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CONSENSUSRECOMMENDATIONSGuidelinesfortheevaluationandtreatmentofperimenopausaldepression:summaryandrecommendationsPaulineM.
Maki,PhD,1*SusanG.
Kornstein,MD,2*HadineJoffe,MD,MSc,3JoyceT.
Bromberger,PhD,4EllenW.
Freeman,PhD,5GeenaAthappilly,MD,6WilliamV.
Bobo,MD,MPH,7LeahH.
Rubin,PhD,8HristinaK.
Koleva,MD,9LeeS.
Cohen,MD,10ClaudioN.
Soares,MD,PhD,MBA,11onbehalfoftheBoardofTrusteesforTheNorthAmericanMenopauseSociety(NAMS)andtheWomenandMoodDisordersTaskForceoftheNationalNetworkofDepressionCentersAbstractThereisanewappreciationoftheperimenopause–definedastheearlyandlatemenopausetransitionstagesaswellastheearlypostmenopause-asawindowofvulnerabilityforthedevelopmentofbothdepressivesymptomsandmajordepressiveepisodes.
However,clinicalrecommendationsonhowtoidentify,characterizeandtreatclinicaldepressionarelacking.
Toaddressthisgap,anexpertpanelwasconvenedtosystematicallyreviewthepublishedliteratureanddevelopguidelinesontheevaluationandmanagementofperimenopausaldepression.
Theareasaddressedincluded:1)epidemiology;2)clinicalpresentation;3)therapeuticeffectsofantidepressants;4)effectsofhormonetherapy;and5)efficacyofothertherapies(eg,psychotherapy,exercise,andnaturalhealthproducts).
Overall,evidencegenerallysuggeststhatmostmidlifewomenwhoexperienceamajordepressiveepisodeduringtheperimenopausehaveexperiencedapriorepisodeofdepression.
Midlifedepressionpresentswithclassicdepressivesymptomscommonlyincombinationwithmenopausesymptoms(ie,vasomotorsymptoms,sleepdisturbance),andpsychosocialchal-lenges.
Menopausesymptomscomplicate,co-occur,andoverlapwiththepresentationofdepression.
Diagnosisinvolvesidentificationofmenopausalstage,assessmentofco-occurringpsychiatricandmenopausesymptoms,appreciationofthepsychosocialfactorscommoninmidlife,differentialdiagnoses,andtheuseofvalidatedscreeninginstruments.
Proventherapeuticoptionsfordepression(ie,antidepressants,psychotherapy)arethefront-linetreatmentsforperimenopausaldepression.
Althoughestrogentherapyisnotapprovedtotreatperimenopausaldepression,thereisevidencethatithasantidepressanteffectsinperimenopausalwomen,particularlythosewithconcomitantvasomotorsymptoms.
Dataonestrogenplusprogestinaresparseandinconclusive.
KeyWords:Antidepressants–Depression–Depressivesymptoms–Estrogen–menopause–Perimenopause–Psychotherapy.
ReceivedMay25,2018;revisedandacceptedJune13,2018.
Fromthe1DepartmentsofPsychiatry,DepartmentofPsychology,Univer-sityofIllinoisatChicago,ChicagoILUSA;2DepartmentofPsychiatryandInstituteofWomen'sHealth,VirginiaCommonwealthUniversity,Rich-mond,VAUSA;3ConnorsCenterforWomen'sHealthandDepartmentofPsychiatry,BrighamandWomen'sHospitalandDanaFarberCancerInstitute/HarvardMedicalSchool,Boston,MA,USA;4DepartmentofEpidemiology,DepartmentofPsychiatry,UniversityofPittsburgh,Pitts-burgh,PA,USA;5DepartmentsofObstetrics&Gynecology,DepartmentofPsychiatry,UniversityofPennsylvania,Philadelphia,PA,USA;6EdithNourseRogersMemorialVeteransHospital,BedfordMA;HarvardMedicalSchool,BostonMAUSA;7DepartmentofPsychiatryandPsy-chology,MayoClinic,Rochester,MN,USA;8DepartmentofNeurology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MDUSA;9UniversityofIowaCarverCollegeofMedicine,IowaCity,IAUSA;10DepartmentofPsychiatry,MassachusettsGeneralHospitalandHarvardMedicalSchool,Boston,MAUSA;and11DepartmentofPsychiatry,Queen'sUniversitySchoolofMedicine,OntarioCA.
*PaulineM.
MakiandSusanG.
Kornsteinareco-firstauthors.
Funding/support:None.
Financialdisclosure/conflictsofinterest:Dr.
MakihasreceivedspeakinghonorariafromMylan.
Dr.
KornsteinhasresearchsupportfromMarinusPharmaceuticals,PalatinTechnologies,Pfizer,andTakedaPharmaceu-ticals,aswellasconsultingfeesfromAlkermes,AMAGPharmaceuti-cals,Lilly,andMarinusPharmaceuticals.
Dr.
JoffehasreceivedgrantsfromMerckandPfizer,aswellasconsultingfeesfromKaNDy,Merck,andSojournix.
Dr.
CohenhasreceivedResearchSupportfromtheNationalPregnancyRegistryforAtypicalAntipsychotics,AlkermesBiopharmaceuticals,Forest/ActavisPharmaceuticals,OtsukaPharma-ceuticals,SunovionPharmaceuticals,Inc,TevaPharmaceuticals,theBrain&BehaviorResearchFoundation,JayMacPharmaceuticals,SAGETherapeutics,andTakeda/LundbeckPharmaceuticals,aswellasconsul-tantfeesfromAlkermesBiopharmaceuticals.
Dr.
SoareshasreceivedhonorariaasaconsultantforBayer,Lundbeck,OtsukaandPfizer.
HehasalsoreceivedgrantsfromtheOntarioBrainInstitute(OBI)andtheOntarioMinistryofTechnology,InnovationandScience.
Drs.
Brom-berger,Freeman,Athappilly,Bobo,Rubin,andKolevahavenoconflictstodisclose.
Thisarticleisbeingco-publishedinJournalofWomen'sHealthandMenopause:TheJournaloftheNorthAmericanMenopauseSociety.
Addresscorrespondenceto:PaulineM.
Maki,PhD,DepartmentofPsychiatry,NeuropsychiatricInstitute,MC913,912SWoodSt.
,ChicagoIL60612.
E-mail:pmaki1@uic.
eduMenopause,Vol.
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1069-1085DOI:10.
1097/GME.
0000000000001174Thisarticleisbeingco-publishedinthejournalsJournalofWomen'sHealthandMenopause2018byMaryAnnLiebert,IncandTheNorthAmericanMenopauseSocietyCopyright@2018TheNorthAmericanMenopauseSociety.
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Theexistenceofhormone-relatedmoodsymptomsor'windowsofvulnerability'forreproductive-relateddepressionacrossthefemalelifecyclehasgainedattentioninrecentdecades.
1,2Epidemiologicfindings,animaldataandclinicalobservationshaveshedsomelightintoplausiblemechanistichypothesesonwhysomebutnotallwomenmaybeparticularlysensitivetochangesinthehormonalmilieuexperiencedpremenstrually,duringthepostpartumperiodorduringthemenopausetransition.
3-9Thenotionofamenopause-associateddepression,however,hasbeenthefocusofclinicalandscientificdebateforyears.
Thelackofconsensusonthisissuehasalsoledtoalackofclarityinhowtoevaluateandtreatdepressioninwomenduringthemenopausaltransitionandpostmenopausalperiod.
Toaddressthisgapandtoprovideguidelinesforhealthcarepractitioners,TheNorthAmericanMenopauseSociety(NAMS)andtheNationalNetworkofDepressionCentersWomenandMoodDisordersTaskGroup(NNDC)collabo-ratedtoconvenean11-memberexpertpaneltosystematicallyreviewthescientificliteratureondepressivedisordersanddepressivesymptomsinperimenopausalandpostmenopausalwomenanddevelopclinicalguidelines.
Thepaneladdressedfivetopicspertainingtodepressivesymptomsanddepressivedisordersduringtheperimenopause,including:1)epidemiol-ogy;2)clinicalpresentation;3)therapeuticeffectsofanti-depressants;4)effectsofhormonetherapy(HT);and5)efficacyofothertherapies(eg,psychotherapy,exercise,andnaturalhealthproducts).
ThisreviewdidnotfocusonthemoodbenefitsofHTandnon-hormonaltreatmentsforvasomotorsymptoms(VMS),asthesearecoveredinNAMSpositionstatements.
10,11GeneralguidelinesforthetreatmentofMajorDepressiveDisorder(MDD)areavailable;12there-fore,thoseissuesarenotcoveredhere.
Instead,theseguide-linesfocusonissuesrelatingspecificallytodepressivesymptomsanddepressivedisordersinmidlifewomen.
METHODOLOGYPanelmembersreviewedthepublishedliteraturerelatedtoperimenopausalandpostmenopausalwomeninthefollowingareas:epidemiologyofdepressivesymptomsanddepressivedisorders(JB,LR);theclinicalpresentationofdepression(HJ,GA);thetherapeuticeffectsofantidepressantmedicationonclinicaldepression(LC,HK);theeffectsofhormonetherapyondepression(CS);andtheeffectofothertherapiesondepression(WB,EF).
Eachsubgroupofexpertsreviewedthepublishedliterature(Medline/PubMed/Psy-chInfo/EMbase)forrelevantclinicalstudiesusingselectsearchterms(seeeachsectionbelow),thentheywroteasummaryoftheirliteraturereviewanddraftedasetofclinicalrecommendations.
Theseweresharedwitheachpanelmem-berviaemailforfeedbackandeachsubgroupwasassignedtocarefullyreviewoneothertopicarea.
Thepanelco-chairs(PM,SK)draftedasetofguidelinesbasedontheliteraturereviews.
Panelmembersvettedtheguidelinesandvotedonafinalsetofrecommendations.
Thepreliminaryguidelineswerepresentedatthe2016NAMSAnnualMeetingandthe2017WorldCongressonWomen'sMentalHealth,andfeedbackfromthosepresentationswasincorporatedintofinalvettingoftheguidelines,includingtheadditionofasectiononSpecificPopulationstoaddressissuesrelatedtodepression,hysterectomywithorwithoutoophorectomyandprimaryovarianinsufficiency.
Theliterature(Englishonly)ineachsectionwasreviewedinasystematicmannerforpublicationsbetween1980and2015.
EachsectionincludedasearchwiththefollowingtermscontainingtheMeSHterms''depression,''''depressed,''''depressive,''''anxiety,''or''mood''incombinationwiththeterms''perimenopause,''''menopausaltransition,''''menopause,''''menopausal,''''postmenopausal,''''preme-nopause,''or''midlife''aswellasadditionaltermsandinclusion/exclusioncriteriaspecifictothatsection.
Additionalsearchtermswereusedforeachtopicareaincludingepi-demiology(''epidemiology,''''prevalence,''or''risk''),clinicalpresentation(''symptoms,''''presentation,''''diag-nosis,''''screening,''''scales,''),antidepressants(''antide-pressant,''''SSRI,''''SNRI''),hormonetherapy(estrogentherapy'',''hormonetherapy'',''hormonereplacementther-apy'',''estrogen,''''oestrogen,''and''estradiol.
'')andothertherapies(''psychotherapy'',''electroconvulsivetherapy,''''neuromodulation,''''transcranialmagneticstimulation,''''vagusnervestimulation,''''deepbrainstimulation,''''luminotherapy,''''brightlighttherapy,''''sleepdepri-vation,''''waketherapy,''''acupuncture,''''exercise,''''Hypericumperforatum,''''St.
John'swort,''''Cimifugaracemosa,''''Blackcohosh,''''S-adenosyl-L-methionine,''''SAMe,''''phytoestrogens,''''ginseng,''''ginkgobiloba,''''folate,''''l-methylfolate,''and''omega3fattyacids'').
Eachofthethreeinterventionsectionsincludedonlythoseclinicaltrialsthatselectivelyenrolledwomenwithclinicaldepressionandexcludedstudiesthatexaminedmoodbenefitsinnon-depressedwomen.
Theepidemiologysectionaddressedthefollowingthreequestionswithsystematicreviews:1)Incross-sectionalstud-ies,whatistherelationshipbetweenperimenopausestageanddepressivesymptoms2)Inlongitudinalstudies,whatistherelationshipbetweenperimenopausestageanddepressivesymptoms3)Inlongitudinalstudies,whataretheriskfactorsfordepressivesymptoms/disorderinperimenopauseFourinclusioncriteriawereapplied:1)community-dwellingsam-ples,notclinicalsettings,2)samplesize!
200,with50ormoreineachmenopausestage,3)astandarddepressioninventorywithavalidatedcutoffscoretoindicate''depres-sivesymptoms''ortheuseofastructuredclinicalinterviewtoindicate''diagnoseddepressivedisorder,''and4)specifica-tionandapplicationofstandardcriteriatodeterminemeno-pausestatus(eg,StagesofReproductiveAgingWorkshopPlus10[STRAW10]13orStudyofWomen'sHealthAcrosstheNation[SWAN]14criteria;specificcriteriaforirregular-ity,numberofmissedperiods,lastbleed).
WeusethedefinitionofperimenopausefromtheSTRAW10criteria,whereperimenopauseisdefinedastheearlyandlatemeno-pausetransitionstagesaswellastheearlypostmenopause.
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NotethatthisdefinitiondiffersfromSWANwhereperimen-opauseincludesearlyandlateperimenopausebutnotthepostmenopause.
Also,giventhattheSWANprovidesthelongestfollow-upperiod–13yearsoffollow-upforasampleofwomenaged42-52atbaseline-itisimportanttorecognizethatthisbodyofworkincludeswomenwithamaximumageof65andisnotmeanttoaddressthetopicofgeriatricdepression.
Additionally,thefollowingtwosectionswereaddedfollowingfeedbackfromNAMS,4)Ishysterec-tomywithandwithoutoophorectomyariskfactorfordepres-sivesymptoms/disordersAnd5)IsPrematureOvarianInsufficiency(POI)linkedtodepressionThesectiononthepresentationofdepressionaddressed:1)Isthereauniqueorcharacteristicclinicalpresentationofdepressivedisordersduringthemenopausetransition2)HowisdepressiondiagnosedduringthemenopausetransitionWhatisthedifferentialdiagnosisofdepressionduringthemenopausaltransition3)Whatsymptomscommonlyco-occurwithdepressioninmidlifewomen4)Whataretheuniquepsychosocialchallengesassociatedwiththemeno-pausetransitionthatmightcontributetodepressivesymp-tomsand,5)WhatscreeningmeasureshavebeenvalidatedforassessingdepressionanddepressivesymptomsStudiesthatwerepublishedinapeer-reviewedjournal,publishedintheEnglishlanguage,andutilizedavalidatedorstandardscreeningscaletoassessoneoroneormoreofthefollowing:i)menopausalsymptoms,ii)psychologicaldistress,iii)depressivedisorders,iv)depressivesymptoms,v)moodsymptomsandvi)qualityoflifeduringmenopause,wereincluded.
Thesectiononantidepressantsaddressedfourquestions:1)Whatarethetherapeuticeffectsofantidepressantsonmajordepressiveepisodes(MDE)inperimenopausalandpostmen-opausalwomen2)Aretheredifferencesinefficacybetweentypesofantidepressantsinthetreatmentofperi-orpostmen-opausalwomenwithMDD3)Doesclinicalresponsetoantidepressantsdifferaccordingtomenopausestatus4)Doesestrogentherapyimproveantidepressantresponseinperi-orpostmenopausalwomenwithMDDOnlystudiesmeetingthefollowingcriterionwereincluded:a)useofvalidatedinstru-mentstomeasuredepression(eg,HamiltonDepressionRat-ingScale[HDRS],Montgomery-AsbergDepressionRatingScale[MADRS],BeckDepressionInventory[BDI],PatientHealthQuestionnaire-9[PHQ-9]).
Thesectiononhormonetherapyaddressedthefollowingquestions:1)DoesHThaveaneffectondepressivedisordersinperimenopausalwomen2)DoesHThaveaneffectondepressivedisordersinpostmenopausalwomenand,3)DoesHTpreventdepressivesymptomsduringthemenopausaltransitionThesectionwasguidedbyarecent,comprehen-sivesystematicreviewontheefficacyofestrogen-basedinterventions.
15Thefollowinginclusioncriteriawereapplied:1)clinicaladministrationofestrogen-basedHT,and2)assessmentofmoodsymptoms/depressionwithstandardizedinstruments.
Noninterventionstudiesandstudiesusingnon–estrogen-basedpreparationsorhormone-analogueagents(selectiveestrogen-receptormodulators[SERMs])wereexcludedfromfurtherconsideration.
Additionally,followingfeedbackfromNAMS,asectiononhormonalcontraceptivesforperimenopausalwomenwasadded.
Thesectiononothertherapiesondepressionaddressedefficacyoftreatmentmodalitiesinclassesthatinclude:1)psychotherapies,2)somatic/physicaltherapies(neuromodu-latorytreatments,lighttherapy,exercise),and3)naturalproducts(ie,nutraceuticaltherapiesandbotanical/herbaltherapies).
EPIDEMIOLOGYOFDEPRESSIVESYMPTOMSANDDEPRESSIVEDISORDERSINMIDLIFEWOMENIncross-sectionalstudies,whatistherelationshipbetweenperimenopausestageanddepressivesymptomsNumerouscross-sectionalstudieshaveaddressedwhetherperimenopausalwomendemonstrateahigherprevalenceoforareatriskfordepressivesymptomscomparedwithpre-menopausalwomen(Table1).
Samplesizesinthesecross-sectionalstudiesrangedfrom376to6,383women(median,927),andmostsamplesincludedwomenagedbetween40and60years,representingsixdifferentcountries,arangeofethnicities,andarangeofeducationalattainment.
Althoughallstudieshadanadequatesamplesizetoprovideanacceptableprevalenceestimateofelevateddepressivesymp-tomsintheoverallsample,comparisonsofelevateddepressivesymptomsinperimenopausalversuspremenopausalwomenmayhavebeenunderpoweredinsampleswithalowprevalenceofelevateddepressivesymptomsandrelativelysmallsamplesizes.
Theanalyticapproachvaried,withsomestudiesreport-ingadjustedresultsandothersunadjusted.
Eightofthe12studiesincludedfoundthatelevateddepressivesymptomsweresignificantlymoreprevalentinperimenopausalversuspremenopausalwomen,andsixofthesewereadjustedforcovariates.
16-20Thesestudiessuggestthat45%to68%ofperimenopausalwomenreportelevateddepressivesymptomscomparedwith28%to31%ofpremenopausalwomen.
17,20Inearlyperimenopause,28%to47%ofwomenreportedelevateddepressivesymptoms16,19andtheoddsofelevateddepressivesymptomsinthisstagewashigherthaninthepremenopausalstage.
Inalargecohortofethnicallydiversewomen,earlyperimenopausalwomenshoweda1.
74-foldincreasedoddsofelevateddepressivesymptomsduringearlyperimenopause19andamongHispanicwomentherewasa2.
45-foldincreasedodds.
16Itisdifficulttoconcludewhetherwomeninthelate-perimenopausestagedemonstrateelevateddepressivesymp-tomsbecauseofthetwocross-sectionalstudiesthatspecificallyincludedthisgroupofwomen,oneincludedonly57womeninthisstage19andtheotheronlyexamineddepressivesymptomscontinuously.
21Inlongitudinalstudies,whatistherelationshipbetweenperimenopausestageanddepressivesymptomsProspectivelongitudinalstudiesfromthreeU.
S.
cohortsaddressedwhethertheperimenopausalstageisaperiodofincreasedriskforbothdepressivesymptomsanddepressivePERIMENOPAUSALDEPRESSIONGUIDELINESMenopause,Vol.
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disordersasmeasuredbydiagnosticclinicalinterviews(SeeTable2).
ThesecohortsincludeSWAN,14,22-24thePennOvarianAgingStudy(POAS),25-28andtheSeattleMidlifeWomen'sHealthStudy.
29Comparedwithcross-sectionalstudies,longitudinalstudiesaremoreoptimallydesignedtoaddresstheassociationbetweenmenopausetransitionstageanddepressionaswellasthedirectionoftheassociation.
Samplesizesinlongitudinalstudiessizesrangedfrom151to3,302(median,332),andmedianlengthoffollow-upwas7years(range,3-15y).
Womenacrossstudieswereethnicallydiverseandprimarilywelleducated.
Ofthe11longitudinalstudiesreviewed,six(54%)suggestanincreasedriskofdepressivesymptomsduringthetransition,14,24,26,27,29,30withestimatesofa1.
30to1.
55increasedlikelihoodofdepressivesymptomsintheearlytransitionand1.
71to2.
89increaseinthelatetransition.
14,24,27Twostudiesindicatethatinwomenwithnoprevioushistoryofdepression,26,27,30thetransitionposesagreaterriskforelevateddepressivesymptomsthandoesremainingpremenopausal,especiallyinthosewithahistoryofadverselifeevents30orvasomotorsymptoms(VMS)duringperimenopause.
30Althoughthemajorityofstudiesfocusedonthemenopausaltransition,thePOASexaminedriskinrelationtothefinalmenstrualperiod(FMP).
Whenasizeablenumberofwomenreachedpostmen-opauseinthePOAS,theriskofelevateddepressivesymptomswassignificantlyhigherbeforetheFMPwithalowerriskaftertheFMP.
25WhetherwomenwithgreaterracialandeconomicdiversityshowthesameriskofMDDisunclear,asselectionbiascanaffectestimatesofnewonsetdepression,particularlyinstudiesselectingforwomenwithnohistoryofMDD.
31TwolongitudinalstudiesevaluatedtheriskofaMDEduringthemenopausetransitionusingthePrimaryCareEvaluationofMentalDisorders(POAS)27ortheStructuredClinicalInterviewforDepression(SWAN).
22Inadjustedanalyses,theSWANreportedthatwomenweretwotofourtimesmorelikelytoexperienceamajordepressiveepisodeduringthemenopausetransitionandearlypostmenopause,whereasnoincreasedriskwasfoundduringtheseperiodsinthePOAS.
26,27InthePOAS,fewwomentransitionedthroughlateperimenopauseandpostmenopause,sothereisgreaterconfidenceinfindingsrelatedtotheearlyperimenopausethanlaterinthetransition.
26,27InSWAN,thewomenatgreatestriskforMDEduringthemenopausetransitionandafterwerethosewithahistoryofMDDbeforemidlife.
23,32Indeed,thelargeststudieshavenotfoundthattheriskofaMDDepisodeduringthetransitionisincreasedwhenthereisnopriorhistoryofMDD.
23AlongitudinalSWANstudycomparedriskfactorsforanMDDepisodein151womenwithahistoryofMDDcomparedto274womenwithoutahistoryofMDD.
23WomenwithahistoryofMDDhadahigherriskofdevelopingMDDduringmidlifecomparedwithwomenwithoutahistoryofMDD(59%vs28%).
23AdditionallytheriskforMDDwashigherintheperi-versuspremenopausalstageonlyforwomenwithahistoryofMDD.
23OveralltheelevatedriskforMDDintheperimenopausecomparedtothepremeno-pausewasprimarilyseenamongwomenwithahistoryofMDD,withinconsistentevidenceofanincreasedriskinwomenwithoutMDDpriortomidlife.
Inlongitudinalstudies,whataretheriskfactorsfordepressivesymptoms/disordersduringtheperimenopauseLongitudinalstudiesfromtheUnitedStates,theNetherlands,andAustraliarevealedawiderangeofriskfactordomainsfordepressivesymptomsanddisordersTABLE1.
Cross-sectionalstudiesofprevalenceoroddsofdepressivesymptomsinperimenopausecomparedtopremenopauseStageStudyNCountrySampleagerangeormean/SDOutcomemeasurePercentofsamplewithelevatedsymptomsEarlyperiLateperiCombinedearly/lateDepressivesymptomsChimetal.
146495Singapore40-60CES-Da6%nanansBrombergeretal.
163,015US42-52CES-D24%"cnanaJuangetal.
1471,273Taiwan40-54HADS-D8%nanansGallicchioetal.
148634US45-54CES-D25%nanansTangenetal.
1496,383Norway42-58HADS-D-nana"Zainaletal.
1503,934Malaysia45-60CES-D54%nana"Brownetal.
17639US45-54CES-D25%nana"bYenetal.
151672Taiwan40-60CES-D38%nanansdTimuretal.
20685Turkey40-60BDI29%nana"bMakietal.
191,170US30-65CES-D38%"nsnaLinetal.
183,359Taiwan40-55TDQ5%nana"Mauasetal.
21376US35-60BDI-II-"b"bna"Increasedoddscomparedtopremenopausalstage.
aCES-D8-itemscale,7cutoff.
bUnadjustedanalysisonlyprovided.
cHispanicsonly.
Associationintheoverallsamplejustmissedstatisticalsignificance.
dOnlysignificantwhenexaminedCES-Dscorescategoricallyandcontinuouslyunadjusted.
BDI,BeckDepressionInventory,17cutpoint;BDI-II,BeckDepressionInventoryII;CES-D,CenterforEpidemiologicalStudiesDepressionScale,20-itemscale,16cutoff;HADS-D,HospitalAnxietyandDepressionScale,depressionsubscale,8cutoff;ns,nosignificantdifference;na,notapplicable;peri,perimenopausal;PRIMEMD,PrimaryCareEvaluationofMentalDisorders;SD,standarddeviation;TDQ,TaiwaneseDepressionQuestionnaire,19cutoff;US,UnitedStates.
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(Table3).
Theseincludedemographiccharacteristics(finan-cialproblems;unemployment;beingblack,Hispanic,orJapanese;1verystressfullifeevent);symptoms(VMS)Woodsetal.
2930215US33-55CES-Ddemographic(#age);health("BMI,hxofpostpartumblues,nolivebirths,currentuseofantidepressants);psychosocial("SLE)Brombergeretal.
243,2968US42-52CES-Ddemographic(#age,#education,Hispanic,Japanese);health(currentsmoker,medicationfornervesordepression,"BMI);hormonal(T);psychosocial("upsettinglifeevents,#socialsupport);symptoms("VMS)Morrisonetal.
2843611US35-47CES-Ddemographic(#age,black);health(smoker)Freemanetal.
2520314US42.
83.
1CES-Dhealth(hxofdepression,currentmedication)DepressionDiagnosisFreemanetal.
273324US35-47PRIMEMDdemographic(Black);health(hxofdepression,hxofseverePMS,currentuseofantidepressants);symptoms("VMS,#sleep)Freemanetal.
262318US35-47PRIMEMDhealth("BMI);hormonal(E2SD)Brombergeretal.
2222110US42-52SCIDhealth("BMI,hxofMDD,psychotropicmedicationuse);psychosocial("upsettinglifeevent)Morrisonetal.
2843611US35-47PRIMEMDdemographic(#age,Black);health(smoker,"BMI)Kravitzetal.
15542512US46.
12.
5SCIDhealth(hxofanxietyorMDD);psychosocial("anxietyanddepressivesymptoms,baselinetraitanxiety,!
2ormoreupsettinglifeevents)Brombergeretal.
2342513US42-52SCIDAmongwomenwithincidentMDD:health(lifetimemedicalcondition,rolephysical);psychosocial(closefriends,traitanxiety)AmongwomenwithrecurrentMDD:demographic(#age);health(lifetimeanxietydisorder,time-varyingdepressivesymptoms);psychosocial(closefriends,privateself-consciousness/ruminative)#number.
aBDI-II,BeckDepressionInventoryII;BMI,bodymassindex;CES-D,10-itemscale,10cutoff;CES-D,CenterforEpidemiologicalStudiesDepressionScale,20-itemscale,16cutoff;E2,estradiol;EDS,EdinburghDepressionScale;FSH,follicle-stimulatinghormone;hx,history;LH,luteinizinghormone;MDD,majordepressivedisorder;na,notapplicable;ns,nosignificantdifference;peri,perimenopausal;PMS,premenstrualsyndrome;PRIMEMD,PrimaryCareEvaluationofMentalDisorders;SCID,StructuredClinicalInterviewfortheDiagnosisofDSM-IVAxisIDisorders;SD,standarddeviation;SLE,stressfullifeevents;T,testosterone;US,UnitedStates;VMS,vasomotorsymptoms.
"Increased.
#Decreased.
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withspontaneous46,XXPOI(54.
5%)comparedwiththegeneralpopulation(20%)andoccurredascommonlybeforeasaftertheonsetofmenstrualirregularity—aproxyfortheearlystagesofovarianinsufficiency.
40Inadditiontomenopausesymptoms,concernsaboutfertilityandlong-termhealthconsequencesareassociatedwithreducedpsychologi-calwellbeinginwomenwithPOI.
41,42CLINICALPRESENTATIONOFDEPRESSIONIsthereauniqueorcharacteristicclinicalpresentationofdepressivedisordersduringthemenopausetransitionDepressionduringmidlife,presentswithclassicdepressivesymptoms,commonlyincombinationwithmenopause-spe-cificsymptomsandpsychosocialchallenges.
ThemenopausetransitionandearlypostmenopausalstagearereproductivestagesassociatedwithincreasedriskforMDE22andarealsotransientwindowsofvulnerabilityforthedevelopmentofsubthresholddepressivesymptoms.
26,27,29,30,43,44Themeno-pausetransitiongenerallyspans4to8years;however,theonsetofthemenopausetransition,comparedwithotherreproductivetransitions,islessdistinctandreflectsunderly-inghormonechangesthatprecedetheclinicalmarkersbyavariableperiodoftime.
45Difficultiesinestablishingthetemporalassociationoftheonsetofmoodchangeswiththemenstrualmarkersofthemenopausetransitionmaypartlyexplaintherelativepaucityofdatadescribinguniquepre-sentationsofclinicaldepressionduringandafterthemeno-pausetransition.
46Inaddition,althoughmajorstrideshavebeenmadetoensurestandardization,historicallytherehasbeenalackofconsistencyindefiningdepressionduringthemenopausetransition,distinguishingtheseveritiesofdepres-sionatthisstageandusinguniformratingtools.
47HowisdepressiondiagnosedduringthemenopausetransitionComprehensivediagnosisofdepressivedisordersduringmidlifemayinvolveanidentificationofthestageofmeno-pauseaswellasclinicalassessmentofdepressivesymptomsandotherpsychiatricconditions.
ThedifferentialdiagnosisofdepressionduringthemenopausetransitionandaftersurgicalmenopauseincludesMDD,subsyndromaldepression,adjust-mentdisorder,psychologicaldistress,bereavement,bipolardepression,andgeneralmedicalcausesofdepression.
MostwomenwhoexperienceaMDEduringthemenopausetransi-tionhavehadahistoryofMDD;therefore,theepisoderepresentsrecurrenceoftheirillness.
23FirstlifetimeonsetofMDDduringthemenopausetransitionislesscommon.
23Duringthemenopausetransitionandpostmenopause,awomanmayexperiencemorelossescomparedwithpreviousstagesofherlife.
Similarly,shemayalsoexperiencelifestressorsuniquetohermidlifestage(eg,caringforagingparents,sometimeswhilecaringforchildren;careershifts);hence,bereavementandadjustmentdisorderareimportanttoconsiderinthedifferentialdiagnosis.
Somewomenalsomayexperiencepsychologicaldistressrelatedtoawarenessofaging,bodychangesassociatedwithreproductiveaging,andconcurrenthealthconditions.
48Althoughsurgicalmenopausemaypresentconcernsaboutfertilityandprematureaging,datasurroundingsurgicalmen-opause'sassociationwithincreasedordecreasedriskofpsy-chologicaldistressarelargelymixed.
49Psychologicaldistressistobedifferentiatedfromsubsyndromalorminordepres-sion.
50MinordepressionischaracterizedbyexhibitingtwotofoursymptomsofaMDE,includingdysphoriaoranhedonia,withassociateddistressand/orfunctionalimpairment.
Moodswingsarealsocommonduringthemenopausetransition.
51Previouspsychiatrichistory,collateral,andcare-fuldelineationofsymptomsmayassistindifferentiatingmoodswingscommonlyexperiencedduringthemenopausetransitionfromadiagnosisofbipolardisorder.
Prospectivestudieshavedemonstratedanincreasedlikelihoodofmoodexacerbation(mooddepressionaswellaselevation)inthosewithahistoryofbipolardisorderduringthelatemenopausetransitionandearlypostmenopause.
52Whatsymptomscommonlyco-occurwithdepressioninmidlifewomenSeveralcommonsymptomsofthemenopausetransitionandnaturalorsurgicalpostmenopause(VMS,sleepandsexualdisturbances,weight/energychanges,cognitiveshifts,andurinarysymptoms)co-occurandoverlapwiththepresen-tationofdepressionduringthisstage.
53Depressionitselfmaypresentwithsleep,sexual,appetite,energy,andconcentrationdifficulties.
VMSandsleepdisturbanceareespeciallycom-monandcanbesevereaftersurgicalmenopause.
54,55Anevaluationoftheco-occurrenceofdepressivesymptomsandmenopausalsymptomswasperformedviaclusteranalysisinasampleof797womenwithnohistoryofMDDwhowereparticipatingintheMSFlashtrials.
56Atbaseline,thereweretwosymptomclustersthatincludedwomenwithelevateddepressivesymptoms.
Inonecluster(14%ofthetotalsam-ple),elevateddepressivesymptomswereclusteredwithhighlevelsofinsomnia,verylowsleepqualityandmoderatelyhighVMS.
Inasmallercluster(7%ofthetotalsample),elevateddepressivesymptomswereclusteredwithelevatedanxietybutminimallywithothersymptoms.
IntheclustercharacterizedbythehighestlevelofVMS(11%ofthesample),depressivesymptomswerelow,indicatingthatdepressivesymptomsarenotuniformlypresent,evenwhenVMSaresevere.
Becausethesesamesymptomsalsomaybesecondarytomenopause,itbecomesdifficulttoparseoutcontributingetiologies,relativecontributionsofeachetiology,andpoten-tialadditiveeffects.
53,57Inaddition,symptomsuniquetothemenopausetransitionandpostmenopause,includingVMSandvaginaldryness,havethepotentialtomagnifyorcom-plicateindividualsymptomsandglobalclinicalexperienceofdepressivedisordersduringthisstage.
58Furthermore,depres-sionmayaffectanindividual'sappraisalofthedegreeofbotherfromsomaticsymptomscommonlyencountereddur-ingthemenopausetransition;thereby,furthermagnifyingtheeffectofsymptomsonqualityoflife.
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VasomotorsymptomsandsleepTheinterrelationshipbetweendepressivesymptoms,VMS,andsleepdisturbanceshasbeenstudied.
Thedominotheoryassertsthatnightsweatsmaybecausallyrelatedtosleepdisturbancesthat,inturn,arecausallyrelatedtodepressivesymptoms.
60Subsequentstudieshavesupportedsomeaspectsofthistheoryandquestionedothers.
61AstudyexaminingtheeffectofVMSonsleepviainductionbyagonadotropin-releasinghormoneagonistdemonstratedacausalrelationshipbetweenVMSanddifficultysleeping.
62InthePOAScohort,whereallwomenwerepremenopausalatbaseline,depressivesymptomsweremorelikelytoprecedeVMSinthemeno-pausetransitionamongwomenwhohadnoexperienceofeithersymptompriortothetransition,findingsthatchallengethecausalrelationshipsofthedominotheoryasauniversalexplanationoftheassociationbetweenthesesymptoms.
63ExperimentalstudiesexaminingtherelationshipofmoodwithconcurrentVMSandsleepdisturbancehaveusedgonad-otropin-releasinghormoneagoniststoinducesymptomsinhealthynon-depressedwomen64and,separately,haveran-domizedwomenwithaMDEtoestrogentherapyorpla-cebo.
65,66ThesestudieshaveshownthatforwomenwithoutMDE,emergenceofdepressivesymptomsongonadotropin-releasinghormoneagonistsislinkedwithemergenceofsleepdisturbance,specificallysleepinterruption,andwithonsetofnocturnalVMS,butnotdaytimeVMS.
64Incontrast,amongwomenwithMDErandomizedtoestrogentherapy,depres-sivesymptomsimproveinconcertwithimprovementinsleepdisturbance,butnotinassociationwithVMS.
66Epidemio-logicstudieshavesimilarlyshownthatVMSarelinkedwithriskofdevelopingsubsequentdepressivesymptoms,24,26,65,66butnotMDE,23,26althoughthereisastatisticaltrendtowardanassociationofVMSwithsubsequentemergenceoffirstlifetimeonsetofMDDinSWAN23andanearlyPOASstudyshowedasignificantassociationbetweenVMSandnewMDDonset.
27Takentogether,theseexperimentalandepide-miologicstudiesprovideevidencethattherelationshipbetweendepressivesymptomsandVMSdiffersbetweenthosewithandwithoutMDE,withassociationsobservedalmostexclusivelyamongthosewithoutMDE.
67Sleepdisturbancehasbeenlinkedwithdepressioninmidlifewomen.
InwomenwithVMS,thesleepcharacter-isticsthatdistinguishthosewithversusthosewithoutadepressivedisorderincludeprolongedsleep-onsetlatency,reducedperceivedqualityofsleep,sleepefficiency,andoveralltotalsleepduration.
61Onthebasisofthesestudies,itappearsthatVMSarecausallyrelatedtodifficultysleeping.
Difficultysleeping,inturn,appearstobeassociatedwithdepressivesymptoms.
64,66Symptomscharacteristicofthemenopausetransitionandearlynaturalorsurgicalpostmeno-pausemayoverlapandcompoundsymptomscommontodepression.
Cognition:Depressionandmenopauseitselfmayexerteffectsonconcentration,therebymakingitdifficulttodisen-tangleindividualcontributions.
53,57Subjectivecomplaintsofcognitivechangesarecommonduringthemenopausetransition;longitudinalstudiesfromSWANprovidesomeobjectivevalidationtothesubjectivecomplaintsbecausetheydemonstrateatransientimpairmentinlearningduringthemenopausetransition.
68Concurrentdepressiveandanxietysymptomswereassociatedwithslowerprocessingspeedandanxietywasalsoassociatedwithworsememory,butnosymptomaccountedforlowerperformanceinlateperimen-opausecomparedtopremenopause.
69ConsistentwithSWAN,thePOASdemonstratedadecreaseinlearningandmemoryaswomentransitionedthroughthemenopauseevenafteraccountingforage,depression,anxietyandotherfactorsthatcaninfluencecognition.
70Midlifewomenwithdepres-sionmayalsopresentwithco-occurringcognitiveslowinganddeficitsinencodingandthushavethepotentialofamplifyingexistingcognitivechangesduringthemenopausetransition.
69,71Fatigue:Inaddition,selectedneurovegetativefeaturesofdepression(decreasedenergy,increasedappetite)mayover-lapwithandcompoundsubjectivecomplaintsoffatigueaswellasweightincreasescommonlyreportedduringandafterthemenopausetransition.
72Sexualfunction:Genitourinarychangesaccompanyingmenopausemayaffectsexualfunctionanddesire.
73Decreasedlibidoalsomaybeasymptomofdepression.
74Thedualeffectofdepressionandthemenopausetransitiononsexualdesireandperformancemaybeadditive,75aneffectthatmaybeespeciallytrueforsurgicalmenopause.
76,77Urinaryincontinence:Thereisasmallandinconsistentliteraturesuggestingabidirectionalassociationbetweenuri-naryincontinenceanddepressioninmidlifewomen.
Prospec-tivecohortstudieshavefounddepressivesymptomstobeariskfactorforpersistenturinaryincontinence.
78,79Othercross-sectionalstudieshavereportedthatpostmenopausalwomenwithurinaryincontinencearemorelikelytohavedepressiveandanxietysymptoms.
80Incontrast,severalotherstudieshavenotobservedaclearlinkbetweendepressionandurinaryincontinenceinmidlifewomenwithdepression.
22,23Thebasisforthispotentialassociationisnotunderstoodbutmightberelatedtodecreasedserotoninlevelsinthecentralnervoussystemthathavebeencorrelatedwithincreasedurinaryfrequencyandbladdercontractions.
81,82WhataretheuniquepsychosocialchallengesassociatedwiththemenopausetransitionthatmightcontributetodepressivesymptomsThepsychosocialfactorsobservedduringthemenopausetransitionandpostmenopausemaybeuniquetomidlife.
Olderstudiespositthatdepressivesymptoms,previouslytermed''involutionalmelancholia,''83arosefroman''emptynest''phenomenon;namely,thatwomenmaybepronetodepressivesymptomswhenchildrenleavethehome.
84Thistheoryhassincebeenrefutedwithempiricdatawhichsuggestanimprovementinwellbeinginwomenwhenchildrenleavethehomeandnoeffectofthereturnofadultchildren(''revolvingdoor'')onmood.
85Nonetheless,menopausemayrepresentauniquelychallengingtimeforwomen.
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womenfaceaseriesofstressorsincludingbutnotexclusivetocaringforagingparents,deathofparents,medicalillnessinselfandfamily,adjustingtoemotionalandphysicalsequelaeofsurgicalmenopauseandotherhealthissuesthatarecom-montothisstageoflife,childrenleavingthehome,andchangesinmaritalstatus.
Withtheonsetofchildbirthatanincreasinglylaterage,womenareoftenfacedwiththedualresponsibilityofraisingyoungchildrenamidcaringforagingparentswhilenavigatingtheircareersandensuingchallenges.
Thesemultipledemandsareoftenfacedwithoutsupportsinplacetoidentifyoraddresstheensuingdistressplacedonawomanduringthisstage.
WhatscreeningmeasureshavebeenvalidatedforassessingdepressionanddepressivesymptomsSeveralgeneralvalidatedscreeningmeasuresforclinicalsettings,includingbutnotexclusivetothePHQ-9,maybeusedforcategoricaldeterminationofmooddisorderdiagno-sesduringthemenopausetransitionastheyareinotherpopulations.
Inresearchsettings,questionnairessuchastheCenterforEpidemiologicalStudiesDepressionScale(CES-D),aswellastheQuickInventoryofDepressiveSymptomatology-Self-Report,alsomaybehelpfulincaptur-ingsymptomseverityandarepredictivealbeitnotdiagnosticofMDDduringmidlife.
86,87Itisimportanttonotethatseveralsymptomscommontothemenopausetransition(VMS,cog-nitivechanges,sleepdisturbances)mayaffectscoring.
57TheHDRSisalsocommonlyusedinresearchstudies,andisclinicianadministered.
88Amenopause-specificmooddisor-derscaledoesnotyetexist,butothermenopause-specificvalidatedsymptomandquality-of-life(QOL)scalesmeasur-ingmoregeneralparametersmaybeuseful.
TheMenopauseRatingScale(MRS)incorporatesarangeofperimenopausemeasuresincludingbutnotexclusivetomood,libido,andvaginaldryness.
89TheMenopause-SpecificQuality-of-LifeScale(MENQOL)assessesandidentifiespsychologicalandsomaticparametersthataffectQOLduringthemenopausetransition.
90OthercommonlyusedscalesincludetheGreeneClimactericScaleandtheUtianQuality-of-LifeScale.
91,92Althoughthesescalesaddressdomainsofpsychiatricsymp-toms,theydonotdistinguishdistressfrommajordepressionorsubsyndromaldepression.
Moreover,theyalsodonotnecessarilycapturethedurationofsymptomsortheeffectofmooddisturbanceonfunction.
89,90THERAPEUTICEFFECTSOFANTIDEPRESSANTMEDICATIONSONCLINICALDEPRESSIONINPERI-ANDPOSTMENOPAUSALWOMENWhatarethetherapeuticeffectsofantidepressantsonMDEinperimenopausalandpostmenopausalwomenTwolargerandomized,double-blind,placebo-controlledtrialsexaminedtheefficacyofdesvenlafaxineforMDDinperimenopausalandpostmenopausalwomendefinedusingSTRAWcriteria(seeTable4).
93,94Short-termtreatmentwith50mgand100-200mgdosesofdesvenlafaxineledtosignifi-cantimprovementindepressivesymptomscomparedwithTABLE4.
Largerandomizedtrialsexaminingtheefficacyofantidepressantsformajordepressivedisorderinwell-definedperimenopausalandpostmenopausalwomenStudyDesignPopulationMedicationResultsKornsteinetal.
2010Randomizeddouble-blind,placebo-controlled8-wktrial387peri-andpostmenopausalwomen(aged40-70y)withMDDDesvenlafaxine(flexibledosing100-200mg/dwithmeandailydose162-176mg/d)vsplaceboSignificantimprovementindepressivesymptoms(HAMD-17)withdesvenlafaxineversusplacebo;Responserate59%vs32%,remissionrate38%vs22%;Effectevidentasearlyasweek1Soaresetal.
2010Randomizeddouble-blind8-wktrialwith6-monthcontinuationphase607postmenopausalwomen(aged40-70y)withMDDDesvenlafaxine100-200mg/dvsescitalopram10-20mg/dNosignificantdifferencesbetweendesvenlafaxineandescitalopramafter8weeksorafter6monthscontinuationphaseClaytonetal.
2013Randomizeddouble-blind,placebo-controlled8-wktrial434peri-andpostmenopausalwomen(aged40-70y)withMDDDesvenlafaxine50mg/dvsplaceboSignificantimprovementindepressivesymptoms(HAMD-17)withdesvenlafaxineversusplacebo;alsosignificantbenefitsonpainandfunctionaloutcomesKornsteinetal.
2014Post-hocanalysisofrandomizeddouble-blind,placebo-controlled8-wktrial135perimenopausaland291postmenopausalwomen(aged40-70)withMDDDesvenlafaxine50mg/dvsplaceboSignificantimprovementindepressivesymptomsinbothperi-andpostmenopausalsubgroupswithdesvenlafaxinevsplaceboKornsteinetal.
2015Pooleddatafrom2randomized,double-blind,placebo-controlled8-wktrials252perimenopausaland546postmenopausalwomen(age40-70y)withMDDDesvenlafaxine(100-200mg/d)for8wks&Desvenlafaxine(50mg/d)for10wksSignificantimprovementindepressivesymptoms(HAMD-17)andsecondaryoutcomes(SDS,MRS)withdesvenlafaxinevsplaceboinbothperi-&postmenopausalwomenHAMD-17,17-itemHamiltonDepressionRatingScale;MDD,MajorDepressiveDisorder;MRS,MenopauseRatingScale;SDS,SheehanDisabilityScale;wks,weeks;y,years.
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placebo.
93,94Post-hocanalysesofpooleddatafromthesetrialsshowedsignificantimprovementwithdesvenlafaxineinboththeperimenopausalandpostmenopausalsubgroups,includinglowersymptomburdenandhigherremissionrates.
95,96Todate,nootherantidepressantshavebeenstudiedinlargerandomizedplacebo-controlledtrialsofwell-definedperimenopausalandpostmenopausalwomenwithMDD.
Therehavebeenanumberofsmallopen-labelstudiesofotherantidepressantsincludingselectiveserotoninreuptakeinhibitors(SSRIs;citalopram,escitalopram,vortioxetine),serotonin-norepinephrinereuptakeinhibitors(SNRIs;venla-faxine,duloxetine)andmirtazapinetotreatMDDinperimen-opausalandpostmenopausalwomenthathavedemonstratedapositiveeffectonmoodaswellasVMS,sleep,anxiety,andpain.
97-99,100-103Bupropion,anorepinephrine-dopaminereuptakeinhibitor(NDRI),issometimesprescribedaloneorincombinationwithanSSRI/SNRItoperimenopausalwomenbecauseitdoesnotleadtoasmuchweightgain,sexualdysfunction,orsleepinessasSSRI/SNRIs.
104How-ever,therearenoRCTsofbuproprioninperimenopausalwomen.
Aretheredifferencesinefficacybetweentypesofantidepressantsinthetreatmentofperi-orpostmenopausalwomenwithMDDAlargerandomizeddouble-blindtrialcomparedtheSNRIdesvenlafaxineandtheSSRIescitalopramonMDDinpost-menopausalwomendefinedusingSTRAWcriteria;nosig-nificantdifferenceinefficacywasseenafter8weeksofacutephasetreatmentnorafter6monthsofcontinuationphasetreatment(seeTable4).
105Thesefindingswereincontrasttoapreviousanalysisofalargepooleddatasetbysexandage(usingacutoffof50)comparingremissionrateswithven-lafaxine,SSRIs,orplacebothatfoundasignificantadvantageinremissionratesfavoringtheSNRIvenlafaxineoverSSRIsinolderwomen.
106Anotherpost-hocanalysisofclinicaltrialdatausingage-definedmenopausestatusshowednodiffer-enceintheefficacyoftheSNRIvenlafaxineversustheSSRIfluoxetineinyoungerorolderwomen.
107Similarly,apooledanalysisofopen-labeltrialsshowednodifferencesinresponseratestoreboxetine,sertraline,orvenlafaxineinolderandyoungerwomen.
108SomestudieshavenotedasuperioreffectofanSSRIoveratricyclicornorepinephrinereuptakeinhibitor(NRI)inpremenopausalwomen,butnosuchdifferenceswerefoundinpostmenopausalwomeninthosestudies.
109-111DoesclinicalresponsetoantidepressantsdifferaccordingtomenopausestatusSeveralstudieshaveexaminedwhethertherearediffer-encesinantidepressantresponseinpremenopausalversuspostmenopausalwomen,allusingageasaproxyformeno-pausestatus.
Inthepooledanalysisofclinicaltrialsofvenlafaxine,SSRIs,andplacebodiscussedabove,poorerresponsetoSSRIswasnotedinpostmenopausalcomparedwithpremenopausalwomen,whereasresponsetovenlafaxinedidnotdifferbymenopausestatus.
106Anotherpooledanaly-sisshowednodifferencesinantidepressantresponsetoeitherbupropionorSSRIsbymenopausestatus,112nordidalargestudyofvenlafaxineandfluoxetine.
107LiketheThase2005106study,severalopen-labelstudieshavedemonstratedrelativeresistancetoSSRIsandotherantidepressantsinpostmenopausalversuspremenopausalwomen,113-115whereasothersdidnotfindadifferencebymenopausestatus.
111,116-118Onlyonestudyexaminedmenopausestatusasapredictorofdepressionrecurrenceduringantidepressanttreatment;ratesofrecurrenceofMDDduringtreatmentwithvenlafaxineorfluoxetinedidnotdifferinpre-versuspost-menopausalwomen.
107Doesestrogentherapyimproveantidepressantresponseinperi-orpostmenopausalwomenTwopost-hocanalysesofrandomizedplacebo-controlledstudiesofSSRIsinolderwomenwithMDDfoundaninteractionbetweenuseofconcomitantestrogentherapyandantidepressanttreatmenteffect,suggestingthatestrogenmayaugmentantidepressantresponsetoSSRIsinpostmen-opausaldepressedwomen.
119,120Twosmallopen-labeltrialsshowedincreasedoracceleratedresponsetoSSRIsinpost-menopausaldepressedwomenwhoalsotookestrogen,121,122whereastwootheropen-labelstudiesshowednodifferenceinresponseorremissionratesinperi-orpostmenopausaldepressedwomentreatedwithSSRIswhoweretakingversusnottakingestrogen.
123,124Intheanalysisofthelargepooleddatasetoftrialsofvenlafaxine,SSRIs,andplacebodiscussedabove,concomitantuseofHTinthepostmenopausalwomeneliminatedthedisparityinresponseratestoSSRIsinpre-versuspostmenopausalwomen;HTdidnotaffectresponseratestovenlafaxine.
106Inasmalldouble-blindplacebo-controlledtrial,estrogenaugmentationimprovedantidepres-santresponseinperimenopausalwomenwithMDDinpartialremission.
125EFFECTSOFHORMONETHERAPYONDEPRESSIONDoesHThaveaneffectondepressivedisordersinperimenopausalwomenAtleastfoursmallstudies—includingtwoRCTs—havedemonstratedtheefficacyofestradiolforthemanagementofdepressivedisorders(eg,MDD,dysthymiaorminordepres-sion)duringperimenopause(SeeTable5).
65,121,126,127ThetwoRCTShadsimilardesignsandareconsideredofhighqualitybecauseoftheuseofstandardizedtoolstoconfirmthediagnosisofdepression,thecharacterizationofmenopausestagingusingFSHlevelsandhistoryofmenstrualirregularity,andmonitoringoftreatmentcompliancewithserumestradiolmeasurements.
65,126Antidepressanteffectswerewelldocu-mented(reductioninCES-D,HDRS,andMADRSscores),andsignificantmoodimprovementwasobservedinthoseexperiencingnew-onsetorrecurrentdepressioninthepres-enceorabsenceofconcomitantVMS.
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period,evenafterre-emergenceofVMSandnightsweats.
126TherearenoRCTsofcombinationestrogenplusprogestogenfordepressioninperimenopausalwomen.
DoeshormonetherapyhaveaneffectondepressivedisordersinpostmenopausalwomenSeveralsmallRCTshaveexaminedtheefficacyofHTonmoodinpostmenopausalwomenwithdepressivedisordersandsuggestthatHTisnotefficaciousinthispopulation.
Inan8-weekstudy,bothtransdermalestradiol(0.
1mg)andplaceboimproveddepressivesymptoms(HDRSscoresorCES-Dscores)inlatepostmenopausalwomen(N57;meanage67y;$16yafterFMP)withmild-to-moderatedepres-sion.
128Ina24-weektrialof129postmenopausalwomen129withminortomajordepressiveepisode(meanage55y)combinationestradiolvalerate(2mg/d)plusdienogest(2mg/d)significantlyimprovedmood(HDRS)comparedwithplacebo.
However,thedropoutratewasunusuallyhighinbothHT(33%)andplacebogroups(58%).
Inan8-weekrandomized,placebo-controlledtrialof72peri-andpostmen-opausalwomen(meanage51y)withdepressionofmildtomoderateseverityandsignificantinsomniaandVMS,trans-dermalestradiol(0.
05mg/d),zolpidem(10mg/d),andpla-ceboeachimproveddepressivesymptoms(MADRSscores)andtherewasnomeaningfuldifferencesbetweenactivetreatmentgroupsandplacebo.
Overallimprovementinmoodwassignificantlycorrelatedwithanincreaseinserumestra-diolovertime(perimenopausalwomenonly)andimprove-mentinperceivedsleepquality(peri-andpostmenopausalwomen),butnottoVMSorchangesinobjectivemeasuresofsleep.
66Thereareinsufficientdataonestrogenplusproges-togenfordepressioninpostmenopausalwomentoguidetreatmentchoice.
Newevidenceindicatesthatcertainwomenareparticularlyvulnerabletodepressedmoodfollowingestrogenwithdrawal.
Asymptomaticpostmenopausalwomen(N56)withhistoryofperimenopausaldepressionwereadministeredtransdermalestradiol(100mg/d)inanopen-labelfashionforthreeweeksandthenwererandomizedtoreceiveeithertransdermalestradiolorplacebofor3additionalweeksinadouble-blindfashion.
130Althoughfreeofdepressivesymptomsduringtheopen-labelestradiolphase,womenwhowerecrossedoverfromestradioltoplacebo–thatis,whoexperiencedestrogenwithdrawal-reportedanincreaseindepressivesymptoms(CES-DandHDRS),whereasthosewhoremainedonestra-dioltherapycontinuedtobeasymptomatic.
Hotflashseverityandplasmaestradiollevelsweresimilarbetweentreatmentandplacebophases.
DoesHTpreventdepressivesymptomsduringthemenopausaltransitionTodateonlyonerandomizedtrialhasinvestigatedtheefficacyofHTinpreventingtheonsetofsignificantdepres-sivesymptomsineuthymicperimenopausalandearlypostmenopausalwomen.
131Atotalof172euthymicperimen-opausalorearlypostmenopausalwomenwererandomlyTABLE5.
Randomizedtrialsofhormonetherapyfordepressedperi-andpostmenopausalwomenAuthorsPopulationStudied(Type,n)DesignInterventionOutcomeMeasuresKeyfindingsSchmidtetal.
,2001Perimenopause-relateddepression(n31)DB,PLParallelstudyfollowedbycrossover,PLcontrolledET(transdermalE2),followedbyMPAHDRS,CES-DscoresETledtosignificantimprovementsindepressivesymptoms(HDRSandCES-Dscores)Soaresetal.
,2001Perimenopause-relateddepression(n45)DB,PLParallelstudyET(transdermalE2)MADRSscoresETledtosignificantimprovementsindepressivesymptoms(MADRSscores)Rudolphetal.
,2004Postmenopausalwomenwithmild/moderatedepressivesymptoms(n129)DB,PLParallelstudyEPT(oralE2valerateprogestin[dienogest])HDRSscoresEPTledtoimprovementsinHDRSscores;highattritionratesinbothgroupsMorrisonetal.
,2004Postmenopausalwomenwithdepressivedisorders(n57)DB,PLParallelstudyET(transdermalE2)followedbyMPAHDRS,CES-DscoresNodifferenceswithactivetreatment(bothgroupsshowedimprovement)Joffeetal.
,2011Mixedperi-andpostmenopausalwomenwithdepressivesymptoms,VMSandinsomnia(n72)DB,PLParallelstudyET(transdermalE2),ZolpidemMADRS,BDI,PSQIscoresNosignificantdifferenceswithrespecttomoodchangesbetweentreatmentandPLgroupsBDI,BeckDepressionInventory;CES-D,CenterforEpidemiologicStudies-DepressionScale;DB-Doubleblind;EPT,estrogen-progestintherapy,E2,estradiol;ET,estrogentherapy;HDRS,HamiltonDepressionRatingScale;MADRS,Montgomery-AsbergDepressionRatingScale;MPA,medroxyprogesteroneacetate;PL,placebo;PSQI,PittsburghSleepQualityIndex.
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assignedtoreceiveeithertransdermalestradiol(0.
1mg/d)plusintermittentoralmicronizedprogesterone(200mg/dfor12daysevery3months)orplacebopatchespluspills.
After12months,womenreceivingactiveHTweresignificantlylesslikelytodevelopelevateddepressionscorescomparedwithwomenreceivingplacebo(32.
3%vs17.
3%).
Theseeffectsweremodifiedbystressfullifeevents,withgreaterbenefitsforwomenwithstressfullifeeventsintheprecedingsixmonths,andasuggestionthatwomenintheearlyperimen-opausalstagemayhavemorebenefitthanwomeninothermenopausestages.
Unexpectedly,VMSandhistoryofMDD(33%ofsample)didnotmodifytheeffectofHTonprevent-ingdepressivesymptoms.
HormonalcontraceptivesinperimenopausalwomenForperimenopausalwomen,hormonalcontraceptivespro-videcontraceptiveaswellasnon-contraceptivebenefits,includingrestoringregularmenses,decreasingdysmenorrhea,reducingheavymenstrualbleeding,andtreatingVMS.
132Althoughthesebenefitshavethepotentialtoimprovemood,therearenopublishedrandomizedtrialsoropen-labeltrialsofhormonalcontraceptivesinwomenwithclinicaldepression.
TheFoodandDrugAdministration(FDA)approveda24/4regimenofdrospirenone(3mg)andethinylestradiol(0.
02mg)pillforthetreatmentofpremenstrualdysphoricdisorder(PMDD).
133,134AcombinationpillthatalsoincludeslevomefolateisalsoFDAapprovedforthetreatmentofPMDD.
Neitherformulation,however,hasbeenstudiedinwomenwithdepression.
Generally,forperimenopausalwomen,continuousoralcontraceptivepills(OCPs)orcyclicOCPswithalow-doseestradiolpatchduringplaceboweekareused.
Duringpill-freedays,perimenopausalwomencanexperienceworseningofmenopausalsymptoms,socontinu-ousoralcontraceptivehormoneuse,whichiseffectiveinsymptomcontrolisgenerallypreferredovercyclicwithpill-freedays.
135Althoughithasnotbeenstudiedindepression,analternativeoptionthatisusedintheperimenopauseistransdermalestrogenplusalevonorgestrelintrauterinesys-tem,whichprovidesendometrialprotectionandcontraceptionanddecreasesVMSinperimenopausalwomen.
136EFFECTOFOTHERTHERAPIESONDEPRESSIONANDDEPRESSIVESYMPTOMSINMIDLIFEWOMENWhatnonpharmacologictherapieshaveatleastpreliminaryevidenceformenopause-relateddepressivedisordersCognitive-behavioraltherapy(CBT).
CBTisatime-limitedpsychotherapytohelppatientsassessandmodifydistorted,depression-promoting,automaticthoughtsaboutthemselves,theircurrentsituations,andtheirfutures.
Thesecognitivetechniquesarepairedwithbehavioralinterventionstocombatpassivedisengagementfromlifeactivities.
CBThasbeenshowntobeeffectiveforreducingsymptomsofdepression,preventingdepressiverelapsesinthegeneralpopulation,137andtreatingdepressivesymptomsinprimarycaresettings.
138Practiceguidelineshavepreferentiallyrecommendedantide-pressantpharmacotherapyoverpsychotherapyforsevereepisodesofdepressioningeneraladultpopulations;however,recentevidencesuggeststhatbaselinedepressionseveritymaynotmoderatedifferencesinantidepressantefficacybetweenCBTandantidepressantpharmacotherapyforadultswithdepression.
139CombiningCBTandantidepressantphar-macotherapymaybemoreeffectiveforreducingdepressivesymptoms,improvingrecoveryrates,andincreasingadher-encetotreatmentthanmedicationalone.
140CBTalsoappearstobeaseffectiveascontinuingantidepressanttreatmentforpreventingrelapses.
141TwoclinicaltrialsprovideinitialevidencethatCBTimprovesdepressionrelatedtothemenopause.
Inthefirststudy,44womenoutpatients(meanage49y,52%peri-menopausal,48%premenopausal)whowerenottakingHTwererandomlyassignedtoreceivetwice-weeklygroupCBT(16sessions)oranundefinedcontrolcondition.
142GroupCBT,butnotthecontrolcondition,ledtoasignificantimprovementindepressivesymptoms(BDI)frombaseline.
Similarresultswereevidentinanalysesofperimenopausalwomenonly.
Inasecondstudy,individualCBT(16sessions)wasdeliveredto353women(meanage42y)whowerenottakingorwerewithdrawnfrompsychotropicmedication.
143Classificationofmenopausalstagewasdefinedaccordingtonon-validatedcriteriawith169classifiedaspremenopausal,76asperimenopausalbasedonagerange(42-51.
5y)andatleastonemenstrualperiodreportedwithintheyearbeforetrialentry,andtheremaining108participantsaspostmenopausal.
Overall,93participants(55%)showedapositivetreatmentresponsedefinedas50%orgreaterimprovementindepres-sivesymptoms(HDRS)frombaseline,andratesdidnotdifferbymenopausestatus.
Twenty(26%)perimenopausaland30(28%)postmenopausalparticipantsachieveddepressivesymptomremission,definedasaHDRStotalscore6orlessatstudyexit.
ThereispreliminarysupportthatthecoreelementsofCBTthathavebeenshowntobeefficaciousindepressiontreatmentinthegeneralpopulationmayalsoapplytopatientswithdepressionrelatedtothemenopausetransition.
However,thelackofappropriatecontrolconditionsandlackofstandard-izedcriteriatodefinemenopausalstagelimitthedataquality.
Large,randomizedtrialsofCBTspecificallydesignedforwomenwithdepressionrelatedtomenopausetransitionareneeded.
However,giventhestrongevidencebasesupportingindividualorgroupCBTfordepressioninthegeneralpopu-lation,therelativelylowriskofharms,andthepreliminaryevidencesupportingtheseinterventionsinperimenopausalandpostmenopausalwomen,CBTisareasonableoptionfortreatmentofdepressionrelatedtothemenopausetransition.
WhattherapiesareeffectivefordepressioningeneralbuthavenotbeenstudiedinthemenopauseSeveraltherapiesarerecommendedfordepressioningen-eralbuthavenotbeenstudiedinthemenopause.
TheseincludethepsychotherapiesinterpersonaltherapyandMAKIETAL1080Menopause,Vol.
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mindfulness-basedcognitivetherapy(MBCT).
Therapiesrecommendedfortreatment-resistantdepressionthathavenotbeenstudiedspecificallyformenopause-relateddepres-sionincludeelectroconvulsivetherapy(ECT),transcranialmagneticstimulation(TMS),andvagusnervestimulation.
Similarly,lighttherapyforpatientswithseasonalaffectivedisorderhasnotbeenstudiedspecificallyforwomeninthemenopausetransition.
ACochranemeta-analysisofclinicaltrialsofexerciseforthetreatmentofMDDinadultsover18foundthatexercisereducesdepressionsymptoms,butinhigh-qualitystudies,exerciseconfersonlysmallbenefits.
144Ameta-analysisofclinicaltrialsofexercisefordepressivesymptomsinmidlifeandolderwomenwithoutMDDfoundthatexerciseimproveddepressivesymptoms.
145SUMMARYANDGUIDELINESOnthebasisofthedata,theexpertpanelmakesthefollowingrecommendationsfortheevaluationandtreatmentofdepressionduringthemenopausetransition.
EpidemiologyTheperimenopauseisawindowofvulnerabilityforthedevelopmentofbothdepressivesymptomsandmajordepressiveepisodes.
Theriskofdepressivesymptomsiselevatedduringtheperimenopauseeveninwomenwithnohistoryofmajordepressivedisorder.
MostmidlifewomenwhoexperienceaMDEduringtheperimenopausehaveexperiencedapriorepisodeofdepres-sion;therefore,theepisoderepresentsrecurrenceoftheirillness.
FirstlifetimeonsetofMDDduringthistimeislesscommon.
Dataaremixedaboutwhetherwomenwhoundergosurgi-calmenopauseareatincreasedordecreasedriskfordevelopingdepressioncomparedwithwomenwhotransi-tionthroughmenopausenaturally.
However,recentlarge-scalestudiesshowanelevatedriskofdepressioninwomenfollowinghysterectomywithandwithoutoophorectomy.
Womenwithprimaryovarianinsufficiencyalsohaveshownelevatedratesofdepression.
Riskfactorsfordepressivesymptomsduringtheperimen-opauseincludepriorMDD,sociodemographicfactors(eg,youngerage,blackrace,financialdifficulties),psychosocialfactors(adverselifeevents,lowsocialsupport),menopausesymptoms(VMS,sleepdisturbance),anxietysymptoms,andreproductive-relatedmooddisturbance(eg,postpartumand/orpremenstrualdepressivesymptoms).
RiskfactorsforMDDduringtheperimenopauseincludementalhealthfactors(priorMDD,currentuseofantide-pressants,anxiety,traitanxiety,premenstrualdepressivesymptoms),sociodemographicfactors(blackrace,highBMI,youngerage),psychosocialfactors(upsettinglifeevents,socialisolation),andmenopausalsymptoms(espe-ciallysleepdisturbance).
ClinicalpresentationDepressionduringmidlifepresentswithclassicdepressivesymptoms,commonlyincombinationwithmenopause-specificsymptoms(ie,VMS,sleepdisturbance)andpsychosocialchallenges.
Severalcommonsymptomsoftheperimenopause(hotflashes,nightsweats,sleepandsexualdisturbances,weight/energychanges,cognitiveshifts)complicate,co-occur,andoverlapwiththepresentationofdepressionduringthisstage.
Vasomotorsymptomsareassociatedwithdepressivesymp-tomsbutnotMDEs,exceptinwomenwithfirstlifetimeonsetofadepressiveepisodeduringtheperimenopause.
Lifestressorsthatarecommonforwomenatmidlife(eg,caringforchildrenandparents,careerandrelationshipshifts,aging,bodychanges)andpersonal/familyillnesscanadverselyaffectmoodbut''emptynest''and''revolvingdoor''havelittleenduringeffect.
AssessmentanddiagnosisEvaluationincludesidentificationofmenopausestage,assessmentofco-occurringandoverlappingmenopauseandpsychiatricsymptoms,considerationofpsychosocialriskfactors,appreciationofthedifferentialdiagnosis,anduseofscalestoaidindisentanglingsymptomsanddistinguishingdiagnoses.
WomenwithpastMDEs(notnecessarilyhormonerelated)andwomenwithseveredepressivesymptomsand/orsui-cidalideationshouldalwaysbeevaluatedforamooddisorder.
Thedifferentialdiagnosisofdepressionduringtheperi-menopauseincludesMDD,subsyndromaldepression,adjustmentdisorder,psychologicaldistress,bereavement,depressiveepisodesassociatedwithbipolardisorder,andgeneralmedicalcausesofdepression.
Amenopause-specificmood-disorderscaledoesnotexist;however,severalgeneralvalidatedscreeningmeasures(eg,PHQ-9)maybeusedforcategoricaldeterminationofmooddisorderdiagnoses.
Validatedmenopausesymptomandhealth-relatedqualityoflifescales(eg,MRS,MENQOL,GreeneClimactericScale,UtianQuality-of-LifeScale)includemooditemsandmaybeusefulinclarifyingthecontributionofmenopause-relatedsymptoms.
TreatmentofMDDwithantidepressantsandpsychotherapyProventherapeuticoptionsfordepression(ie,antidepres-sants,CBTandotherpsychotherapies)shouldremainasfront-lineantidepressanttreatmentsforMDEsduringtheperimenopause.
ExistingdataonvariousSSRIandSNRIantidepressants(includingcitalopram,desvenlafaxine,duloxetine,escita-lopram,fluoxetine,sertraline,andvenlafaxine)suggestgoodefficacyandtolerabilityatusualdoses.
InwomenwithahistoryofMDD,aprioradequateresponsetoaparticularantidepressantshouldguidetreatmentselectionwhenMDDrecursduringmidlifeyears.
Onlydesvenla-faxinehasbeenstudiedandprovenefficaciousinlargerandomizedplacebo-controlledtrialsofwell-definedperi-andpostmenopausaldepressedwomen.
Selectionofantidepressantsduringtheperimenopauseshouldconsiderthewoman'spriorantidepressanttrialsandresponses,availabledataonefficacyandtolerabilityinPERIMENOPAUSALDEPRESSIONGUIDELINESMenopause,Vol.
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thisspecificpopulation,managementofchallengingadverseeffects(eg,sexualdysfunction,weightchanges)andsafety(eg,drug-druginteractions),giventhelikelihoodofconcomitantuseofothermedicationsduringthisstageoflife.
InadditiontotheirefficacyintreatingMDD,manyanti-depressants(SSRIsandSNRIs)alsoimprovemenopause-relatedcomplaints(eg,VMS,pain).
Cliniciansshouldalsoconsidertreatingco-occurringsleepdisturbanceandnightsweatsaspartoftreatmentformenopause-relateddepression.
EstrogentherapyThereissomeevidencethatEThasantidepressanteffectsofsimilarmagnitudetothatobservedwithclassicantidepressantagentswhenadministeredtodepressedperimenopausalwomenwithorwithoutconcomitantVMS.
Estrogentherapyisineffectiveasatreatmentfordepres-sivedisordersinpostmenopausalwomen.
SuchevidencesuggestsapossiblewindowofopportunityfortheeffectiveuseofETforthemanagementofdepressivedisordersduringtheperimenopause.
ThereissomeevidencethatETenhancesmoodandimproveswell-beinginnon-depressedperimenopausalwomen.
Hormonalcontraceptives—particularlywhenusedcontin-uously—haveshownsomebenefitsformoodregulationandmayimprovedepressivesymptomsinwomenapproachingmenopause.
Transdermalestradiolwithintermittentmicronizedpro-gesteronemaypreventtheonsetofdepressivesymptomsineuthymicperimenopausalwomen,buttheevidenceisnotsufficienttorecommendestrogen-basedtherapiesforpreventingdepressioninasymptomaticperi-orpost-menopausalwomenandtherisksandbenefitsmustbeweighed.
Estrogen-basedtherapiesmayaugmentclinicalresponsetoantidepressantsinmidlifeandolderwomenbuttheiruseshouldbeconsideredwithcaution–ie,preferablywhenalsoindicatedforotherconcurrentconditionssuchasVMS.
MoststudiesonHTforthetreatmentofdepressionexam-inedtheeffectsofunopposedestrogen.
DataoncombinedHT(estrogenplusprogestogen)orfordifferentprogesto-gensaresparseandinconclusive.
EstrogenisnotFDAapprovedtotreatmooddisturbance.
AlternativetherapiesTheavailableevidenceisinsufficientforrecommendinganybotanicalorcomplementary/alternativeapproachesfortreatingdepressionrelatedtotheperimenopause.
Itisreasonabletorecommendexerciseinperi-andpost-menopausalwomenwithdepression,particularlywhenusedincombinationwithrecommendedpsychotherapiesandpharmacotherapies.
Acknowledgments:TheauthorswouldliketothankDr.
NicoleJaffforherhelpfulsuggestionsandcarefulreviewofthemanuscript.
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