedinformationandsupporttodiscontinue.42
Reportsofweightgainasanadversehealthoutcome withlong-termSSRIusecoincideswithrecentinterest inpotentialmetabolicchangesrelatedtolong-term SSRIuse.Inalargecohortofyouthsinsuredby Medicaid(119,608youths5to20yofage),theuseof SSRIsorserotonin-norepinephrinereuptakeinhibitors themostcommonlyusedantidepressantsubclasses
wereassociatedwithanincreasedriskoftype2 diabetesthatintensifiedwithincreasingdurationof use,cumulativedose,andaveragedailydose.43 ResearchhasshownthatuseofatleastsomeSSRIsis associatedwithclinicalandbiochemicalelementsof themetabolicsyndrome.44 Currentresearchsuggests thatpatientstakingSSRIsshouldbecarefullymonitoredforobesityanddyslipidemia.Thestudyoutcomes raisetheneedforfurtherinvestigationsintothepossibleadversemetaboliceffectsoflong-termSSRI medicationinyouthandothersusceptibleindividuals.
AlthoughtherelativesafetyofSSRIsinthegeneral populationhasbeendemonstratedrepeatedly,data onthesafetyofSSRIsinspecificpopulationssuchas youth,pregnantwomen,andtheelderlyarejust emerging.Olderadults(65yofageandolder)may presentadifferentriskprofilethanthegeneralpopulation.Aretrospectivecohortstudyof60,746 patients65yearsofageandoverwhowereprescribed anantidepressantfordepressionfoundthatSSRIs wereassociatedwithfeweradverseoutcomesthan otherclassesofantidepressants.45 However,SSRIs hadthehighestadjustedHRsforfalls(1.66,95% confidenceinterval:1.58-1.73)andhyponatremia (1.52,95%confidenceinterval:1.33-1.75).Differences inthecharacteristicsofthepatientsprescribeddifferentantidepressantmedicationsmayaccountfor someofthedifferencesinassociationsbetweenthe classesofantidepressantmedicationandadverse outcomes,althoughtheanalysesattemptedtoadjust formanypotentialconfoundingvariables.Several studieshavesuggestedthatolderadultstaking antidepressantmedicationsareatagreaterriskfor fallsandfracturesthanindividualsofsimilaragewho donottakeantidepressants.46 SSRIshavenotbeen showntobesignificantlydifferentthanotherantidepressantsintheirassociationwithriskforfallsand fractures.Itisevidentthatolderpatientsareat greaterriskforadverseeventsthanyoungerpatients, buttheevidenceremainstobedevelopedforacausal relationshipbetweenSSRIuseandfallsand fractures.47 Overall,whiletheriskofadverseeffects ofSSRIsinolderpatientsisundeniablygreaterthan inyoungerpatients,therisksoffailingtotreatarefar greater.48
Wangetal49 conductedaretrospectivecohort studyinvolving3688patients60yearsofageor olderwithoutdementiawhowereenrolledina depressionscreeningstudyinprimarycareclinics andwhowerefollowedoverthecourseof5years.
TheindividualswhowereprescribedSSRIshada significantlyhigherincidentriskofdementiathan similarindividualswithseveredepressionwhodid nottakeSSRIs(HR = 2.26, P = 0.0005).Although this findinghasmanypotentialconfoundsand artifacts,itraisesthequestionofwhetherSSRIs arecausallyimplicatedincognitivedecline.
Althoughcurrentresearchcontinuestosupportthe relativesafetyofSSRImedications,cliniciansmust considerthepotentialthattheremaybeadverseconsequencesoflong-termuse.Regardlessofthemagnitudeofanyriskthatcanbedefinitivelyattributedto themedication,thegoalwouldnotbetoexclude patientsfromlong-termtreatmentwithSSRIs,butto consciouslymanagethepotentialforadversehealth outcomes.Continuedmaintenancetreatmentwith SSRIsshouldbeforaclearindication,withconcurrent managementofcomorbidconditions,prescribedonly afterafullconsiderationofpotentialrisksandbenefits, appropriatelymonitored,anddiscontinuedwhenthere isnolongeranindicationorwhenanyemergentriskto thepatientexceedsthepotentialbenefit.
ofpriorantidepressantuse,ashortertimebetween previousrecurrences,andincompleteremissionof symptoms.53 Theseclinical findingsseemtobeconsistentwiththe findingintheSTAR*Dtrialthatonly 19%ofpatientswhohadnotrespondedtothe first2 antidepressanttrialsrespondedtosubsequentmedicationtrials,andthatalmosthalfofthosewhodid respondhadarelapsewithin1year.54 Patients withmoreseveredepression,especiallymelancholic depression,maybeathigherriskoftachyphylaxis; however,itisnotclearthatpatientswhohaverecoveredfromapsychoticdepressiveepisodehaveahigher riskofrecurrenceofdepressionwhiletakingmedicationsthanpatientswhohadamajordepressive episodewithoutpsychoticfeatures.55
DiscontinuationSyndrome
Tachyphylaxis
Antidepressanttachyphylaxis,colloquiallyreferredto as “Prozacpoop-out,” isfrequentlyencounteredduring clinicalpractice.Tachyphylaxisoccurswhenapatient’s depressionhasinitiallyremittedorsubstantially respondedwithantidepressanttreatment,butrecurs whilethepatientremainsonantidepressantmedications.Psychiatristsstudyinglossofefficacyofcontinuedantidepressanttreatmenthavestipulatedthat thepatientcontinuethedosetheyweretakingat remissionoratleastadosewellwithinthetherapeutic rangeinordertodefinearecurrenceastachyphylaxis. Thisphenomenonisnotsoevidentindrugtrials, whichareroutinelyquiteshort,rarelylastinglonger than1year.50 anditoftenconfoundscliniciansbecause patientswithtachyphylaxismayhaveasymptom profilethatdiffersfromtheiroriginalpresentation, frequentlywithfewerneurovegetativeandmoremood symptoms.51 Earlytachyphylaxissuggeststhatthe patientmayhavehadaplaceboresponse,ratherthan anactualpharmacologicalresponse.
Thereportedprevalenceofantidepressanttachyphylaxisrangesfrom9%to33%.52 Riskfactorsfor antidepressanttachyphylaxisincludeahighernumber ofpriordepressiveepisodes,amoreextensivehistory
SSRIdiscontinuationsyndrome,definedasthe emergenceofdistressingnew-onsetphysicaland neuropsychiatricsymptomswithindaystoweeks followingSSRIdiscontinuationorsignificantdose reduction,hasbeenextensivelydescribedsince shortlyaftertheintroductionofthisclassofmedications.Numeroussymptomshavebeenreported overtheyears.Berber56 proposedamnemonic “FINISH” tocategorizethesesymptoms: flu-like symptoms,insomnia,nausea,imbalance,sensory disturbances,andhyperarousal.Commonneurologic symptomsincludeparesthesiasandsensationsthat areoftendescribedas “electricshocks”;moodsymptomsmayincludeanxiety,agitation,andhypomania. Inaddition,alargeretrospectivenestedcase-control studyidentifiedasignificantlyincreasedriskforsuicideattemptsinthe first14daysfollowingabrupt antidepressantdiscontinuation.57
Accordingtoarecentreview,symptomstypically start1to10daysafterdiscontinuationoramarked dosereductionandresolvespontaneouslyover2to 3weeks.58 ReintroductionoftheoriginalantidepressantoranotherSSRIresultsinsymptom improvementwithin2to3days.Whilemanycases aremildandself-limited,othersaremoresevere andprotracted.Inasystematicreviewof14studies withvaryingmethodologies,incidenceratesranged from27%to86%,withaweightedaverageof56%;4 largestudiesreportedthatalmost46%ofpatients chosethemostextremelevelofseveritytocharacterizetheirsymptoms.59 Thatsamereviewincluded
10studiesthatexaminedthedurationofwithdrawalreactions,withonelargesurveyreporting that25%ofpatientsexperiencedanxietyformore than12weeksandanotherinternationalsurvey reportingwithdrawalsymptomsinsomepatients lastingformorethan3years.59 Thedelayedonset ofreboundpanicsymptoms,anxiety,andinsomnia hasbeenreportedfollowingabruptdiscontinuation ofparoxetine.60 Itisgenerallyacceptedthatthe SSRImusthavebeentakencontinuouslyforat least4to6weeksforthesyndrometodevelop.The DSM-5criteriaforantidepressantdiscontinuation syndromerequireaminimumof1monthofcontinuoususe.61 Patientstakingparoxetine,theSSRI withtheshortesthalf-life,seemtobeathighest risk,butdiscontinuationsymptomshavealsobeen reportedwithserotonin-norepinephrinereuptake inhibitorsandotherSSRIs,including fluoxetine, whichhasthelongesthalf-lifeoftheSSRIs.Risk factorsassociatedwithdiscontinuationsymptoms includeyoungerageofonsetofdepression,comorbidanxietydisorder,andahistoryofdiscontinuationsymptoms.WhetheradurationofSSRI therapylongerthan4to6weeksandthelengthof medicationtaperpredicttheriskofdeveloping discontinuationsymptomsiscontroversial.42,58
Whilethemechanismunderlyingthewithdrawal syndromehasnotbeenclearlyestablished,itmay berelatedtoarelativedeficiencyofserotonin resultingfromdown-regulationofserotoninreceptorsfollowinginhibitionoftheserotonintransporterbySSRIs.Symptomsmayalsoreflect changesinotherneurotransmittersystemsmodulatedbyserotonin(eg,norepinephrine,dopamine, andgamma-aminobutyricacid),aswellaschanges inneuronaltissueswithserotoninreceptorslocated outsidethebrain,suchasthegut.62
Timeandtimingdistinguishdiscontinuation symptomsfromrelapseorrecurrence.Rapidreturnof depressivesymptomsresemblingreboundmayoccur followingSSRIdiscontinuationandmayimprove rapidlyafterSSRIreintroduction.Persistentpostwithdrawaldisordershavealsobeendescribed,63 whichmaybeamanifestationofpotentialtoxicity associatedwiththesemedications.64 Theemergence ofsymptomsaffectingmultipleorgansystemsshortly afterstoppingSSRIs(discontinuationsyndrome) shouldbedifferentiatedfromtheinsidiousreturnof depressivesymptomsaftersustainedsymptomrelief characteristicofrelapseorrecurrence.58 Historically
theterm “discontinuationsyndrome,” ratherthan “withdrawal,” hasbeenusedtoreducestigmaand differentiateSSRIsfrompsychoactivedrugscausing addictionanddependence.However,theauthorsof2 recentreviews59,65 havesuggestedthatthisterm minimizespotentialSSRI-relatedvulnerabilitiesand shouldbechangedto “withdrawalsyndrome.”
RECOMMENDATIONSFORCLINICAL MANAGEMENT
Depressiveandanxietydisordersarehighlyprevalentworldwideandsignificantlycontributetothe globalburdenofdisease.TheWHOrankeddepressionasthesinglelargestcontributortoglobaldisability,whileanxietydisorderswererankedthesixth largestcontributor.66 Effectiveclinicalmanagement beginswithadiagnosticassessmentandsubsequent biopsychosocialtreatmentplansincludingevidencebasedpharmacologicandnonpharmacologicinterventions.Baseduponthechronicityandhigh morbidityofdepressiveandanxietydisorders,and therelativesafetyoflong-termuseofSSRIs,the benefitsoflong-termSSRIusewilllikelyoutweigh therisksofdiscontinuationformanypatients.Given thelimitednumberofpsychiatrists,primarycare providers,nursepractitioners,physicianassistants, andothernonpsychiatricprescribersofteninitiate SSRIuse.Asaresult,psychiatristsoftenseepatients whoarealreadytakingSSRIs.Theimportanceof effectiveinterprofessionalmentalhealthcarewill continuetogrow.Psychiatristsandothermental healthprovidersneedtolearnhowtoworkcollaborativelyinordertoprovideoptimalcare.Recognizing thatmanypatientsmayremainonSSRIsformany years,thereareseveralfactorsthatprescribers shouldconsideriftheychoosetouseanSSRIwhen initiatingtreatment,duringlong-termmonitoring, andwhenthepatientandprescriberelectatrialof discontinuationofthemedication.Theuseofvalid psychometricassessmenttools,measurement-based careinstruments,67 andstandardizedmonitoringof long-termadverseeffectscanassistprovidersin makingtreatmentdecisionsconcerningSSRIuse.
Inadditiontobecomingablockbustersuccessforthe pharmaceuticalindustry,SSRIshavehadatremendousimpactonthetreatmentofdepression.Although nodatademonstratingclinicalsuperiorityover firstgenerationtricyclicshaveeverbeenreported,the “improved” sideeffectprofileoftheSSRIsandlower
medianlethaldoseresultedinasignificantincreasein SSRIuse,particularlyintheprimarycaresetting.The easeofuse,includingoncedailydosing,alsocontributedtotheircommercialsuccess.
However,initiatingSSRIsstillrequiresathorough initialdiagnosticassessmenttoruleoutmedical mimickers(certaincancersandhematologic,infectious,thyroid,andcardiacdisease),medicationmisuseorsideeffects,concussion,lifestressors,hormonal changes,and/orsubstanceuse/abuse.Theinitial diagnosticassessmentshoulddeterminetheseverity ofthedisorder.Formildtomoderatedisorders,atrial ofpsychotherapyshouldbeconsideredbeforestarting antidepressanttreatment.
Inaddition,discussingpatientexpectationsofa medicationresponseisessential.Manypatientsbelieve thatamedicationwillsolvealltheirlifeproblemsand willbetheonlynecessaryinterventiontorelievethe fullspectrumofdepressivesymptoms.Whilethecore symptomsofadisorder,suchasissuesrelatedtosleep, mood,andenergy,areoftenimprovedbythemedication,itmaybeunrealistictoexpectallareasoflife distresstobeeliminated.Cliniciansareadvisedto discusswithpatientswhoaresufferingfromdepression whattoexpectwheninitiatingpharmacotherapy, emphasizingtheneedfornonpharmacologicinterventions,suchasstressreduction,enjoyableexercise, psychotherapy(eg,cognitivebehavioraltherapy,interpersonaltherapy),andhealthylifestylechoices.68
psychotherapy,stressreduction,andhealthylifestyle choices),andtheneedforongoingmonitoringofthe clinicalresponse.Thepatientshouldalsobeinformed oftheneedtomonitorforsignsofphysicalillness andtokeepthephysicianupdatedontheuseof supplements/othernewmedicationsduetotheriskof drug-druginteractions.Followingabiopsychosocial perspective,theroleofnew,orongoing,psychosocial stressorsondepressionrecoveryshouldbediscussed, emphasizingthecriticalroleofpsychotherapyasan adjuncttopharmacotherapy.Anoverarchinggoalisto havethepatientbeanactive “participant/collaborator” inhisorhercare.Thisapproachwillprovidean opportunityforthepatient tofeelwell-informedandin morecontrolofhisorherlifeandtreatment.Finally, providersshouldbeopenwithpatientsabouthow professionalguidelinesondecidingwhentostopan SSRIarenotwelldevelopedandthatpatientsmay ultimatelytendtowardlong-termcontinuationofa medicationthathasbeenhelpfulduetofearsaboutthe potentialadverseconsequencesofstopping.69
ManagementofTachyphylaxis
Long-termMonitoringofPatientsonSSRIs
Fordepressedoranxiouspatientswhohavehada positivetherapeuticresponsetotreatmentwithan SSRI,asignificantriskfactorforrelapseisdiscontinuingthemedicationtoosoon.Thevexing clinicalconcernis: “Howlongislongenough?” Whendoestherisk-benefitratioleantowarddiscontinuingmaintenancetherapy,avoidingtherisk ofadverseeffectswhilepreventingrelapse?
Morethan3decadesofprescribingSSRIshave helpedshapegoodclinicalpractices.Thistreatment approachbeginswithadiscussionwiththepatient beforethe firstprescriptioniseverwritten.Following establishedinformedconsentprinciples,theclinician shouldeducatethepatientaboutallexpectedtherapeuticeffects(andpotentialsideeffects),lengthof timeforaclinicalresponse(3to5wk),expectedlength oftreatment,theimportanceofothertreatments(eg,
Whatshouldyoudoifyoususpectthatapatient hasSSRI “poop-out”?First,makesurethepatient understandstheinstructionsforthemedication andisadheringtotheregimen.Reviewthepatient’s medicationsandmedicalstatustoruleout pharmacokineticcausesforlossofefficacy.Clearly, psychosocialstressorsubstanceabusecouldtipa previouslystabilizedpersonintodepression.Look criticallyatthepatient’ssymptomsandmental statusandconsiderwhetherinfactthepatientis havingamixedmanicorhypomanicepisode.When thesepossibilitieshavebeenruledout,themain optionsfortreatmentareincreasingtheantidepressantdose,switchingtoadifferentantidepressant,oraddinganotherantidepressantfrom adifferentclass.Therearenocleardataonwhichof theseoptionsismoreeffectiveandthechoicewill needtobeindividualizedtothepatientandhisor herparticularcircumstances.
ConsiderationsforDiscontinuingSSRIs
ThedecisiontodiscontinueSSRItreatmentisone thatneedstobemadebyboththeproviderand patient.Itisnotuncommonforpatientstostop
antidepressantsabruptly,withoutconsultingtheir prescribers,andexperiencediscontinuationsymptoms.Itisoptimalforthepsychiatristtodiscuss discontinuationofanSSRIbeforethemedicationis evenprescribed.Whenthedecisionismade,itis criticalforthepatienttoreceivepsychoeducationon therisksofdiscontinuationandfortheclinicianto monitorthepatientcloselyforothersymptoms includingrecurrenceofdepression,anxiety,andsuicidalthinking.Theuseofobjectivemeasures,suchas theDiscontinuation-EmergentSignsandSymptoms (DESS)Scale,70 canassistincharacterizingand monitoringthewidevarietyofsymptomsandtheir timecourseduringthediscontinuationprocess. ManagementofSSRIdiscontinuationsymptoms shouldbeginwithpatienteducationbeforeinitiationof antidepressanttreatment.Educationshouldaddress thedecisiontotreat,thechoiceofantidepressant,the possibilityandnatureofdiscontinuationsymptoms, theneedforregularmedicationadherence,and avoidanceofabruptdiscontinuationorinadvertently missingdoses.WhendiscontinuingSSRIs,thegeneral consensusisthattaperingisnotnecessaryifthe patienthasbeentakingtheantidepressantfor4weeks orless.Afterlongerperiodsoftreatment,themedicationshouldbetaperedoverweekstomonths. Milddiscontinuationsymptomsmaybemanaged conservatively,butformoreseveresymptoms,the medicationshouldbere-startedandtaperedmore gradually.Switchingtoalongeractingagentsuchas fluoxetinemayreducetheincidenceorseverityof symptoms,andconsiderationmaybegiventoadjunctivecognitivebehavioraltherapytohelpreduce patientdistress.Somecasesofdiscontinuationsyndromemaybesevereandprotracted,creatingthe potentialformisdiagnosisasrelapse.71 Education, reassurance,andshareddecision-makingshouldbe maintainedthroughoutthediscontinuationprocess. DespitethewidespreadclinicaluseofSSRIs,recent commentarieshavenotedthatsystematicresearchis lackingandisneededtofurtherstudythelongitudinal effectsofSSRIsanddiscontinuationstrategies.64,72
Withregardtotaperingguidelines,ageneralrecommendationistotaperoverthecourseof2weeks(for moderatehalf-lifeSSRIssuchasescitalopramor fluvoxamine)oraminimumof4weeks(forshorterhalflifeSSRIsincludingsertraline,paroxetine,andcitalopram),withnotaperbeingneededfor fluoxetine duetoitslongerhalf-life.73 Whilethisrecommendation mayaccountforthepharmacokineticsoftheSSRI,itis
alsoimportanttoconsiderotherclinicalfactorswhen determiningthedurationoftaper.Gradualtapering overlongerperiodsmaybeclinicallyindicatedto monitorforrecurrentsymptoms,butagradualtaper maynotpreventwithdrawalreactions.65
CONCLUSIONS
SSRIsareamongthemost commonclassesofmedicationsusedinpsychiatryandprimarycare.Theyare usedtotreatanumberofpsychiatricdisorders,mostof whicharechronicorrelapsing-remittingconditions. Becauseofthenaturalhistoryofthesedisorders,the strongevidence-baseforcontinuationofSSRIstopreventrecurrenceofsymptoms,andgenerallyfavorable risk-benefitprofile,long-termSSRIuseisacommon andrecommendedpsychiatricpracticeinmanysituations.However,theremaybespecificpopulationsfor whomlong-termuseismorerisky,suchasveryyoung orolderpatientsandpregnantpatients.Thedecisionto continueortodiscontinueaSSRIshouldbeanactive one,involvingboththepatientandprescriber,and shouldberevisitedperiodically.Theextantclinicalliteraturesupportsaninitialtrialof4to6weeksata therapeuticdose.Discontinuationcanbeconsidered, barringadversesideeffects,whenthepatienthasbeen freeofcoresymptomsforatleast3months. Prematurediscontinuationisaknownriskfactorforreemergenceofdepressivesymptoms.Inaddition,subsequentboutsofdepressionrequirelongermedication treatment(inadditiontootherformsoftreatment). Patientswhoremainon SSRIsforthelong-term shouldalsohaveperiodicmonitoringtoreassessthe risk-benefitratioofremainingontheSSRI,aswellas toassessthesafety,tolerability,andefficacyofthe medication.Ifthedecisionismadetodiscontinue treatmentwiththeSSRI,thedecisionshouldbemade collaborativelybetweenpatientandprescriber,with carefulmonitoringfortheemergenceofdiscontinuationsymptoms.
REFERENCES
1.BrodyDJ,GuQ.Antidepressantuseamongadults:United States,2015-2018.NCHSDataBrief.2020;377:1 8.
2.YonkersKA,SimoniMK.PremenstrualDisorders. NewYork,NY:Mosby;2018.
3.WorldHealthOrganization(WHO).SuicideData2019. Geneva,Switzerland:WHO;2019.Availableat:https:// www.who.int/teams/mental-health-and-substance-use/sui cide-data.AccessedAugust4,2021.
4.MeierSM,MattheisenM,MorsO,etal.Mortalityamong personswithobsessive-compulsivedisorderinDenmark. AmericanMedicalAssociation.JAMAPsychiatry.2016;73: 268 274.
5.LohrJB,PalmerBW,EidtCA,etal.Ispost-traumatic stressdisorderassociatedwithprematuresenescence?A reviewoftheliterature.AmJGeriatrPsychiatry.2015;23: 709 725.
6.LamD,GormanDA,PattenS,etal.Thepharmacoepidemiologyofselectiveserotoninreuptakeinhibitorsfor childrenandadolescentsinCanadafrom2005to2009:a databaseanalysis.PaediatrDrugs.2013;15:319 327.
7.SchatzbergA,DeBattistaC.ManualofClinicalPsychopharmacology.Arlington,VA:AmericanPsychiatricPublishing;2015.
8.NewmanDL,MoffittTE,Caspi A,etal.Psychiatricdisorder inabirthcohortofyoungadults:prevalence,comorbidity, clinicalsignificance,andnewcaseincidencefromages11to 21.JConsultClinPsychol.1996;64:552 562.
9.BirmaherB,ArbelaezC,BrentD.Courseandoutcomeof childandadolescentmajordepressivedisorder.Child AdolescPsychiatrClinNorthAm.2002;11:619 637.
10.MuellerTI,LeonAC,KellerMB,etal.Recurrenceafter recoveryfrommajordepressivedisorderduring15years ofobservationalfollow-up.AmJPsychiatry.1999;156: 1000 1006.
11.PaykelES,RamanaR,CooperZ,etal.Residualsymptoms afterpartialremission:animportantoutcomeindepression. PsycholMed.1995;25:1171 1180.
12.ScholtenWD,BatelaanNM,vanBalkomAJ,etal. Recurrenceofanxietydisordersanditspredictors.J AffectDisord.2013;147:180 185.
13.SpinhovenP,BatelaanN,RhebergenD,etal.Prediction of6-yrsymptomcoursetrajectoriesofanxietydisorders bydiagnostic,clinicalandpsychologicalvariables.J AnxietyDisord.2016;44:92 101.
14.KennedySH,LamRW,McIntyreRS,etal.Canadian NetworkforMoodandAnxietyTreatments(CANMAT) 2016ClinicalGuidelinesfortheManagementofAdults WithMajorDepressiveDisorder:Section3.PharmacologicalTreatments.CanJPsychiatry.2016;61:540 560.
15.GelenbergAJ,MarleneFreemanCP,MarkowitzJC, etal.PracticeGuidelinefortheTreatmentofPatients WithMajorDepressiveDisorder,3rded.Washington, DC:AmericanPsychiatricAssociation;2010.
16.SteinMB,GoinMK,PollackMH,etal.Practice GuidelinefortheTreatmentofPatientsWithPanic Disorder,2nded.Washington,DC:AmericanPsychiatric Association;2010.
17.HughesCW,EmslieGJ,CrismonML,etal.Texas Children’sMedicationAlgorithmProject:UpdateFrom TexasConsensusConferencePanelonMedicationTreatmentofChildhoodMajorDepressiveDisorder.JAmAcad ChildAdolescPsychiatry.2007;46:667 686.
18.GilaberteI,MontejoAL,delaGandaraJ,etal.Fluoxetine inthepreventionofdepressiverecurrences:adouble-blind study.JClinPsychopharmacol.2001;21:417 424.
19.FranchiniL,GasperiniM,PerezJ,etal.Dose-response efficacyofparoxetineinpreventingdepressiverecurrences:arandomized,double-blindstudy.JClinPsychiatry.1998;59:229 232.
20.KellerMB,KocsisJH,ThaseME,etal.Maintenance phaseefficacyofsertralineforchronicdepression:a randomizedcontrolledtrial.JAMA.1998;280:1665 1672.
21.TerraJL,MontgomerySA.Fluvoxaminepreventsrecurrenceofdepression:resultsofalong-term,double-blind,
placebo-controlledstudy.IntClinPsychopharmacol.1998;13: 55 62.
22.HochstrasserB,IsaksenPM,KoponenH,etal.Prophylacticeffectofcitalopraminunipolar,recurrentdepression:placebo-controlledstudyofmaintenancetherapy.Br JPsychiatry.2001;178:304 310.
23.KornsteinSG,BoseA,LiD,etal.Escitaloprammaintenance treatmentforpreventionofrecurrentdepression:a randomized,placebo-controlledtrial.JClinPsychiatry.2006; 67:1767 1775.
24.PundiakTM,CaseBG,PeselowED,etal.Discontinuation ofmaintenanceselectiveserotoninreuptakeinhibitor monotherapyafter5yearsofstableresponse:anaturalistic study.JClinPsychiatry.2008;69:1811 1817.
25.MarjoribanksJ,BrownJ,O ’ BrienPM,etal.Selectiveserotoninreuptakeinh ibitorsforpremenstrual syndrome.CochraneDatabaseSystRev.2013;2013: CD001396.
26.IsmailiE,WalshS,O’BrienPMS,etal.Fourthconsensusof theInternationalSocietyforPremenstrualDisorders (ISPMD):auditablestandardsfordiagnosisandmanagementofpremenstrualdisorder.ArchWomensMentHealth. 2016;19:953 958.
27.ShahNR,JonesJB,AperiJ,etal.Selectiveserotonin reuptakeinhibitorsforpremenstrualsyndromeand premenstrualdysphoricdisorder:ameta-analysis.Obstet Gynecol.2008;111:1175 1182.
28.FreemanEW,RickelsK,SammelMD,etal.Timeto relapseaftershort-orlong-termtreatmentofsevere premenstrualsyndromewithsertraline.ArchGenPsychiatry.2009;66:537 544.
29.HalbreichU,SmollerJW.Intermittentlutealphasesertralinetreatmentofdysphoricpremenstrualsyndrome.JClin Psychiatry.1997;58:399 402.
30.YonkersKA,KornsteinSG,GueorguievaR,etal. Symptom-onsetdosingofsertralineforthetreatmentof premenstrualdysphoricdisorder:arandomizedclinical trial.JAMAPsychiatry.2015;72:1037 1044.
31.KornsteinSG,PearlsteinTB,FayyadR,etal.Low-dose sertralineinthetreatmentofmoderate-to-severepremenstrualsyndrome:efficacyof3dosingstrategies.J ClinPsychiatry.2006;67:1624 1632.
32.McKinlaySM,BrambillaDJ,PosnerJG.Thenormal menopausetransition.AmJHumBiol.1992;4:37 46.
33.GordonJL,GirdlerSS,Meltzer-BrodySE,etal.Ovarian hormonefluctuation,neurosteroids,andHPAaxisdysregulationinperimenopausaldepression:anovelheuristic model.AmJPsychiatry.2015;172:227 236.
34.BrombergerJT,MatthewsKA,SchottLL,etal.Depressivesymptomsduringthemenopausaltransition:The StudyofWomen’sHealthAcrosstheNation(SWAN).J AffectDisord.2007;103:267 272.
35.BrombergerJT,KravitzHM,ChangYF,etal.Major depressionduringandafterthemenopausaltransition: StudyofWomen’sHealthAcrosstheNation(SWAN). PsycholMed.2011;41:1879 1888.
36.SchmidtPJ,HaqN,RubinowDR.Alongitudinal evaluationoftherelationshipbetweenreproductive statusandmoodinperimenopausalwomen.AmJ Psychiatry.2004;161:2238 2244.
37.FreemanEW,SammelMD,LinH,etal.Associationsof hormonesandmenopausalstatuswithdepressedmoodin womenwithnohistoryofdepression.ArchGenPsychiatry. 2006;63:375 382.
38.SchmidtPJ,NiemanLK,DanaceauMA,etal.Differentialbehavioraleffectsofgonadalsteroidsinwomen
withandinthosewithoutpremenstrualsyndrome.N EnglJMed.1998;338:209 216.
39.BlochM,SchmidtPJ,DanaceauM,etal.Effectsof gonadalsteroidsinwomenwithahistoryofpostpartum depression.AmJPsychiatry.2000;157:924 930.
40.SantarsieriD,SchwartzTL.Antidepressantefficacyand side-effectburden:aquickguideforclinicians.Drugs Context.2015;4:212290.
41.DragiotiE,SolmiM,FavaroA,etal.Associationof antidepressantusewithadversehealthoutcomes:asystematicumbrellareview.JAMAPsychiatry.2019;76:1241 1255.
42.CartwrightC,GibsonK,ReadJ,etal.Long-termantidepressantuse:patientperspectivesofbenefitsandadverse effects.PatientPreferAdherence.2016;10:1401 1407.
43.BurcuM,ZitoJM,SaferDJ,etal.Associationof antidepressantmedicationswithincidenttype2diabetes amongMedicaid-insuredyouths.JAMAPediatrics. 2017;171:1200 1207.
44.RaederMB,BjellandI,VollsetSE,etal.Obesity, dyslipidemia,anddiabeteswithselectiveserotonin reuptakeinhibitors:TheHordalandHealthStudy.JClin Psychiatry.2006;67:1974 1982.
45.CouplandCA,DhimanP,BartonG,etal.Astudyofthe safetyandharmsofantidepressantdrugsforolder people:acohortstudyusingalargeprimarycare database.HealthTechnolAssess.2011;15:1 202;ii iv.
46.BrännströmJ,LövheimH,GustafsonY,etal.Associationbetweenantidepressantdruguseandhipfracturein olderpeoplebeforeandaftertreatmentinitiation.JAMA Psychiatry.2019;76:172 179.
47.IaboniA,MaustDT.Astatusupdateontheassociation betweenantidepressantsandfractures:breakingup? JAMAPsychiatry.2019;76:113 114.
48.TaylorWD.Shouldantidepressantmedicationbeusedin theelderly?ExpertRevNeurother.2015;15:961 963.
49.WangC,GaoS,HendrieHC,etal.Antidepressantusein theelderlyisassociatedwithanincreasedriskof dementia.AlzheimerDisAssocDisord.2016;30:99 104.
50.FornaroM,AnastasiaA,NovelloS,etal.Theemergence oflossofefficacyduringantidepressantdrugtreatment formajordepressivedisorder:anintegrativereviewof evidence,mechanisms,andclinicalimplications.PharmacolRes.2019;139:494 502.
51.KinrysG,GoldAK,PisanoVD,etal.Tachyphylaxisin majordepressivedisorder:areviewofthecurrentstateof research.JAffectDisord.2019;245:488 497.
52.ByrneSE,RothschildAJ.Lossofantidepressantefficacy duringmaintenancetherapy:possiblemechanismsand treatments.JClinPsychiatry.1998;59:279 288.
53.FranchiniL,RossiniD,BongiornoF,etal.Willasecond prophylactictreatmentwithahigherdosageofthesame antidepressanteitherpreventordelaynewdepressive episodes?PsychiatryRes.2000;96:81 85.
54.RushAJ,TrivediMH,WisniewskiSR,etal.Acuteand longer-termoutcomesindepressedoutpatientsrequiring oneorseveraltreatmentsteps:aSTAR*Dreport.AmJ Psychiatry.2006;163:1905 1917.
55.SolomonDA,LeonAC,MuellerTI,etal.Tachyphylaxis inunipolarmajordepressivedisorder.JClinPsychiatry. 2005;66:283 290.
56.BerberMJ.FINISH:rememberingthediscontinuation syndrome.Flu-likesymptoms,Insomnia,Nausea,Imbalance, Sensorydisturbances,andHyperarousal(anxiety/agitation). JClinPsychiatry.1998;59:255.
57.ValuckRJ,OrtonHD,LibbyAM.Antidepressant discontinuationandriskofsuicideattempt:aretrospective, nestedcase-controlstudy.JClinPsychiatry.2009;70: 1069 1077.
58.JhaMK,RushAJ,TrivediMH.WhendiscontinuingSSRI antidepressantsisachallenge:managementtips.AmJ Psychiatry.2018;175:1176 1184.
59.DaviesJ,ReadJ.Asystematicreviewintotheincidence, severityanddurationofantidepressantwithdrawal effects:areguidelinesevidence-based?AddictBehav. 2019;97:111 121.
60.BhanjiN,ChouinardG,KolivakisT,etal.Persistent tardivereboundpanicdisorder,reboundanxietyand insomniafollowingparoxetinewithdrawal:areviewof rebound-withdrawalphenomena.CanJClinPharmacol. 2006;13:e69 e74.
61.AmericanPsychiatricAssociation(APA).Diagnosticand StatisticalManualofMentalDisorders,FifthEdition (DSM-5).Arlington,VA:APA;2013:712 713.
62.HorowitzMA,TaylorD.TaperingofSSRItreatmentto mitigatewithdrawalsymptoms.LancetPsychiatry. 2019;6:538 546.
63.ChouinardG,ChouinardVA.Newclassificationof selectiveserotoninreuptakeinhibitorwithdrawal.PsychotherPsychosom.2015;84:63 71.
64.FavaGA,CosciF.Understandingandmanagingwithdrawalsyndromesafterdiscontinuationofantidepressantdrugs.JClinPsychiatry.2019;80:e1 e6.
65.FavaGA,GattiA,BelaiseC,etal.Withdrawalsymptoms afterselectiveserotoninreuptakeinhibitordiscontinuation:asystematicreview.PsychotherPsychosom. 2015;84:72 81.
66.GBD2017DiseaseandInjuryIncidenceandPrevalence Collaborators.Global,regional,andnationalincidence, prevalence,andyearslivedwithdisabilityfor354 diseasesandinjuriesfor195countriesandterritories, 1990-2017:asystematicanalysisfortheGlobalBurdenof DiseaseStudy2017.Lancet.2018;392:1789 1858.
67.TrivediMH,RushAJ,WisniewskiSR,etal.Evaluationof outcomeswithcitalopramfordepressionusingmeasurement-basedcareinSTAR*D:implicationsforclinical practice.AmJPsychiatry.2006;163:28 40.
68.ChekroudSR,GueorguievaR,ZheutlinAB,etal. Associationbetweenphys icalexerciseandmental healthin1.2millionindividualsintheUSAbetween 2011and2015:across-sectionalstudy.LancetPsychiatry.2018;5:739 746.
69.Verbeek-HeidaPM,MathotEF.Bettersafethansorry whypatientsprefertostopusingselectiveserotonin reuptakeinhibitor(SSRI)antidepressantsbutareafraid todoso:resultsofaqualitativestudy.ChronicIlln.2006; 2:133 142.
70.RosenbaumJF,FavaM,HoogSL,etal.Selectiveserotonin reuptakeinhibitordiscontinuationsyndrome:arandomized clinicaltrial.BiolPsychiatry.1998;44:77 87.
71.WilsonE,LaderM.Areviewofthemanagementof antidepressantdiscontinuationsymptoms.TherAdv Psychopharmacol.2015;5:357 368.
72.JhaMK.Discontinuingantidepressants:howcanclinicians guidepatientsanddriveresearch?JClinPsychiatry. 2019;80:e1 e5.
73.OgleNR,AkkermanSR.Guidanceforthediscontinuation orswitchingofantidepressanttherapiesinadults.JPharm Pract.2021;26:389 396.