Effects of Gepirone-ER on Sexual Function in Patients With Major Depressive Disorder

Abstract

Objective:

To describe effects of gepirone extended-release (ER), an azapirone, on sexual function in patients receiving treatment for major depressive disorder (MDD).

Methods:

Sexual function was assessed in 1,767 patients (67% women) across five Phase 3 randomized controlled clinical trials comparing gepirone-ER against placebo or active treatment with selective serotonin reuptake inhibitors (SSRIs) for treatment of MDD. All five trials assessed sexual functioning in the short term (8 weeks), with three including long-term extensions of 16, 20, or 44 weeks. Sexual function was assessed prospectively and throughout trials via clinical interview and well-validated survey measures.

Results:

Across studies, gepirone-ER was equivalent to placebo on sexual side effects and treatment-emergent sexual dysfunction. Relative to SSRIs, gepirone-ER was associated with significantly better effect on sexual function across time points studied. Evidence from patients without sexual dysfunction at baseline demonstrates superiority of gepirone-ER over SSRIs in the first few weeks of treatment, when patients are most vulnerable to the negative effects of sexual side effects on medication nonadherence/discontinuation. Importantly, these benefits were maintained across treatment.

Conclusions:

Gepirone-ER was not associated with sexual dysfunction in patients with MDD. Rates of sexual side effects and treatment-emergent sexual dysfunction with gepirone-ER were comparable to those reported for placebo and lower than sexual side effects reported for active treatment with SSRIs.

There is a critical need for treatment options for major depressive disorder (MDD) without risk of iatrogenic sexual dysfunction.¹ Although sexual problems are common in mood disorders, there is ample evidence of new or worsening sexual dysfunction with selective serotonin reuptake inhibitor (SSRI) or selective serotonin and norepinephrine inhibitor (SNRI) treatment.^1–5 Importantly, SSRI sexual side effects typically emerge within the first 2 weeks of treatment^6,7 before antidepressant efficacy is evident, causing significant issues with treatment noncompliance and potential relapse/persistence of depressive symptoms.⁸ Treatment-emergent sexual dysfunction (TESD) contributes to relationship distress, worsening mood symptoms, and even suicidality.^9–12 Although sexual side effects are relatively less likely to cause discontinuation from treatment than other antidepressant side effects such as agitation,¹³ they are also the most commonly experienced adverse event (impacting 40%–70% of patients)^13,14 and thus responsible for significantly decreased quality of life in the greatest number of patients. As such, the US Food and Drug Administration (FDA) requires providers to educate patients about sexual side effects, to consider this information when discussing patient preferences regarding adverse events and collaborating with patients on choice of medication prescribed.

The mechanism most often cited to explain SSRI and SNRI sexual side effects is their broad action on serotonin (5-hydroxytryptamine [5-HT]) systems that regulate sexual function and pleasure.^15–18 However, medications that do not act on serotonin reuptake and instead selectively target the 5-HT_1A receptor such as azapirones (e.g., buspirone) have considerably lower impact on sexual function and weight gain.^4,19–21 This may be due to 5-HT_1A receptors upregulating activity in dopaminergic reward systems relevant for sexual desire,^22,23 or action on the postsynaptic 5-HT_1A autoreceptor²⁴ downregulating serotonergic tone in neural regions that contribute to sexual inhibition and blockade of orgasmic reflexes.²⁵ Thus, from a mechanistic viewpoint, 5-HT_1A agonism may be less likely to cause sexual side effects or exacerbate or maintain existing sexual dysfunction.

Gepirone extended-release (ER) is the first selective 5-HT_1A partial agonist to be FDA-approved for the treatment of MDD. Data from the 17 pivotal efficacy trials submitted to the FDA indicated that a lower percentage of patients randomized to gepirone-ER spontaneously reported sexual adverse events (2%) than those randomized to either placebo (3%) or any of the other antidepressants (10% fluoxetine, 17% paroxetine, and 14% imipramine). However, relying on spontaneously reported adverse events underestimates iatrogenic sexual effects by 4-fold,²⁶ as many patients are hesitant to report on their sexual functioning without direct prompting.^27,28 Thus, we here present a comprehensive analysis from prospectively collected sexual function measures from placebo- and active treatment-controlled clinical studies of gepirone-ER in MDD.

METHODS

Study Design and Participants

We examined data from the 5 randomized, double-blind, placebo-controlled trials of gepirone-ER for MDD in which sexual functioning was prospectively assessed using validated patient-reported sexual functioning scales. All 5 trials included an initial short-term (8-week) placebo controlled study phase (study numbers 134001, 134002, 134004, 134006, and 134017). Patients completing studies 134004, 134006, or 134017 could continue to receive double-blind study medication in their respective long-term extension studies: 134502 (44 weeks), 134503 (20 weeks), and 134506 (16 weeks). In study 134502, patients had the option to continue their assigned treatment or switch therapy in the extension study. All studies were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki, and all participants provided informed consent. Protocols were approved by the Independent Review Board of each participating trial site. Trials were conducted from June 1999 to January 2004, predating the requirements for trial registration. Trials were funded by Organon & Co and Fabre-Kramer Pharmaceuticals.

All 1,767 patients (ages 18–69 years) met MDD criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV²⁹). All participants were free of antidepressants and other medications that could interfere with sexual function with at least 2 weeks off antidepressants other than fluoxetine, which required a minimum washout of 4 weeks. Also, in study 134017, the protocol required eligible participants to be sexually active and have normal sexual functioning prior to enrollment.

Detailed data on trial design and the effectiveness of gepirone-ER in treatment of MDD symptoms are presented elsewhere^30–33 and summarized in Supplementary Tables 1 and 2. In sum, gepirone showed efficacy in treatment of MDD in adult patients as well as efficacy in relapse prevention in adult patients whose MDD had remitted with treatment. Also see supplementary materials for gender breakdown across studies (Supplementary Table 2), schedule of sexual function assessments during the treatment period of each study (Supplementary Table 3), and patient disposition across studies (Supplementary Table 4).

Randomization and Masking

Permuted block randomization allocated patients to treatment with gepirone-ER, placebo, or an SSRI (fluoxetine or paroxetine). Randomized double-blind, double-dummy techniques were used from randomization until study completion and data unblinding, with placebo administered in identically appearing over-encapsulated tablets, packaging, and instructions for use. Patients in the medication switching trial (134004) were able to continue their assigned treatment or switch during the extension phase; however, patients remained blinded to study condition.

Drug Administration

Each study started gepirone-ER doses at 20 mg/day and increased to 40 mg/day after 4–7 days; depending on clinical response and tolerability, doses were further titrated to 60 mg/day at day 7 and 80 mg/day at day 14. Active control drugs (fluoxetine, studies 134004 and 134017; paroxetine, study 134006) were given at levels within the approved dose range (fluoxetine 20–40 mg/day or paroxetine 20–60 mg/day).

Assessment of Sexual Function

There were 3 separate types of sexual function assessment: spontaneous report of adverse events, clinical diagnosis, and patient-reported outcomes. Each provided parallel, but distinct forms of evidence of sexual effects of trial antidepressants, allowing evaluation of convergence of findings across assessment type.

Adverse event reporting.

Adverse events (AEs) were collected at each study visit and coded using an established dictionary (MedDRA³⁴). The following codes were used to define sexual dysfunction AE: sexual function and fertility disorders, orgasmic disorders and disturbances, sexual arousal disorders, and sexual desire disorders.

Diagnosis.

Investigators interviewed patients to determine whether they met DSM-IV diagnostic criteria for the following disorders: sexual desire disorders (DSM-IV codes 302.71 or 302.79), sexual arousal disorder (DSM-IV code 302.72), orgasmic disorder (DSM-IV codes 302.73 and 302.74), and premature ejaculation (men only; DSM-IV code 302.75). Diagnostic interviews occurred at baseline; weeks 2, 4, and 8; and approximately every 4 weeks during the extension period of each study.

Rating scales.

Across all 5 studies, validated clinical rating scales gave additional information on both overall sexual function and individual domains.

Derogatis Interview for Sexual Functioning (DISF) and Derogatis Interview for Sexual Functioning Self-Report (DISF-SR).

Four studies (134001, 134002, 134004, and 134006) and their extensions used the DISF or DISF-SR. The DISF/DISF-SR³⁵ are brief instruments with 25 items that assess sexual functioning across 5 domains: sexual cognition/fantasy, sexual arousal, sexual behavior/experience, orgasm, and sexual drive/relationship. In validation studies, reliabilities of the total scale and subscales were good to excellent (Cronbach α=0.70–0.80) and inter-rater reliability of the interview version was similarly excellent (IRR = 0.84–0.92).³⁶ Gender-specific male and female versions were used in the present analyses. Items are rated on either a 0–4 Likert scale (8 items) or a 0–8 Likert scale (17 items), for a total score that ranges from 0 to 168. Higher scores denote better sexual function, and a change of 3–5 points in total score is considered clinically meaningful (i.e., a more rigorous metric than statistical significance alone).

Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14).

Sexual function in one study (134017) and its extension was assessed using the CSFQ.³⁷ The CSFQ-14 is a self-report instrument with 14 items that capture sexual functioning in 5 domains: sexual pleasure, sexual desire/frequency, sexual desire/interest, sexual arousal, and orgasm. Items are scored on a 1–5 Likert scale, for a total score ranging from 14–70. Higher scores denote better sexual function, with thresholds indicating sexual dysfunction for total scores ≤41 for women and ≤47 for men.³⁷ A 2–3 point change/difference in total score is considered clinically meaningful. In validation studies, reliability of the measure was good to excellent (Cronbach α=0.64–0.8).^36,38,39

Analytic Plan

All analyses were conducted in SAS version 9.4.

Data pooling and treatment of missingness.

The individual studies were powered to detect a treatment effect for changes in depression symptoms, not for changes in sexual functioning. For this reason, studies of similar design that used the same assessment tool were pooled to improve power. All treated participants with at least one post-baseline assessment of sexual function were used for analysis. Out of all 1,767 participants receiving treatment in these 5 studies, a total of 1,520 participants (86%) had at least one post-baseline evaluation of sexual function (Supplementary Table 4). The percentage of participants providing sexual function data was relatively high in each of the treatment groups: gepirone (82%), placebo (84%), fluoxetine (96%), and paroxetine (91%). The missingness of individual items across measures was low (average=9.6%) and not related to effects of interest (e.g., due to clerical error) and thus was addressed using imputation from the average of nonmissing items within the subscale and with use of mixed-effects models robust to missingness.

Primary analyses.

Descriptive statistics present the incidence of sexual AEs and diagnoses coded for each study, alongside binomial tests evaluating differences in proportions between each pair of treatment groups.

Treatment effects on sexual function scale scores were evaluated using mixed models for repeated measures, with change from baseline score as the dependent variable. The models included fixed effects for treatment, center (or study for pooled analyses), visit, and treatment-by-visit interaction, with visit as the repeating factor and patient as a random effect, and baseline score as a covariate. An unstructured covariance matrix was specified for repeated measures (i.e., within-participant correlations). The scores on the relevant rating scale (DISF or CSFQ) obtained prior to the first dose of study drug served as each patient’s baseline value.

We evaluated 2 paradigms: evidence of no negative effect of medication, and evidence of superiority relative to active control. To establish no effect on sexual functioning, data had to show medication did not increase sexual dysfunction compared to placebo in a study with an active control that did show a significantly negative effect on sexual function, demonstrating assay sensitivity.²⁸ Assay sensitivity was declared if the active control was associated with significantly more sexual dysfunction than placebo, with P ≤ .05. If this test was positive, gepirone-ER’s effect on sexual function was interpreted based on the 2-sided 95% CI for the difference (gepirone-ER vs placebo). In Tables 1 and 2, we highlight instances where the lower limit of the CI exceeds −1, indicating the drug is not inferior to placebo; this 1-point margin is greater than the change deemed clinically meaningful for either scale (2–3 points for CSFQ and 3–5 points for DISF). Superiority of gepirone-ER was indicated when pairwise treatment comparisons (gepirone-ER vs SSRI and gepirone-ER vs placebo) of total scores on rating scales favored gepirone-ER with P ≤ .05. Sub-domains of the sexual function scores were evaluated in a similar manner.

Table 1.

Change in DISF Total Scores From Baseline at Each Visit (Pooled Studies 134004 and 134006)

DISF total score	Gepirone (N = 257)a	Placebo (N = 267)	SSRI (N = 261)	Treatment difference
				Gepirone—placebo	SSRI—placebo	SSRI—gepirone
All participants
Week 2
n	230	251	244
Meanb	3.1	0.1	−6.0	3.0	−6.1	−9.1
95% CI				−0.06, 6.12	−9.14, −3.05	−12.24, −6.01
P value				.0546	<.0001	<.0001
Week 4
n	209	236	228
Mean	6.1	2.8	−4.7	3.3	−7.4	−10.8
95% CI				−0.32, 6.97	−11.02, −3.88	−14.44, −7.10
P value				.0734	<.0001	<.0001
Week 8
n	187	213	208
Mean	7.2	3.8	−0.4	3.4	−4.2	−7.6
95% CI				−0.88, 7.63	−8.37, −0.06	−11.87, −3.31
P value				.1197	.0469	.0005
Overall c
n	234	256	261
Mean	6.3	3.0	−2.4	3.3	−5.4	−8.7
95% CI				−0.16, 6.78	−8.81, −2.00	−12.22, −5.22
P value				.0617	.0019	<.0001
Women
Week 2
n	156	176	175
Mean	2.4	−2.6	−8.7	5.0	−6.0	−11.0
95% CI				1.17, 8.82	−9.72, −2.30	−14.84, −7.18
P value				.0105	.0015	<.0001
Week 4
n	141	164	169
Mean	5.9	1.3	−6.1	4.6	−7.4	−12.0
95% CI				0.22, 9.02	−11.62, −3.19	−16.40, −7.65
P value				.0395	.0006	<.0001
Week 8
n	124	145	154
Mean	6.7	2.1	−1.6	4.5	−3.7	−8.2
95% CI				−0.84, 9.91	−8.82, 1.42	−13.56, −2.92
P value				.0977	.1559	.0025
Overall
n	158	178	179
Mean	5.8	1.2	−3.9	4.6	−5.1	−9.7
95% CI				0.30, 8.95	−9.23, −0.95	−14.01, −5.42
P value				.0361	.0161	<.0001
Men
Week 2
n	74	75	69
Mean	0.2	1.5	−3.8	−1.4	−5.4	−4.0
95% CI				−6.46, 3.74	−10.60, −0.10	−9.26, 1.27
P value				.6009	.0458	.1359
Week 4
n	68	72	59
Mean	2.1	1.1	−5.9	1.0	−7.0	−8.0
95% CI				−5.57, 7.47	−13.82, −0.27	−14.82, −1.16
P value				.7739	.0416	.0220
Week 8
n	63	68	54
Mean	3.6	2.5	−2.6	1.2	−5.0	−6.2
95% CI				−5.64, 7.97	−12.09, 2.08	−13.34, 0.99
P value				.7354	.1653	.0910
Overall
n	76	78	69
Mean	2.7	1.9	−3.7	0.7	−5.6	−6.4
95% CI				−5.02, 6.51	−11.63, 0.35	−12.42, −0.34
P value				.7989	.0650	.0384

^aN = participants with DISF total scores at baseline and at least one post-baseline visit.

^bLeast-squares means and P values from a mixed model with fixed effects for treatment, study, week, gender (for all participants analysis), and treatment-by-week interaction term, with week as the repeating factor, patient as a random effect, and baseline score as a covariate. Positive mean change (blue font) denotes improvement in sexual function from baseline; negative mean change (red font) denotes worsening. Cells are highlighted in blue if the lower limit of the 95% CI is above −1.0, indicating that gepirone’s effect is noninferior to placebo. P values ≤ .05 (2-sided) are in boldface.

^cOverall tests based on contrasts of the least-squares means weighted across weeks for each treatment pair.

Abbreviation: DISF = Derogatis Interview of Sexual Functioning.

Table 2.

Changes in CSFQ Total Scores From Baseline at Each Visit in Patients With Normal Baseline Sexual Function (Study 134017)

CSFQ total score	Gepirone (N = 155)a	Placebo (N = 155)	SSRI (N = 159)	Treatment difference
				Gepirone-placebo	SSRI-placebo	SSRI-gepirone
Week 2
n	100	118	108
Meanb	0.2	−0.0	−1.8	0.3	−1.8	−2.1
95% CI				−1.04, 1.59	−3.09, −0.52	−3.42, −0.73
P value				0.6812	0.0062	0.0025
Week 4
n	86	113	103
Mean	1.5	−0.6	−2.1	2.1	−1.5	−3.6
95% CI				0.36, 3.86	−3.21, 0.14	−5.43, −1.86
P value				0.0180	0.0717	<0.0001
Week 8
n	79	105	90
Mean	1.7	0.3	−2.2	1.4	−2.5	−3.9
95% CI				−0.42, 3.26	−4.25, −0.71	−5.79, −2.01
P value				.1290	.0062	<.0001
Overall c
n	101	122	109
Mean	1.4	−0.0	−2.1	1.5	−2.1	−3.6
95% CI				−0.03, 2.94	−3.54, −0.68	−5.09, −2.05
P value				.0547	.0039	<.0001

^aN = Participants with CSFQ total scores at baseline and at least one post-baseline visit.

^bLeast-squares means and P values from a mixed model with fixed effects for treatment, center, week, gender, and treatment by week interaction term, with week as the repeating factor, patient as a random effect, and baseline score as a covariate. Positive mean change (blue font) denotes improvement in sexual function from baseline; negative mean change (red font) denotes worsening. Cells are highlighted in blue if the lower limit of the 95% CI is above −1.0, indicating that gepirone’s effect is noninferior to placebo. P values ≤ .05 (two-sided) are in bold font.

^cOverall tests based on contrasts of the least-squares means weighted across weeks for each treatment pair.

Abbreviations: CSFQ = Changes in Sexual Functioning Questionnaire.

Subgroup analyses.

Sexual function scores were analyzed by gender and by presence or absence of pretreatment sexual dysfunction as determined by established cutoffs for DISF and CSFQ total scores.^32,37,40 As patients were medication free at baseline, these analyses examined changes in preexisting sexual dysfunction, potentially associated with the major depressive episode.

RESULTS

Participant Demographics and Clinical Characteristics

Participants were predominantly White (81%) and women (67%), with an average age of 39 years. For roughly half of participants, the duration of the current depressive episode was less than 1 year; the average age at first episode was 25 years. Treatment groups were comparable with respect to baseline age, gender, racial distribution, depression severity, and prevalence of sexual dysfunction. Pretreatment sexual function scores were comparable among treatment groups, but higher in men than women in each study. See Supplementary Tables 5 and 6 for detailed demographic data and mean pretreatment sexual functioning data at baseline for all participants.

Sexual AEs

Figure 1 illustrates pooled safety data from the 5 short-term studies, showing the overall incidence of sex-related AEs was lower during treatment with gepirone-ER (3%) compared to placebo (5%) and each of the SSRI comparators: fluoxetine (15%) and paroxetine (28%). SSRI treatment was associated with a 4-fold higher risk of sex-related AE vs placebo (RR = 4.21, P < .0001), whereas patients treated with gepirone-ER had a 40% lower risk of experiencing a sex-related AE than patients treated with placebo (RR = 0.60, P = .0805).

Figure 1.

Incidence of Sexual Dysfunction Adverse Events (Pooled Studies)

^aSSRI significantly higher than placebo (P < .0001) and gepirone-ER (P < .0001).

^bGepirone-ER significantly lower than placebo (P < .05).

^cAdverse effects included MedDRA high-level group terms: sexual function and fertility disorders, orgasmic disorders and disturbances, sexual arousal disorders, and sexual desire disorders.

Abbreviations: ER = extended-release, SSRI = selective serotonin reuptake inhibitor.

Diagnosis of Sexual Dysfunction

TESD was defined as a newly diagnosed sexual disorder (by DSM-IV criteria) that was not present at baseline. Among patients without a sexual disorder at baseline (72%–87% of the population in each study), the incidence of TESD for gepirone-ER (9%) was comparable to placebo (10%) and significantly less than in the SSRI group (27%). Disorders related to sexual desire and orgasm were significantly more common with use of SSRIs than either gepirone-ER or placebo (Supplementary Table 7). See Supplementary Materials for detailed data on incidence of TESD across different domains of sexual function (Supplementary Table 7) and by gender (Supplementary Table 8).

Rating Scales

Overall effects of treatment on sexual functioning scores.

Table 1 summarizes results from analysis of DISF total scores and each of the 5 DISF domains. Patients treated with SSRIs demonstrated statistically significant reductions in total DISF scores compared to placebo and gepirone-ER at all visits. The mean change in DISF scores from baseline was numerically (although not always significantly) better for gepirone-ER than placebo at every visit. Likewise, the lower 95% confidence limit on the difference between mean scores (gepirone-ER vs placebo) exceeded −1 in many instances, providing evidence that gepirone-ER’s effect on sexual function was no worse than placebo. The direction of treatment effects was similar across genders, with greater effects in women. Likewise, similar patterns were observed across all 5 subdomains (Supplementary Table 9). Gepirone-ER treatment was associated with better function in every domain relative to placebo; the lower limit of the 95% CI (gepirone-ER vs placebo) exceeded −1.0 in all but 2 instances and never fell below −1.11.

Effects of treatment on sexual functioning in patients without sexual dysfunction at baseline.

In 1 study (134017), the protocol required participants to be sexually active prior to enrollment and excluded participants with sexual arousal disorder, anorgasmia, premature ejaculation, erectile dysfunction, dyspareunia, or vaginismus. In this group with normal sexual function at baseline, CSFQ scores showed a sharp and significant decline during fluoxetine treatment, significant improvement with gepirone-ER, and no change in the placebo group (Figure 2; Table 2). At week 8 (study end point), patients treated with fluoxetine had a mean reduction in CSFQ total score of −2.2±0.68, which was statistically significant compared to increase in CSFQ total score observed on placebo (+0.3±0.64, P=.006) and gepirone-ER (+1.7±0.73, P<.001). Of note, the mean improvement in CSFQ scores at week 4 on gepirone-ER was also statistically significant and clinically meaningful (i.e., differences of 2 points or more) when compared to placebo (2.1, 95% CI, 0.4–3.9, P=.018) and fluoxetine (3.6, 95% CI, 1.9–5.4, P<.0001).

Figure 2.

Change in Sexual Functioning Among Participants With No Sexual Dysfunction at Baseline (Study 134017)

Abbreviations: CSFQ = Changes in Sexual Functioning Questionnaire, ER = extended-release, LS = least squares.

These results are supported by pooled analysis of data from participants without sexual dysfunction at baseline in the 2 active comparator studies that used the DISF scale (Figure 3). The reduction in DISF total score averaged across all study weeks was statistically significant in the SSRI group (−15.1±2.3) compared to placebo (−5.4±2.0, P=.002) and gepirone-ER (−1.7±2.2, P<.001) based on a mixed model analysis. On average, patients on gepirone-ER showed less reduction in DISF scores than placebo (+3.7, 95% CI, −2.2 to +9.6).

Figure 3.

Change in Sexual Functioning Among Participants With No Sexual Dysfunction at Baseline (Pooled Studies 134004 and 134006).

Abbreviations: DISF = Derogatis Interview for Sexual Functioning, ER = extended-release, LS = least squares.

Switching from SSRI to Gepirone-ER.

Participants who completed the 8-week study 134004 had the option to continue their assigned treatment or switch therapy in the 44-week extension study 134502. Supplementary Figure 1 shows the change in DISF scores in participants who finished 8 weeks of treatment with fluoxetine in the acute study and either switched to gepirone-ER (n = 54) or continued fluoxetine (n = 39) during the extension study. Those who switched to gepirone-ER experienced greater improvement in sexual function than those who continued the SSRI. This effect was mainly driven by women who made up the majority of participants in this cohort (65%; Supplementary Figures 2 and 3). It should be noted that depressive symptoms (as measured by the Hamilton Depression Rating Scale) also improved in participants who switched treatments in this study, with improvement in participants who switched from fluoxetine to gepirone-ER as well as those who switched from gepirone-ER to fluoxetine.

DISCUSSION

Data from 5 randomized, double-blinded controlled clinical trials suggest that gepirone-ER does not adversely affect sexual function in depressed patients and, in some cases, may improve sexual dysfunction. Patients without sexual dysfunction at baseline were less likely to meet diagnostic criteria for TESD and showed less decline in scores on validated patient-reported sexual functioning measures with gepirone-ER than those assigned to either placebo or SSRIs. Among patients who reported sexual dysfunction prior to randomization, treatment with gepirone-ER was associated with significantly greater improvement in sexual function than either placebo or SSRI. Finally, patients who had previously experienced sexual side effects of SSRIs showed significant improvement of sexual function after switching to gepirone-ER. Collectively, these results point to a favorable sexual functioning profile for gepirone-ER in patients with MDD. Other azapirones (such as buspirone)¹⁹ and serotonin reuptake inhibitors with 5-HT_1A receptor agonism as an additional mechanism (such as vilazodone)⁴¹ also have lower rates of sexual side effects than SSRIs, pointing to 5-HT_1A receptor agonism as a mechanism that preserves, and in some cases improves, sexual function in patients with MDD. These data support the inclusion of gepirone-ER in the clinician’s toolkit of novel-mechanism antidepressants lacking negative effect on sexual function.

When evaluating antidepressant effects on sexual dysfunction, two kinds of clinical questions must be addressed²⁸: how the agent compares against existing (iatrogenic) treatments and how the agent compares to placebo. Both must be answered with evidence from designs that use well-validated instruments with prospective assessment of sexual function prior to initiating treatment, both because sexual dysfunction is a common presenting symptom of MDD^42,43 and because fewer than 20% of patients who experience sexual side effects will report them unless specifically prompted to do so.^27,44 All 5 of the trials reported here met these rigorous criteria: all used doses sufficient to generate significant improvements on MDD symptoms, all conducted measurement of sexual function at baseline and end of study (with 3 studies conducting measurement periodically during the study), and all used scales highlighted by expert consensus for their validity and utility in capturing changes in sexual functioning.^28,45,46

To assess if a medication causes no more sexual dysfunction than placebo, supporting evidence must include both placebo and active control conditions to verify that the trial was truly able to detect sexual dysfunction. If both the placebo and the experimental drug show no effect on sexual function, this could be a true null effect, or could reflect a design that is unable to detect any changes in sexual function. Thus, establishing true lack of effect must be made with data showing a negative effect of an active control drug, establishing assay sensitivity. The data presented here meet that criterion, with 2 separate trials demonstrating no decline in sexual function for gepirone-ER and placebo conditions but a significant decline for SSRIs.

When assessing comparative superiority to existing treatments, evidence should include trials with patients who have experienced sexual dysfunction on the active comparator, as one of the strongest predictors of sexual side effects with a new medication is prior experience of sexual side effects, even when subsequent treatment is from a different medication class.⁴⁷ The data presented here also meet this criterion, showing that not only is gepirone-ER significantly less likely to cause TESD relative to SSRIs but it also is associated with significant benefits to sexual function in patients switching from SSRIs. Given the limited number of empirically supported treatments that address SSRI-induced sexual dysfunction^19,48—particularly in women⁴⁹—these data are promising.

Although the relative superiority of gepirone-ER was observed well into the maintenance phase (more than 6 months), the distinctions between gepirone-ER and SSRIs are particularly noteworthy in the acute adjustment phase within the first few weeks of treatment initiation. The first 4 weeks of treatment are a critical period for treatment success, as patients start to experience side effects but not depressive symptom reduction.^6,7 Patients who experience sexual side effects within the first 4 weeks of antidepressant therapy are significantly more likely to discontinue treatment prior to remission^6,8,12 and report significantly worsened quality of life.¹³ These data thus provide evidence that gepirone-ER is associated with significantly fewer distressing side effects during a particularly critical treatment period.

There were some limitations that must be considered. As is common in active-control antidepressant trials,⁵⁰ attrition prevented the estimation of treatment effects in all patients randomized to treatment. While the rate of attrition was not higher than typical for depression treatment studies (25%–30%) and our analyses used statistical methods robust to missingness, it cannot be ruled out that participants who experienced worsening of sexual function were more likely to drop out. However, there is no reason to expect that dropout due to sexual side effects differed by treatment arm, and, thus, comparisons across treatments are likely sound. No data are available on the relationship status of participants in these trials, which may contribute to error in sexual functioning measures.⁵¹ However, this limitation is partially mitigated in one study (134017) by use of the CSFQ, which incorporates direct assessment of sexual (in)activity into scoring. Across studies, there was a gender imbalance with more women than men participating. While this disparity is representative of population-level gender differences in MDD⁵² and in clinical trials for MDD, and the sample of men was sufficiently large to power stratified analyses, the higher proportion of women in these data should be taken into account when interpreting overall effects. The samples were predominantly White and non-Hispanic, which limits generalizability. It is unknown how racial disparities in mental health care access and bias⁵³ may influence the effects reported here. Despite these limitations, there were also considerable strengths in multiple converging lines of evidence using well-controlled trials with prospective, validated measures of sexual functioning.

CONCLUSION

Across studies, gepirone-ER demonstrated equivalence to placebo and superiority to SSRIs on sexual functioning outcomes, in patients both with and without existing sexual dysfunction at baseline. Results were similar across genders and phases of sexual function. Importantly, patients randomized to gepirone-ER did not experience the precipitous decline in sexual function during the first 2–4 weeks of treatment that is characteristic of SSRIs, suggesting that gepirone-ER may be better tolerated during this critical window. Moreover, these differences were observed well into longer term follow-up, suggesting the persistence of both the negative effects of SSRIs and null or beneficial effects of gepirone-ER on sexual function. In sum, these findings suggest that gepirone-ER is not associated with sexual dysfunction in patients diagnosed with MDD and in some cases is associated with improvements in sexual functioning.

Clinical Points.

• Antidepressant sexual side effects are a significant clinical concern, contributing to low treatment adherence and poor quality of life.

• Gepirone-ER, a novel antidepressant recently approved for treatment for major depressive disorder (MDD), may have a lower burden of negative sexual effects and in some cases may improve existing sexual dysfunction in patients with MDD.

• Across 5 placebo controlled randomized clinical trials, gepirone-ER was associated with significantly lower rates of treatment-emergent sexual dysfunction than selective serotonin reuptake inhibitors (SSRIs), and no difference from placebo.