Post-SSRI sexual dysfunction

According to diagnostic criteria submitted by David Healy et al. in 2022, a diagnosis of PSSD requires that the subject has previously taken an SSRI or other SRI, and has experienced new (i.e. not present before starting the SRI) symptoms of sexual dysfunction for at least three months after the last dose of the SRI;[6] others have proposed a timeline of at least six months of sexual dysfunction symptoms after cessation of the SRI. Other potential causes of sexual dysfunction should be considered and excluded before a diagnosis is made.[12][6]

The following symptoms have been reported in association with PSSD:

• Erectile dysfunction[11][12]
• Loss of vaginal lubrication[12]
• Genital numbness[15]/reduced genital sensitivity (genital anesthesia)[12]
• Inability to achieve orgasm (anorgasmia)[16][17][18][7][5][19][11]
• Reduced pleasure associated with orgasm[11][20][12]
• Premature ejaculation[12]
• Reduced sexual desire/libido[20][12]
• Reduced ability to become sexually aroused[20]
• Decreased penile or testicular size[12]
• Changes in menstrual cycle[12]
• Testicular pain[12]
• Decreased seminal volume and/or quality[6][12]
• Anhedonia[11][6]
• Emotional blunting/numbing[6][11]
• Difficulty thinking or concentrating ("brain fog")[6]
• Issues with memory and recall[17][21]
• Depersonalization[6]
• Derealization[4][22]
• Pelvic floor dysfunction[6]
• Interstitial cystitis/painful bladder syndrome, often diagnosed as recurrent urinary tract infections in females or as recurrent prostatitis in males[6]

In many cases, PSSD sufferers report that their symptoms will transiently improve for short periods (usually no more than one or two days) before returning to their previous state.[10]

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has issued informational leaflets and/or labels containing warnings about post-discontinuation sexual side effects for Sertraline (Zoloft),[23][24] Citalopram (Cipramil),[25][26][27] Paroxetine (Paxil/Seroxat),[28][29] and Fluvoxamine (Luvox/Faverin).[30][31] The FDA has issued a leaflet for Fluoxetine (Prozac/Sarafem) containing similar warnings.[32]

Warnings about post-discontinuation sexual dysfunction associated with SSRIs can be found in the British National Formulary (BNF),[33][34][35][36][37][38] the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5),[39] the Textbook of Rare Sexual Medicine Conditions,[40][41] and the textbook Psychiatry and Sexual Medicine: A Comprehensive Guide for Clinical Practitioners.[42][43]

On the 11th of June 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that a possible relationship exists between SSRI use and persistent sexual dysfunction after cessation of use. The committee concluded that a warning should be added to the label of SSRIs and SNRIs regarding this possible risk.[44][45] The Hong Kong Department of Health,[46][47] Health Canada[45][48] and the NHS[49] have also issued warnings about PSSD.

To date, the biological mechanism responsible for causing PSSD, as well as why the symptoms persist long after discontinuation of SSRIs/SNRIs, remain unknown. Researchers have formulated several hypotheses as to the cause of PSSD, starting with the already known molecular mechanisms underlying sexual side effects during SSRI/SNRI treatment. These include increased serotonin, dopaminergic inhibition, inhibition of nitric oxide synthase, increased prolactin, reduced testosterone levels, blockade of cholinergic and alpha-1 adrenergic receptors, effects on proopiomelanocortin and melanocortin, and dysregulation of the hypothalamic–pituitary–gonadal axis.[19][61]

Furthermore, neurochemical changes related to sexual dysfunction during the use of antidepressants have been noted in the peripheral nervous system. This is noteworthy because 95% of serotonin receptors are located outside the brain.[62] It has therefore been hypothesized that PSSD may involve serotonin levels in peripheral nerves.[61]

Hypotheses that attempt to explain the long-term persistence of PSSD symptoms have suggested that epigenetics,[63][64] peripheral sensory neuropathy at the expense of ion channels,[65] bioelectric changes in the resting potential of cells,[66] persistent alteration of neurosteroid levels in the central and peripheral nervous system, and alterations to the gut microbiome[67][68][14] may be potential causative or contributing factors.

A 2020 study found a high incidence of penile tissue fibrosis in a sample of 43 male patients with PSSD, especially among those who had severe erectile dysfunction.[51]

There is as yet no established treatment for PSSD. In an unknown fraction of cases, symptoms are reported to resolve spontaneously with time,[10] but the duration of symptoms appears to vary widely among patients. Many anecdotal self-reports exist in which various approaches, ranging from pharmacological or psychiatric treatments to dietary or lifestyle changes, allegedly correlate with improvement in PSSD symptoms, but these results have not been independently verified or replicated. Several studies have been conducted which attempt to identify viable treatments for PSSD,[17][18][65] but in general these have suffered from a small sample size and lack of controls, limiting their informative utility.

Since 2006,[69] a number of news articles have been published by various outlets on the subject of PSSD.[70][71][72][73][74][75][76][77]

Several online support communities for PSSD exist, including the PSSD Network,[78] PSSD forum,[79] and the PSSD subreddit (r/PSSD on Reddit).

In December 2020, patients in the community started a fundraising campaign to enable the continuation of research into the aetiology of PSSD.[80]

On 21 June 2022, the advocacy organization RxISK began a research fund to support and stimulate interest in PSSD research;[81] the group has also offered a prize of $100,000 USD to anyone who can identify a reliable cure for persistent sexual side effects after stopping antidepressants, finasteride (Propecia), or isotretinoin (Accutane).[82]

In June 2023, the BBC documentary series Panorama released an episode on antidepressant use, titled "The Antidepressant Story". This episode contained a segment discussing PSSD, which included testimonies from PSSD sufferers and an interview with David Healy.[83]

Several medical practitioners, including David Healy[84] and Josef Witt-Doerring,[85] have made efforts to increase awareness of PSSD.

PSSD is one of several known iatrogenic syndromes characterized by persistent sexual dysfunction after stopping a medication; others include:[6]

• Post-Finasteride Syndrome (PFS), a condition affecting some individuals treated with the hair-loss drug finasteride (Propecia)[14][86]
• Post-Retinoid Sexual Dysfunction (PRSD) or Post-Accutane Syndrome (PAS), a condition affecting some individuals treated with the acne medication isotretinoin (Accutane)[6]
• Hard Flaccid Syndrome (HFS), which has been reported to occur following the use of bremelanotide[87]
• Persistent Genital Arousal Disorder (PGAD), which has been reported to occur in some female patients either while taking or after stopping SSRIs[88][89]

In 2014, a review of 120 reports submitted to RxISK from more than 20 countries concluded that PSSD, PFS and PRSD/PAS exhibit extensively overlapping symptom profiles.[90]

The drug 3,4-methylenedioxymethamphetamine (MDMA), which acts to stimulate the release and inhibit the reuptake of serotonin, can in some cases produce adverse effects that persist long after the drug has been withdrawn, including neurocognitive impairments such as mood disorders[91] and sexual dysfunction.[15] The mechanism behind MDMA neurotoxicity is not fully understood,[91] but a similar mechanism has been suggested to potentially play a role in PSSD.[15]