About half of patients who take a selective serotonin reuptake inhibitor (SSRI) develop sexual side effects on the antidepressant, but can those side effects persist after stopping it? Reports of post-SSRI sexual dysfunction (PSSD) are growing. Patient groups have gathered to support the concept, and some medical organizations have endorsed it, but PSSD is controversial. In this article, I’ll look at the science behind the syndrome.

Reports of PSSD date to the 1990s, but it has received recognition from regulatory agencies only recently. In 2019, the European Medicines Agency acknowledged that sexual dysfunction could persist after discontinuation of treatment with serotonergic antidepressants, leading to updates in product labels. In the US, the FDA recognizes this risk on the label of fluoxetine (Prozac). Now, the medical community is giving more attention to PSSD, prompted by comprehensive literature reviews and advocacy from affected individuals.

The scientific literature on PSSD consists of case reports, case series, and observational data from internet forums, totaling over 550 published cases (Reisman Y et al. Post-SSRI Sexual Dysfunction (PSSD). In: Reisman Y et al, eds. Textbook of Rare Sexual Medicine Conditions. Springer; 2022). The prevalence of PSSD is not known, and we have only a rough estimate in men from a large but problematic study.

That was a 19-year study that used new prescriptions for erectile dysfunction medications in men who had stopped an SSRI or a serotonin/norepinephrine reuptake inhibitor (SNRI) within the past year as a rough marker for PSSD. After excluding patients with medical or psychiatric causes of erectile dysfunction, they arrived at a rate of 0.46% (4/866). The true rate may be much higher or lower, as this study used a rough marker, looked at only one aspect of PSSD (erectile dysfunction), and could not fully control for other causes of the problem (Ben-Sheetrit J et al, Ann Gen Psychiatry 2023;22(1):15).

Outside of that study, most knowledge about PSSD comes from case reports, highlighting core symptoms like genital anesthesia, anorgasmia, and loss of libido. Nonsexual symptoms, such as anhedonia and blunted affect, are also common. Men often report erectile dysfunction, loss of desire, and genital anesthesia, while women often experience loss of desire, genital anesthesia, and anorgasmia (Reisman et al, 2022). Sexual issues usually arise during treatment and persist afterward (Tarchi L et al, Pharmacopidemiol Drug Saf 2023;32(10):1053–1067). Recovery is mixed, with some patients improving over time while others experience permanent dysfunction. Rare cases involve permanent genital anesthesia after minimal doses or permanent sexual dysfunction after discontinuation. No standard diagnostic criteria exist, but one proposed definition requires three months of sexual issues after stopping a serotonergic antidepressant (Healy F et al, Int J Risk Saf Med 2022;33(1):65–76).

The biological basis for PSSD is unclear. Hypotheses involving epigenetics and serotonin neurotoxicity remain untested (Peleg LC et al, Sex Med Rev 2022;10(1):91–98). Studies in rats show that SSRI exposure in early life may lead to irreversible sexual dysfunction, though evidence quality is low (Simonsen AL et al, Int J Risk Saf Med 2016;28(1):1–12).

What is missing in this literature is a clear causal link between serotonergic antidepressants and persisting sexual dysfunction. For example, depression itself can cause sexual dysfunction, as can many medical and psychiatric conditions (see the sidebar “Medical Causes of Sexual Dysfunction”). In short, the evidence is limited to case reports, and no randomized controlled trials have explored the phenomenon.

Caring for your patient

Patients with PSSD have often read about the problem online and may have had invalidating reactions from clinicians. The first step is to understand how they see the cause and validate their experience. Next, assess for all possible causes of sexual dysfunction, including psychiatric and medical causes. In particular, look for modifiable factors that may be contributing to sexual dysfunction, such as obesity, smoking, and low testosterone, and address them as part of treatment.

Other medications can also cause persisting sexual dysfunction, and two with particular relevance to the PSSD story are the hair-loss medication finasteride (Propecia) and the acne treatment isotretinoin (Accutane).

Ask about the full range of sexual symptoms and assess their timing in relation to antidepressant use. If the sexual dysfunction did not start after the initiation of the antidepressant, it is unlikely to be PSSD. Rule out medical and psychiatric causes before considering PSSD. One symptom to look for in particular is genital or nipple anesthesia, which is more specific to PSSD than depression and is associated with the severity of the problem (Tarchi et al, 2023).

Treatment is equally unclear. Attempts to treat PSSD with dopaminergic medications like bupropion and dextroamphetamine, as well as dopamine agonists like pramipexole, have shown no proven efficacy in available case reports. Similarly, PDE-5 inhibitors (such as sildenafil) and testosterone used for erectile dysfunction symptoms in PSSD have had limited success. Cognitive behavioral therapy has been used in PSSD to address negative cognitions pertaining to sexual inadequacy and low self-esteem (Reisman et al, 2022; Tarchi et al, 2023).

Carlat Verdict

Sexual dysfunction can persist after stopping a serotonergic antidepressant, but it's not yet clear whether the cause is the medication or other factors. Without scientific evidence to fully prove or disprove the phenomenon, clinicians should start with the basics: empathy, validation, and pursuit of all causes with an open mind.