Objective: Erectile dysfunction and depression are highly associated. Previous studies have shown benefits of phosphodiesterase-5

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1 Article Efficcy nd Tolerbility of Vrdenfil in Men With Mild Depression nd Erectile Dysfunction: The Depression-Relted Improvement With Vrdenfil for Erectile Response Study Rymond Rosen, Ph.D. Ridwn Shbsigh, M.D. Mrk Berber, M.B.M.R.C.G.P., M.R.C.Psych., F.R.C.P.C. Pierre Asslin, M.D. Mthew Menz, M.D. Luis Rodriguez-Vel, M.D. Robert Porto, M.D. Keith Bngerter, Ph.D. Monic Seger, Ph.D. Frncesco Montorsi, M.D. The Vrdenfil Study Site Investigtors Objective: Erectile dysfunction nd depression re highly ssocited. Previous studies hve shown benefits of phosphodiesterse-5 inhibitor tretment for erectile dysfunction ssocited with ntidepressnt therpy or subsyndroml depression. The present study ssessed the sfety nd efficcy of vrdenfil in men with erectile dysfunction nd untreted mild depression. Method: In this 12-week, multicenter, rndomized, flexible-dose, prllel-group, double-blind study, 28 men with erectile dysfunction for t lest 6 months nd untreted mild mjor depression received plcebo or vrdenfil, 1 mg/dy, for 4 weeks, with the option to titrte to 5 mg/ dy or 2 mg/dy fter ech of two consecutive 4-week intervls. Endpoints included Interntionl Index of Erectile Function erectile function domin nd 17- item Hmilton Depression Rting Scle (HAM-D) scores. Results: Vrdenfil produced sttisticlly significnt nd cliniclly meningful improvement in ll erectile function prmeters. The Interntionl Index of Erectile Function erectile function domin score ws 22.9 with vrdenfil compred to 14.9 with plcebo. The HAM-D score ws lower in the vrdenfil group (7.9) thn in the plcebo group (1.1). Tretment with vrdenfil ws the most importnt predictor for return to norml erectile function. Improvement in Interntionl Index of Erectile Function erectile function domin score ws the most importnt predictor of remission in depressive symptoms. Conclusions: Vrdenfil ws well tolerted nd highly efficcious in men with erectile dysfunction nd untreted mild mjor depression. Significnt improvements in erectile function nd depression were observed in ptients treted with vrdenfil versus plcebo. Erectile dysfunction tretment should be considered component of therpy for men with depression nd erectile dysfunction. (Am J Psychitry 26; 163:79 87) Erectile dysfunction is highly prevlent mong men between 4 nd 7 yers of ge, nd the estimted lifetime prevlence of mjor depression (6% to 1%) is considerble (1). A loss of interest in nd withdrwl from ll regulr nd plesurble ctivities re often ssocited with depression (2). Sexul disorders re lso common in ssocition with depression; however, the mechnisms underlying the link between depression nd sexul dysfunction re complex. Erectile dysfunction my contribute to, or be consequence of, depression. Severl fctors cn be involved, including loss of self-esteem, performnce nxiety, nd reduced qulity of life (3). The Msschusetts Mle Aging Study showed tht men with untreted depression hd 1.8-fold greter chnce of experiencing erectile dysfunction thn men without depression, nd erectile dysfunction incresed with incresing degree of depression (4, 5). Phosphodiesterse-5 (PDE-5) inhibitors hve been used to effectively nd sfely tret erectile dysfunction in ptients with depression, including ptients treted with ntidepressnt therpy (6 1). To our knowledge, none of the studies reported to dte hs investigted the potentil mentl helth benefits of PDE-5 inhibitor therpy in men with erectile dysfunction nd untreted mild mjor depressive disorder. Becuse this popultion represents lrge cohort of men, mny of whom re reluctnt to use ntidepressnt therpies, tretment for erectile dysfunction tht hs positive impct on depressive symptoms my be n ttrctive therpeutic option (5 9). Vrdenfil is potent selective PDE-5 inhibitor tht hs been shown to be highly efficcious in men with erectile dysfunction, irrespective of severity or disese clssifiction (orgnic, psychogenic, or mixed) (11) or underlying etiology (12). The drug is well tolerted nd is ssocited with rpid nd relible tretment response. The objective of the Depression-Relted Improvement With Vrdenfil for Erectile Response Study ws to evlute the efficcy of vrdenfil in the tretment of men with erectile Am J Psychitry 163:1, Jnury

2 VARDENAFIL FOR ERECTILE DYSFUNCTION dysfunction nd cliniclly dignosed but untreted mild mjor depressive disorder. Method Study Prticipnts This 12-week, flexible-dose, prllel-group, double-blind study ws conducted in 44 centers comprising the disciplines of urology, psychitry, generl prctice, nd endocrinology in the United Sttes, Cnd, Frnce, Spin, nd Itly between Dec. 3, 22, nd Nov. 27, 23. Of totl of 488 men screened, 28 were subsequently rndomly ssigned. The subjects were 18 yers of ge nd hd experienced erectile dysfunction for >6 months ccording to Ntionl Institutes of Helth criteri (13). Inclusion criteri were prticiption in stble heterosexul reltionship for more thn 6 months nd hving dignosed but untreted mild mjor depressive disorder. During the erly prt of the investigtion, the subjects were included if they hd 17-item Hmilton Depression Rting Scle (HAM-D) score between 13 nd 23 t visits 1 nd 2 nd Center for Epidemiologic Studies Depression Scle (CES-D Scle) (14) score >13 t visit 1. HAM-D rting ws performed by n interview with blinded expert who ws generlly not wre of the response to tretment. At the request of the steering committee but in the bsence of ny tretment-relted serious dverse events, entry criteri for depression severity in the study were modified. The protocol ws mended while the study ws in progress to include only subjects with HAM-D scores between 11 nd 17 rther thn between 13 nd 23. The subjects were not in psychotherpy or tking ntidepressnt mediction. The subjects mde t lest four ttempts t sexul intercourse on 4 seprte dys during the untreted bseline period. For inclusion in the study, t lest 5% of the ttempts t sexul intercourse filed becuse of prtil erections, unsuccessful penetrtion, or unsuccessful intercourse. Written informed consent ws obtined from the subjects fter complete description of the study hd been given to them. Exclusion criteri included ny unstble medicl condition or substnce buse; serious suicidl or homicidl risk (ptients who scored > on item 3 of the HAM-D or who mde suicide ttempt in the 12 months before screening); or history of bipolr disorder, schizophreni, schizoffective disorder, delusionl disorder, pnic disorder, posttrumtic stress disorder, or personlity disorder. Three ptients were excluded becuse of dysthymi. were lso excluded bsed on the presence of penile ntomicl bnormlities, primry hypoctive sexul desire, erectile dysfunction relted to spinl cord injury, prior nonresponse to sildenfil, retinitis pigmentos, or rdicl prosttectomy. Study Design After 4-week run-in period without mediction, the subjects were rndomly ssigned to receive plcebo or vrdenfil, 1 mg/ dy, for 4 weeks. Erectile function ws ssessed bsed on subjective ptient diry responses to questions evluting ech sexul experience. At week 4, the investigtor nd ech ptient reviewed the efficcy nd tolerbility of the initil dose, nd clinicl decision ws mde s to whether the initil dose ws mintined, incresed to 2 mg/dy, or decresed to 5 mg/dy for the next 4 weeks. At week 8, the investigtor nd ech ptient gin discussed nd evluted the efficcy nd tolerbility nd djusted the dose by one step or mintined the previous dose for the finl 4 weeks of the study. Primry endpoints were the Interntionl Index of Erectile Function erectile function domin score (15), in which cliniclly significnt improvement ws defined s chnge of 5 points, nd HAM-D totl score t lst observtion crried forwrd if the erectile function nlysis ws successful. In this study, significnt improvement in mood ws considered to be decrese of 3.5 points on the HAM-D scle in vrdenfil-treted ptients compred to plcebo. Secondry erectile function endpoints included the Sexul Encounter Profile Questionnire (vilble from the first uthor), in which ptients responded yes or no to the following questions fter ech sexul ttempt: Were you ble to insert your penis into your prtner s vgin? (question 2), nd Did your erection lst long enough for you to hve successful intercourse? (question 3). Other erectile function indices included dditionl domins from the Interntionl Index of Erectile Function, including orgsmic function, sexul desire, intercourse stisfction, overll stisfction, nd response to globl ssessment question in which ptients responded yes or no to the question, Hs the tretment you hve been tking over the pst 4 weeks improved your erections? Other ssessments included the CES-D Scle nd the Rosenberg Self-Esteem Scle (16). The mgnitude of HAM-D improvement ws summrized by the following: HAM-D responses corresponding to remission (finl HAM-D score 7), response ( decrese in HAM-D score 5%), or improvement ( decrese in HAM-D score >3.5 points). A 24-hour follow-up fter the lst dose of study drug ws performed to monitor for serious dverse events. Sttisticl Anlysis The number of subjects required in this study ws bsed on the primry efficcy vribles, which were tested in hierrchicl fshion. The Interntionl Index of Erectile Function erectile function domin score ws nlyzed first, nd if the nlysis ws successful, then the HAM-D score ws ssessed. Becuse of the predefined testing sequence of the primry vribles, no lph djustment ws mde. The group size clcultions ssumed stndrd devition of 1. for erectile function domin scores on the Interntionl Index of Erectile Function nd 7.5 for HAM-D totl scores. With pproximtely 86 (Interntionl Index of Erectile Function erectile function domin) nd 98 (HAM-D) subjects per tretment group with dt for the primry nlyses, this study hd power of pproximtely 9%. On the bsis of n estimted postrndomiztion dropout rte of 25%, 131 subjects per tretment group were needed for rndom ssignment. The intent-to-tret group included ptients who took t lest one dose of study mediction nd who hd bseline nd ny postbseline efficcy dt. Anlysis of the Interntionl Index of Erectile Function erectile function domin score, HAM-D score, nd other efficcy vribles ws bsed on the intent-to-tret group by using the lst-observtion-crried-forwrd method to ccount for dropouts. Anlysis of the diry vribles ws lso bsed on this group, s ws the overll postbseline per-ptient success rte for ech vrible. The Interntionl Index of Erectile Function erectile function domin nd HAM-D scores were nlyzed with nlysis of covrince (ANCOVA), with bseline response s covrite nd terms for center nd tretment. The difference in lest squres mens between vrdenfil-treted ptients nd ptients receiving plcebo t p<.5 ws considered to be significnt. Responses to the second nd third questions of the Sexul Encounter Profile were nlyzed with n ANCOVA on per-ptient success rte nd included bseline s covrite. The per-ptient success rte ws clculted s the number of successes divided by the number of sexul ttempts with the number of responses for the question. The globl ssessment question ws nlyzed with logistic regression nlysis. To explore which prmeters my be predictive of return to norml erectile function (Interntionl Index of Erectile Function erectile function domin score 26 or HAM-D score 7), retrospective stepwise logistic regression nlyses were performed. Entry-level criteri for ech predictor of p<.1 were stipulted, nd ech predictor ws removed from the model if the p vlue ex- 8 Am J Psychitry 163:1, Jnury 26

3 ROSEN, SHABSIGH, BERBER, ET AL. TABLE 1. Demogrphic nd Clinicl Chrcteristics of the Sfety Group in the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Chrcteristic Plcebo (N=133) Vrdenfil (N=132) Men SD Men SD Age (yers) Body mss index (kg/m 2 ) Durtion of erectile dysfunction (yers) Bseline Interntionl Index of Erectile Function erectile function domin score Bseline 17-item Hmilton Depression Rting Scle score Etiology of erectile dysfunction N % N % Orgnic Psychogenic Mixed Prior sildenfil use N=132. ceeded.15. For explortion of the fctors predictive of return to norml erectile function, independent vribles included the Interntionl Index of Erectile Function erectile function domin bseline score, the HAM-D bseline score, ge, durtion of erectile dysfunction, tretment, HAM-D chnge in score, nd HAM-D return to norml score. For explortion of fctors predictive of return to norml HAM-D score, independent vribles included Interntionl Index of Erectile Function erectile function domin bseline score, HAM-D bseline score, ge, durtion of erectile dysfunction, tretment, Interntionl Index of Erectile Function erectile function domin chnge in score, nd Interntionl Index of Erectile Function erectile function domin return to norml score. Results Study Design After 4-week untreted run-in period, this 12-week, multicenter, flexible-dose, prllel-group, double-blind study rndomly ssigned 28 men to tretment with plcebo (N=143) or 1 mg/dy of vrdenfil (N=137) for 4 weeks. At the end of weeks 4 nd 8, the subjects, in collbortion with their physicins, hd the option to titrte their dose to 5 mg/dy or 2 mg/dy of vrdenfil or the equivlent of plcebo. The mjority of ptients tking plcebo (N=122, 93.8%) or vrdenfil (N=95, 73.1%) opted to titrte to the 2 mg/dy dose by the end of tretment; 111 of the subjects in the plcebo group (78%) nd 118 in the vrdenfil group (86%) completed the study. Premture discontinution ws most commonly ttributed to dverse events (2 of 143, 1%, in the plcebo group versus 4 of 137, 3%. in the vrdenfil group), insufficient therpeutic effect (N=1, 7%, versus N=2, 1%), withdrwn consent (N= 9, 6%, versus N=3, 2%), or loss to follow-up (N=1, 7%, versus N=5, 4%). Ptient Group Profile Bseline Interntionl Index of Erectile Function erectile function domin scores indicted moderte erectile dysfunction, with sfety group scores of 12.7 (SD=5.6) in the vrdenfil group nd 13.1 (SD=5.3) in the plcebo group. The subjects were dignosed with erectile dysfunction n verge of 3.5 yers (SD=4.3) before the screening. Erectile dysfunction ws of orgnic, psychogenic, or mixed etiology, with mixed etiology being the most common. Approximtely 75% of the ptients were Cucsin, 8% were blck, 2% were Asin, <1% were Americn Indin, <1% were Hispnic, nd 14% were ptients from Frnce, where rce ws not reported. In generl, the ptients were overweight (men weight=85 kg, SD=15), s ssessed by body mss (men=27 kg/m 2, SD=4) nd Broc (men=1.1, SD=.2) indices. Men ge ws 53 yers (SD=11). Approximtely 49% of the ptients were nonsmokers, nd 51% were pst or present smokers. Twenty-nine percent of the group suffered from vsculr hypertensive disorders, 15% hd dibetes mellitus, 12% hd elevted cholesterol, nd ll hd mild mjor depressive disorder. Depression ws dignosed or confirmed by trined nd qulified clinicins ccording to DSM-IV criteri with structured interview (the Mini Interntionl Neuropsychitric Interview [17] or the Structured Clinicl Interview for DSM-IV). About 59% of the ptients hd previously used sildenfil, which improved erections in ll of the ptients. Sildenfil nonresponders were excluded from this study. During the study, the protocol ws mended so tht bseline entry-level criteri scores for the HAM-D decresed from to Consequently, 25% of the subjects were enrolled under the initil criteri, nd s result, <9% of the totl ptient group hd HAM-D scores tht were bove the rnge t bseline. Overll, the tretment groups were blnced with respect to these demogrphic nd disese vribles (Tble 1). Efficcy for Erectile Function Erectile function domin scores. Vrdenfil tretment resulted in sttisticlly significnt nd cliniclly meningful improvement in ll erectile function prmeters. A sttisticlly significnt difference in Interntionl Index of Erectile Function erectile function domin scores between the vrdenfil-treted nd plcebo groups ws seen t the 12-week endpoint nd t the lst observtion crried forwrd (Figure 1). The Interntionl Index of Erectile Func- Am J Psychitry 163:1, Jnury

4 VARDENAFIL FOR ERECTILE DYSFUNCTION FIGURE 1. Efficcy of Vrdenfil for Erectile Dysfunction t 12-Week Endpoint, Lst Observtion Crried Forwrd, nd Overll for Sexul Encounter Profile Questions 2 nd 3 in the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Lest Squres Men Score Erectile function domin of Interntionl Index of Erectile Function N=18 N=116 N=13 N=13 Week 12 Lst Observtion Crried Forwrd Lest Squres Men Per-Ptient Success Rte (percent) Were you ble to insert your penis into your prtner s vgin? N=12 N=113 N=13 N=129 N=13 N=129 Week 12 Lst Observtion Overll Crried Forwrd Lest Squres Men Per-Ptient Success Rte (percent) Did your erection lst long enough to hve successful intercourse? N=12 N=113 N=13 N=129 N=13 N=129 Week 12 Lst Observtion Crried Forwrd Overll Significnt difference between groups. Intent-to-tret group. Yes Response (percent) Hs the tretment you hve been tking over the pst 4 weeks improved your erections? N=18 N=116 N=13 N=13 Week 12 Lst Observtion Crried Forwrd Plcebo Vrdenfil Bseline TABLE 2. Other Erectile Function Scores for the Intent-to- Tret Group of the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Plcebo (N=13) Score Vrdenfil (N=129) Mesure Lest squres men of Interntionl Index of Erectile Function domin scores of lst observtion crried forwrd Intercourse stisfction Orgsmic function Overll stisfction 4.9 b 7.1 Sexul desire ,c Lest squres men per-ptient percent ffirmtive diry response Erectile hrdness stisfction Sexul experience stisfction p<.1 versus plcebo. b N=129. c N=13. tion domin scores for erectile function t the lst observtion crried forwrd showed lest squres men improvement of 1. for vrdenfil-treted subjects compred to 2. for the plcebo group (t=8.78, df=215, p<.1). The results were similr for those who completed the tretment period. Other Interntionl Index of Erectile Function domin scores evluting intercourse stisfction (1.9 for vrdenfil versus 7.8 for plcebo) (t=7.43, df=214, p<.1), orgsmic function (7.7 versus 5.9) (t=4.93, df= 214, p<.1), overll stisfction (7.1 versus 4.9) (t=6.87, df=214, p<.1), nd sexul desire (7.3 versus 6.4) (t= 4.39, df=215, p<.1) ll showed sttisticlly significnt differences between vrdenfil- nd plcebo-treted ptients (Tble 2). Diry mesures Question 2: vginl penetrtion? The insertion success rte on the first ttempt ws pproximtely 1.5 times higher with vrdenfil tretment thn with plcebo. If insertion ws successful on the first ttempt, the ptients tking vrdenfil were successful on pproximtely 89% of their subsequent ttempts. Among ptients who did not chieve insertion on the first ttempt, the ptients tking vrdenfil were successful on pproximtely 49% of their subsequent ttempts. A sttisticlly significnt difference in penetrtion rtes between the vrdenfil-treted nd plcebo groups ws seen t the 12-week endpoint, t the lst observtion crried forwrd, nd overll (Figure 1). Overll, the lest squres men penetrtion success rte in the vrdenfil-treted group ws 76.7% compred to 52.4% for the plcebo-treted group (t=6.64, df=214, p<.1). Question 3: erection mintennce to completion of intercourse? The success rte for mintining n erection to completion of intercourse on the first medicted ttempt ws 1.8 times higher with vrdenfil compred to plcebo Am J Psychitry 163:1, Jnury 26

5 ROSEN, SHABSIGH, BERBER, ET AL. FIGURE 2. Efficcy of Vrdenfil for Depression t 12-Week Endpoint nd Lst Observtion Crried Forwrd in the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Lest Squres Men Score Score on 17-Item Hmilton Depression Rting Scle N=18 N=115 N=13 N=13 Week 12 Lst Observtion Crried Forwrd Significnt difference between groups. Intent-to-tret group. Percent Ctegoriztion of response bsed on score on 17-Item Hmilton Depression Rting Scle N=13 N=13 N=13 N=13 N=13 N=13 Remission (score 7) Response (score decrese of 5%) Improvement (score decrese of >3.5) Plcebo Vrdenfil Bseline If intercourse ws completed successfully on the first ttempt, the ptients tking vrdenfil were ble to mintin their erection to successful completion on pproximtely 83% of their subsequent ttempts. Among ptients who were not ble to successfully complete intercourse on their first ttempt, the ptients tking vrdenfil were ble to mintin their erection to successful completion on pproximtely 47% of their subsequent ttempts. A sttisticlly significnt difference in intercourse success rtes between the vrdenfil-treted nd plcebo groups ws seen t the 12-week endpoint, t the lst observtion crried forwrd, nd overll (Figure 1). Overll, the lest squres men intercourse success rte ws 66.4% with vrdenfil tretment nd 38.1% with plcebo (t=7.4, df=214, p<.1). Overll, per-ptient diry yes responses to questions concerning stisfction with erection hrdness (55.2% versus 25.%) (t=7.4, df=214, p<.1) nd sexul experience (6.% versus 27.5%) (t=8.15, df=214, p<.1) lso showed sttisticlly significnt efficcy in the vrdenfiltreted group (Tble 2). Globl ssessment question. A sttisticlly significntly greter proportion of vrdenfil-treted ptients responded yes to the globl ssessment question t the 12- week endpoint nd t the lst observtion crried forwrd compred to the plcebo-treted ptients (Figure 1). At the lst observtion crried forwrd, the estimted rte of positive responses ws 83% (N=13) for vrdenfil nd 3% (N=13) for plcebo (χ 2 =51.96, df=1, p<.1). Efficcy for Depression Vribles TABLE 3. Lest Squres Men Scores for the Center for Epidemiologic Studies Depression Scle (CES-D Scle) nd the Rosenberg Self-Esteem Scle for the Intent-to-Tret Group in the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Plcebo (N=17) c Score Lst Observtion 12 Weeks Crried Forwrd b Vrdenfil (N=113) Plcebo (N=117) d Vrdenfil (N=121) Mesure nd Time CES-D Scle Bseline Endpoint Rosenberg Self-Esteem Scle Bseline Endpoint For the CES-D Scle dt, t= 2., df=179, p=.469 for the comprison between plcebo nd vrdenfil. For the Rosenberg Self- Esteem Scle dt, t=1.76, df=177, p=.81 for the comprison between plcebo nd vrdenfil. b For the CES-D Scle dt, t= 1.93, df=195, p=.553 for the comprison between plcebo nd vrdenfil. For the Rosenberg Self- Esteem Scle dt, t=2.29, df=193, p=.232 for the comprison between plcebo nd vrdenfil. c N=15 for the Rosenberg Self-Esteem Scle dt. d N=115 for the Rosenberg Self-Esteem Scle dt. HAM-D overll score. Bseline HAM-D scores indicted mild mjor depressive disorder, with men scores of 14.3 (SE=.23) nd 14.4 (SE=.24) for plcebo nd vrdenfil groups, respectively. The HAM-D totl score t the lst observtion crried forwrd ws only evluted if the Interntionl Index of Erectile Function erectile function domin nlysis ws successful. The difference between vrdenfil tretment nd plcebo ws sttisticlly significnt t the lst observtion crried forwrd for the following HAM-D questions: question 1: depressed mood, question 2: feelings of guilt, question 4: erly insomni, question 5: middle insomni, question 8: psychomotor retrdtion, question 1: psychic nxiety, nd question 14: genitl symptoms. HAM-D totl scores showed sttisticlly significnt differences t week 12 (t= 4.12, df=182, p<.1) nd t the lst observtion crried forwrd (t= 3.9, df=215, p=.1) (Figure 2). Lest squres men HAM-D scores t the lst observtion crried forwrd were 7.9 (SE=.47) in the vrdenfil-treted group versus 1.1 (SE=.45) with plcebo nd were similr for ptients who completed tretment. Am J Psychitry 163:1, Jnury

6 VARDENAFIL FOR ERECTILE DYSFUNCTION TABLE 4. Fctors Predicting Return to Norml Erectile Function nd Predicting Remission to Depression Intensity on the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Anlysis Predictive Fctors nd Mesure Explntion χ 2 df p Fctors predicting return to norml erectile function (Interntionl Index of Erectile Function erectile function domin score 26) Tretment Vrdenfil ptients more likely to return to norml erectile func <.1 Chnge in 17-item Hmilton Depression Rting Scle (HAM-D) score Interntionl Index of Erectile Function erectile function domin score t bseline tion thn ptients receiving plcebo Ptients with lrge HAM-D improvement more likely to return to norml Interntionl Index of Erectile Function erectile function domin score High Interntionl Index of Erectile Function erectile function domin score t bseline equtes to less severe erectile dysfunction, therefore more likely to return to norml erectile function < <.14 Durtion of erectile dysfunction Shorter erectile dysfunction durtion, therefore more likely to return to norml erectile function Age Younger ptients more likely to return to norml erectile function <.78 Fctors predicting remission in depression intensity (HAM-D score 7) Chnge in Interntionl Index of Erectile Function erectile function domin score Interntionl Index of Erectile Function erectile function domin score t bseline HAM-D score t bseline Lrge erectile function improvement, therefore more likely to improve mood High Interntionl Index of Erectile Function erectile function domin score t bseline mens less severe dysfunction nd more likely to improve mood Low HAM-D score t bseline mens less severe nd more likely to improve mood < < <.77 HAM-D remission, tretment response, nd tretment improvement rtes. A decrese to totl score of 7 points or less in HAM-D totl score ws considered to be complete remission of depressive symptoms (remitters). A positive response to tretment ws defined s decrese in HAM-D totl score 5% compred to bseline (responders), nd tretment improvement ws defined s decrese >3.5 points (improvers). According to these criteri, significnt difference ws observed in remission of depressive symptoms with vrdenfil compred to plcebo (75 of 13, 58%, versus 41 of 13, 32%) (χ 2 =17.99, df= 1, p<.1) (Figure 2). A decrese of more thn 3.5 points ws chieved by pproximtely 1.4 times more ptients in the vrdenfil tretment condition thn with plcebo (94 of 13, 72%, versus 66 of 13, 51%). The decrese of t lest 5% (responders) ws chieved by lmost twice s mny ptients in the vrdenfil group s in the plcebo group (72 of 13, 55%, versus 39 of 13, 3%). Results for ptients in North Americ nd Europe were similr for the two primry endpoints. Other psychometric outcomes. Other efficcy vribles for depression showed improvements in depressive symptoms with vrdenfil tretment compred to plcebo. Improvements in depressive symptoms were evidenced by improvements in CES-D Scle rtings, with sttisticlly significnt difference between plcebo nd vrdenfil t week 12, with lest squres men scores of 13.5 (SE=.86) for the vrdenfil-treted group nd 15.6 (SE=.88) for the plcebo group (t= 2., df=179, p=.469). Bseline scores were 21.9 (SE=.83) nd 22.4 (SE=.85) for the vrdenfil nd plcebo groups, respectively, indicting depressive symptoms. The Rosenberg Self- Esteem Scle showed sttisticlly significnt difference between the lest squres men totl score for vrdenfil (31., SE=.43) nd plcebo (29.8, SE=.43) t the lst observtion crried forwrd (t=2.29, df=193, p=.232) but not t week 12 (p<.9) (Tble 3). Correltion between improvement in erectile function nd depressive symptoms. The ssocition between chnges in sexul function nd depression sttus ws exmined, nd positive correltion between remission of depression nd normliztion of erection ws observed. A return to norml ws considered to be n Interntionl Index of Erectile Function erectile function domin score 26 nd HAM-D score 7 (remitters); 38% of vrdenfil-treted subjects versus 13% of subjects in the plcebo group showed return to norml ccording to both criteri (χ 2 =21.9, df=1, p<.1). Ptients treted with vrdenfil or in the plcebo group who chieved norml erectile function (Interntionl Index of Erectile Function erectile function domin score 26) hd men HAM-D totl score of 6.4 (SE=.52) fter tretment compred to 1.3 (SE=.4) for those who filed to chieve normliztion of erectile function. Predictors of normliztion of erection nd depression remission. Results of stepwise logistic regression nlyses reveled tht tretment with vrdenfil ws the most significnt predictor of erection normliztion (Interntionl Index of Erectile Function erectile function domin score 26). In descending order of importnce, other significnt predictors included reduction in HAM-D score, higher bseline Interntionl Index of Erectile Function erectile function domin score, shorter erectile dysfunction durtion, nd younger ge (Tble 4). The most significnt predictor of normliztion of depressive symptoms, s mesured by HAM-D totl score, ws im Am J Psychitry 163:1, Jnury 26

7 ROSEN, SHABSIGH, BERBER, ET AL. provement in the Interntionl Index of Erectile Function erectile function domin score, followed by the Interntionl Index of Erectile Function erectile function domin bseline score nd the HAM-D score t bseline (Tble 4). Sfety Vrdenfil ws generlly well tolerted by this ptient group. The most frequently reported dverse events included hedche, nsl congestion, nd flushing (Tble 5), events consistent with the mechnism of ction of gents of the PDE-5 inhibitor clss. Symptoms were mild to moderte nd trnsient in nture. No plcebo ptients nd one vrdenfil-treted ptient reported severe dverse events; this ptient reported severe depression tht ws considered unrelted to study mediction. There were no tretment-relted psychitric events nd no deths during the study. The overll rte of dverse events leding to discontinution of study drug ws <1% in the plcebo group compred to 3% in the ptients receiving vrdenfil. No single dverse event led to discontinution of the study drug in more thn one ptient per tretment group. Discussion TABLE 5. Tretment-Emergent Adverse Events Occurring in t Lest 2% of the Sfety Group of the Depression-Relted Improvement With Vrdenfil for Erectile Response Study Plcebo (N=133) Vrdenfil (N=132) Adverse Event N % N % Hedche Flushing Nsl congestion 4 3 Insomni 4 3 A strong ssocition hs been observed mong erectile dysfunction, overll lck of life stisfction, nd symptoms of depression (18 21). Improvements in life stisfction my result from positive chnges in self-confidence, mood, nd fmily nd sexul reltionships, nd improved erectile function in men with erectile dysfunction my ply decisive role in the complex network of fctors tht contribute to overll qulity of life (22). The results presented here strongly support the hypothesis tht improvements in sexul function in men with erectile dysfunction re ssocited with lessening of depressive symptoms, which my hve clinicl implictions for the mngement of brod popultion of men with mild depression who my lso suffer from erectile dysfunction. Although previous studies hve demonstrted the benefits of PDE-5 inhibitor therpy in men with both treted (7 1) nd untreted symptoms of depression (6), this study is the first, to our knowledge, to evlute PDE-5 inhibitor therpy for erectile dysfunction in men with untreted mild mjor depressive disorder. A robust nd cliniclly significnt improvement in essentilly ll sexul function vribles ws seen fter ctive tretment, nd vrdenfil dministrtion ws lso ssocited with mrked reduction in depressive symptoms. More thn hlf of the ptients receiving vrdenfil chieved depressive symptom remission ccording to the usul severity criteri (HAM-D 7), supporting the clinicl significnce of the results. In ddition, tretment with vrdenfil resulted in improvements in CES-D Scle nd Rosenberg Self-Esteem Scle scores reltive to plcebo. Thus, improvements in ll depression efficcy vribles were consistent, regrdless of the outcome vrible or type of mesure employed. The correltion between improvement in erectile dysfunction nd HAM-D score remission provides further evidence tht tretment of sexul dysfunction in these ptients cn ffect other res of ptient function. The subjects treted with vrdenfil were more likely to chieve normliztion of erection thn those treted with plcebo, s would be expected from tretment with PDE- 5 inhibitor. Notble, however, ws tht improvement in HAM-D scores ws significnt predictor of normliztion of erectile function. This study lso showed tht improvement in erectile function ws the most significnt predictor of depression remission, followed in significnce by the Interntionl Index of Erectile Function erectile function domin bseline nd the HAM-D bseline scores. These results hve importnt implictions for the tretment of erectile dysfunction in ptients with comorbid depression nd support the concept tht reducing residul symptoms, such s erectile dysfunction, my result in more robust recovery from mjor depression. These results lso extend the body of literture in which PDE-5 inhibition hs been shown to improve erectile dysfunction in ptients with subsyndroml (6) or treted mjor depression (7, 8, 1). The study group investigted in the present study is unique in tht it consisted of subjects with untreted mild mjor depressive disorder. Such ptients my not use helth cre resources to the sme extent s ptients with more severe depressive symptoms nd my therefore represent lrger group thn tht evluted in previous studies (6). Becuse subjects were untreted for depressive illness, there were no confounding fctors ssocited with phrmcologiclly induced sexul dysfunction (3, 5). Despite concerns t the outset of the study bout potentil psychitric sfety issues, it is noteworthy tht no increses were observed in serious dverse events either medicl or psychitric during the course of the study. These results suggest tht erectile dysfunction therpy could be offered to ll mle ptients with comorbid depression, regrdless of their depression tretment sttus. For ptients with mild or subsyndroml depression, erectile dysfunction therpy my be undertken prior to, or in conjunction with, ntidepressnt therpy. PDE-5 inhibitors my lso be used in combintion with ntidepressnt therpy in ptients with more severe depression (1). Am J Psychitry 163:1, Jnury

8 VARDENAFIL FOR ERECTILE DYSFUNCTION Vrdenfil ws well tolerted in this study, with few discontinutions due to dverse events. Similr low dverse event rtes were observed in other flexible-dose studies conducted with vrdenfil (23). Collectively, these results demonstrte tht when vrdenfil is used in ccordnce with product lbeling (titrtion from the 1 mg/dy strting dose), tretment with vrdenfil for erectile dysfunction is esily optimized with respect to both efficcy nd tolerbility. A limittion of this study is the reltively short durtion of tretment (12 weeks). Further studies re needed to evlute the durbility or mintennce of chnge in both erectile dysfunction nd depressive symptoms. Long-term studies with vrdenfil demonstrte its efficcy nd tolerbility for up to 2 yers in ptients with erectile dysfunction nd other comorbid medicl conditions; however, there re no long-term studies of chnges in depressive symptoms ssocited with erectile dysfunction therpy, to our knowledge. Additionlly, the results of this study should not be generlized to ptients with more severe depression, where primry therpy usully consists of ntidepressive mediction nd/or psychotherpy. For ptients suffering from both mild mjor depressive disorder nd erectile dysfunction, concomitnt use of serotonin reuptke inhibitors nd PDE-5 inhibitors cn be beneficil (1). No ttempt ws mde in the present study to determine the primcy or cusl reltionship between symptoms of erectile dysfunction nd depression. The subjects were not queried s to whether their depressive symptoms preceded their erectile dysfunction or vice vers. The ptients were dignosed with erectile dysfunction nd comorbid mild mjor depressive disorder, but the two syndromes my or my not hve been cuslly relted. It could be hypothesized tht improvement in mood or qulity of life improvement would hve been greter in ptients who identified erectile dysfunction s n importnt underlying fctor in the genesis of their depression. The results presented here suggest tht vrdenfil tretment cn improve depressive symptoms in men with comorbid erectile dysfunction nd mild mjor depressive disorder, independent of whether erectile dysfunction ws cuslly relted to their depression. It is highly unlikely tht vrdenfil exerts direct ntidepressnt effects becuse it is not known to penetrte the blood-brin brrier. Improvement in symptoms of depression is more likely ttributble to incresed self-esteem nd qulity of life ssocited with improved sexul function nd stisfction with the prtner, fmily, nd reltionship (22). This reinforces the concept tht tretment of physicl symptoms in depression cn enhnce tretment outcomes nd overll qulity of life nd reduce the risk of relpse (22, 24, 25). Presented in prt t the 14th Europen Assocition of Urology Congress in Vienn, Mrch 24 27, 24; n bstrct ws published in Eur Urol 24; 3:235. Received Oct. 14, 24; revision received Feb. 24, 25; ccepted April 13, 25. From the Deprtment of Psychitry, University of Medicine nd Dentistry of New Jersey Robert Wood Johnson Medicl School. Address correspondence nd reprint requests to Dr. Rosen, Deprtment of Psychitry, UMDNJ Robert Wood Johnson Medicl School, 675 Hoes Lne, Pisctwy, NJ 8854; rosen@umdnj.edu (e-mil). Funded by Byer Helthcre Phrmceuticls nd GlxoSmith- Kline. See the online version of this rticle for dditionl informtion on the Vrdenfil Study Site Investigtors. References 1. Kessler RC, McGongle KA, Swrtz M, Blzer DG, Nelson CB: Sex nd depression in the Ntionl Comorbidity Survey, I: lifetime prevlence, chronicity nd recurrence. J Affect Disord 1993; 29: Sdock BJ, Sdock VA (eds): Kpln nd Sdock s Comprehensive Textbook of Psychitry, 7th ed. Phildelphi, Lippincott Willims & Wilkins, 2 3. Ferguson JM: The effects of ntidepressnts on sexul functioning in depressed ptients: review. 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J Clin Psychitry 23; 64(suppl 1): Lbbte LA, Croft HA, Oleshnsky MA: Antidepressnt-relted erectile dysfunction: mngement vi voidnce, switching ntidepressnts, ntidotes, nd dpttion. J Clin Psychitry 23; 64(suppl 1): Nurnberg HG, Hensley PL, Gelenberg AJ, Fv M, Luriello J, Pine S: Tretment of ntidepressnt-ssocited sexul dysfunction with sildenfil: rndomized controlled tril. JAMA 23; 289: Dontucci C, Erdley I, Buvt J, Gittlemn M, Kell P, Segerson T, Homering M, Montorsi F, Vrdenfil Study Group: Vrdenfil improves erectile function in men with erectile dysfunction irrespective of disese severity nd disese clssifiction. J Sex Med 24; 1: Porst H, Young JM, Schmidt AC, Buvt J: Efficcy nd tolerbility of vrdenfil for tretment of erectile dysfunction in ptient subgroups. Urology 23; 62: Ntionl Institutes of Helth Consensus Development Pnel on Impotence: NIH consensus conference: impotence. JAMA 1993; 27: Rdloff LS: The CES-D Scle: self-report depression scle for reserch in the generl popultion. J Applied Psychol Mesurement 1977; 1: Cppelleri JC, Rosen RC, Smith MD, Mishr A, Osterloh IH: Dignostic evlution of the erectile function domin of the Interntionl Index of Erectile Function. Urology 1999; 54: Rosenberg M: Society nd the Adolescent Self-Imge. Princeton, NJ, Princeton University Press, Sheehn DV, Lecrubier Y, Sheehn KH, Amorium P, Jnvs J, Weiller E, Herguet T, Bker R, Dunbr GC: The Mini Intern Am J Psychitry 163:1, Jnury 26

9 ROSEN, SHABSIGH, BERBER, ET AL. tionl Neuropsychitric Interview (MINI): The development nd vlidtion of structured dignostic psychitric interview for DSM-IV nd ICD-1. J Clin Psychitry 1998; 59(suppl 2) Shbsigh R, Klein LT, Seidmn S, Kpln SA, Lehrhoff BJ, Ritter JS: Incresed incidence of depressive symptoms in men with erectile dysfunction. Urology 1998; 52: Althof SE: Qulity of life nd erectile dysfunction. Urology 22; 59: Seidmn SN: Exploring the reltionship between depression nd erectile dysfunction in ging men. J Clin Psychitry 22; 63(suppl 5): Seidmn SN, Roose SP: Sexul dysfunction nd depression. Curr Psychitry Rep 21; 3: Rosen RC, Seidmn SN, Menz MA, Shbsigh R, Roose SP, Tseng LJ, Orzem J, Siegel RL: Qulity of life, mood, nd sexul function: pth nlytic model of tretment effects in men with erectile dysfunction nd depressive symptoms. Int J Impot Res 24; 16: Htzichristou D, Cuzin B, Mrtin-Morles A, Buvt J, Porst H, Lferriere N, Bndel TJ, Montorsi F, Vrdenfil Study Group: Vrdenfil improves stisfction rtes, depressive symptomtology, nd self-confidence in brod popultion of men with erectile dysfunction. J Sex Med 25; 2: Pykel ES: Remission nd residul symptomtology in mjor depression. Psychopthology 1998; 31: Sdovsky R: Integrting erectile dysfunction tretment into primry cre prctice. Am J Med 2; 19(suppl 1):22 28 Am J Psychitry 163:1, Jnury