Antidepressants and Sexual Dysfunction: Is Vortioxetine Among the Exceptions?

Depression is associated with impaired sexual functioning. ¹ Most antidepressant drugs include reduced sexual desire, erectile dysfunction, or orgasmic dysfunction in their adverse effect profile. ² So, in patients who are treated with antidepressants, antidepressant-related sexual dysfunction may replace depression-related sexual dysfunction, creating a situation that is far from desirable.

What is the mechanism of antidepressant-induced sexual adverse effects? Antidepressant drugs that inhibit serotonin reuptake, such as the selective serotonin reuptake inhibitors (SSRIs), may decrease sexual desire and delay or prevent sexual orgasm.^3,4 Antidepressant drugs that are anticholinergic, such as the tricyclic antidepressants, may interfere with erection. ⁵ Obviously, antidepressants that have both mechanisms, such as clomipramine, could have a wider range of negative action on sexual functioning. ⁶

Few antidepressants that are presently available carry a low to no risk of treatment-emergent sexual dysfunction. These include bupropion, mirtazapine, agomelatine, vilazodone, and vortioxetine.^7-9 Agomelatine has failed as an antidepressant in India; bupropion and vilazodone do not enjoy a large market share; and mirtazapine, while effective and popular as an antidepressant, carries the disadvantage of increasing sleep, appetite, and weight. ⁸ So, that leaves vortioxetine.

But first, both vilazodone and vortioxetine inhibit the reuptake of serotonin; so why are they free from sexual adverse effects? A possible explanation is that both also act on 5HT1a receptors at which vilazodone is a partial agonist ¹⁰ and vortioxetine is a full agonist ¹¹ ; this action may be a mitigating element against the sexual dysfunction that is related to serotonin reuptake inhibition.

If one discounts atypical antidepressants such as brexanolone and esketamine, vortioxetine is the most recent antidepressant, worldwide. Vortioxetine was approved for the treatment of major depressive disorder (MDD) by the US Food and Drug Administration in September 2013, and by the European Medicinal Agency in October 2013. Since then, vortioxetine has been approved for marketing in about 80 countries across the world, and, very recently, in India, the second largest country by population.

Vortioxetine is associated with a favorable adverse effect profile, with most of its treatment-emergent adverse events reported at or near placebo level; ¹² it carries a low risk of treatment-emergent suicidal ideation ¹² and, because of its long half-life, ¹³ a low risk of discontinuation syndrome, even upon sudden withdrawal of the drug. ¹² So, what is the evidence for the favorable sexual adverse effect profile of vortioxetine?

In the regulatory, industry-driven, short-term randomized controlled trials (RCTs), the incidence of treatment-emergent sexual adverse events was 1.6% to 1.8% with vortioxetine (5-20 mg/d) as compared with 1.0% with placebo. ¹² In an industry-driven RCT conducted in 361 healthy adult volunteers, ¹³ paroxetine (20 mg/d) but not vortioxetine (10 and 20 mg/d) was associated with increased sexual adverse effects relative to placebo; whereas both doses of vortioxetine were associated with less sexual adverse effects than paroxetin, this was statistically significant only with the 10 mg/d dose.

In a pooled analysis from 7 short-term, industry-driven RCTs conducted in patients with MDD or generalized anxiety disorder, Jacobsen et al ¹⁴ found that treatment-emergent sexual adverse events were not significantly higher with any dose of vortioxetine (5-20 mg/d) as compared with placebo; however, only the 5 mg/d dose was non-inferior to placebo. Establishing the assay sensitivity of the pooled analysis, sexual adverse events were significantly higher with duloxetine 60 mg/d as compared with placebo, vortioxetine 5 mg/d, and vortioxetine 10 mg/d (but not vortioxetine 15 and 20 mg/d).

Perhaps the most important RCT of all was that of Jacobsen et al. ¹⁵ These authors examined sexual adverse events in a direct comparison between vortioxetine and escitalopram. The sample comprised 447 patients who had responded to sertraline, paroxetine, or citalopram. The mean age of the sample was about 40 years. The sample was 59% female. These patients were randomized to receive vortioxetine (10-20 mg/d) or escitalopram (10-20 mg/d) for 8 weeks; more than three quarters of the sample in each group received the 20 mg/d dose (vortioxetine, 76%; escitalopram, 81%). In both treatment groups, antidepressant efficacy was maintained and to a comparable extent. Both groups showed improvements in ratings on the Sexual Functioning Questionnaire Short Form; improvement was significantly greater with vortioxetine than with escitalopram (8.8 vs 6.6 points, respectively). The advantage for vortioxetine over escitalopram was statistically significant from week 4 onwards. The sexual benefits of vortioxetine were greater in males, in patients <41 years of age, and in less severely ill patients. Vortioxetine was specifically superior to escitalopram for all sexual phases: desire, arousal, and orgasm. These findings suggest that a switch to vortioxetine is a viable treatment strategy in depressed patients who improve but experience sexual dysfunction with an SSRI.

What are the take-home messages from this body of literature? It appears that, especially at lower doses, such as 5 and 10 mg/d, vortioxetine is associated with a low and perhaps placebo level of sexual adverse effects. At higher doses, which are likely to be associated with greater therapeutic benefit, ¹⁶ the sexual adverse effects appear to increase; yet, for all phases of sexual functioning, the sexual adverse effects are less than those associated with escitalopram.

A caveat is that the literature reviewed is entirely based on industry-driven RCTs; one looks forward to independent investigator research on the subject, and, of course to clinical experience with the drug. In this context, readers may note that a placebo level of sexual adverse events does not mean no sexual adverse events.