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Discussion of common sexual side effects is crucial in the informed consent process before initiating serotonergic antidepressants. How would you prefer to inform your patients about the potential for irreversible erectile dysfunction after using SSRIs for several months or even days?
Paul Zarkowski here from the Psychopharmacology Institute. Most practitioners believe that the sexual dysfunction caused by SSRIs is reversible—either by reducing the dosage, transitioning to a different antidepressant, or introducing a 5-HT2A blocker. Multiple case studies advocate for the occasional use of cyproheptadine, a 5-HT2A blocker, specifically on evenings when sexual activity is anticipated, administered 1–2 hours prior. Trazodone, another 5-HT2A blocker, has demonstrated effectiveness in countering SSRI-induced sexual dysfunction in all domains, as evidenced by an open-label study involving 20 patients.
However, could these studies have overlooked individuals with permanent sexual dysfunction? Researchers in Israel posed this question, drawing from an extensive database of 309,000 patients from the Tel Aviv district of Israel’s preeminent HMO. To summarize their findings, they identified 4 cases of post-SSRI sexual dysfunction from 866 men who began SSRI treatment. This determination was made after ruling out other potential causes. Numerous exclusions applied, which encompassed a range of conditions and medication linked with erectile dysfunction, from cardiovascular diseases to beta blockers. They eliminated individuals with a BMI over 25, those with a history of tobacco or substance use disorders, and anyone older than 49, resulting in a healthy cohort of 12,000 younger men. For context, I personally classify individuals under 50 years as young.
From this 12,000 member cohort, 866 started on a serotonergic antidepressant. Seventy-four of these individuals then commenced treatment with a phosphodiesterase inhibitor for erectile dysfunction. However, 50 of the 74 had already been on a phosphodiesterase inhibitor before the antidepressant. Consequently, only 24 might have experienced antidepressant-induced erectile dysfunction. Fifteen of these were subsequently excluded due to the timing of their phosphodiesterase inhibitor commencement. Of the remaining 9, 2 still consumed the antidepressant. Two were nonadherent and possibly remained depressed, leaving 4 young men with erectile dysfunction persisting over a month post-antidepressant discontinuation without any evidence of depression or anxiety.
The authors’ commitment to omitting cases with ongoing depression or anxiety is commendable. In a meta-analysis spanning 49 studies, depression was linked with a 1.39-fold increased risk of erectile dysfunction. Conversely, erectile dysfunction amplified depression risk by a factor of 2.92. This bidirectional relationship was also reflected in this study, which showed double the number of men treated for erectile dysfunction prior to being diagnosed with major depression vs the reverse. The study’s exclusion of ongoing depression or anxiety was based on the absence of a recorded diagnosis. The authors cite the diagnostic accuracy in their database as being previously validated in 2 distinct studies. However, these 2 referenced studies were predicated on the presence of a diagnosis, not its absence. One even stated they couldn’t determine diagnostic validity due to the study’s service-based nature. The second one highlighted their study’s primary limitation as the absence of diagnostic validation. I sought clarification from the primary author but remain awaiting a response.
Does this study spotlight a concerning yet infrequent side effect? Or do these 4 instances, amidst such a vast database, underscore the limitations inherent in service-based records? Informing patients about potential irreversible sexual side effects might influence their receptivity to treatment, especially given humans’ propensity to overvalue the likelihood of rare events. Nonetheless, this finding necessitates replication in a broader study that employs detailed measures of depression or anxiety, such as specific rating scales to confirm remission. Although epidemiological studies offer the advantage of a large sample size over extended periods, the lack of a placebo group can render particularly rare side-effect reports more challenging to interpret.
Abstract
Estimating the Risk of Irreversible Post-SSRI Sexual Dysfunction (PSSD) due to Serotonergic Antidepressants
Joseph Ben-Sheetrit, Yehonathan Hermon, Shlomo Birkenfeld, Yehiel Gutman, Antonei B Csoka, Paz Toren
Background: Sexual dysfunction is a common side effect of Serotonergic antidepressants (SA) treatment, and persists in some patients despite drug discontinuation, a condition termed post-SSRI sexual dysfunction (PSSD). The risk for PSSD is unknown but is thought to be rare and difficult to assess. This study aims to estimate the risk of erectile dysfunction (ED) and PSSD in males treated with SAs.
Methods: A 19-year retrospective cohort analysis was conducted using a computerized database of the largest HMO in Israel. ED was defined by phosphodiesterase-5 inhibitors prescriptions. 12,302 males aged 21-49 met the following criteria: non-smokers, no medical or psychiatric comorbidities or medications associated with ED, no alcohol or substance use. Logistic regression was used for estimation of ED risk in SA-treated subjects compared to non-SA-treated controls, assessed with and without the effects of age, body mass index (BMI), socioeconomic status (SES), depression and anxiety, yielding crude and adjusted odds ratios (cOR and aOR, respectively).
Results: SAs were associated with an increased risk for ED (cOR = 3.6, p < 0.000001, 95% CI 2.8-4.8), which remained significant after adjusting for age, SES, BMI, depression and anxiety (aOR = 3.2, p < 0.000001, 95% CI 2.3-4.4). The risk for PSSD was 1 in 216 patients (0.46%) treated with SAs. The prevalence of PSSD was 4.3 per 100,000.
Conclusions: This work offers a first assessment of the small but significant risk of irreversible ED associated with the most commonly prescribed class of antidepressants which should enhance the process of receiving adequate informed consent for therapy.
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Reference
Ben-Sheetrit, J., Hermon, Y., Birkenfeld, S., Gutman, Y., Csoka, A. B., & Toren, P. (2023). Estimating the risk of irreversible post-SSRI sexual dysfunction (PSSD) due to serotonergic antidepressants. Annals of General Psychiatry, 22(1),15.
