ORIGINAL INVESTIGATION. Predictive Relationship Between Depression and Physical Functioning After Coronary Surgery

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1 ORIGINAL INVESTIGATION Preditive Reltionship Between Depression nd Physil Funtioning After Coronry Surgery Friederike Kendel, PhD; Götz Gelbrih, PhD; Mrkus Wirtz, PhD; Elke Lehmkuhl, MD; Nin Knoll, PhD; Rolnd Hetzer, MD; Ver Regitz-Zgrosek, MD Bkground: Depression is prevlent ondition in ptients undergoing oronry rtery bypss grft surgery (CABG) nd is often ssoited with less fvorble helth sttus. The im of this study ws to investigte the reltionship between depression nd physil funtioning in ptients undergoing CABG. Methods: The nlyses were bsed on smple of 883 onseutive subjets (ged yers; 19.8% women) undergoing CABG. Depression ws ssessed using the Ptient Helth Questionnire (PHQ); the subsle physil funtioning ws tken from the 36-Item Short- Form Helth Survey. Questionnires were dministered 1 to 3 dys before surgery (T1) nd 2 months (T2) nd 1 yer (T3) fter surgery. Results: A ross-lgged pth nlyti model showed tht n inrese in depressive symptoms predited derese in physil funtioning ( T1-T2 = 0.15 [P.001]; T2-T3 = 0.17 [P.001]), but not the other wy round. Multigroup omprisons reveled one modertor effet: in ptients with systoli hert filure (left ventriulr ejetion frtion [LVEF], 45%), the effet of depression on physil funtioning from T2 to T3 ws signifintly stronger thn in ptients with preserved LVEF ( T2-T3 = 0.30 [P.001] vs T2-T3 = 0.14 [P.001]; 2 diff=3.885 [P=.049]). Conlusions: More ttention should be pid to dignosis nd tretment of depression in ptients undergoing CABG. After surgery, ptients with systoli hert filure nd depressive symptoms in prtiulr seem t risk of deteriortion of their physil funtioning. Arh Intern Med. 2010;170(19): Author Affilitions: Institute of Medil Psyhology (Drs Kendel nd Knoll), Institute of Gender in Mediine (Dr Regitz-Zgrosek), nd Center for Crdiovsulr Reserh (Dr Regitz-Zgrosek), Chrité-Universitätsmedizin Berlin, Berlin, Germny; Coordintion Center for Clinil Trils, Leipzig, Germny (Dr Gelbrih); Institute of Psyhology, University of Edution, Freiburg, Germny (Dr Wirtz); nd Deutshes Herzzentrum Berlin, Berlin (Drs Lehmkuhl, Hetzer, nd Regitz-Zgrosek). NO OTHER HUMAN ORGAN IS s losely ssoited with vitlity nd pbility s the humn hert. It is not surprising tht people with oronry hert disese (CHD) develop depressive symptoms in retion to their illness or tht ptients undergoing oronry rtery bypss grft surgery (CABG) often beome depressed owing to hnges in lifestyle fter surgery. Beuse the dignosis of depression inludes somti symptoms suh s hnges in ppetite, sleeping problems, nd loss of energy, symptoms of depression nd symptoms of CHD overlp to ertin extent. Yet severl studies hve shown tht depression is n independent risk ftor for funtionl impirment 1 nd rdi events 2 nd is lso ssoited with mortlity fter CABG. 3 With respet to depression, severl onfounding vribles hve been reported. In ptients with ongestive hert filure (HF), depression shows prevlene of up to 40% 4 nd is strong preditor for the worsening of HF symptoms. 5,6 Higher prevlene rtes of depression in CABG ptients hve lso been reported for women ompred with men, 7,8 younger ptients, 1 nd soilly isolted ptients. 9 However, studies hve not yet shown lerly how the influene of depression on vrious outomes differs mong these subgroups of ptients. Even though depression hs been shown to hve onsiderbly negtive impt on the physil funtioning of ptients undergoing CABG, the other wy round is lso likely: bd helth sttus my led to n inrese in depressive symptoms. In this se, depressive symptoms ould be primrily n epiphenomenon of the somti illness. Sttements on the diretion of influene n only be mde within model tht longitudinlly onsiders both pths (from depression to helth sttus nd from helth sttus to depression). For orreltive dt, ross-lgged pnel designs tht ontrol for multivrite dependenies mong the entrl study vribles re the most vlid designs. 10 Surprisingly, the diretion of pre Amerin Medil Assoition. All rights reserved.

2 b T1 T2 Depression T1 Depression T2 Depression T3 ditive inferene hs not yet been lrified for this ontext: Is depression preditive of deteriortion in helth sttus fter the surgery or is hnge in helth sttus for the worse preditive of n inrese in depression? To nswer this question, we tested the longitudinl, rosslgged ssoitions between depressive symptoms nd physil funtioning within single model. In ddition, we sought to explore whether the reltionship between depression nd physil funtioning ws moderted by gender, ge, prtner sttus, or HF. METHODS T3 Figure 1. The ross-lgged pnel design showing ross-lgged longitudinl (), ross-setionl (b), nd longitudinl () pths. indites physil funtioning; T1,1 to 3 dys before surgery; T2, 2 months fter surgery; nd T3, 1 yer fter surgery Of 1917 onseutive ptients onsented 1570 Were inluded nd returned first questionnire 1129 (71.9%) Responded nd returned seond (2-month) questionnire 989 (62.9%) Responded nd returned third (12-month) questionnire Figure 2. Flowhrt of prtiipnts. PROCEDURE AND MEASUREMENT After the institutionl review bord pproved the study protool, potentil ndidtes were identified through dily sreening of the dmission reords. The initil smple onsisted of 1570 onseutive ptients undergoing CABG t the Deprtment of Crdiothori nd Vsulr Surgery, Deutshes Herzzentrum (Germn Hert Institute) Berlin, Berlin, Germny, between Jnury 1, 2005, nd July 31, Exlusion riteri were (1) inbility to red or nswer the study questionnires (eg, dementi, diffiulties with the lnguge) nd (2) ge younger thn 18 yers. All ptients prtiipting provided written onsent. Questionnires were dministered 1 to 3 dys before surgery (T1), 2 months fter surgery (T2), nd 1 yer fter surgery (T3). Clinil nd soiodemogrphi dt were bstrted from se report forms. The depression module of the 9-Item Ptient Helth Questionnire (PHQ-9) 11 ws used to ssess depressive symptoms. The b 12 (0.7%) Did not meet inlusion riteri for isolted CABG; 28 (1.7%) did not return questionnire 441 Of 1570 (28.1%) did not respond 581 Of 1570 (37.0%) did not respond 883 (56.2%) Completed ll 3 ssessments b sum sore rnges from 0 to 27, with higher vlues inditing higher levels of depression. The Germn version 12 hs shown exellent relibility, vlidity, 13 nd sensitivity. 14 The subsle physil funtioning () from the 36-Item Medil Outomes Study Short-Form helth survey (SF-36) 15 ws used to ssess the subjetive. The sle onsists of 10 items eliiting onrete subjetive responses bout physil limittions due to helth, suh s using stirs nd lifting objets. The rw sore ws trnsformed to sore rnging from 0 (severe impirment) to 100 (no impirment). Exellent psyhometri properties hve been reported for the Germn version of the SF STATISTICAL ANALYSES Struturl eqution modeling ws used to estimte nd evlute the ross-setionl nd prospetive ssoitions of depression nd. For orreltive dt in pnel studies, ross-lgged pnel designs llow for diret test of the preditive reltionship between 2 vribles. This method tkes into ount time preedene 17 nd ontrols for multivrite dependenies of the nteedent preditor vribles. 10 Therefore, in ddition to the ross-lgged pths between depression nd nd between nd depression (Figure 1, pth ), the longitudinl struturl pths refleting hnges in depression nd, respetively (Figure 1, pth ) s well s the ross-setionl ovrines between depression nd (Figure 1, pth b) were tken into ount. The preditive priority of either or depression ould be ssumed only if the respetive preditor (depression or ) mde n independent ontribution to the rossed riterion ( or depression, respetively) fter ontrolling for the effets t erlier time points nd ross-setionl ssoitions. Beuse ross-lgged pth models re bsed on ontinuous vribles, the sles for depression nd were used in their ontinuous form. Depression nd were understood s ltent onstruts, whih were estimted by 2 rndomly seleted split-hlf subtests t ll 3 mesurement points. 18 To detet modertor effets, onstrints tht required the ross-lgged pths to be equl were imposed on the model nd tested through hierrhil model omprisons. The following subgroups were tested for differenes in the ross-lgged pths: (1) ptients with systoli HF, s defined by left ventriulr ejetion frtion (LVEF) below 45%, vs preserved LVEF 19 ; (2) ge below vs bove the medin of 67 yers; (3) men vs women; nd (4) ptients living lone vs living with prtner. The sttistil nlyses were performed using AMOS for struturl eqution modeling. Sttistil softwre SPSS 16.0 ws used to ondut t tests for independent smples; if the vribles were tegoril, 2 tests were used. Chnges in depression nd over time were tested by ANOVAs. For ll nlyses, P.05 ws onsidered sttistilly signifint. MISSING DATA ANALYSIS Of 1917 onseutive ptients, 1610 onsented to the study; 1570 ptients fulfilled the inlusion riteri nd returned the questionnire t the first mesurement point (Figure 2). Of these ptients, 112 (7.1%) died during the 1-yer follow-up. For ll ptients who were not identified s deesed, we were ble to onfirm vitl sttus by diretly ontting the ptient or his or her generl prtitioner. A totl of 883 ptients (56.2%) responded t ll 3 time points ( ontinuer smple ). Missing dt due to item nonresponse were estimted using the expettion mximiztion lgorithm. 21 To show potentil effets of ttrition on unit level, Tble 1 gives ll study vribles for the full smple s well s for ontinuers nd nonontinuers seprtely. A higher proportion of nonontinuers ompred with ontinuers were living without prtner, were more Amerin Medil Assoition. All rights reserved.

3 Tble 1. Bseline Chrteristis for Full Smple, Continuers, nd Nonontinuers Chrteristi Full Smple (N=1570) Men (SD) Continuers (n=883) Nonontinuers (n=687) P Vlue Age, y (9.04) (8.40) (9.82).41 Living lone, % Femle, % LVEF, % (13.97) (13.28) 52.0 (14.48).001 Depressive symptoms 5.99 (4.61) 5.38 (4.09) 6.76 (5.09).001 Physil funtioning (27.03) (26.07) 46.1 (27.32).001 Abbrevition: LVEF, left ventriulr ejetion frtion. often femle, nd reported higher levels of depression nd lower levels of. Beuse ptient dropout did not our ompletely t rndom, we deided to repet the nlyses using the full informtion mximum likelihood proedure 22 s implemented in AMOS to estimte the empiril ovrine mtrix from ll vilble informtion inluding ll vilble dt from the full smple (N=1570). RESULTS Desriptive dt re presented in Tble 1. The following results re presented for the ontinuer smple (n=883; 19.8% women) unless otherwise speified. Men ge ws yers (rnge, yers), men LVEF ws 56.29%. The prevlene for mjor depression in our ptient popultion ws 8.5%, ompred with rte of 3.8% obtined from Germn representtive smple lso using the PHQ Over 1 yer, improved signifintly (min effet for time: F 2,882 =80.809; P.001). Aordingly, there ws deline in depressive symptoms (min effet for time, F 2,882 =3.132; P=.04). PREDICTIVE RELATIONSHIP OF DEPRESSION AND 0.50 T1 Surgery T2 T Depression Depression Depression Figure 3 displys the empiril estimtes for the rosslgged pnel model, whih llows the identifition of the preditive diretionlity between the onstruts depression nd (overll model fit, 2 =275.28; P.001). Indies of pproximte fit tht re robust to smple size showed suffiiently lose fit of model vribles (CMIN/df [minimum vlue of the disrepny funtion divided by degrees of freedom], 6.714; RMSEA [root men squre error of pproximtion], 0.08; CFI [omprtive fit index], 0.98; nd NFI [normed fit index], 0.97). The model fit n thus be lssified s eptble to good. Controlling for the respetive ross-setionl nd bseline sores, depressive symptoms showed pronouned preditive priority over. This preditive priority ould be demonstrted for both time intervls: from bseline (T1) to 2 months fter surgery (T2) nd from 2 months (T2) to 1 yer fter surgery (T3). In ontrst, the pths from prior to lter depression were not signifint (Figure 3). Nested multigroup model omprisons were onduted to detet modertor effets. Stndrdized regression weights ( ) for ll subgroups re given in Tble 2. Assuming group independent model prmeters by simultneously restriting ll model pths to be equl between ptients with systoli HF nd ptients with preserved LVEF, no overll group differenes ould be found ( 2 diff=8.712; P=.07). However, on pth-speifi level the pth leding from depression 2 months fter surgery to 1 yer fter surgery indited signifint group differenes ( 2 diff=3.885; P=.049). Thus, in ptients with systoli HF, hnges in depression over this period were signifintly more losely relted to hnges in ompred with ptients with preserved LVEF (Tble 2). No modertor effets were found for gender ( 2 diff=4.393; P=.36), ge ( 2 diff=1.876; P=.76), nd prtner sttus ( 2 diff=2.009; P =.73). For these groups, the unonstrined initil model ws vlid. To void interprettion bis used by dropout of ptients, the nlyses were repeted on the full smple (N=1570) (see Methods setion). Agin, stndrdized regression weights indited tht depressive symptomtology ws relted to deteriortion of ( T1-T2 = 0.12 [P.001]; T2-T3 = 0.18 [P.001]; ontinuer smple, T1-T2 = 0.15 [P.001]; nd T2-T3 = 0.17 [P.001]), wheres there ws no evidene for preditive inferene from to depressive symptomtology ( T1-T2 = 0.01 [P =.71]; T2-T3 = 0.04 [P =.26]; ontinuer smple, T1-T2 = 0.03 [P=.44]; nd T2-T3 = 0.01 [P=.74]). Model fits were lso good (CMIN/df, 3.934; RMSEA, 0.04; CFI, 0.98; nd NFI, 0.97). In ordne with the nlyses bsed 0.49 Figure 3. Cross-lgged reltionships between depressive symptoms nd physil funtioning () over time (n=883). Ovls indite unobserved ltent vribles. Vlues re stndrdized regression weights ( ). All pths shown re signifint exept for those drwn with broken line. ***P.001. Testing for the preditive priority of depression vs physil funtioning: 2 diff=26.624; P Amerin Medil Assoition. All rights reserved.

4 Tble 2. Vribles Moderting the Reltionship Between Physil Funtioning nd Depression in 883 Continuers T1 T2 Modertor Vribles DEP DEP DEP DEP LVEF, % b, b, 0.04 Age, y Gender Femle Mle Prtner sttus Living lone Living with prtner on the ontinuer smple, no modertor effets were found for gender, ge, nd prtner sttus. In ptients with systoli HF, the pth from depression 2 months fter surgery to 1 yer fter surgery ws signifint ( T2-T3 = 0.34 [P.001]; ontinuer smple, T2-T3 = 0.30 [P.001]). Thus, the dnger of n error, ie, the dnger of postulting differene where there is none, ws minimized. COMMENT T2 T3 Abbrevitions: DEP, depressive symptoms; LVEF, left ventriulr ejetion frtion;, physil funtioning; T1,1 to 3 dys before surgery; T2, 2 months fter surgery; nd T3, 1 yer fter surgery. Vlues re stndrdized regression weights ( ). b Signifint differene between ptients with LVEF of 45% or lower nd LVEF higher thn 45% ( 2 diff=3.885; P=.049). P.001. The present study provides strong support for the ssumption tht depression my led to deteriortion of in ptients fter CABG, but bd helth sttus is not preditive of n inrese in depression in this ontext. The influene of depression on the ourse of reovery fter rdi events or bypss opertion hs been the objet of intense debte over the pst few yers. Findings of Rumsfeld et l 23 nd Mllik et l 1 showed tht depression ppered to be strong inverse risk ftor for worse qulity of life fter CABG. In study testing the opposite pth, post-cabg depression sttus ws predited by somti ftors suh s hroni nonrdi illnesses, postopertive ftigue, nd shortness of breth. 8 Surprisingly, to our knowledge, no study to dte hs ssessed the bidiretionl influenes of depression on nd on depression in the ontext of CABG. To meet the methodologil hllenge tht is onneted to this question, the present study pplied ross-lgged pnel design. Three ssoitions were possible: (1) poorer ould be preditive of n inrese in depressive symptoms, (2) higher level of depression ould be preditive of deteriortion in, or (3) there ould be reiprol reltionship with no superiority of either pth. In the present study, depressive symptoms lerly predited, but did not predit depressive symptomtology. The preditive priority of depression over ould be demonstrted for both time intervls of interest: from bseline to 2 months fter surgery nd from 2 months to 1 yer fter surgery. With the use of multigroup omprisons in struturl eqution modeling, it ws lso possible to diretly ompre severl subgroups with respet to the previously desribed longitudinl pths. The strength of these pths did not differ with respet to gender, thus deprting from the results of other studies, whih reported stronger reltionship between depression nd in women thn in men. 8,24 It should be noted tht omprison with these studies is of limited vlue, beuse none of these studies ontrolled for the ross-setionl nd ross-lgged reltionships. Our results indite tht only in the subgroup of ptients with systoli HF did the pths differ from tht of ptients without HF. Two months fter surgery, there ws signifint effet from depression on in ptients with systoli HF, whih ould not be shown in ptients with preserved LVEF. Severl studies hve explored the reltionship between depression nd self-reported qulity of life 23,25 or risk of funtionl deline 26 in ptients with HF. In ptients undergoing bypss surgery, longstnding HF my hve lredy led to redution of resoures nd my thus mplify the stress tht is indued by the surgery, wheres ptients without history of HF my hve psyhologil resoures tht enble them to ope better with the dditionl stressor of CABG surgery. Severl psyhologil mehnisms by whih depression my produe inresed risk for ptients with CHD hve been studied. For exmple, depression is ssoited with number of behviorl risk ftors 27 nd nondherene to medition. 28 How these mehnisms influene the reltionship between depression nd is not yet ler. As our study ws not experimentl in design, the existene of dditionl vribles influening the ssoition between depression nd nnot be exluded nd should be subjet to further studies. Further studies re lso needed to eluidte possible behviorl nd pthophysiologil pthwys for the ssoition of depression nd in CABG ptients. There re possible limittions to this study, whih should be tken into ount when interpreting the results. First, the PHQ-9 is brief sreening instrument to ssess severity of depressive symptoms nd nnot reple forml linil dignosis of depression. However, sine there is strong evidene for both high sensitivity nd speifiity when dignosing mjor depression, 14 this instrument seems pproprite for the investigtion of epidemiologil questions. Seond, with respet to the first mesurement point, it nnot be exluded tht nxiety nd the exeptionl mentl stte before surgery my hve influened the response to the depression items t the first mesurement point. Third, the study hd to fe substntil dropout rte owing to mortlity nd morbidity. In ddition, we nnot exlude minor ssoitions between ognitive impirment nd ompletion of questionnires. To void systemti bis by interpreting results bsed on the redued smple, ll nlyses were repeted using the full dt set, estimting the missing units. These nlyses provide dditionl support for our min finding tht depression is preditive for. Fourth, ll ptients were reruited t single enter, the Deutshes Amerin Medil Assoition. All rights reserved.

5 Herzzentrum Berlin. Given the high reputtion of this institution, it is possible tht more omplited ses my hve been referred to this hospitl nd thus the study smple my represent less helthy popultion. Our results emphsize the vitlly importnt role depression plys in the CABG reovery proess. This ws onfirmed by evidene of unidiretionl reltionship of depression with. On the bsis of these results, sreening for depression should be reommended both before nd fter CABG tretment. After surgery, this seems to be prtiulrly importnt for ptients with hert filure. Aepted for Publition: July 30, Correspondene: Friederike Kendel, PhD, Institute of Medil Psyhology, Chrité Universitätsmedizin Berlin, Luisenstrße 57, Berlin, Germny Author Contributions: Study onept nd design: Kendel, Gelbrih, Lehmkuhl, nd Regitz-Zgrosek. Aquisition of dt: Kendel, Lehmkuhl, nd Hetzer. Anlysis nd interprettion of dt: Kendel, Gelbrih, Wirtz, Lehmkuhl, nd Knoll. Drfting of the mnusript: Kendel nd Wirtz. Critil revision of the mnusript for importnt intelletul ontent: Kendel, Gelbrih, Wirtz, Lehmkuhl, Knoll, Hetzer, nd Regitz-Zgrosek. Sttistil nlysis: Kendel, Gelbrih, Wirtz, nd Knoll. Obtined funding: Regitz- Zgrosek. Administrtive, tehnil, nd mteril support: Gelbrih nd Lehmkuhl. Study supervision: Knoll, Hetzer, nd Regitz-Zgrosek. Finnil Dislosure: None reported. Funding/Support: This study ws funded by the Germn Federl Ministry of Edution nd Reserh (BMBF). Additionl Contributions: Elizbeth Morrison nd Ann Jonen provided editoril ssistne. REFERENCES 1. Mllik S, Krumholz HM, Lin ZQ, et l. Ptients with depressive symptoms hve lower helth sttus benefits fter oronry rtery bypss surgery. Cirultion. 2005;111(3): Connerney I, Shpiro PA, MLughlin JS, Bgiell E, Slon RP. Reltion between depression fter oronry rtery bypss surgery nd 12-month outome: prospetive study. Lnet. 2001;358(9295): Blumenthl JA, Lett HS, Bbyk MA, et l; NORG Investigtors. 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