Fifty partial and non-responders (Clinical Global Impression-Sexual Function (CGI-SF) score>2), out of 76 men who completed a 6-week, double-blind, placebo-controlled trial of sildenafil treatment for serotonergic antidepressant–associated sexual dysfunction, were eligible for an additional 6-week trial of open-label sildenafil (50 mg adjustable to 100 mg) under the same protocol, with blind maintained to initial assignment. Participation (double-blind and open-label) required major depressive disorder in remission (MDD-R) and continuing antidepressant medication. Forty-three entered open-label study: 16/17 initially randomized to sildenafil (sildenafil/sildenafil) and 27/33 initially randomized to placebo (placebo/sildenafil). Thirty-five of 43 (81%) achieved full response (CGI-SF⩽2): placebo/sildenafil 23/27 (85%); sildenafil/sildenafil 12/16 (75%); P<0.0001 for changes and P=0.4 between groups. Secondary measures of erectile function and overall satisfaction improved in both groups (P<0.03). Hamilton Depression Rating Scale scores improved (placebo/sildenafil; P⩽0.05) or remained stable (sildenafil/sildenafil). In men with MDD-R who maintained antidepressant adherence, 81% of double-blind partial and non-responders treated with open-label sildenafil responded fully.
Use of serotonin reuptake inhibitor (SRI) antidepressants is widespread.1 Despite evidence demonstrating efficacy in up to 75% of patients with major depressive disorder (MDD) in clinical trials,2, 3 80–90% response rates to the first or second agent prescribed, and that rates of relapse, recurrence and disability are reduced with continued treatment,3 the anticipated clinical effectiveness has not been achieved. In large part, this is because many patients do not continue their prescribed medication for a sufficient period.3 Withdrawal rates of up to 68% are reported within the first 3 months of treatment.4 Adverse events, patient confusion regarding the duration of treatment and rare physician follow-up are among the reasons associated with discontinuation or switching of antidepressants.4 The odds of discontinuing or switching the initially prescribed antidepressant were tripled in patients experiencing one or more moderately or extremely bothersome adverse events.4 Premature discontinuation of antidepressant medication significantly increases the risk for relapse, recurrence, morbidity, mortality and chronic disability of MDD.5
One of the most common and bothersome adverse events leading patients to change, skip, switch doses and prematurely stop taking their antidepressant is SRI-antidepressant-associated sexual dysfunction (SRI-AASD).6, 7 Reported in 36–43% of patients assessed by structured questionnaire,8 SRI-AASD generally occurs early in treatment and is persistent.7 Although physicians underestimate the occurrence of iatrogenic sexual dysfunction, it is a major influence in their selection or switching of antidepressant agents9 because bothersome adverse effects are associated with treatment discontinuation.7, 10 Consequently, without established evidence-based treatments, patients with SRI-AASD have been exposed to excess random pharmacology to manage adverse events and tolerate long-term medication treatment.
Of the numerous management strategies that have been proposed for SRI-AASD, sildenafil (a selective phosphodiesterase type 5 inhibitor (PDE5i)) has the ‘largest and most consistent’ evidence base.11 Sildenafil is the first treatment to demonstrate significant and meaningful efficacy for SRI-AASD in a prospective, randomized, parallel-group, double-blind, placebo-controlled study in men with MDD in remission (MDD-R); we reported that 55% of men assigned to sildenafil (50 mg adjustable to 100 mg taken 1–2 h before sexual activity) compared with 4% of men assigned to placebo were full responders (P<0.001), defined as ‘much/very much improved’ (score of ⩽2 on a Clinical Global Impression Scale adapted for Sexual Function (CGI-SF)).12 Erectile function, ejaculation, orgasm, sexual interest and overall satisfaction domain measures also improved significantly in patients receiving sildenafil compared with patients receiving placebo. All patients remained on their SRI antidepressant at full effective dose and maintained 17-item Hamilton Depression Rating Scale (HAM-D17) scores consistent with remission. These results are consistent with other double-blind, placebo-controlled trials13, 14, 15, 16, 17, 18, 19, 20 of PDE5i treatment efficacy for erectile dysfunction (ED) in men with ED and subthreshold depression, ED of various etiologies and concurrently taking an SRI, residual ED (i.e., ED present at MDD diagnosis that persisted following treatment of depression to remission, independent of antidepressant discontinuation), ED and untreated mild MDD, and ED with congestive heart failure or postprostatectomy and associated depressive symptoms.
Treatment practice guidelines for MDD recommend 4–6 months continuation of antidepressant treatment following acute treatment resolution. However, a significant number of patients included in our double-blind study (particularly placebo-assigned patients) would remain with troublesome antidepressant-associated sexual side effects and significant risk for premature antidepressant discontinuation. Consequently, the protocol was designed to permit patients who maintained SRI antidepressant treatment an opportunity for continued active treatment of their SRI-AASD following the initial 6-week, double-blind, placebo-controlled phase, regardless of their assignment (sildenafil or placebo) or response (full, partial and non-responder) in the double-blind. Double-blind full responders were offered open-label sildenafil extension treatment. Double-blind partial or non-responders were offered an additional 6 weeks of per-protocol treatment with open-label sildenafil, the results of which are reported herein, before open-label sildenafil extension treatment. The aims of the additional 6 weeks of per-protocol treatment with open-label sildenafil were as follows:
To determine whether patients with SRI-AASD and MDD-R, initially randomized to placebo, who were partial or non-responders during initial double-blind treatment, achieve improvement in ED and other sexual dysfunction domains during 6 weeks of subsequent, per-protocol, open-label sildenafil treatment (50 or 100 mg); and how that improvement compares with the outcome in patients initially randomized to sildenafil.
To determine whether patients with SRI-AASD and MDD-R, initially randomized to sildenafil, who were partial or non-responders during initial double-blind treatment, improve in ED and other sexual dysfunction domains during 6 weeks of subsequent, per-protocol, open-label sildenafil treatment (50–100 mg).
To determine whether MDD-R is maintained during antidepressant adherence and PDE5i-sildenafil treatment of SRI-AASD.
To compare and quantify the difference in response rates between double-blind, placebo-controlled treatment (efficacy) and open-label treatment (effectiveness) as a measure of nonspecific treatment effects (e.g., placebo, confidence, treatment expectations) that contribute to the overall clinical treatment outcome.
The initial double-blind phase is described in detail in a separate report.12 At enrollment, eligible men with MDD-R and aged 18–55 years had taken an SRI antidepressant for at least 12 weeks, were on a stable dose for at least 6 weeks, had Hamilton Depression and Anxiety Rating Scale scores ⩽10 and had SRI-AASD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Participants had some form of regular sexual activity that was to be continued for the study period, were in good general physical health and reported satisfactory sexual function before the current onset of depression and/or antidepressant treatment. Any prior sexual dysfunction was limited to previous episodes of depression (and remitted on clinical improvement) or to antidepressant treatment (and had remitted on discontinuation of medication).
Men who completed the initial double-blind phase and were full responders (CGI-SF⩽2) underwent a 3-week washout to rule out SRI-AASD remission before proceeding to 8 weeks of open-label sildenafil extension treatment. Men who completed the initial double-blind phase and were partial or non-responders, who are the focus of this report, were eligible to repeat the per-protocol 6 weeks of treatment, but with open-label sildenafil and with the initial double-blind assignment concealed to minimize its influence on the open-label treatment response. Partial and non-responders salvaged by the additional 6 weeks of open-label sildenafil treatment (e.g., attaining a CGI-SF⩽2) were then eligible for the 3-week washout and 8-week open-label extension treatment that had been offered to the full responders to double-blind, placebo-controlled treatment. Men who proceeded to open-label sildenafil must have maintained MDD-R and were required to continue on stable-dose SRI.
This prospective, parallel-group, flexible-dose, additional 6-week outpatient study was conducted simultaneously at three outpatient medical centers: the University of New Mexico, the University of Arizona and Massachusetts General Hospital. The protocol was approved by the Institutional Review Boards of all three institutions. All subjects provided full written informed consent after complete description of the study and before study enrollment.
Procedures were the same as for the double-blind, placebo-controlled phase. Sildenafil dose was 50 mg and could be adjusted to 100 mg as tolerated based on the investigator's judgment of efficacy and tolerability. Only one dose taken approximately 1–2 h before sexual activity was allowed in each 24-h period, and at least two attempts at sexual activity were to be made each week. Sexual function (all domains) and psychiatric status were assessed at open-label baseline (end of double-blind) and every 2 weeks thereafter. Drug accountability, concomitant antidepressant treatment, vital signs and self- and physician-rated symptom reports were assessed at each biweekly visit. Adverse events were recorded as to severity and relationship to study drug.
Validated instruments were administered at open-label baseline and end point to measure outcome. The primary was the CGI-SF, a clinician-rated instrument scored on a 7-point scale from 1 (highest) to 7 (lowest).21 Secondary measures were (1) the patient-rated, 15-item International Index of Erectile Function (IIEF) for detecting treatment-related changes in sexual function in the domains of erectile function, ejaculation and orgasm, desire, intercourse satisfaction and overall satisfaction;22, 23 (2) the 5-item, patient-rated Arizona Sexual Experience Scale-male version (ASEX);24 (3) the 5-item, clinician-rated Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ)25 and (4) the 5-item, clinician-rated, University of New Mexico–Sexual Function Inventory (UNM–SFI).26 The UNM-SFI is a Likert-type, dimensional instrument derived from and similar to the ASEX and the MGH-SFQ, which is scored on a 6-point scale from 1 (good function) to 6 (poor function). In addition, the UNM-SFI evaluates pre-existing sexual dysfunction independent of disease state or medication (e.g., desire, arousal, erection, orgasm and overall satisfaction). The HAM-D17 was administered to monitor depression severity.27
Data were compared between patients who were initially assigned, during the double-blind phase, to placebo (placebo/sildenafil group) or sildenafil (sildenafil/sildenafil group). Adjusted means (±s.d.) were determined. Where applicable, 95% confidence intervals (CIs) were provided. Analyses were performed with SAS version 8.01 (SAS Institute Inc., Cary, NC, USA).
Baseline demographics, safety, tolerability, antidepressant history and sexual history were compared using descriptive statistics by independent group t-test, χ2 test and Fisher's exact test. Intent-to-treat (ITT) and last-observation-carried-forward analyses were performed on all variables and include data from all patients who received at least one dose of study medication and had at least one assessment, regardless of protocol violation or whether they completed the study. The change in sexual functioning, as measured by the IIEF and the UNM-SFI, from baseline to each patient's end point was the dependent measure. Within treatment group, changes from baseline to end point were analyzed using paired t-test. Independent group t-test was used to compare measures between the study groups at end point. χ2 analysis was used to evaluate group differences in categorical measures. Repeated-measures analysis of variance was also used to determine any between-group difference in change from baseline to end point for efficacy and depression measure. Findings were confirmed with analysis of covariance and Wilcoxon rank sum tests.
All statistical tests were two-sided, and hypotheses were evaluated at the 5% significance level. To correct for multiple comparisons used to measure sexual dysfunction, a Bonferroni adjustment correction was applied, and only P-values <0.03 were considered significant for the sexual dysfunction scales.
The double-blind treatment phase was completed by 76 (41 sildenafil and 35 placebo) of 83 men initially randomized and treated as per the protocol (Figure 1). Among the 76 completers, 26 (24 sildenafil and two placebo) were full responders (CGI-SF ⩽2) and the remaining 50 (17 sildenafil and 33 placebo) were partial or non-responders eligible for the additional 6-week, open-label, sildenafil treatment. Of the 50 partial or non-responders, seven declined and 43 (86%) agreed to participate: 16 (37%) initially assigned to sildenafil (sildenafil/sildenafil group) and 27 (63%) initially assigned to placebo (placebo/sildenafil group) during the double-blind phase (Figure 1). There was no difference in demographic or clinical characteristics between the partial and non-responders who declined and those who agreed to participate. Thirty-four of 43 men (79%) completed 6 weeks, six (14%) completed 4 weeks and three (7%) completed 2 weeks of open-label sildenafil treatment.
Age, duration of antidepressant therapy, number and types of sexual problems and baseline values for sexual function did not differ significantly between the sildenafil/sildenafil and the placebo/sildenafil groups (Table 1) or between those completing 6 weeks of open-label sildenafil treatment, those who stopped open-label treatment earlier and those who declined to proceed to the open-label treatment. There was no statistically significant difference between the sildenafil/sildenafil group and the placebo/sildenafil group in the percentage of men using each antidepressant (fluoxetine (n=16 overall), paroxetine (n=11), sertraline (n=7), citalopram (n=4), venlafaxine (n=3) and tricyclics (one each on nortriptyline and clomipramine)). All 43 patients adhered to their SRI antidepressant at steady dose during open-label treatment.
Regardless of double-blind assignment, open-label sildenafil treatment improved measures of sexual function. Full response according to CGI-SF⩽2 was achieved by 35 of 43 men (81%; 95% CI, 67–92%; P=0.0001): 23 of 27 (85%; 95% CI, 66–96%) in the placebo/sildenafil group and 12 of 16 (75%; 95% CI, 48–93%) in the sildenafil/sildenafil group (Table 2). The difference was not statistically significant between groups (P=0.4). Improvement (decrease) in mean CGI-SF scores from baseline to end point was significant in the placebo/sildenafil group (4.1±0.5 to 1.6±0.8; P<0.0001) and the sildenafil/sildenafil group (3.8±0.4 to 1.9±1.0; P<0.0001) (Table 3). The 0.6-point difference in mean CGI-SF score change between the placebo/sildenafil group and the sildenafil/sildenafil group was not statistically significant (Table 3). In sensitivity analysis, the number of patients excluded did not affect the outcome.
In the placebo/sildenafil group, there was significant improvement from baseline to end point in mean IIEF scores and UNM-SFI scores (Table 3). In the sildenafil/sildenafil group, there was significant improvement from baseline to end point in mean IIEF and UNM-SFI scores (in total, IIEF domains of Erectile Function and Overall Satisfaction, and UNM-SFI questions of erectile function, orgasm and overall satisfaction) (Table 3). There were significant correlations between the results for CGI-SF, IIEF, UNM-SFI, and the results for the ASEX and the MGH-SFQ (r=0.83−0.98; P<0.001; data not shown). Consequently, for considerations of space, ASEX and MGH-SFQ results are not reported but are available on request.
Mean depression severity (HAM-D17) scores improved (decreased) significantly from baseline to end point in the placebo/sildenafil group (4.3±3.3 to 3.4±3.3; P<0.05) and remained stable in the sildenafil/sildenafil group (3.8±3.7 to 4.9±5.3; P=0.2) (Table 3).
Sildenafil was well tolerated in the open-label phase. The most common adverse events were headache (n=8 (19%)), flushing (n=6 (14%)), indigestion (n=5 (12%)), nasal congestion (n=5 (12%)) and palpitations (n=3 (7%)). There were single reports of premature ejaculation, nose bleed and visual disturbance. No adverse event led to discontinuation, and there were no serious adverse events related to study drug.
With open-label PDE5i sildenafil treatment of SRI-AASD in partial responders and non-responders to randomized, double-blind, placebo-controlled treatment, 81% (35/43) became full responders, achieving ‘much/very much improved’ sexual function regardless of initial assignment to placebo or sildenafil. Seventy-five percent (12/16) of partial and non-responders to double-blind sildenafil treatment became full responders to open-label sildenafil treatment. This did not differ significantly from the 85% (23/27) of partial and non-responders to double-blind placebo who became full responders to open-label sildenafil treatment. IIEF and UNM-SFI demonstrated significant improvement in measures of erectile function, overall satisfaction and total score in both groups. MDD-R persisted in all subjects continuing stable-dose SRI antidepressant treatment; in association with improved sexual function, mean HAM-D17 depression scores improved 21% among the double-blind partial or non-responders to placebo. Sildenafil was well tolerated, with no discontinuations attributed to adverse events. Overall, additional open-label treatment salvaged 70% (35/50) of all men who completed double-blind, placebo-controlled treatment with less than a full response, and who otherwise would have been at increased risk for premature antidepressant treatment discontinuation and, consequently, MDD relapse or recurrence.
During the previously reported double-blind phase of this trial, the response rate to sildenafil treatment of SRI-AASD was 55% (24/44) in the ITT population12 and 59% among the 41 men who completed double-blind treatment. In contrast, the response rate to open-label sildenafil treatment among partial and non-responders to double-blind treatment was 81% (35/43), an improvement of greater than 20 percentage points over the double-blind outcome. This improvement could reflect nonspecific placebo effects that randomized, double-blind, placebo-controlled trials are designed to minimize. However, randomized clinical trials are also associated with ‘nocebo effects,’ where negative expectations amplify ambiguous sensations and dampen positive changes, causing medication effects to be misattributed.28 In contrast, patients in the clinical practice setting know that they are receiving an active treatment, which engenders greater confidence, certainty and expectation of treatment success (enhancing effectiveness); greater tolerance of adverse effects; and less likelihood of treatment discontinuation.4 By maintaining the blind for initial assignment to sildenafil or placebo during the subsequent open-label phase, we hoped to reduce the influence of patient preconceptions of prior efficacy on the open-label treatment results. Such methodological modifications to traditional ‘gold-standard’ randomized, double-blind, placebo-controlled trials can (1) provide additional data relevant to a more comprehensive overall assessment of therapeutic performance, (2) enable a larger number of study participants seeking treatment to have an opportunity for exposure to active medication, (3) address ethical concerns over withholding treatment to study participants assigned to placebo and (4) enable more patients completing double-blind treatment to continue recommended treatment guidelines. In our study population, 91% (69/76) received 4–6 months of SRI antidepressant continuation treatment after remission of MDD, consistent with recommended treatment guidelines.
Other considerations to account for the higher rate of full response during subsequent open-label treatment may be that some patients require more attempts (i.e., priming) to achieve a maximum response to PDE5i sildenafil treatment of ED over time,29 are influenced by expectations for success when they know they are receiving active treatment,30 or develop tolerance to SRIs.5 One cannot rule out that improvements in sexual dysfunction might not have occurred with a longer double-blind treatment duration, or that the lower but not significantly different open-label response rate in the sildenafil/sildenafil group compared with the placebo/sildenafil group reflects a measurement artifact in which positive effects of sildenafil during the double-blind phase, although insufficient to achieve full response, blunted the range for further improvement during the open-label phase.
Enhanced therapeutic performance by subsequent open-label sildenafil treatment is consistent with the results of Lydiard et al.31 in the treatment of MDD, in which the response rate was 87% during open-label (clinical practice) treatment versus 73% during double-blind treatment with the same antidepressant agent. Most data on open-label treatment of SRI-AASD with PDE5i's are limited to case reports,32, 33, 34, 35, 36 small samples37, 38 or insufficient systematic assessment. An open-label study found that 86% of men treated with sildenafil in dosages up to 100 mg achieved ED remission,38 which compares with the current study's response rate of 85% in the placebo/sildenafil group. Studies of tadalafil treatment of depression-associated or antidepressant-associated ED showed that 58% of men attained successful intercourse during double-blind, placebo-controlled treatment39 compared with 77% during open-label treatment.40 These results are consistent with a higher treatment effect in open-label compared with double-blind administration. However, unlike the current study, in which the same patients received the same PDE5i under the same conditions other than the absence of blinding, the tadalafil comparison is confounded by differences in doses, etiologies, severity, expectancy and patients.
This report has additional limitations to generalizability to those in the double-blind, placebo-controlled report.12 Adequate power was established for the double-blind phase, but cannot be assumed in this open-label continuation phase. Consequently, type II error cannot be excluded in between-group comparisons. Secondly, although sildenafil acts at the end organ to treat ED, cause and effect between antidepressant and sexual dysfunction is not definitive. Therefore, other causal factors, such as age, lifestyle risk factors (e.g., smoking, alcohol, obesity, stress), coincident conditions, MDD trait markers, subsyndromal conditions, halo effects or interactions, cannot be entirely ruled out. Iatrogenic SRI-AASD is dose related, reversible and usually related to ejaculatory/orgasm delay, which seems to exceed the patient's functional capacity to sufficiently maintain erectile function. Thus, reversible SRI-AASD may reflect different endophenotypes and mechanisms to non-reversible ED (e.g., prostatectomy, diabetes, cardiovascular disease). These findings are restricted to sildenafil effects on the specific group of men who fulfilled protocol criteria and cannot be generalized to other subgroups or to women.
The significant efficacy and effectiveness of double-blind and subsequent open-label PDE5i sildenafil treatment, respectively, in men with depression in remission and SRI-AASD suggests an important adjunct to maintaining long-term antidepressant therapy and provides a benchmark for treatments of adverse medication effects on sexual function. Although prospective, randomized, double-blind, placebo-controlled studies in systematically assessed patients are necessary to establish efficacy, they are not sufficient for more informed clinical decision making, which needs to incorporate nonspecific treatment factors (confidence, choice, expectations, adverse effect tolerability, etc.) to determine the most effective treatment. In an effort to extend efficacy (minimizing) into effectiveness (maximizing), we followed an identical protocol under double-blind and subsequent open-label conditions, with the same medication treatment in both phases and with blind to double-blind assignment maintained. With such a procedure, it may be possible to quantify nonspecific and specific drug treatment effects by comparing outcomes during double-blind and open-label phases by treatment (placebo versus active agent) among full, partial and non-responders. This case of sildenafil for SRI-AASD suggests a 20% additive nonspecific medication treatment effect. Further study is needed for nonspecific treatment effects in research and clinical practice settings using different groups of medications and conditions.
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This study was supported by an independent investigator-initiated grant from Pfizer Inc., New York, NY. Editorial support was provided by Deborah M Campoli-Richards.
Previous presentations: 157th Annual Meeting of the American Psychiatric Association, New York, NY, May 1–6, 2004.
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