Sexual Dysfunction May Continue Even After SSRIs Are Ended

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A recent issue of Sexual Medicine Reviews includes an extensive field review on post-SSRI sexual dysfunction (PSSD), a medical condition tied to stopping SSRI and SNRI antidepressants that was formally recognized in Europe in 2019.

The review authors—led by Liran C. Peleg at a private clinic and Ilan Gruenwald at the Neuro-Urology Unit at the Rambam Medical Center in Haifa, Israel—assess the latest findings on the condition’s “biological plausibility, symptoms, diagnosis, and presumed risk factors,” with a view to educating researchers, clinicians, and prescribers about its severity, distinguishing symptoms, and underlying neurobiology.

Post-SSRI sexual dysfunction (PSSD) is, they summarize, an “iatrogenic [drug-related] syndrome, the underlying neurobiological mechanisms of which are unclear.”

In 1998, researchers first described a condition known as “Antidepressant-induced sexual dysfunction,” which was found to be widespread. Its post-SSRI counterpart is, by contrast, characterized as “a rare syndrome…[that] affects both genders…and does not appear in most individuals treated with SSRIs,” though its precise “incidence and prevalence…is not known.”

Concerning “antidepressant-induced sexual dysfunction” during treatment, most studies recorded high prevalence rates. As noted on this blog, one study involving 1,022 outpatients determined in 2001, “The incidence of sexual dysfunction with SSRIs and venlafaxine (Effexor) is high, ranging from 58 percent to 73 percent, as compared with serotonin-2 (5-HT2) blockers.” In the same study, citalopram (Celexa) was found to have the highest incidence, at 72.7 percent, with paroxetine (Paxil) recording 70.7 percent, and fluoxetine (Prozac), sertraline (Zoloft), and fluvoxamine (Luvox) all producing outcomes in the 58-62 percent range—at the time, “much higher than official figures advised.”

Several key points emerge from the current review, updating medical understanding of the condition’s post-SSRI counterpart:

• PSSD is “a medical condition that persists after discontinuation of SSRI’s and SNRI’s.”
• Its symptoms can be distinguished from those of depression.
• It can cause “substantial and prolonged suffering, with devastating effects on quality of life that lead to significant loss of function."
• “Misdiagnosing this syndrome might lead to harmful treatments, including [the] reinstatement of medications that generated PSSD.”

In their call for “well-designed neurobiological research in this domain,” the researchers sum up the most-promising paths so far, most of which concern “elevated levels of serotonin in the limbic system,” with implications for “androgen and estrogen receptor signaling in the hypothalamus.”

We propose that down-regulation of the pre-synaptic autoreceptors is part of the underlying mechanism of PSSD. By helping to block the reuptake of serotonin, SSRI and SNRI antidepressants may contribute to the downregulation or desensitization of 5HT1A pre-synaptic autoreceptors, worsening anhedonia and emotional blunting—also symptoms of PSSD.

Rat studies have demonstrated a permanent reduction in the sensitivity of 5HT1A receptors following the discontinuation of fluoxetine. Moreover, studies of the chronic use of SSRIs in very young rodents resulted in a sustained reduction in sexual behavior in adulthood, with observed long-term neurological sequelae... Desensitization of the post-synaptic 5HT1A receptors in several brain regions [e.g., the amygdala, the hypothalamus, and the prefrontal cortex] may underlie part of the mechanisms behind PSSD occurrence.”

Although depression and antidepressants are both associated with sexual dysfunction, a reason misdiagnosis can worsen PSSD’s longer-term sequelae, the authors are clear about the need to distinguish the two: “The treatment of depression with SSRI antidepressants is itself an independent cause of sexual dysfunction,” an independence established when it emerged that “SSRI-induced sexual dysfunction may persist following cessation of SSRI treatment.”

The core symptoms of PSSD, they write, are “genital anesthesia, loss of pleasure derived from genital stimulation, pleasure-less or weak orgasms (anhedonic orgasm), decreased sex drive, erectile dysfunction (ED), premature ejaculation, diminished vaginal lubrication, and diminished tactile sensitivity of nipples.” Additionally, according to their comprehensive review, “accumulated data of numerous case-reports suggest…non-sexual symptoms of PSSD, including anhedonia, apathy, and blunted affect.” These need inclusion in subsequent studies.

Physicians and prescribers concerned about mistaking depression-related sexual dysfunction for its post-SSRI counterpart are advised: “Diminution of genital sensation is a common symptom of PSSD, and appears to be unique to it.”

Treatment options remain “challenging, and many strategies have been suggested without definitive outcomes.” Ultimately, the authors conclude, as “no rational or consistent treatment has been found for this disorder, it is imperative for clinicians to be aware of [its] non-sexual symptoms and to be able to differentiate between PSSD-associated sexual dysfunction and depression-related sexual dysfunction.”