As with vilazodone, there is a tenuous neurotransmitter case to be made that vortioxetine might be cleaner sexually than SSRIs, because among its many effects on various serotonin receptors, it is an agonist at 5-HT1A. A pooled analysis of seven placebo-controlled trials found that higher doses of vortioxetine caused progressively more TESD per the table below.
In terms of the statistics, this was a “noninferiority trial,” a diabolically confusing study design that has come into vogue over the last several years. In a standard clinical trial, a statistical test is done to see whether a new treatment is superior or equivalent to another treatment. In a non-inferiority trial, by contrast, statistical tests are run to show that a drug is not “unacceptably worse” than placebo. Vortioxetine passed this low bar for the two lowest doses—5 mg and 10 mg. We can therefore say with confidence that low-dose vortioxetine is not significantly inferior to placebo with regard to sexual side effects.
But what about those higher vortioxetine doses of 15 mg or 20 mg, doses that are more likely to be needed for a robust antidepressant effect? These doses cause higher rates of SD than placebo numerically (42.9% and 46.1% vs. 32% for placebo)—but these differences were not statistically significant. The 48.2% rate of SD caused by duloxetine, on the other hand, was significantly higher than placebo, and was also higher than the lowish rates of SD caused by 5 mg and 10 mg of vortioxetine.
According to the authors, interpretations are limited by the fact that these data were taken from different studies, none of which were designed specifically for making statistical comparisons of sexual side effects. Nor were any statistical adjustments made for multiple comparisons, which increases the probability that any differences, or lack thereof, may have been due to chance. Nonetheless, given that the rates of SD went up steadily with increasingly higher vortioxetine doses, it’s reasonable to conclude that vortioxetine does, in fact, cause SD to some degree—though possibly a somewhat smaller degree than duloxetine.
In another study, researchers tested whether switching patients who had SSRI-induced SD to vortioxetine would improve their sex lives more than switching them to another SSRI, in this case escitalopram (Jacobsen PL et al, J Sex Med 2015;12(10):2036–2048). This is an important clinical issue, since we often must decide which antidepressant to switch patients to when the first one is causing SD. The best answer to this quandary is generally going to be bupropion or mirtazapine, but some patients may not do as well on those agents.
A total of 447 patients were enrolled and randomly assigned to double-blind treatment with either vortioxetine or escitalopram, and dosing was identical for both drugs, starting at 10 mg/ day for one week and increasing to 20 mg/day thereafter. Sexual functioning was assessed with the CSFQ. After 8 weeks, patients assigned to vortioxetine improved by 8.8 points on the scale, significantly more than the 6.6-point improvement with escitalopram (the scale ranges from 14 to 70). In terms of the percent of patients whose sexual functioning significantly improved, vortioxetine also beat escitalopram on this outcome numerically (75% vs. 66.2%) but not quite statistically (p = 0.057); nonetheless, that’s a low enough p value for many to consider the difference real. In practical terms, the number needed to treat is 12. This means that you would have to switch 12 patients to vortioxetine to finally arrive at a patient whose SD would not have improved on escitalopram. Given vortioxetine’s brand-name expense and high rate of nausea, its slight potential sexual side effect advantage over escitalopram is probably not enough to convince us to prescribe it.
The only sexual side effect information we have about levomilnacipran is from the package insert, which lists erectile dysfunction (ED) as one of the “common” side effects of Fetzima. ED is reported as occurring in 6% of men as opposed to 1% of men on placebo. Ejaculation problems occurred in 5% of men on Fetzima and fewer than 1% of men on placebo. Fewer than 2% of female patients on Fetzima reported SD (http://www.allergan.com/assets/pdf/fetzima_pi#page=1). As you might have surmised, these numbers were based on spontaneous reports, so it is highly likely they significantly underestimate the true sexual side effect burden.
TCPR VERDICT: All three of these newer antidepressants cause significant SD. Vilazodone might be slightly less likely to cause SD in men than citalopram. Vortioxetine may have a slight advantage over duloxetine for new-onset SD, and over escitalopram for decreasing preexisting TESD. The specifics of levomilnacipran are anybody’s guess, but it probably will not have side effect advantages over venlafaxine or duloxetine, the other two SNRIs. If you are looking for a sexually neutral antidepressant, your number one choice is still bupropion.