Mentalhealthupdate.com

Sildenafil Treatment of Women With
Antidepressant-Associated Sexual Dysfunction
A Randomized Controlled Trial
Context Antidepressant-associated sexual dysfunction is a common adverse effect
that frequently results in premature medication treatment discontinuation and for which no treatment has demonstrated efficacy in women.
Objective To evaluate the efficacy of sildenafil for sexual dysfunction associated with
selective and nonselective serotonin reuptake inhibitors (SRIs) in women.
Design, Setting, and Participants An 8-week prospective, parallel-group, ran-
domized, double-blind, placebo-controlled clinical trial conducted between September 1, 2003, and January 1, 2007, at 7 US research centers that included 98 previously sexu- ally functioning, premenopausal women (mean [SD] age 37.1 [6] years) whose major depression was remitted by SRIs but who were also experiencing sexual dysfunction.
Intervention Forty-nine patients were randomly assigned to take sildenafil or pla-
cebo at a flexible dose starting at 50 mg adjustable to 100 mg before sexual activity.
ence for premature discontinuation ofantidepressant treatment, which leads to Main Outcome Measures The primary outcome measure was the mean differ-
ence in change from baseline to study end (ie, lower ordinal score) on the Clinical Global
treatment failure and costly disease man- Impression sexual function scale. Secondary measures included the Female Sexual Func- tion Questionnaire, the Arizona Sexual Experience scale-female version, the Univer- is recognized as being associated with se- sity of New Mexico Sexual Function Inventory-female version, a sexual activity event log, and the Hamilton Depression Rating scale. Hormone levels were also assessed.
Results In an intention-to-treat analysis, women treated with sildenafil had a mean
Clinical Global Impression–sexual function score of 1.9 (95% confidence interval [CI], 1.6-2.3) compared with those taking placebo (1.1; 95% CI, 0.8-1.5), with a mean end point difference of 0.8 (95% CI, 0.6-1.0; P=.001). Assigning baseline values car- ried forward to the 22% of patients who prematurely discontinued resulted in a mean end point in the sexual function score of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil compared with 0.9 (95% CI, 0.6-1.3) among women taking placebo with a mean end point difference of 0.6 (95% CI, 0.3-0.8; P=.03). Baseline endocrine levelswere within normal limits and did not differ between groups. The mean (SD) Hamil- ton scores for depression remained consistent with remission in both groups (4.0 [3.6]; P = .90). Headache, flushing, and dyspepsia were reported frequently during treat- with first- or second-generation agents,2 ment, but no patients withdrew because of serious adverse effects.
Conclusion In this study population, sildenafil treatment of sexual dysfunction in
women taking SRIs was associated with a reduction in adverse sexual effects.
proaches 70% in the first months oftreatment and leads to increased re- Trial Registration clinicaltrials.gov Identifier: NCT00375297
source utilization by affected pa-tients.3 However, the literature in this Author Affiliations: Department of Psychiatry, Health
ington (Dr Heiman); and Stanford University School Sciences Center, University of New Mexico School of of Medicine, Palo Alto, California (Dr DeBattista).
Medicine, Albuquerque (Drs Nurnberg and Hensley, Corresponding Author: H. George Nurnberg, MD, De-
and Ms Paine); The Croft Group, San Antonio, Texas partment of Psychiatry, University of New Mexico School (Dr Croft); the Kinsey Institute for Research in Sex, Gen- of Medicine, 2400 Tucker NE, MC 09 5030, Albuquer- der, and Reproduction, Indiana University, Bloom- que, NM 87131-0001 (gnurnberg@salud.unm.edu).
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 23/30, 2008—Vol 300, No. 4 395
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS est, genital sensitivity, and vaginal lu- nafil in the treatment of women, specifi- order is in remission while taking a stable orgasm (delay) or arousal (lubrication).5 monal variability on nitric oxide signal- antidepressants at rates of 2 to 1 and can disorder; (2) to determine whether silde- nafil treatment is associated with change number of patients needing relief.5 With- placebo.14 A protocol-specified trial in- pare adverse events occurring with silde- baseline estrogen and androgen levels re- Trial Design
controlled, 8-week trial to test the effi- receive either a flexible dose of between cians fail to inquire, misattribute it as a center’s institutional review board ap- effects with their physician.7,8 Sexual dys- found that a single dose of 50 mg of silde- function associated with SRIs is dose re- ment, and rarely remits spontaneously.
with a copy of the information sheets.
alafil), which are effective and well tol- erated for treatment of erectile dysfunc- ports18 and open-label studies19 have also Patients
to use a protocol—similar to our previ- jor depressive disorder in remission, (4) 396 JAMA, July 23/30, 2008—Vol 300, No. 4 (Reprinted)
2008 American Medical Association. All rights reserved.
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS Figure. Flow of Patients Through the Trial
nism for at least 8 weeks (at a stabledose for at least 4 weeks), and (5) were experiencing persistent sexual dysfunc-tion for at least 4 weeks. Other eligi- form of regular sexual activity (ie, mas- turbation, oral sex, intercourse) at least tinue efforts at sexual activity at least study, and satisfactory sexual func-tion before onset of depression or an- provement and discontinuation ofmedication.
wasdiagnosedaccordingtoDiagnosticandStatistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria.22 function; or (3) inability to attain or main- tain until completion of sexual activity an adequate lubrication or swelling response are clinician rated on a 5-point scale from 0 (absent) to 4 (severe).23 The remission threshold score of 10, rather than 7, was selected to adjust for sexual dysfunction associated with SRI treatment potentially inflating the score.24 In addition, women colaou test results indicating further as- orrhea over 1 year; or situational sexual DSM-IV criteria for substance-induced Study Protocol
paired desire, arousal (lubrication), and vertisements, postings, and referrals.
defined by at least 1 of the following cri- teria that caused significant distress: (1) infarction within the last 6 months, cur- (FIGURE). In addition to an assess-
inability to have an orgasm (anorgasmia), relationship changes, proliferative reti- masturbation or intercourse that, accord- ing to the woman’s opinion, represents a 2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 23/30, 2008—Vol 300, No. 4 397
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS function consistent with the DSM-IV di- agnostic criteria. Anchored 5- or 7-point 5) with the higher scores indicating bet- posite–section scores add to a total score range of 30 to 167: sexual desire (range, cago, Illinois), an unrestricted, computer- Outcome Measures
developed by the study statistician (S.P.) patients to receive active sildenafil and 49 to receive identical placebo. The only restriction to this randomization was that sion Scale adapted for sexual function.26 groups at any point in the trial was 4 (ex- Sexual Function Questionnaire,27 the Ari- zona Sexual Experience scale–female ver- age of successful intercourse attempts, the number of satisfactory attempts at orgasm the study. Patients were instructed to take and at weeks 2, 4, and 8 (or last visit) for sexual activity, not more than once daily over the 8-week trial period and were re- diary and discussion with the patient for and 8 (final or last visit) with anchored function questionnaire is a 34-item, mul- (desire, sexual arousal, ability to achieve ries with instructions for recording trial medication use and sexual activity. Silde- and overall satisfaction) to quantify pres- nafil and placebo were provided by Pfizer guages.27 It quantifies sexual function in ter or improvement in sexual function).
398 JAMA, July 23/30, 2008—Vol 300, No. 4 (Reprinted)
2008 American Medical Association. All rights reserved.
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS tocol-treated patients and all trial com- confirm DSM-IV–defined major depres- Biochemical Measures
baseline to each patient’s own end point (follicular phase), were stored at −80°C criteria (ie, lack of acceptable and veri- sachusetts General Hospital, Boston.
rank sum tests for primary analyses.
the 5% significance level. The F test Statistical Analysis
tics from those who entered the trial and was expected to detect a significant dif- Ͻ5). Independent samples t tests com- ror rate of ␣=.05 between sildenafil and (SD) age of the women was 36.7 (7.1)pared baseline patient characteristics 2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 23/30, 2008—Vol 300, No. 4 399
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS Baseline Prevalence
signed treatment groups (TABLE 1).
of Sexual Dysfunction
Efficacy Measures
placebo group (P=.21), with 95.8% of Clinical Global Impression. The dif-
which showed a significant difference
of 0.8 (95% CI, 0.6-1.0, P = .001)
between groups (TABLE 2). To adjust
Table 1. Demographics and Baseline Characteristics
Sildenafil
P
ence between groups (P = .03). Clini- Sexual Function Questionnaires.
g ro u p h a d a h i g h e r m e a n ( S D ) In the other 3 women, the primary diagnoses were dysthymia, depressive disorder not otherwise specified, or anxiety b Women who were not able to have an orgasm were not asked about delay.
400 JAMA, July 23/30, 2008—Vol 300, No. 4 (Reprinted)
2008 American Medical Association. All rights reserved.
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS (P=.90) indicating persisting remis- 0.1-1.0; P = .01) for reaching orgasm (95% CI, 0.1-1.3; P=.01) for the New Endocrine Levels. Mean (SD) base-
line values for all endocrine values were (TABLE 3). Independent of treatment as-
Table 2. Sexual Functiona
Mean (SD)
Sildenafil
Change From Baseline
P
Baseline
Study End
Baseline
Study End
(95% Confidence Interval)b
Abbreviations: ANOVA, analysis of variance; ASEX, Arizona Sexual Experience scale; BCF, baseline carried forward; ITT, intent to treat; LOCF, last observation carried forward; SFQ, Sexual Function Questionnaire; UNM-SFI, University of New Mexico Sexual Function Inventory.
a Thirty-seven of 49 women (75.5%) in the placebo group and 39 of 49 women (79.6%) in the sildenafil group completed all 8 end point assessments.
b Differences in the change from baseline to each patient’s own end point for the change in sexual functioning measured by Clinical Global Impression of Sexual Function improve- c Calculated as part of the repeated measures ANOVA and using the last-observation-carried-forward algorithm.
d The intent-to-treat analysis using the last observation carried forward measured by the mean difference in baseline to study end improvement in placebo-treated group was 1.1 (95% confidence interval [CI], 0.8-1.5) vs sildenafil-treated group 1.9 (95% CI, 1.6, 2.3). The effect size was 0.7 (95% CI, 0.5-0.9).
e For patients not completing trial the mean difference in baseline to end point in placebo-treated group was 0.9 (95%CI, 0.6-1.3) vs sildenafil-treated 1.5 (95% CI, 1.1-1.9). The effect size was 0.5 (95%CI; 0.3,0.7).
f See the “Methods” section for the 7 SFQ domain scoring ranges. All randomized women providing responses to all domain questions at baseline or study end of treatment, or time of discontinuation, were included in analysis of that domain. Nonapplicable responses were treated as missing.
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 23/30, 2008—Vol 300, No. 4 401
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS Table 3. Endocrine Levels at Baseline (Total n = 98)a
Mean (SD)
Mean (SD)
Sildenafil
P
Nonresponders
Responders
P
Hormones
Abbreviations: ANOVA, analysis of variance; FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone–binding globulin; T4, tetraiodothyronine (thyroxine); TSH, thyroid-stimulating hormone; T4, thyroxine.
SI Conversion factors: To convert cortisol to nmol/L, multiply by 27.588; estradiol to pmol/L, multiply by 3.671; FSH to IU/L, multiply by 1.0; LH to IU/L, multiply by 1.0; progesterone to nmol/L, multiply by 3.18; prolactin to pmol/L, multiply by 43.478; SHBG to nmol/L, multiply by 8.896; testosterone to nmol/L, multiply by 0.0347; TSH to IU/L, multiply by 1.0; and T4to pmol/L, multiply by 12.871.
a See the “Methods” section for the hormone analysis assays.
b Calculated as part of the repeated measures analysis of variance and using the last-observation-carried-forward algorithm.
Adverse Events. The most common
Table 4. Most Common Adverse Eventsa
Sildenafil
P
taking placebo (P=.09). Less frequent Adverse Event
were flushing, 24% vs 0% (PϽ.001); dys- pepsia, 12% vs 0% (P=.01); nasal con- gestion, 37% vs 6% (PϽ.001); and tran- (P = .03), respectively. Adverse events vs 2% (P=.01) and anxiousness 6% vs 2% (P=.31). No serious adverse events ported (TABLE 4).
Of the 100 patients eligible for the study, 2 women were excluded prior to randomization and did not receive study b Urinary, psychiatric symptoms, dry mouth, fatigue, body warmth, gastrointestinal tract, infection. The adverse events that were more common in women treated with placebo than with sildenafil were nausea (15% vs 1%) and anxious- fects, measured by the Clinical GlobalImpression sexual function, that com-pared sildenafil with placebo among line levels of free testosterone (PՅ.01) stable-dose antidepressant treatment.
and thyroxine (P Յ .01) among SRI- Study Drug Use. At study end, 76.9%
402 JAMA, July 23/30, 2008—Vol 300, No. 4 (Reprinted)
2008 American Medical Association. All rights reserved.
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS sildenafil treatment effect for sexual de- or that it might reflect a bias for select- attenuates effects on desire.39 The limi- arousal, perhaps due to erectile dysfunc- tors are effective in both sexes for this phosphodiesterase type 5 inhibitors. Sig- tion found in this trial is consistent with tions (eg, lack of biological criterion for disorder,14,15,17 in open-label studies re- SRI-associated sexual dysfunction,18,19 in function,9 in trials that include treated tivity (direct or indirect) can improve in- tive evidence-based treatments for treat- poactive sexual desire,15 low estrogen– Author Contributions: Dr Nurnberg and had full ac-
cess to all of the data in the study and takes respon- sibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Nurnberg, Hensley, Paine.
Acquisition of data: Nurnberg, Hensley, Heiman, Croft, ria of this study. The specific entry cri- Debattista.
Analysis and interpretation of data: Nurnberg, Hensley, teria requirements in this trial, includ- Drafting of the manuscript: Nurnberg, Hensley,Heiman, Paine.
Critical revision of the manuscript for important in- tellectual content: Nurnberg, Hensley, Heiman, Croft,Debattista, Paine.
Statistical analysis: Nurnberg, Paine.
Administrative, technical, or material support:Nurnberg, Hensley, Heiman, Croft, Debattista.
Study supervision: Nurnberg, Hensley.
2008 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 23/30, 2008—Vol 300, No. 4 403
SILDENAFIL AND SEXUAL DYSFUNCTION ASSOCIATED WITH ANTIDEPRESSANTS Financial Disclosures: Dr Nurnberg reports having re-
demiology of major depressive disorder: results from demiology, biology, and treatment. Arch Gen ceived research support from Bristol-Myers Squibb Co, the National Comorbidity Survey Replication (NCS-R).
Psychiatry. 1998;55(7):580-592.
Eli Lilly & Co, Lilly-Icos, Pfizer Inc, Wyeth, and Bayer; JAMA. 2003;289(23):3095-3105.
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