Sexual inactivity may worsen SSRI side effects in women with depression

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A recent analysis of data from a phase 3 clinical trial suggests that sexual inactivity may significantly worsen the sexual side effects of selective serotonin reuptake inhibitors (SSRIs) in women being treated for major depressive disorder (MDD). The findings were presented at the International Society for the Study of Women's Sexual Health (ISSWSH) Annual Meeting and compared the effects of fluoxetine (an SSRI), gepirone-ER (an azapirone), and a placebo on sexual functioning over an 8-week period.

Sexual dysfunction is a well-documented side effect of SSRIs, often impairing the sexual quality of life for patients. As a result, health care providers have increasingly turned to antidepressants with alternative mechanisms of action, such as azapirones, which selectively target 5HT1A receptors and are associated with fewer sexual side effects. Gepirone-ER, recently approved by the FDA for treating MDD, was included in the study to evaluate its impact on sexual function compared to fluoxetine and placebo.

Researchers assessed sexual function using the Derogatis Interview for Sexual Functioning (DISF), a validated self-report scale. The study involved 495 patients, 64% of whom were women. Sexual activity status was categorized based on responses to the DISF's sexual behavior subscale, dividing participants into 3 groups: sexually active with a partner, engaging in masturbation only, or not sexually active at all. Mixed repeated measures linear models were used to analyze the data separately for men and women.

The findings showed that in women, sexual activity status was a significant predictor of changes in total sexual functioning scores across all 3 treatment groups [F(2, 647) = 7.67, p = 0.005]. Women who were not sexually active reported significantly greater declines in sexual function compared to those who were sexually active, either with a partner or through masturbation. Notably, the detrimental impact of sexual inactivity was most severe in the fluoxetine group, where follow-up contrast analyses indicated a significantly greater decline in sexual function compared to gepirone or placebo (contrast t = -2.04, p = 0.04).

In contrast, women taking gepirone-ER did not experience significant differences in sexual function compared to those taking a placebo. This suggests that gepirone-ER may mitigate some of the sexual side effects commonly associated with SSRIs. The selective action of gepirone-ER on 5HT1A receptors might play a role in preserving sexual motivation as depressive symptoms improve.

The analysis revealed no significant impact of sexual activity status on changes in sexual functioning for men in any of the treatment groups. This sex-specific difference highlights the need for further research to understand how antidepressants differentially affect sexual function in men and women.

These findings have important clinical implications for prescribing antidepressants to women, particularly those who are not sexually active at the start of treatment. Given that gepirone-ER showed a side effect profile similar to placebo in terms of sexual dysfunction, it may offer a promising alternative for women who are concerned about the sexual side effects of SSRIs.

The authors of the study suggest that considering sexual activity status when selecting antidepressants could help mitigate the risk of sexual dysfunction in women with MDD. They also emphasized that further analysis of specific domains of sexual functioning is ongoing and will provide additional insights into the underlying mechanisms of these effects.

These results highlight the potential of gepirone-ER as a treatment option that could preserve sexual function in women undergoing treatment for depression, offering a valuable alternative to SSRIs for patients who prioritize sexual health as part of their overall well-being.

Reference:

Lorenz T, Clayton A. Effect of Sexual Activity Status on Sexual Side Effects of Azapirones vs. Selective Serotonin Reuptake Inhibitors (SSRI): Results From a Randomized Controlled Trial. Poster. Presented at: International Society for the Study of Women's Sexual Health (ISSWSH) Annual Meeting. https://www.isswshmeeting.org/2025/program