DISCLAIMER: This publication is intended for healthcare professionals. The information provided aims to update on medication safety issues and should not substitute clinical judgment. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss arising from the use of or reliance on this publication.

 

Overview of Products

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are classes of antidepressants that primarily work by inhibiting the reuptake of specific neurotransmitters in the brain. SSRIs work by blocking only serotonin reuptake, which increases serotonin levels in the brain, while SNRIs increase both serotonin and norepinephrine levels.¹ In Malaysia, 81 products containing these agents are currently registered with the Drug Control Authority (DCA), comprising 52 SSRI-containing products and 29 SNRI-containing products.² These products are available in oral tablet or capsule form, with the following active ingredients:

• SSRIs (6 types): Sertraline, escitalopram, citalopram, paroxetine, fluoxetine, fluvoxamine
• SNRIs (3 types): Duloxetine, venlafaxine, desvenlafaxine

SSRIs and SNRIs are generally indicated for the treatment of various psychiatric disorders such as depression, anxiety, obsessive-compulsive disorder (OCD) and panic disorder.³

 

Overview of Safety Concerns

SSRIs and SNRIs have been associated with a recognized risk of persistent sexual dysfunction following treatment discontinuation, a condition referred to as post-SSRI sexual dysfunction (PSSD) or post-SSRI-SNRI sexual dysfunction.^4-7 Reported adverse events occurred in both males and females and included reduced sexual desire (loss of libido), erectile difficulties, orgasm disorders, genital or nipple numbness, painful intercourse, and prolonged erections.^4,5,8

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned from the Therapeutic Goods Administration (TGA), Australia, about the risk of persistent sexual dysfunction arising from both SSRI/ SNRI use.⁸ These effects may last from weeks to years and can significantly affect quality of life. Although considered rare, persistent symptoms after treatment cessation are likely underreported, and the true prevalence is unknown. All SSRIs and SNRIs in Australia currently carry warnings on sexual dysfunction in their Product Information (PI). However, not all products include information on persistent sexual dysfunction. The TGA is therefore mandating PI updates for all SSRI and SNRI products to include this risk.

 

Background of the Safety Issue

The exact mechanism by which SSRIs and SNRIs cause sexual dysfunction is not fully understood. Proposed mechanisms include increased serotonergic activity, particularly overactivation of post-synaptic 5-HT2A receptors, reduced dopamine and noradrenaline activity, increased prolactin leading to reduced free testosterone, and disruption of oxytocin and nitric oxide signalling, which may reduce genital blood flow.^5,7,9-10 Long-term use may also cause persistent downregulation of 5-HT1A receptors through epigenetic changes, potentially sustaining symptoms after discontinuation.^5,10 Both central and peripheral pathways are thought to contribute to these effects.

Reports of sexual dysfunction associated with SSRI and SNRI use indicate that symptoms may appear at treatment initiation and can persist long after discontinuation. In some cases, sexual dysfunction lasted for weeks to years after stopping treatment.^5-6,8,10 Diagnosing PSSD can be challenging, as its symptoms may overlap with those of the underlying mental illness.¹⁰ Diagnosis involves a comprehensive review of the patient’s clinical history, including prior drug use, symptom onset, and premorbid conditions, while excluding other potential causes of sexual dysfunction. A thorough assessment, from physical examination to a formal sexual health inquiry, is essential to confirm that symptoms are attributable to SSRI/SNRI use.

Currently, there is no definitive treatment for PSSD.^5,11 Several management approaches have been proposed, although evidence of effectiveness remains limited. These include lowering the SSRI dosage which may reduce sexual side effects but could compromise the underlying treatment objective and non-pharmacological strategies such as cognitive-behavioural therapy. Pharmacological interventions tested with varying degrees of success include trazodone, donepezil, ketamine, metformin, mirtazapine, vortioxetine, bupropion, tadalafil, and certain nutraceuticals. Experimental modalities such as low-power laser irradiation and phototherapy have shown promising results in small studies.

 

Local Adverse Drug Reaction Reports¹²

To date, the NPRA has received 1,399 reports comprising 2,815 adverse events suspected to be associated with SSRI- and SNRI-containing products. The most frequently reported events were nausea (164 cases), headache (152 cases), and dizziness (143 cases). Of these, 22 reports involved sexual dysfunction. However, no information on persistent sexual dysfunction was identified in the reported cases.

 

Regulatory Actions

The NPRA has completed a review of the potential risk of persistent sexual dysfunction associated with SSRIs and SNRIs. On 7 October 2025, a directive [NPRA.600-1/9/13(70) Jld 1] was issued for all registration holders of SSRI- and SNRI-containing products to update the local package inserts to reflect this safety information.

 

Advice for Healthcare Professionals

• Remain vigilant for the risk of prolonged or persistent sexual dysfunction associated with SSRI and SNRI use, which may continue for an extended period after treatment discontinuation, in both male and female patients.
• Proactively counsel patients on this potential risk, advise them to monitor for symptoms, and encourage prompt reporting of such events.
• During consultations, actively inquire about symptoms such as reduced sexual desire, erectile difficulties, problems with orgasm, genital or nipple numbness, painful intercourse, or prolonged erection.
• If sexual dysfunction is reported, review the patient’s medication history for SSRI/SNRI use and conduct a thorough assessment to exclude other potential causes. Confounding factors may include age, smoking, alcohol or substance use, and medical conditions such as diabetes, hypertension, or depression.
• Treatment discontinuation or switching to an alternative therapy may be considered based on clinical judgement.
• Report all suspected adverse events related to SSRI/SNRI-containing products to the NPRA.

 

References:

1. Cleveland Clinic. SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors).[Internet]. 2023 May 3 [cited 2025 Aug 8]. Available from: https://my.clevelandclinic.org/health/treatments/24797-snri
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Aug 8). Available from https://www.npra.gov.my
3. Pharmaceutical Services Program, Ministry of Health Malaysia. Sertraline, escitalopram, fluoxetine, fluvoxamine, duloxetine, venlafaxine and desvenlafaxine [cited 2025 Aug 8]. Formulasi Ubat KKM (FUKKM) [Internet]. Available from: https://pharmacy.moh.gov.my/ms/apps/fukkm
4. Health Canada. Summary Safety Review - Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-norepinephrine Reuptake Inhibitors (SNRIs) - Assessing the Potential Risk of Sexual Dysfunction despite Treatment Discontinuation {Internet] 2021 Jan 6. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR00254
5. Tarchi L, Merola GP, Baccaredda-Boy O, Arganini F, Cassioli E, Rossi E, et al. Selective serotonin reuptake inhibitors, post-treatment sexual dysfunction and persistent genital arousal disorder: A systematic review. Pharmacoepidemiol Drug Saf. 2023;32(4):1053-1067. Available from: https://doi.org/10.1002/pds.5653
6. Pukall C. Post-SSRI/SNRI sexual dysfunction: a review. J Sex Med. 2021;20(suppl 3):qdad068.019. Available from: https://doi.org/10.1093/jsxmed/qdad068.019
7. Alipour-Kivi A, Eissazade N, Shariat SV, Salehian R, Soraya S, Askari S, Shalbafan M. The effect of drug holidays on sexual dysfunction in men treated with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine: an 8-week open-label randomized clinical trial. BMC Psychiatry. 2024;24:67. Available from: https://doi.org/10.1186/s12888-024-05507-7
8. Therapeutic Goods Administration (TGA). Updated warnings about persistent sexual dysfunction for antidepressants [Internet] 2024 May 23 (cited 2025 Aug 11). Available from: https://www.tga.gov.au/news/safety-updates/updated-warnings-about-persistent-sexual-dysfunction-antidepressants
9. Safak Y, Azizoglu SI, Alptekin FB, Kuru T, Karadere ME, Kaya SNK, Yılmaz S, Yıldırım NN, Kılıçtutan A, Ay H, Burhan HŞ. Antidepressant-associated sexual dysfunction in outpatients. BMC Psychiatry. 2025;25:317. Available from https://doi.org/10.1186/s12888-025-06751-1
10. Bala A, Nguyen HMT, Hellstrom WJG. Post-SSRI sexual dysfunction: a literature review. Sex Med Rev. 2017;:1-6. Available from: https://doi.org/10.1016/j.sxmr.2017.07.002
11. New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE). Medicines Adverse Reactions Committee. Serotonin reuptake inhibitors and persistent sexual dysfunction after discontinued treatment [Internet] 2019 Sep 12 (cited 2025 Aug 18). Available from: https://medsafe.govt.nz/committees/MARC/reports/179-3.2.2SSRIsAndPersistentSexualDysfunction.pdf
12. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Jul 31]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Noor'ain Shamsuddin

Reviewed/Edited by: Dr Rema Panickar, Norleen Mohamed Ali