Increased Antidepressant Drug Exposure in Psoriasis Patients: A Longitudinal Population-based Cohort Study

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1 Act Derm Venereol 2013; 93: CLINICAL REPORT Incresed Antidepressnt Drug Exposure in Psorisis Ptients: A Longitudinl Popultion-sed Cohort Study Emmili A. Dowltshhi 1, Mrlies Wkkee 1, Ronld M. C. Herings 2,3, Loes M. Hollestein 1 nd Tmr Nijsten 1 Deprtments of 1 Dermtology nd 3 Helth Policy nd Mngement, Ersmus Medicl Center, Rotterdm, nd 2 PHARMO Institute for Drug Outcomes Reserch, Utrecht, The Netherlnds Psorisis hs mjor impct on helth-relted qulity of life. The present cohort study investigted the use of ntidepressnt drugs in psorisis ptients nd reference cohort, using phrmcy nd hospitliztion dt from 1998 to 2008 for more thn 2.5 million Dutch residents. Multivrite Cox regression ws used to compre the risk of first ntidepressnt use, nd Poisson regression to compre the numer of episodes of ntidepressnt use. A totl of 25,691 psorisis cses nd 128,573 reference sujects were followed for more thn 9 yers. The incidence of first ntidepressnt use ws 21 nd 9 per 1,000 person yers, respectively, nd the djusted hzrd rtio (HR) ws 1.55 (95% confidence intervl (CI) ). Within the psorisis cohort, the HR of receiving n ntidepressnt ws significntly higher fter the first ntipsoritic tret ment (HR 1.07, 95% CI ). Psorisis ptients hve two-fold increse in ntidepressnt use, the period fter ntipsoritic tretment eing chrcterized y further increse in ntidepressnt drug dispenses. Key words: psorisis; cohort study; ntidepressnt use; comoridity; phrmcoepidemiology. Accepted Oct 15, 2012; Epu hed of print Mr 25, 2013 Act Derm Venereol 2013; 45: Tmr Nijsten, Deprtment of Dermtology, Ersmus Medicl Center, Burgemeester s Jcoplein 51, NL-3015 CA Rotterdm, The Netherlnds. E-mil: t.nijsten@ersmusmc.nl In recent yers much ttention hs een drwn to psychitric disorders mong ptients with dermtologicl conditions, often referred to s psychodermtology (1). Reports of suicidl idetion mong ptients with skin diseses hve led to incresing concerns (2, 3). In psorisis, studies hve demonstrted significnt impirment of helth-relted qulity of life (HRQoL) nd higher likelihood of developing depression (4). Although the correltion etween severity of psorisis nd impct on HRQoL is wek (5), the chnce of psychitric comoridity seems to increse with the severity of psorisis (6). Two lrge helthcre-dtse studies, focussing on mjor psychitric disorders, hve confirmed significnt nd positive ssocition with psorisis (6, 7). Remrkly, the prcticl implictions of ctul ntidepressnt drug dispenses hve received only limited ttention. Two studies hve investigted drug prescriptions in generl, including ntidepressnts in psorisis ptients, during restricted time-period: one cross-sectionl study showed tht, t the time of hospitl dmission, psorisis ptients hd 1.4-times higher risk of using n ntidepressnt drug compred with helthy individuls (8), while nother cse-control study focusing on the period 3 yers efore the dte of psorisis dignosis oserved no incresed use of ntidepressnts (9). Furthermore, other studies investigted self-reported ssessment of depressive symptoms, which cn is the outcome definition (4, 10 12), nd hd cross-sectionl study design, limited smple size, or lcked comprtive control group. The ojective of the present study ws to longitudinlly compre ntidepressnt use nd episodes in psorisis ptients from 1997 to 2008 with non-psoritic reference cohort from lrge smple of the generl popultion, focusing specificlly on the time efore, during nd fter tretment initition for psorisis. MATERIALS AND METHODS Dt source Dt were retrieved from the Phrmo Record Linkge system, lrge ptient-centric dt network linking multiple oservtionl dtses, including drug dispensing nd hospitliztion dt for pproximtely 2.5 million residents in the Netherlnds (13, 14). Informtion on ech prescription includes product nme, Antomicl Therpeutic Chemicl (ATC) clssifiction of the drug, dte of dispensing, quntity dispensed, dosge nd regimen. Study popultion Psorisis ptients were identified using previously descried lgorithm sed on dispensed drugs nd hospitliztions for psorisis nd psoritic rthropthy (15 17). The index dte for psorisis ptients ws the dte of the first ville ctive tretment for psorisis, vrying from topicl corticosteroids to systemic ntipsoritic therpies. The reference popultion consisted of sujects without psorisis, who were ssigned rndom index dte. Five reference sujects were rndomly selected for every psorisis ptient, using frequency mtching for the index dte. The eligiility dte represents the dte of first registrtion in phrmcy linked to the Phrmo system. Between 1997 nd 2008 ll sujects were followed from the eligiility dte to the yer of lst ville prescription, the dte when registered sujects moved wy, or the dte of deth, whichever cme first The Authors. doi: / Journl Compiltion 2013 Act Dermto-Venereologic. ISSN

2 Antidepressnt use in psorisis ptients 545 Drug exposure Antidepressnts (ATC code N06A) were selective serotonin reuptke inhiitors (SSRIs), tricyclic ntidepressnts (TCAs) or other ntidepressnts. The strt of n episode of ntidepressnt use ws defined s the dte of dispensing of the first prescription for ny ntidepressnt. The length ws the numer of dys for which the prescried quntity nd prescried dosge would suffice, nd the end of n episode ws defined s no new prescription within 4 months fter the end dte of the lst ntidepressnt prescription. According to the Americn College of Neuropsychophrmcology nd other guidelines, recovery from mjor depressive episode cn e scried fter t lest 4 months of remission hve een scertined (18, 19). An episode of ntidepressnt use is not equivlent to mjor depressive episode, which is sed on ssessment of depressive symptoms; however ccording to the ville recommendtions, this seemed to e the most pproprite wy to define n episode. Covrites The covrites gender nd ge t eligiility dte included in the multivrite models were determined priori. In order to djust for comoridities, we clculted the numer of unique prescriptions t ATC second level (numer of unique therpeutic min groups) during the 6 months efore the index dte. This method hs een descried previously (16). To void over-djustment, we excluded ntidepressnts from this count. Sttisticl nlyses Student s t-test ws used to test for differences etween continuous vriles nd χ 2 test for ctegoricl vriles. To quntify first ntidepressnt use we clculted incidence rtes (IR) per 1,000 person yers with 95% confidence intervl (CI). Multivrile Cox proportionl-hzrds nlyses compred hzrds for the first ntidepressnt use etween the 2 cohorts. We verified tht the hzrds for ctegoricl vriles were proportionl using the log minus log function. Poisson regression model compred IRs of numer of episodes of ntidepressnt use, where oservtion time from eligiility dte until the end of follow-up ws used s n offset. To investigte the pttern of ntidepressnt use, we clculted cumultive IRs nd incidence rte rtios (IRR) of episodes of ntidepressnt use in oth cohorts for the entire follow-up using time windows of 6 months, nd plotted these rtes with their respective 95% CI ginst time since dignosis of psorisis (± 10 yers). We conducted n internl comprison within the psorisis cohort using psorisis ptients s their own controls nd clculted the hzrd rtio (HR) of ntidepressnt use efore nd fter the index dte using Cox proportionl hzrds model with roust stndrd errors (20). We report the men numer of episodes efore nd fter the index dte nd the IRR using generlized estimting equtions (GEE) for counts with unstructured correltion mtrix, roust stndrd errors nd exposure time s n offset (21). Sensitivity nlyses We nlysed ntidepressnt use 7 months efore nd fter the index dte (4 months is the mximum durtion etween 2 prescriptions in the sme episode nd 3 months is the usul mximum durtion of prescription in the Netherlnds) nd lso in n nlysis excluding the time round the index dte. The effect of disese severity ws studied, wherey dispensing of topicl ntipsoritic mediction served s proxy for mild disese nd systemic psorisis mediction nd hospitliztion for psorisis s proxy for moderte to severe disese. Sttisticl nlyses were conducted using SAS version 9.2 (SAS Institute Inc., Cry, NC, USA) nd SPSS version 17.0 (SPSS inc., Chicgo, IL, USA). The present study ws conducted nd reported ccording to the guidelines elorted in the STROBE sttement (Strengthening the Reporting of Oservtionl Studies in Epidemiology) (22). RESULTS Study popultion This study included 25,691 psorisis ptients nd 128,573 reference sujects. Gender distriution ws similr in the cohorts, while the men ge ws 6 yers higher in the psorisis cohort (Tle I). In oth cohorts the men follow-up time ws pproximtely 9.5 yers. Antidepressnt use ws more thn twice s frequent in psorisis sujects s in the reference popultion (17.8% Tle I. Bseline chrcteristics of the reference nd psorisis cohorts Reference cohort Psorisis cohort p-vlue Totl numer of sujects (n = 154,264), n (%) 128,573 (83.3) 25,691 (16.7) Gender, mle, n (%) 62,141 (48.3) 12,494 (48.6) 0.38 Age t eligiility dte, yers, medin (interqurtile rnge) 33.0 (18.0; 50.0) 42.0 (28.0; 56.0) < Yers of follow-up, men Antidepressnt use Any ntidepressnt, n (%) 10,137 (7.88) 4,576 (17.81) < Selective serotonin reuptke inhiitor, n (%) 6,630 (5.16) 3,014 (11.73) < Tricyclic ntidepressnt, n (%) 3,336 (2.59) 1,650 (6.42) < Other ntidepressnts, n (%) 2,784 (2.16) 1,359 (5.29) < Episodes of ntidepressnt use, n (%) 1 6,326 (4.92) 2,593 (10.09) < ,020 (1.57) 959 (3.73) (0.62) 471 (1.83) (0.34) 239 (0.93) (0.18) 127 (0.49) (0.23) 167 (0.65) Yers of follow-up from eligiility dte to the end of follow-up in Phrmo dtse. Vlues do not dd up to sum of ll ntidepressnts ecuse ptients could hve more thn one type of ntidepressnt.

3 546 E. A. Dowltshhi et l. Tle II. First ntidepressnt use in reference nd psorisis cohorts Reference cohort Psorisis cohort First ntidepressnt use 10,137 4,576 Person yers 1,148, ,562 IR/1,000 person yers (95% CI) 8.83 ( ) ( ) Crude hzrd rtio (95% CI) ( ) Adjusted hzrd rtio, c ( ) Sum of numer of person yers from eligiility dte to dte of first prescription for n ntidepressnt or to the end of follow-up in Phrmo dtse. Adjusted for ge, gender nd numer unique prescriptions 6 months efore index dte. c COX regression. IR: Incidence rte; CI: confidence intervl. vs. 7.9%, p < 0.001). In prticulr, SSRIs were the most commonly prescried ntidepressnts in oth popultions (Tle I). Multiple episodes of ntidepressnt use were oserved in 7.6% of the psorisis nd 2.9% of the reference popultion (p < 0.001). Antidepressnt use in the psorisis cohort compred with the reference popultion First ntidepressnt use. The undjusted incidence rte (IR) of ntidepressnt use per 1,000 person yers ws significntly incresed in psorisis ptients (21.2, 95% CI ) compred with the reference popultion (8.8, 95% CI ). The crude HR ws 2.37 (95% CI ), demonstrting tht psorisis ptients were pproximtely 2.4 times more likely to use ntidepressnt drugs without djusting for fctors tht my confound this ssocition (Tle II). Adjusting for ge nd gender hd only limited effect on the HR (djusted HR 2.19, 95% CI ), while djusting for unique prescriptions dispensed 6 months efore index dte hd remrkle effect, since the HR decresed to 1.55 (95% CI ), ut remined significnt. Episodes of ntidepressnt use. Psorisis ptients hd more thn twice s mny episodes of ntidepressnt use thn the reference popultion, 37 vs. 15 per 1,000 person yers (IRR 2.54, 95% CI ) (Tle III). After Poisson regression, the djusted HR of 1.47 (95% Tle III. Episodes of ntidepressnt use in reference nd psorisis cohorts Reference cohort Psorisis cohort Episodes of ntidepressnt use, n 18,070 8,961 Person yers 1,206, ,934 IR/1,000 person yers, 95% CI ( ) ( ) Crude IRR, 95% CI ( ) Adjusted IRR,c, 95% CI ( ) Sum of numer of person yers from eligiility dte to the end of follow-up in Phrmo dtse. Adjusted for ge, gender nd numer unique prescriptions 6 months efore index dte. c Poisson regression using entire follow-up time of ech ptient s offset. IR: Incidence rte; IRR: Incidence rte rtio; ICI: confidence intervl. CI ) ws comprle to the djusted HR of the nlysis on first ntidepressnt use. We compred IRs of episodes of ntidepressnt use in the psorisis cohort with those of the reference popultion during 10 yers efore nd fter first tretment for psorisis (index dte) (Fig. 1) nd plotted the cumultive IRRs (Fig. 2). The IRRs grdully incresed from yers efore to yers efore first ntipsoritic tretment. The IRRs were highest within the first 6 months fter psorisis tretment, nmely 2.79, nd slowly decresed in the 5 yers therefter to rech plteu t n IRR of pproximtely 2.64 until the end of follow-up fter 10 yers. Looking t the entire period efore nd fter the index dte nd excluding the yer round the index dte, the IRR for episodes of ntidepressnt use is higher in the yers fter the index dte thn in the yers efore. If we djusted these crude rtes for ge, gender nd comoridity, the risk of dispensing n ntidepressnt ws reduced, ut still remined 50% higher in the psorisis cohort. The djusted risk of ntidepressnt use followed the pttern of the crude dt, y peking round the index dte (djusted HR 7 months efore index dte 1.54, 95% CI , djusted HR 7 months fter index dte 1.89, 95% CI ) nd when excluding the 7 months efore nd fter index dte, the djusted HR were higher in the yers fter (djusted HR 1.73, 95% CI ) thn efore the index dte (djusted HR 1.33, 95% CI ). Internl comprison of ntidepressnt use within the psorisis cohort When restricting the nlysis to the psorisis cohort nd compring ntidepressnt use efore nd fter the index dte, psorisis ptients were pproximtely 7% more likely to receive ntidepressnt drugs fter the index dte, when controlling for within-ptient vrition using the GEE model (HR 1.07, 95% CI ) (Tle IV). However, there ws no significnt difference in the men numer of episodes efore nd fter the index dte, nd 0.037, respectively (IRR 1.03, 95% CI , p = 0.26). Effect of psorisis severity on ntidepressnt drug use Ptients with mild psorisis hd 2.3-times higher risk (95% CI ) of using ntidepressnt drugs compred with reference sujects. In multivrite COX regression model, the ge, gender nd comoridity djusted HR for ntidepressnt use remined significnt (djusted HR 1.55, 95% CI ) in this sugroup of ptients. Ptients with more severe psorisis hd crude HR of 2.81 (95% CI ) nd n djusted HR of 1.57 (95% CI ) compred with the non-psorisis cohort. Psorisis ptients with severe disese were t higher risk of hving

4 Antidepressnt use in psorisis ptients 547 Fig. 1. Incidence rtes of ntidepressnt use in psorisis nd reference cohorts. first ntidepressnt thn ptients with mild disese, with n overll p-vlue < DISCUSSION This study shows tht dispensing of ntidepressnts is two-fold higher in psorisis ptients nd tht they hve twice s mny episodes of ntidepressnt use thn the reference popultion. The longitudinl study design enled us to demonstrte tht ntidepressnt use is lredy incresed efore psorisis ptients seek medicl tretment for their skin nd tht it peks round the time of tretment initition, ut lso remins incresed therefter. Our outcomes re in line with prescription dt from Germn hospitlized psorisis ptients, showing 1.4-times higher risk of using n ntidepressnt (8) nd re lso comprle to the times higher risk of mjor psychitric disorders in psorisis oserved in the Generl Prctice Dtse from the UK nd Fig. 2. Incidence rte rtio of ntidepressnt use in the psorisis cohort compred with the reference popultion. n interdisciplinry dministrtive outptient dtse from Germny (6, 7). Adjusting for unique numer of prescription drugs 6 months prior to the index dte, s proxy for the generl helthcre consumption pttern, resulted in considerle decrese in the risk of using n ntidepressnt. This effect could e explined y detection is, i.e. ptients with psorisis visit their physicin more often, which eqully increses their risk of dignosis nd tretment of other diseses, including depression (23). This effect ws lso confirmed y other studies, showing tht the likelihood of eing dignosed with depression increses with the numer of physicin visits due to psorisis (6) nd tht, on verge, psorisis ptients with severe disese receive more different systemic drugs thn the generl popultion (8). The incresed risk of ntidepressnt use fter djustment my e explined y the effect of psorisis on the HRQoL, leding to stigmtiztion, shme, difficulties in dily ctivities nd coping prolems (11, 24 26), which Tle IV. Anlysis of ntidepressnt use within the psorisis cohort efore nd fter index dte (n = 25,691) Before index dte After index dte First ntidepressnt use in psorisis ptients Antidepressnt users, n 1,977 3,480 Person yers, n 74, ,241 IR/1,000 person yers, 95% CI ( ) ( ) Hzrd rtio (95% CI) ( ) Episodes of ntidepressnt use in psorisis ptients Episodes of ntidepressnt use, n 2,810 6,151 Person yers c, n 78, ,064 IR/1,000 person yers, 95% CI ( ) ( ) Men numer of episodes, 95% CI ( ) ( ) IR rtio d, 95% CI ( ) Sum of numer of person yers from eligiility dte to dte of first ntidepressnt or to index dte (for nlysis efore the index dte) nd from index dte to first ntidepressnt fter index dte or to the end of follow-up in Phrmo dtse (for nlysis fter the index dte). Cox proportionl hzrd model with roust stndrd errors. c Sum of numer of person yers from eligiility dte to index dte (for nlysis efore the index dte) nd from index dte to the end of follow up in Phrmo dtse (for nlysis fter the index dte). d Poisson regression model using generlized estimting equtions with unstructured correltion mtrix nd roust stndrd errors. IR: Incidence rte; CI: confidence intervl.

5 548 E. A. Dowltshhi et l. my result in depressive symptoms (27). An lterntive explntion my e reverse cuslity; depression my led to self-neglecting ehviour, isoltion nd therefore induces lifestyle chnges, such s smoking, lcoholism nd oesity, which in turn cn led to incresed inflmmtion nd eventully to psorisis. However, since the effects of generlized inflmmtion mostly ecome pprent fter long induction period, the ssocition etween depression, lifestyle chnges nd psorisis would tke yers to mnifest itself (28, 29). Genetics could ply role in the ssocition etween psorisis nd depression. Genome-wide ssocition studies on psorisis susceptiility loci (30 34) nd on genes for mjor depressive disorder (35) showed no common genes. However, recent study on inflmmtion-relted genes in depression identified tht the gene PSMB4, criticl for T-cell function, ws ssocited with susceptiility to mjor depressive disorder (36). Susceptiility to psorisis hs lso een ssocited with the re of chromosome 1q21 (PSORS4) tht encodes for the PSMB4 gene (34). The pttern of ntidepressnt use in this study shows 3 discernle periods (Fig. 2): first, during the yers efore the index dte, ntidepressnt use grdully increses nd reches mximum in the proximity of the index dte. Therefter, ntidepressnt use does not decline to its level from efore the index dte, ut remins constntly high nd reches plteu until the end of follow-up. The use of ntidepressnt drugs remined incresed fter the index dte, lso when djusting for confounders. Assuming tht the index dte represents the dte of first dignosis of psorisis, the period of more thn one yer efore the index dte would represent period without ctive psorisis or where psoritic disese hs not yet mnifested itself. The risk difference of ntidepressnt use etween the 2 cohorts in this first period my, therefore, e explined y intrinsic fctors t work, such s unhelthy lifestyle fctors, different helthcre consumption ttitudes nd genetic fctors, leding to higher use of ntidepressnts thn in sujects who do not develop psorisis. Interestingly, other studies hve shown tht psorisis ptients re lredy more oese efore the mnifesttion of psoritic disese (28), which my lso led to depression (37). We then oserved devition of ntidepressnt use strting 1.5 yers prior to the first dispensing of ntipsoritic mediction until 1.5 yers therefter in the psorisis cohort nd in the nlyses compring the psorisis cohort with the reference popultion. This increse in ntidepressnt use my not merely e explined y incresed helthcre consumption in psorisis ptients. Antidepressnt use ttins mximum round the index dte, whereupon the ptient seeks medicl cre due to psorisis de novo or excertion of disese, nd thus the severity of disese in this cute phse my hve more pronounced impct on the psychologicl condition of the ptient. If there is cusl reltionship etween psorisis nd depression, then this my e reflected in the risk difference of 0.5 compring the period efore nd fter the index dte (Fig. 2) where the IRR of ntidepressnt use increses from 2.2 to 2.7. The oservtion tht, eyond the index dte, the risk of ntidepressnt use does not return to the level prior to the index dte suggests tht it remins difficult to control psorisis in the long-term, nd tht disese severity remins reltively stle in time (38). Therefore, the significnt increse in risk of ntidepressnt dispensing eyond the index dte could e ttriuted to the impct of chronic skin disese on ptients HRQoL. On the other hnd, study compring QoL scores in n 11-yer period demonstrted significnt decrese of pproximtely 25% in the overll psychosocil impct of psorisis on ptients HRQoL, suggesting tht this group of ptients ccommodte to the impct of their disese over time (39). Strengths nd limittions The present study is the lrgest popultion-sed longitudinl study compring ntidepressnt prescriptions during n lmost 10-yer oservtion period in psorisis ptients to reference cohort. It is sed on prescription dt from 2.5 million Dutch residents, nd is therefore well representtive of the Dutch popultion. The longitudinl study design enled us to focus in detil on drug prescriptions round the time of initition of psorisis therpy. Besides nlyzing unique prescriptions, we lso investigted multiple episodes of ntidepressnt use, which resulted in comprle outcomes. The otined risk estimtes confirm the estimtes found in studies on the ssocition etween psorisis nd mjor psychitric disorders (6, 7), lso strengthening our definition of depressive episodes sed on ntidepressnt prescription dt. We re wre tht ntidepressnt drug use does not imply the dignosis of depression, ut my lso represent other psychitric moridities. In the Dutch generl prctice, 45% of ntidepressnt users hd depression, 17% hd nxiety nd pnic disorders, nd 9% hd sleeping disorders (40). Our definition of psorisis ws sed on drug nd hospitliztion lgorithm; nevertheless it hd 98.2% sensitivity nd 80.2% specificity (16). This could result in non-differentil misclssifiction of psorisis cses, which might led to underestimtion of the effect of psorisis on ntidepressnt use. As is lso the cse in other secondry dtse studies, residul confounding ws likely ecuse dt on potentil confounders, such s weight, smoking, lcohol consumption, physicl ctivity or socioeconomic sttus, were not ville. However, the risk estimtes were stle cross the different nlyses including the within ptient nlysis, in which the effect from unmesured confounding fctors

6 Antidepressnt use in psorisis ptients 549 etween psorisis cses nd reference sujects ws ttenuted. We clculted the exposure to ntidepressnts from dispensed phrmcy prescriptions ssuming good drug complince. However, the rte of non-dherence to ntidepressnt tretment cn vry from 40% to 75% (41), especilly mong long-term users, which ws not the ojective of this study. Although the men followup ws lmost decde, it is possile tht ptients hd depression efore they were registered in the dtse, resulting in non-differentil misclssifiction. To minimize the impct of this is, prevlent ntidepressnt users (n = 143) who hd chnged phrmcists nd who hd n ntidepressnt drug dispensed in the first phrmcy where they were registered, were excluded from the nlysis. Conclusion Psorisis ptients use more ntidepressnt mediction thn the generl popultion, especilly t the time when they seek medicl cre for their psorisis nd therefter. Physicins should e wre tht ptients who seek cre for chronic dermtologicl conditions such s psorisis my hve n incresed risk of experiencing psychologicl or psychitric disorders. ACKNOWLEDGEMENTS The uthors would like to thnk M. Mols, from the Deprtment of Biosttistics of the Ersmus Medicl Centre, for his help in progrmming mcros for SAS nd dvice on the sttisticl methods. Funding source: This study ws sponsored y n unrestricted grnt from Aott. Conflicts of interest: E. A. Dowltshhi, M. Wkkee nd L. M. Hollestein hve no conflicts of interest to declre. T. Nijsten served s speker nd consultnt for Aott, Celgene, Leo Phrm, Schering Plough (Merck) nd Wyeth (Pfizer). As n employee of the PHARMO Institute dr. RM.C. Herings is not llowed to hve ny personl profit from contcts with clients, i.e. phrmceuticl industry or others. The sence of personl finncil rewrds for dr. R.M.C. Herings is true for ll studies nd ll ctivities he is involved in. 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