Antidepressant-induced Sexual Dysfunction

Primer

Antidepressant-induced Sexual Dysfunctions are a very common side effect that is often under-recognized, and for some individuals can be protracted even after antidepressant discontinuation. There are unfortunately few well-designed studies to address this problem, and there are also high placebo-response rates for treatments.

Mechanism

Most antidepressants modulate serotonin, and elevated serotonin levels (via increased stimulation/agonism) are thought to cause sexual dysfunction. Sexual function can be broken down into 3 parts:

  1. Libido or sexual interest – occasionally decreased by SSRIs (most frequently decreased by venlafaxine)
  2. Erection (potency) (males) – rarely affected by SSRIs
  3. Ejaculation and orgasm – frequently affected by SSRIs
  • 5HT2A and 5HT2C stimulation (agonism) are thought to cause sexual dysfunction (in addition to other possible antidepressant side effects such as insomnia, and activation/anxiety). Specifically, increased spinal cord 5HT-2A receptor activity (agonism) is thought to cause these changes.[1] Serotoninergic nerve terminals also target dopamine and norepinephrine pathways in the brain and inhibit their activity, and these pathways are involved in the desire and arousal phases of the sexual response cycle.
  • Other antidepressant such as paroxetine may inhibit nitric oxide synthase (NOS) activity. Nitric oxide (NO) is a key mediator of penile smooth muscle relaxation and penile erection, and sexual dysfunction can also occur when this pathway is affected.[2]

Medications

  • All serotonergic antidepressants may cause a decline in libido or sexual functioning despite improvement of depression symptoms. Studies suggest that escitalopram and paroxetine are likely to cause more sexual dysfunction, while bupropion, agomelatine, mirtazapine, vilazodone, and vortioxetine have a lower risk.[3]

Treatment

Bupropion, buspirone, cyproheptadine, mirtazapine, or sildenafil to existing antidepressant treatment may resolve symptoms. These medications better address ejaculation and orgasm, while decreased libido may be more difficult to resolve.

Cyproheptadine

Cyproheptadine, a 5HT-2 antagonist with antihistaminergic and adrenolytic properties, may help.[4]

Vortioxetine

Vortioxetine may reduce sexual side effects at low doses.[5]

Bupropion

Adding bupropion SR 150 mg as a PRN prior to sexual activity, or as a daily adjunct may be helpful.[6]

Mirtazapine

Adjunctive mirtazapine may be helpful.[7]

Sildenafil

Sildenafil (phosphodiesterase-5 inhibitor) improves peripheral vasodilatation due to smooth muscle relaxation caused by enhanced nitric oxide release. Other sexual side effects—such as delayed orgasm/ejaculation—may improve because of indirect effects of increased penile and clitoral blood flow caused by vasodilatation. Dosing between 50 to 100 mg, 1 hour before sexual activity, in men may be effective.[8] Evidence is more limited in women.

Resources

Research
Articles

References

1) Higgins, Agnes, Michael Nash, and Aileen M. Lynch. "Antidepressant-associated sexual dysfunction: impact, effects, and treatment." Drug, healthcare and patient safety 2 (2010): 141.
2) Higgins, A., Nash, M., & Lynch, A. M. (2010). Antidepressant-associated sexual dysfunction: impact, effects, and treatment. Drug, healthcare and patient safety, 2, 141.
3) Kennedy, S. H., Lam, R. W., McIntyre, R. S., Tourjman, S. V., Bhat, V., Blier, P., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. The Canadian Journal of Psychiatry, 61(9), 540-560.
4) Aizenberg, D., Zemishlany, Z., & Weizman, A. (1995). Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clinical neuropharmacology.
5) Jacobsen, P. L., Mahableshwarkar, A. R., Chen, Y., Chrones, L., & Clayton, A. H. (2015). Effect of vortioxetine vs. escitalopram on sexual functioning in adults with well-treated major depressive disorder experiencing SSRI-induced sexual dysfunction. The journal of sexual medicine, 12(10), 2036-2048.
6) Clayton, A. H., Warnock, J. K., Kornstein, S. G., Pinkerton, R., Sheldon-Keller, A., & McGarvey, E. L. (2004). A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. The Journal of clinical psychiatry, 65(1), 62–67.
7) Farah, A. (1999). Relief of SSRI-induced sexual dysfunction with mirtazapine treatment.
8) Nurnberg, H. G., Hensley, P. L., Gelenberg, A. J., Fava, M., Lauriello, J., & Paine, S. (2003). Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. Jama, 289(1), 56-64.