Sexual Dysfunction, SSRIs, and Depression

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RESEARCH UPDATE

Although the reasons for sexual dysfunction in patients with MDD are complex, the SSRI/5-HT1A receptor partial agonist vilazodone may offer an advantage over other SSRI-based regimens because of its 5-HT1A receptor partial agonism component.¹ However, general improvement in depressive symptoms by whatever means also appears to have a salutary effect on sexual function.²

The findings come from a recently published experimental study¹ and a post-hoc analysis2 of a phase 4 double-blind, placebo-controlled, randomized clinical trial (RCT) of vilazodone (NCT01473381).³ The experimental study, which had a crossover design, attempted to confirm the role of combined 5-HTT inhibition and 5-HT1A receptor partial agonism on sexual behaviors (specifically, ejaculation frequency and latency and copulatory efficiency).¹

This was accomplished by comparing the effects of acute (1-day), subchronic (8-day), and chronic (15-day) administration of vilazodone, paroxetine, paroxetine plus the 5-HT1A receptor partial agonist buspirone, and placebo in “normal-performing” male rats exposed to estrous female rats.

A significant decrease in sexual behavior was observed in rats that were subchronically or chronically exposed to paroxetine compared with the other treatments (P < .001). This finding is not surprising, since SSRIs are known to dampen sexual function. Sexual dysfunction is a major complaint and, in turn, a major reason for treatment nonadherence among patients who take SSRIs.⁴

Although rats exposed to paroxetine plus buspirone fared better than those receiving paroxetine alone, they had reduced ejaculation frequency following chronic treatment (P < .05 vs placebo; P < .01 vs vilazodone) and reduced copulatory efficiency following subchronic treatment (P < .001 vs vehicle and vilazodone) and chronic treatment (P < .05 vs placebo; P < .01 vs vilazodone).

The researchers noted that 5-HT1A receptor partial agonism mitigates the impact of SSRIs on sexual function but that factors yet to be completely determined may compromise buspirone’s 5-HT1A receptor occupancy, which may be why vilazodone outperformed the paroxetine/buspirone combination. No change in sexual function was seen in rats receiving vilazodone or placebo, and when rats receiving paroxetine or paroxetine plus buspirone were switched to vilazodone or placebo, sexual behaviors normalized.

The RCT compared the efficacy and safety of vilazodone 20 mg/d and 40 mg/d with placebo and an active control, which was the SSRI citalopram.3 Its ensuing post-hoc analyses,² which included 1047 patients with MDD, assessed sexual function via the Changes in Sexual Functioning Questionnaire (CSFQ), a 14-item self-report that evaluates 5 domains of the sexual cycle, including pleasure, desire/frequency, desire/interest, arousal, and orgasm, and also satisfaction. About 55% of male study participants and 60% of female participants had sexual dysfunction at baseline.

By week 10, CSFQ total scores increased for both men and women across all treatment groups: improvement was most dramatic for women receiving vilazodone 40 mg/d and men receiving placebo. CSFQ scores for women increased by a mean 3, 2.0, 1.9, and 1.2 points for vilazodone 40 mg, placebo, vilazodone 20 mg, and citalopram, respectively. For men, mean scores increased by 3.5, 2.4, 2.2, and 1.2 points for placebo, vilazodone 20 mg, citalopram, and vilazodone 40 mg, respectively.

Treatment responders, defined as a 50% or greater improvement in Montgomery-Åsberg Depression Rating Scale score, fared better than nonresponders-with scores improving up to 5.06 points in men who received placebo. This finding led the researchers to conclude that improved sexual function may simply be associated with improvement in depressive symptoms.

These findings were nuanced compared with the more cut-and-dried results seen in animal studies, but the RCT investigators commented that depression itself can instigate sexual dysfunction, and improvement in depressive symptoms may outweigh potential direct negative effects of SSRIs on sexual function.

References:

1. Oosting RS, Chan JS, Olivier B, Banerjee P. Vilazodone does not inhibit sexual behavior in male rats in contrast to paroxetine: a role for 5-HT1A receptors?Neuropharmacology. 2016;107:271-277.
2. Clayton AH, Gommoll C, Chen D, et al. Sexual dysfunction during treatment of major depressive disorder with vilazodone, citalopram, or placebo: results from a phase IV clinical trial.Int Clin Psychopharmacol. 2015;30:216-223.
3. Mathews M, Gommoll C, Chen D, et al. Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol. 2015;30:67-74.
4. Ashton AK, Jamerson BD, Weinstein WL, Wagoner C. Antidepressant-related adverse effects impacting treatment compliance: results of a patient survey. Curr Ther Res Clin Exp. 2005;66:96-106.