Relationship between depression and frailty in older adults : a systematic review and metaanalysis

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ContentslistsavailableatScienceDirect

Ageing

Research

Reviews

j o ur na l h o me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / a r r

Review

Relationship

between

depression

and

frailty

in

older

adults:

A

systematic

review

and

meta-analysis

Pinar

Soysal

a

_,

_Nicola

_Veronese

b,c

,

Trevor

Thompson

d

,

Kai

G. Kahl

e

,

Brisa

S. Fernandes

f,g

,

A. Matthew

Prina

h

_,

_Marco

_Solmi

c,i,j

,

Patricia

Schofield

k

,

Ai

Koyanagi

l,m

,

Ping-Tao

Tseng

n

,

Pao-Yao

Lin

o,p

,

Che-Sheng

Chu

q

,

Theodore

D. Cosco

r,s

,

Matteo

Cesari

t,u

,

Andre

F. Carvalho

v

_,

_Brendon

_Stubbs

h,k,w,∗

a_Kayseri_Education_and_Research_Hospital,_Geriatric_Center,_Kayseri,_Turkey b_National_Research_Council,_Neuroscience_Institute,_Aging_Branch,_Padova,_Italy c_Institute_of_Clinical_Research_and_Education_in_Medicine_(IREM),_Padova,_Italy d_Faculty_of_Education_and_Health,_University_of_Greenwich,_London,_United_Kingdom

e_Department_of_Psychiatry,_Social_Psychiatry_and_{Psychotherapy,}_Hannover_Medical_School,_{Carl-Neuberg-Str.}_1,₃₀₆₂₅_Hannover,_Germany f_IMPACT_Strategic_Research_Centre,_Deakin_University_School_of_Medicine,_and_Barwon_Health,_Geelong,_VIC,_Australia

g_Laboratory_of_Calcium_Binding_Proteins_in_the_Central_Nervous_System,_Department_of_{Biochemistry,}_Federal_University_of_Rio_Grande_do_Sul,_Porto_Alegre, Brazil

h_Health_Service_and_Population_Research_Department,_Institute_of_Psychiatry,_Psychology_and_{Neuroscience,}_King’s_College_London,_De_Crespigny_Park, London,BoxSE58AF,UnitedKingdom

i_Department_of_{Neurosciences,}_University_of_Padova,_Padova,_Italy j_Local_Health_Unit_17,_Mental_Health_Department,_Padova,_Italy

k_Faculty_of_Health,_Social_Care_and_Education,_Anglia_Ruskin_University,_Chelmsford,_United_Kingdom

l_Research_and_Development_Unit,_Parc_Sanitari_Sant_Joan_de_Déu,_Universitat_de_Barcelona,_Fundació_Sant_Joan_de_Déu,_Dr._Antoni_Pujadas,_42,_Sant_Boi_de Llobregat,Barcelona08830,Spain

m_Instituto_de_Salud_Carlos_III,_Centro_de_{Investigación}_Biomédica_en_Red_de_Salud_Mental,_CIBERSAM,_Monforte_de_Lemos_3-5_Pabellón_11,_Madrid_28029, Spain

n_Department_of_Psychiatry,_Tsyr-_Huey_Mental_Hospital,_Kaohsiung_Jen-Ai’s_Home,_Taiwan

o_Department_of_Psychiatry,_Kaohsiung_Chang_Gung_Memorial_Hospital_and_Chang_Gung_University_College_of_Medicine,_Kaohsiung_City,_Taiwan p_Institute_for_{Translational}_Research_in_Biomedical_Sciences,_Kaohsiung_Chang_Gung_Memorial_Hospital,_Kaohsiung,_Taiwan

q_Kaohsiung_Veterans_General_Hospital,_Kaohsiung_City,_Taiwan

r_MRC_Unit_for_Lifelong_Health_and_Ageing_at_UCL,₃₃_Bedford_Place,_London_WC1_B5JU,_United_Kingdom s_Oxford_Institute_of_Population_Ageing,_University_of_Oxford,₆₆_Banbury_Road,_Oxford,_OX2_6PR,_United_Kingdom t_Inserm_UMR1027,_Université_de_Toulouse_III_Paul_Sabatier,_Toulouse,_France

u_{Gérontopôle,}_Centre_Hospitalier_{Universitaire}_de_Toulouse,_Toulouse,_France

v_{Translational}_Psychiatry_Research_Group_and_Department_of_Clinical_Medicine,_Faculty_of_Medicine,_Federal_University_of_Ceará,_Fortaleza,_CE,_Brazil w_{Physiotherapy}_Department,_South_London_and_Maudsley_NHS_Foundation_Trust,_Denmark_Hill,_London_SE5_8AZ,_United_Kingdom

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received2February2017

Receivedinrevisedform7March2017 Accepted21March2017

Availableonline31March2017

Keywords: Depression Frail Geriatrics Olderadults Meta-analysis Psychiatry

a

b

s

t

r

a

c

t

Aim:Depressionandfrailtyareprevalentandburdensomeinolderage.However,therelationships betweentheseentitiesareunclearandnoquantitativemeta-analysisexists.Weconductedasystematic reviewandmeta-analysistoinvestigatetheassociationsbetweendepressionandfrailty.

Methods:TwoauthorssearchedmajorelectronicdatabasesfrominceptionuntilNovember-2016for cross-sectional/longitudinalstudiesinvestigatingdepressionandfrailty.Thestrengthofthereciprocal associationsbetweenfrailtyanddepressionwasassessedthroughoddsratios(ORs)adjustedforpotential confounders.

Results:From2306nonduplicatedhits,24studieswereincluded.Theoverallprevalenceof depres-sionin8023peoplewithfrailtywas38.60%(95%CI30.07–47.10,I2₌_94%)._Those_with_frailty_were_at increasedoddsofhavingdepression(ORadjustedforpublicationbias4.42,95%CI2.66–7.35,k=11), alsoafteradjustingforpotentialconfounders(OR=2.64;95%CI:1.59–4.37,I2₌_55%,_k₌_4)._The preva-lenceoffrailtyin2167peoplewithdepressionwas40.40%(95%CI27.00–55.30,I2₌_97%)._People_with depressionwereatincreasedoddsofhavingfrailty(OR=4.07,95%CI1.93–8.55,k=8).ThepooledORfor incidentfrailty,adjustedforamedianof7confounders,was3.72(95%CI1.95–7.08,I2₌_98%,_k₌_4),_whilst intwostudiesfrailtyincreasedtheriskofincidentdepressionwithanOR=1.90(95%CI1.55–2.32,I2₌_0%).

∗_{Corresponding}_author_at:_{Physiotherapy}_Department,_South_London_and_Maudsley_NHS_Foundation_Trust,_Denmark_Hill,_London,_United_Kingdom. E-mailaddress:[email protected](B.Stubbs).

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Conclusion:Thismeta-analysispointstoareciprocalinteractionbetweendepressionandfrailtyinolder adults.Specifically,eachconditionisassociatedwithanincreasedprevalenceandincidenceoftheother, andmaybeariskfactorforthedevelopmentoftheother.However,furtherprospectiveinvestigations arewarranted.

Contents

1. Introduction...79

2. Materialsandmethods...80

2.1. Searchstrategy...80

2.2. Studyselection...80

2.3. Dataextraction...80

2.4. Outcomes...80

2.5. Assessmentofstudyquality...80

2.6. Statisticalanalysis...80

3. Results ... 80

3.1. Studyandparticipants’characteristics...81

3.2. Measurementoffrailty...81

3.3. Measurementofdepression...82

3.4. Cross-sectionalmeta-analysisfindings...82

3.4.1. Prevalenceofdepressioninpeoplewithfrailty...82

3.4.2. Oddsofdepressioninpeoplewithfrailtyversuscontrols...82

3.4.3. Prevalenceoffrailtyinpeoplewithdepression...82

3.4.4. Oddsoffrailtyinpeoplewithdepressionversuscontrols...83

3.5. Longitudinalmeta-analysisfindings...83

3.5.1. Studiesinvestigatingincidentfrailtyinolderpeoplewithdepression ... 83

3.5.2. Studiesinvestigatingincidentdepressionamongpeoplewithfrailty...83

4. Discussion...83

5. Limitations...85

Conflictofinterest...86

Financialdisclosure...86

AppendixA. Supplementarydata...86

References...86

1. Introduction

Frailtyanddepressionaretwocommonandpervasive medi-calconditionsamongolderadults.Theprevalenceofdepression inolderagerangesfrom10to20%(Roddaetal.,2011)andthe prevalence of frailty is estimated to be similar (Collard et al., 2012).Recentstudieshavesuggestedthat16–35%offrail individ-ualshave alsoexperiencedco-existing depression,and thatthe prevalenceofdepression infrail individualsis ashighas46.5% ınolderadults(Buiguesetal.,2015).Bothdepressionandfrailty areassociatedwitharangeofdeleteriousoutcomesinolderage suchaslower qualityof life(QOL), increaseduseof healthcare services,increased morbidity and mortality(Clegget al., 2013; FugateWoodsetal.,2005;Hareetal.,2014;Roddaetal.,2011). Furthermore,co-existingdepressionandfrailtyisassociatedwith particularlyworseoutcomessuchasacceleratedcognitive impair-mentanddisability(Potteretal.,2016).Thereareseveralreasons thatmay accountfor thehighlevelsofcommorbidity between depressionandfrailty.Oneistheoverlapinsomeareasofdiagnostic criteria,e.g.unintentionalweightloss,makingitdifficultto distin-guishfromeachother,particularlywithadvancingage.Another factoristhatdepressionandfrailtyhavesomecommonetiology thatmakesdisentanglementdifficult(Brownetal.,2014).Giventhe highlevelsofdepression(Buiguesetal.,2015)andfrailty(Soysal etal.,2016)inolderageandthedeleteriousoutcomeswhenthey co-exist,understandingtherelationshipbetweenthesefactorsis ofutmostimportance.

Despitethepublichealthimportance,theprevalenceand inci-denceofdepressionamongpeoplewithfrailtyandtheopposite

relationship is largelyunknown.The convergence of thefrailty anddepressionspectruminmid-andlate-lifealsogiverisetothe hypothesisof‘overlappingsyndromes’(Katz,2004),withpossible biologicalmechanismsaccountingforbothsyndromes(Vaughan etal.,2015).Mostevidencetodatesuggeststhatthefrailtyand depressioncriteriaconsistofahighlyoverlappingbutdistinct sub-population(Mezuketal.,2013);moreover,theassociationbetween thetwoconstructscannotbefullyexplainedbytheoverlapping oftheirsymptoms(Lohman,2013)sofrailtyanddepressionmust beconsideredinterrelatedratherthanoverlappingsyndromes.To date,previousnarrativeand/orselectivereviewshavesuggested theremaybearelationshipbetweenfrailtyanddepression(Brown et al., 2016; Buigues et al., 2015; Mezuket al., 2012; Benraad etal.,2016;Dreyetal.,2011).Forinstance,oneprevious narra-tivesystematicreview(Vaughanetal.,2015)suggestedthatthe co-occurrenceofdepressionand frailtywasgreaterthan10%in olderadults ≥55years old,but notedthat thereis considerable variationintheestimatesandameta-analysiswasnotconducted. Todate,tothebestofourknowledge,nometa-analysishasbeen conductedtoconsidertherelationshipbetweendepressionand frailty.

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2. Materialsandmethods

This systematic review was conducted according to the Strengthening the Reporting of Observational Studies in Epi-demiology [STROBE] criteria (von Elm et al., 2008) and the recommendationsinthePreferredReportingItemsforSystematic Reviewsand Meta-Analyses[PRISMA]statement(Liberatietal., 2009).Thereviewfollowedapredetermined,butunpublished pro-tocol.

2.1. Searchstrategy

Twoindependentauthors(BSandNV)searchedMedline(via Ovid), Psychinfo and EMBASE for studies from inception until 11/2016withnolanguagerestrictions.Thesearchtermsusedwere (frailtyorfrail*)and(depress*ordepressiveormajordepressive disease).Conferenceabstractswerealsoincludedandtheauthors werecontactedforobtainingmissinginformationatleasttwotimes inamonth.

2.2. Studyselection

Includedstudieswerepublishedquantitativestudiesofacross sectionalorlongitudinaldesignthat:(1)Reportedtheprevalence orincidenceof frailty<--->depression in olderadults witha meanage over 60 years and older;(2) Capturedfrailtywith a recognizedcriteria (e.g.Fried’s criteria (Fried et al., 2001)); (3) Captureddepressionaccordingtostructuredinterviewdiagnostic criteria(e.g.DSMandmajordepressivedisorder(MDD))or depres-sivesymptomswithavalidateddepressionscreeningmeasure(e.g. CenterforEpidemiologicStudiesDepressionScale(CES-D)(Radloff, 1977))(henceforthcalled‘depression’,althoughwherepossiblein theresultswedifferentiatebetweenMDDanddepressive symp-toms);and(4) includeda controlgroup(pre-frailandrobustas separateentitiesortogether).

Studieswereexcludedifthey(1)didnotuseaclear diagnos-ticcriteriaforfrailtyoronlyusedoneitemforitsdiagnosis(e.g. lowgaitspeed)or (2)reporteddepression withanunvalidated screeningtoolormeasure.

2.3. Dataextraction

Twoauthors(NV,PS)independentlyextracteddatafromthe selectedstudies in a standardized Microsoft Excel spreadsheet. Anydisagreementwasresolvedbyconsensuswithathirdauthor (BS).Thefollowinginformationwasextracted:1)characteristics ofthestudypopulation(e.g.samplesize,demographics,country inwhichthestudywasperformed);2)settinginwhichthestudy wasperformed;3)diagnosticcriteriaforfrailtyanddepression;4) demographiccharacteristics(meanageandpercentageofwomen) byfrailtyanddepressionstatus;5)typeandnumberofadjustments inthemultivariateanalyses(forlongitudinalstudies);6)follow-up period(onlyforlongitudinalstudies).

Ifwerequiredadditionaldatatoeitherconfirmorenablestudy inclusion,wecontactedtheprimaryauthorsuptothreetimesover amonthperiod.

2.4. Outcomes

The primary outcomes were a) the prevalence and comor-bidoddsofdepression/depressivesymptomsinfrailtyandb)the prevalenceand comorbidoddsoffrailtyinpeoplewith depres-sion/depressivesymptoms.Inaddition,wecalculatedtheincidence ofc)depression/depressivesymptomsonsetinpeoplewithfrailty, andd)frailtyonsetinpeoplewithdepression/depressive symp-toms.

2.5. Assessmentofstudyquality

Studyqualitywasassessedbytwoinvestigators(PS,BS)using theNewcastle-Ottawa Scale (NOS) (Wells et al., 2012). A third reviewerwasavailableformediation(NV).TheNOSassignsa max-imumof 9pointsbased onthree qualityparameters:selection, comparability,andoutcome(Wellsetal.,2012).

2.6. Statisticalanalysis

Analyseswereperformedbytwoindependentinvestigators(BS, NV)using ComprehensiveMeta-Analysis (CMA) 3(http://www. meta-analysis.com).Duetotheanticipatedheterogeneity,a ran-dom effects meta-analysis was undertaken. The analyseswere conductedinthefollowingsteps.First,theprevalenceofdepression amongpeoplewithfrailtytogetherwith95%confidenceintervals (CIs)wascalculated.Second,theoddsratioand95%CIoffrailty amongpeoplewithandwithoutdepressionwascalculated.Third, theprevalenceoffrailtyamongpeoplewithdepressionand95%CI wascalculated.Fourth,theoddsratioand95%CIoffrailtyamong peoplewithandwithoutdepressionwascalculated.Foreachofthe aboveanalyses,whenpossible,weconductedsubgroupanalyses investigatingdifferencesaccordingtogeographicalregion,study setting, depression classification(structured clinical assessment versusscreeningmeasure)andfrailtymeasure(e.g.Friedcriteria versusothers)(Friedetal.,2001).Whereavailable,adjusted esti-matesoftheassociationbetweenfrailtyanddepression (orthe contrary)wereextractedandpooledasORs.Finally,ORsadjusted forthemaximumnumberofcovariatesavailableforeachstudy wereusedtoassesstheassociationbetweenfrailty(ordepression) atthebaselineandincidentdepression(orfrailty)atfollow-up.

StudyheterogeneitywasmeasuredusingtheCochran’sQand I-squaredstatistics,assumingthata p≤0.10 fortheformer and a value≥50%for thelatterindicated asignificantand substan-tialheterogeneity(HigginsandThompson,2002).Givensignificant heterogeneity,ameta-regressionanalysiswasperformedusing dif-ferencesinmeanage,bodymassindex(BMI)andpercentageof females amonggroups (frail,pre-frail,robust)asmoderators in singlemetaregression.Publicationbiaswasassessedbyvisually inspectingfunnelplots,andtoaccountforpublicationbias,weused theDuvalandTweedietrim-and-fillmethod(DuvalandTweedie, 2000),basedontheassumptionthattheeffectsizesofallthe stud-iesarenormallydistributedaroundthecenterof afunnelplot; intheeventofasymmetries,itadjustsforthepotentialeffectof unpublishedstudies.

3. Results

Thesearchidentified2306non-duplicatedpotentiallyeligible studies.Followingadetailedreviewoftitleandabstracts,atotal of63fulltextarticleswerereviewed.Theeligibilitycriteriawere appliedand 39 articles wereexcluded (reasons summarized in

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Fig.1. PRISMAflow-chart.

etal.,2016)didnotcontainanydatathatcouldbeincludedinthe meta-analysis.

3.1. Studyandparticipants’characteristics

Studyandparticipants’characteristicsofcross-sectionalstudies are summarized in SupplementaryTables 1 and 2. The major-ity of the studies were conducted among community-dwellers (n=19 (79.1%))and in North America (n=12 (50.0%)),followed byEurope(n=4),Asia(n=3),Australia(n=3),andLatinAmerica (n=2).(SupplementaryTable1).Theoverallqualityofthestudies, assessedthroughNOS,wasgenerallygoodwithamedianscore=8 (range=5–9)(FulldetailsareavailableinSupplementaryTable5). Overall12cross-sectionalstudies(Jarschiketal.,2012;Pegorari andTavares,2014;Fengetal.,2014;Matheusetal.,2016;Dentand Hoogendijk,2014;Changetal.,2010;Sanchez-Garciaetal.,2014; PatriciodeAlbuquerqueSousaetal.,2011;Friedetal.,2001;Fugate Woodsetal.,2005;Jungetal.,2016; McAdams-DeMarcoetal., 2016)investigatedtheprevalenceofdepressioninfrailtyincluding atotalof8023frailolderparticipantswithameanageof74.6years, ofwhom94.0%werefemale.Theseparticipantswerecompared with45,775participantswithnofrailty(meanage:70.2;88.1% females).Furthermore,the8crosssectionalstudiesinvestigating theprevalenceoffrailtyinpeoplewithdepression(Collardetal., 2014;Lohmanetal.,2016;Almeidaetal.,2015;Brownetal.,2014;

Lohmanetal.,2014;Mezuketal.,2013;PaulsonandLichtenberg, 2013;Almeidaetal.,2016)included2164depressedolderadults

withameanageof69.3years,66.5%ofwhichwerefemales.These subjectswerecomparedwith14,932subjectswithnodepression. Inaddition,therewere311frailolderadultsinthe3 longitudi-nalstudies(Fengetal.,2014;Makizakoetal.,2015;Moninetal., 2016)(meanage75.1,39.1%females)investigatingtheincidenceof depressionoverameanfollowupof4.67years.Thesesubjectswere comparedwith5801subjectswithnofrailtyatbaseline.Finally, therewere6404depressedolderadultsin4longitudinalstudies (FugateWoodsetal.,2005;PaulsonandLichtenberg,2013;Lakey etal.,2012;Hajeketal.,2016)thatinvestigatedtheincidenceof frailtyoverameanfollowupof2.87years.Theseparticipantswere comparedwith51,610participantswithnodepression (Supple-mentaryTables3and4).

3.2. Measurementoffrailty

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Table1

Meta-analysisresultsofprevalenceandoddsofdepressioninolderpeoplewithfrailty.

Analysis Numberof study estimates

Numberof participants

Meta-analysis Between groupp value

Trimandfilleffect size(95%CI) [adjustedstudies]

I2

Prevalenceofdepressioninolderpeoplewithfrailty

Prevalence 95%CI

Mainanalysis 11 8023 38.60% 30.07 47.10 Unchanged 94

Geographicalregion 0.751

NorthAmerica 5 7478 41.08% 29.02 54.31 Unchanged 97

Asia 2 211 34.63% 17.57 56.83 N/A 46

Europe 2 147 30.12% 14.93 51.44 N/A N/A

LatinAmerica 2 190 44.02% 24.78 65.24 N/A N/A

StudySetting 0.737

Community 10 7830 39.00% 30.05 48.13 Unchanged 94

Communityandinpatients 1 96 34.02% 13.84 62.32 N/A N/A

Depressionoutcome 0.737

Screeningmeasure 10 7830 39.00% 30.05 48.13 Unchanged 94

Structuredinstrument 1 96 34.02% 13.84 62.32 N/A N/A

Frailtymeasure <0.001

Fried 10 1302 40.04% 33.60 47.60 Unchanged 83

WHI-OS 1 6619 26.16% 12.98 45.70 N/A N/A

Oddsofdepressioninolderpeoplewithfrailty

OR 95%CI

Mainanalysis 11 53626 3.94 2.36 6.58 <0.001 4.42(2.66–7.35)[1] 96

NorthAmerica 5 49181 6.700 2.92 15.34 <0.001 Unchanged 98

Asia 2 2207 4.582 1.24 18.92 0.02 N/A 69

Europe 2 889 1.298 0.23 7.12 0.763 N/A N/A

LatinAmerica 2 1349 2.437 0.45 13.12 0.299 N/A N/A

StudySetting 0.28

Community 10 53260 4.420 2.57 7.65 <0.0001 4.99(2.93–8.51)[1] 96 Outpatientsandinpatients 1 366 1.240 0.24 6.20 0.86 N/A N/A

Depressionoutcome 0.28

Screeningmeasure 10 53260 4.420 2.57 7.65 <0.0001 4.99(2.93–8.51)[1] 96 Structuredinstrument 1 366 1.240 0.24 6.20 0.86 N/A N/A

Frailtymeasure 0.34

Fried 10 12969 4.074 1.96 8.84 0.001 4.65(2.30–9.38)[1] 96

WHI-OS 1 40657 2.855 0.28 28.69 0.372 N/A N/A

Key:N/A=notapplicable,CI:Confidenceinterval;OR:Oddsratio;WHI-OS:Women’sHealthInitiativeObservationalStudy.

and lossof weight(≥3criteria) (Abellan vanKan et al.,2008); theadaptedfrailtyindexincludingthefollowing:wasting, weak-ness,slowness,fatigueorexhaustion,andfalls(n=1)(Paulsonand Lichtenberg,2013);andClinicalFrailtyScalerangingfrom1(very fit)to7(severelyfrail)(n=1)(Rockwoodetal.,2005).

3.3. Measurementofdepression

Depressive symptoms were assessed using the CES-D scale (n=11),theGeriatricDepressionScale(GDS)(n=8)(Radloff,1977), and Composite International Diagnostic Interview (CIDI) (n=2) (Wittchenetal.,1991).Threestudiesadopteddifferentmethods includingthePatientHealthQuestionnaire(PHQ-9)(requiringat least5/9 symptoms)(Kroenkeet al.,2001), interview schedule basedontheDiagnosticandStatisticalManualofMentalDisorders (DSMIII-R)andtheBurnam8-itemdepressionscreening instru-ment(Burnametal.,1988).

3.4. Cross-sectionalmeta-analysisfindings

3.4.1. Prevalenceofdepressioninpeoplewithfrailty

Fulldetailsoftheprevalenceofdepressioninpeoplewithfrailty aresummarizedinTable1.Theoverallprevalenceofdepressionin 8023peoplewithfrailtywas38.6%(95%CI30.07–47.10,I2₌_94%). Table1showstheprevalenceofdepressioninfrailpeoplestratified bygeographicalregion,studysetting,depressionoutcomeand def-initionoffrailty.Thesemoderatorsdidnotsignificantlyaffectour results,althoughtheprevalenceoffrailtywashigherinstudiesin

LatinAmerica,amongcommunity-dwellers,usingscreening mea-suresfordepressivesymptoms(insteadofstructuredinterviews forMDD)andusingthecriteriasuggestedbyFriedetal.(Table1). Avisualinspectionoffunnelplots(availablefromcorresponding authoronrequest)didnotsuggestpublicationbiasandthetrim andfillanalysesallremainedunchangedwhenanypotential pub-licationbiaswasadjustedfor(Table1).

3.4.2. Oddsofdepressioninpeoplewithfrailtyversuscontrols

Acrosselevenstudies,takingpeoplewithoutfrailtyasthe ref-erence group,frailpeople had higherodds of havingcomorbid depression(OR=3.95,95%CI2.36–6.58,p<0.001).Afteradjusting forpublicationbias,theORincreasedto4.42(95%CI2.66–7.35). Thebetweengrouppvaluesforthesubgroupanalysesremained non-significant(Table1),however,someresultsinthesubgroups becamenon-significantwhichmaybeduetoasmallnumberof studiesinsomegroupings.Nostudyreportedtheoddsof depres-sioninpeoplewithfrailty,adjustedforpotentialconfounders.

3.4.3. Prevalenceoffrailtyinpeoplewithdepression

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Table2

Meta-analysisresultsofprevalenceandoddsoffrailtyinolderpeoplewithdepression.

Analysis Numberof study estimates

Numberof participants

Meta-analysis Between grouppvalue

Trimandfilleffect size(95%CI) [adjustedstudies]

I2

Prevalenceoffrailtyinolderpeoplewithdepression

Prevalence 95%CI

Mainanalysis 8 2167 40.40% 27.00 55.30 Unchanged 97

NorthAmerica 5 1381 31.26% 17.32 49.67 Unchanged 97

Australia 2 398 72.9% 39.1 91.9 N/A N/A

Europe 1 378 27.24% 0.64 67.38 N/A N/A

Studysetting 0.576

Community 7 1789 42.60% 27.10 59.70 Unchanged 97

Communityandinpatient 1 378 27.24% 5.450 70.86 N/A N/A

Depressionclassification 0.03

Screeningtool 6 1701 49.50% 32.50 66.60 Unchanged 97

Structuredinterview 2 466 17.62% 5.460 44.22 N/A 90

Frailtymeasure 0.007

Fried 5 1592 27.12% 15.9 49.29 Unchanged 96

Friedadapted 1 167 51.49% 20.04 81.80 N/A N/A

IanaTask 2 408 85.45% 54.31 96.67 N/A N/A

Oddsoffrailtyinolderpeoplewithdepression

OR 95%CI

Mainanalysis 8 17099 4.068 1.93 8.55 <0.001 Unchanged 96

NorthAmerica 5 9185 2.256 1.00 5.08 0.05 Unchanged 96

Australia 2 7404 19.35 3.91 95.76 <0.001 N/A 93

Europe 1 510 3.745 0.573 24.48 0.168 N/A N/A

Studysetting 0.675

Community 7 16589 4.11 1.82 9.28 0.001 Unchanged 97

Communityandinpatient 1 510 3.74 0.42 33.31 0.23 N/A N/A

Depressionclassification 0.655

Screeningtool 6 15906 4.60 1.93 11.80 0.001 Unchanged 96 Structuredinterview 2 1193 2.67 0.55 12.78 0.29 N/A N/A

Frailtymeasure 0.056

Fried 5 11680 2.18 0.93 5.09 0.09 Unchanged 95

Friedadapted 1 580 4.22 0.60 29.34 0.145 N/A N/A

IanaTask 2 4839 19.12 1.23 16.13 <0.001 N/A N/A

Key:N/A=notapplicable,CI:Confidenceinterval;OR:Oddsratio.

althoughsomecautionshouldbegivenduetosmallnumberof studies in each group (Table 2).The trim and fill analyses all remainedunchanged.

3.4.4. Oddsoffrailtyinpeoplewithdepressionversuscontrols

Takingtheparticipantswithnodepressionasreference,people withdepressionhadanincreasedriskofhavingfrailty(OR=4.07, 95% CI 1.93–8.55, p<0.0001; I2₌_96%) ₍_Table ₂_). _This associa-tion was significant in five studies including North Americans (OR=2.25;95%CI1.00–5.08,p=0.05;I2₌_96%)_compared_to_other settings (Table 2). As shown in Table 2, publication bias was unlikely.

Fourstudies(Changetal.,2010;deAlbuquerqueSousaetal., 2012;Jarschiketal.,2012;PegorariandTavares,2014)reportedthe ORforfrailtyinadjustedanalysesindepressedvs.nonedepressed people,takingrobustparticipantsasreference.Afteradjustingfora medianof6potentialconfounders(range:3–12),thepooledORwas 2.64(95%CI:1.59–4.37;I2₌_55%;_Fig.₂_)._Another_study₍_Jung_et_al., 2016)reportedthatanORof5.25(95%CI:2.55–10.83)forfrailtyvs. pre-frailty/robustness,afteradjustingfor4potentialconfounders.

3.5. Longitudinalmeta-analysisfindings

3.5.1. Studiesinvestigatingincidentfrailtyinolderpeoplewith depression

Overall, 6404olderadults with depression atbaseline were followedoverameanof2.87yearsinvestigatingincidentfrailty (FugateWoodsetal.,2005;PaulsonandLichtenberg,2013;Lakey

etal.,2012;Hajeketal.,2016).ThepooledORforincidentfrailty, adjustedfor amedian of7potentialconfounders (range:0–21) (SupplementaryTable3),was3.72(95%CI1.95–7.08;p<0.0001; I2₌_98%),_as_shown_in_Fig.₃_.

3.5.2. Studiesinvestigatingincidentdepressionamongpeople withfrailty

Overall,twolongitudinalstudies(Fengetal.,2014;Makizako et al., 2015) including 4852 older adults investigated incident depressionastheoutcome.Thesetwostudiesfoundthatfrailtyat thebaselineincreasedtheriskofincidentdepressionbyabout90% (OR=1.90;95%CI1.55–2.32,p<0.0001;I2₌_0%),_after_adjusting_for 11covariates(Fig.4;SupplementaryTable4).Onestudy(Monin et al.,2016)withnometa-analyzabledatareportedan associa-tionbetweendepressionandfrailtyin1260community-dwelling marriedcouples.

4. Discussion

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Fig.2. Oddsoffrailtyinpeoplewithdepressionversuscontrols.

Fig.3.Oddsforincidentfrailtyinolderpeoplewithdepression.

Fig.4.Oddsforincidentdepressionamongpeoplewithfrailty.

inolderpeoplewithdepressionversusthosewithoutdepression. Longitudinalstudiessubstantiallyconfirmedthesefindingsdespite beingmorelimitedinnumber.

Frailty,isamultifactorialgeriatricsyndrome,whichcouldbe influencedbypain,mobilityandbalanceproblems,weakness,poor enduranceetc.Alloftheseriskfactorsmayleadtodisability,or functionaldependence,andthusleadtodepression(FugateWoods etal.,2005).Ontheotherhand,depressionmayalsopredict indi-catorsoffrailtyduetothedecreaseinsocialties,gaitspeed,and lessphysicalactivities,orduetotheincreaseinsedentarylife,fall risk,weightloss,andmalnutrition,whichmayincreasethe per-petuationofaffectivesymptoms typicalof depressionincluding sadness,anhedonia,andhelplessness(Hajeketal.,2016;Paulson andLichtenberg,2013).Additionally,depressionmaynotonlybe

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Grow-ingevidencealsosupportsapositiveassociationbetweenfrailty andtheinflammatorycytokines,suchasinterleukin6(IL6)(Soysal et al., 2016), which is also known to be elevated in individu-alswithlatelifedepression(Vaughanetal.,2015).Inflammatory cytokinesare associatedwithboth decreased musclemass and strength,andalsonegativelyaffectthecentraldopaminergic func-tion,whichmayresultindepressiveaffect,fatigue,andcognitive andmotorslowing(Brownetal.,2016).Mitochondrialdysfunction hasalsobeenidentifiedinnumerousneurodegenerativediseases aswellasdepression.Musclebiopsiesinpatientswithdepression haveshowndecreasedATPproduction,andadultswithdepression hadalsoimpairedmitochondrial respirationinperipheralblood mononuclearcells,moststronglycorrelatingwiththesymptom of fatigue (Brown et al., 2016).The detrimental cycle between declinedactivity,mobility,andenergylevelsresemblestheclinical presentationofdepressionaswellasthosewiththefrailty syn-drome(Brownetal.,2016).AnotherhypothesisisthatHPAaxis dysregulation,aswellasaberrationsinothermediators,suchas insulin-likegrowthfactor,andtestosterone(Belvederietal.,2014), have beenreported in frail personswith significantdepressive symptomsandmayaccountforthereciprocalassociationherein observed(vonZerssenetal.,1986).Moreover,thebeneficialeffects of theapproaches topreventfrailty ordepression may protect theother.Forexample, thesuccessfultreatmentof the depres-sionitselfmayresultinincreasedbehavioralandsocialactivation, therebyincreasingphysicaland socialactivitylevels,improving musclemassandstrength,andtheelder’soverallenergylevels, thereby, reducing frailty(Lakey etal., 2012).Similarly, increas-ingphysicalactivityisaneffectiveinterventionforfrailtyinolder adults,andcanprotectandmanagedepressivesymptomsinthe elderlythroughpotentialneurobiologicalchangesandasa con-sequenceofsocialandphysicalengagement(Brownetal.,2016;

Schuchetal.,2016a,b).Otherinterventionssuchasimproving bal-anceandmusclestrength,andvitaminDsupplementationmayalso playaroleinpreventingortreatingfrailty(Brouwer-Brolsmaetal., 2013).DepressivesymptomsmaycausevitaminDdeficiencyvia decreasedsunexposure,poorerdietaryintakeandmoresmoking (Brouwer-Brolsmaetal.,2013).Infact,allthesefindingssupport thebidirectionalityofthedepression–frailtyrelationship.Clearly, futureresearchisrequiredtoexploreandunderstandsuch rela-tionships.

Ourcomprehensivemeta-analysisresultsadvancetheliterature frompreviouslypublishednarrativeand/orselectivereviewsthat haveconsideredtherelationshipbetweendepressionandfrailty. Meta-analysesenablethelogicalpoolingofdataandenableamore preciseestimateoftheprevalenceand/oroddsofanoutcomethan whenmakingsubjectiveconsiderationsofindividualstudies sep-aratelysuchasthoseinpreviousnarrativereviews(Ioannidisand Lau,1999).Nonetheless,thepreviousreviewshaveillustratedsome interestingfindings.Onereview,including28studies,reportedthat frailtyanddepressionarecomorbidgeriatricsyndromesina sub-groupofolderindividuals,andthatfrailtyisalsoariskfactorfor thedevelopmentandpersistenceofdepressivesymptoms(Buigues etal.,2015).Anotherreview,includingbothcross-sectional(n=16) andcohortstudies(n=23)indicatedthatfrailty,itscomponents, andfunctionalimpairmentareriskfactorsfordepression(Mezuk etal.,2012).Ontheotherhand,anotherreviewfoundthatthe rela-tionshipbetweendepressivesymptomatologyandincreasedrisk ofincidentfrailtywasrobust,whiletheoppositerelationshipwas lessconclusive(Vaughanetal.,2015).However,thepotentialrole ofantidepressantmedicationsonfrailtyhasnotbeenclearly eval-uatedinanyofthesereviews.Because,asshowninthereviewby Benraadetal,geriatriccharacteristicsarerarelytakenintoaccount intrialsonantidepressantdrugsinlate-lifedepression(Benraad etal.,2016).Todifferentiatefromthesepreviousreviews,the meta-analysiswasperformedinthepresentstudy(Buiguesetal.,2015;

Mezuketal.,2012).Specificallyourdataestablishedthatfrailolder peoplearefourtimesmorelikely tohave depressioncompared tocontrols, withsimilarincreasedodds forfrailtyamongthose withdepressionversuscontrols.Whilecross-sectionalstudiesare unable toclarify the directionalityof the relationship between frailtyanddepression,itclearlyindicatesthatthereisahighlevel ofcomorbidity.Whetherornotthisisattributedtomutually exclu-siveoroverlappingsymptomologyofeachconditionisnotclearand futureprospectiveresearchmayhelptodisentanglethis relation-shipandexplorepotentialoverlappingsymptomologyanddisease onset.Nonetheless,thelimitednumberprospectivestudiesdoes suggestthatafteradjustingforconfounders,peoplewith depres-sionareatincreasedriskofdevelopingfrailty,whilsttheconverse relationshipalsoappearstobeevident.However,thesmall num-beroflongitudinalstudiesprecludesanydefinitiveconclusionsand futurelongitudinalresearchisrequiredtospecificallyattemptto differentiatebetweenthesignsandsymptomsofbothconditions. Somefactorswereidentifiedinouranalysesasbeing poten-tiallyimportantinexplainingtheassociationbetweendepression andfrailty.Theprevalenceofdepressioninfrailpeople,infact,was higherinstudiesfromLatinAmerica,amongcommunity-dwellers, those using depression screening measures (instead structured interviews)andinstudieswhichconsideredcriteriasuggestedby

Friedetal.(2001)Arecentinternationalstudydemonstratedthat depressivesymptomsaremorepronouncedwithintraditional fam-ilybasedvaluepatterns,likeLatinAmerica, possiblybecauseof higherexpectationsoftheavailabilityoffamilysupportthatare oftenonlypartiallyfulfilledduetorecentchangesinfamily struc-ture(Yllietal.,2016).Fried’scriteriasharessymptomswiththe CES-Dandthiscouldpartiallyexplainthehighcorrelation. How-ever,somestudieshavefoundthatthestrongassociationbetween frailtyanddepressionisnotuniquetoasingledefinitionoffrailty suchastheClinicalFrailtyIndex, andthus,ourfindings donot seemtobefullyexplainedbysharedsymptomatology(Lohman etal.,2014).Wealsoexaminedtheoppositerelationship,i.e.the prevalenceofdepressionamongthefrailandtheoddsand inci-denceofdepressioninfrailolderindividualscomparedtorobust ones.Depressedpeopleshowedsignificantlyhigherlevelsoffrailty (∼40%),mainlyinNorthAmericanstudiesandinoneAustralian study(Almeidaetal.,2015).

Prospectivestudiesoftherelationshipbetweendepressionand incidentfrailtyalsosuggestthatdepressionmayincreasetherisk of frailty (Vaughan et al., 2015).Depression is associated with increasedweakness,mobilitydeficits,andfatigue,whichmaythus increasetheriskoffrailtyandincreasedmortalityoveraperiod ofupto5years (Veroneseetal.,2016).Theroleof antidepres-santdrugtreatmentintherelationshipbetweendepressionand frailtydeserve furtherinvestigation.Antidepressants have been associatedwithahigherriskofincidentfrailty(Lakeyetal.,2012). Thisassociationcouldsimplybeexplainedbyamoresevereand chronicformofdepressionthatrequiredtheuseofantidepressant drugs(Vaughanetal.,2015),butalargeprospectiveobservational studyreportedthatevenintheabsenceofdepressivesymptoms, antidepressantusewasassociatedwithbecomingfrail(Lakeyetal., 2012).Therefore,non-pharmacologicalinterventionsmaybean importantapproachfordepressedfrailolderadults.Clearlyfurther researchisneededtoelucidatethepossibleroleofdrugsinthe depression-frailtyrelationship(Mezuketal.,2012).

5. Limitations

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betweenthesetwoconstructsisnotclear.Inaddition,the num-berofprospectivestudieswaslimited,thereforefutureprospective research is required to allow a better elucidation of potential moderatorswhichcouldinfluencethereciprocalprospective asso-ciationsbetweendepressionandfrailty.Asecondlimitationisthe highheterogeneityobserved. Thedifferentmethods and differ-entcut-offvaluesusedfordefiningfrailtyanddepressionmight playarole,butourfindingssuggestthatthesefactorscannot com-pletelyexplaintheobservedreciprocalassociations.Third,there waslimitedinformationonimportantmoderatorssuchasphysical activity,medicationuse,presenceofdementia,andinflammatory cytokines.Fourth,depressionwasdiagnosedthroughnon-original methods(DSM),andonlyfourstudies(Anandetal.,2012;Feng etal.,2014;Friedetal.,2001;Lakeyetal.,2012)reporteddata regardingantidepressants,thusprecludingthepossibilityto con-ductameta-analysis.However,inonelargelongitudinalstudy,the useofantidepressantswasassociatedwithahigherincidenceof frailtyindicatingthatthisfactorisofimportanceintheassociation betweendepressionandfrailty(Lakeyetal.,2012).Thus, future researchshouldconsidertherelationshipbetweenantidepressant medicationandfrailty/depression.Finally,thepresenceof depres-sivesymptomsintheconstructoffrailtymayartificiallycontribute totherelationshipbetweenfrailtyanddepression.Moreresearchis requiredtoinvestigatetherelationshipbetweenmajordepression andclearlydefinedfrailtyinparticular.Suchresearchmightalso considertherelationshipofimportantpotentialmoderatorssuch asphysicalactivity,antidepressantmedicationandinflammatory markers.

Inconclusion,ourresultsprovideevidenceforaconsistent bidi-rectionalrelationshipbetweenfrailtyanddepressionamongolder people. However, the precise mechanisms underpinning those reciprocalepidemiologicalassociationsdeservefurther investiga-tion.Ourdatasuggestthatoverathirdofpeoplewithfrailtyhave depressionandasimilarproportionofpeoplewithdepressionhave frailty,whiletheoddsofeachconditionarefourtimeshigherthan controls.Therefore,interventionsdesignedtodecreaseoneofboth syndromescanpreventtheemergenceofother.Ourdataisof pub-lichealthimportanceandmayopenimportantperspectivesforthe preventionandtreatmentofthosehighlyco-occurringand preva-lentconditions.

Conflictofinterest

None.

Financialdisclosure

Soysal, Veronese, Thompson, Kahl, Fernandes, Prina, Solmi, Schofield,Koyanagi,Tseng,Lin,Chu,Cosco,Cesari,Carvalho,Stubbs havenothingtodisclose.

AiKoyanagi’sworkissupportedbytheMiguelServetcontract financedbytheCP13/00150andPI15/00862projects,integrated intotheNationalR+D+IandfundedbytheISCIII–GeneralBranch EvaluationandPromotionofHealthResearch–andtheEuropean RegionalDevelopmentFund(ERDF-FEDER).TDCissupportedby aCanadianInstitutesofHealthResearchPostdoctoralFellowship (MFE-146676).

BrendonStubbsissupportedbytheNationalInstituteforHealth Research(NIHR) Collaborationfor Leadershipin Applied Health ResearchandCareSouthLondonatKing’sCollegeHospitalNHS FoundationTrust.Theviewsexpressedarethoseoftheauthor(s) andnotnecessarilythoseoftheNHS,theNIHRortheDepartment ofHealth

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.arr.2017.03.005.

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