new antidepressant medsSince 2011, 3 new antidepressants have been approved by the FDA, and another (ketamine) has been generating buzz as a potential off-label medication for depression. In this article, we’ll take a step back and review the data on vilazodone (Viibryd), levomilnacipran (Fetzima), vortioxetine (Brintellix), and ketamine.

Vilazodone (Viibryd)

Vilazodone was approved by the FDA in January of 2011, making it the oldest of the newer antidepressants. Those who like tracking mechanisms of action are calling vilazodone a “SPARI, which stands for serotonin partial agonist/reuptake inhibitor. The drug inhibits reuptake of serotonin (like SSRIs) and has partial agonism at 5-HT1A receptors (like buspirone). So, theoretically, giving your patients vilazodone is similar to giving them both an SSRI and buspirone at the same time. Is that a good thing? Nobody knows for sure. In the STAR*D trial, buspirone had a cameo appearance in one of the steps, being used as an augmenter of citalopram, and it worked as well as bupropion augmentation—a finding that may or may not have any relevance to vilazodone.

When the drug was first approved, the word on the street was that it (1) may work faster than other antidepressants, (2) may have fewer sexual side effects, and (3) may be more effective for anxiety. We were skeptical of these claims then, as was the FDA (see TCPR, April 2011 and But new data have accumulated since then. We’ll rely mainly on a review published in 2015, which included 4 later-stage and post-marketing studies, as opposed to the pre-approval studies that the FDA reviews (Hellerstein DJ et al, Core Evid 2015;10:49–62).

Onset of action

The idea of faster onset of action was originally based on one piece of animal data and one piece of human data. The animal data showed that vilazodone quickly enhanced serotonin transmission in rats via 2 distinct mechanisms: 5-HT1A partial agonism and regular serotonin reuptake. In the human study, vilazodone showed statistically significant reduction in depression scores compared to placebo quite early, by week 1, although there was no active drug comparison (Rickels K et al, J Clin Psychiatry 2009;70(3):326–333).

Two more recent studies showed greater improvement versus placebo as early as week 2 (Croft HA et al, J Clin Psychiatry 2014;75(11):e1291– e1298; Mathews M et al, Int Clin Psychopharmacol 2015;30(2):67–74). However, antidepressant response at 2 weeks is not unique to vilazodone. Early improvement is the rule and not the exception for many antidepressants (Szegedi A et al, J Clin Psychiatry 2009;70(3):344–353). In addition, when researchers focused on remission instead of response, vilazodone took 6 full weeks to outperform placebo. The bottom line is that there is no convincing evidence that vilazodone has a faster onset of action than any of its competitors.

Sexual side effects

Early studies suggesting a cleaner sexual side effect profile for vilazodone were problematic. First, there was no SSRI comparator, which would have been necessary to make any claims that vilazodone had an advantage over other agents. Second, most of the patients enrolled had preexisting sexual dysfunction before being randomized to vilazodone or placebo. One can argue that this design has the advantage of being generalizable to many of our patients, who have underlying sexual dysfunction due to depression or age, for example. On the other hand, it’s akin to testing whether a drug has a headache side effect by giving it to a bunch of people who already had headaches. Any new onset headaches would be obscured by the pathology already there. And indeed, in the company-funded study, treatment with vilazodone didn’t worsen the already high burden of sexual side effects—in fact, it was no different from placebo, both of which resulted in a slight improvement in sexual functioning (Rickels K et al, J Clin Psychiatry 2009;70(3):326–333).

In a more recent industry-funded post-hoc analysis of patients with normal baseline sexual function who were randomized to vilazodone, citalopram, or placebo, there were no significant differences in onset of new sexual side effects. The rates were: placebo: 12%; vilazodone 20 mg/day: 16%; vilazodone 40 mg/day: 15%; and citalopram 40 mg/ day: 17% (Mathews MG et al, Abstract 45, ASCP 2014; There was also no significant difference among those who had baseline sexual dysfunction: 33% of patients on placebo, 35% on vilazodone 20 mg/day, 30% on vilazodone 40 mg/ day, and 28% on citalopram patients improved to normal sexual function by the end of the study.

According to the website, there are ongoing studies of vilazodone addressing the sexual function issue. Until those results are published, we continue to consider the low sexual side effect claims as unsubstantiated.

Efficacy in anxiety

There’s a theoretical argument to be made that vilazodone’s 5-HT1A partial agonism might give it special anti-anxiety power. The only clinical trial evidence thus far is based on comparisons with placebo. As is true for many other antidepressants, vilazodone reduces scores on the Hamilton Anxiety Rating Scale more than placebo (Rickels K et al, J Clin Psychiatry 2009;70(3):326– 333; Khan A et al, J Clin Psychiatr 2011;72(4):441–447). Another analysis of these data found that vilazodone may be more effective for the subgroup of anxious depressed patients than for the non-anxious depressed (Thase ME et al, Int Clin Psychopharmacol 2014;29(6):351–356). Promising, but we’d need data comparing this medication with other antidepressants to be convinced that it has an advantage.

TCPR Verdict: Based on this second look at vilazodone, we don’t see any new evidence that it works faster, has fewer sexual side effects, or is preferred in depressed patients with significant anxiety. We consider this a second-line antidepressant to be used after generics have failed.

Levomilnacipran (Fetzima)

Levomilnacipran was approved by the FDA in July 2013 for major depressive disorder. It is the close chemical cousin (an enantiomer) of milnacipran (Savella), approved in the U.S. in 2009 for fibromyalgia and approved for depression in other countries. Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI), which puts it in the same class as duloxetine (Cymbalta), venlafaxine (Effexor XR), and desvenlafaxine (Pristiq). However, levomilnacipran is more selective for inhibiting norepinephrine reuptake than the others—studies have shown that it has a 15-fold higher selectivity for norepinephrine than for serotonin. This selectivity disappears at higher doses.


This article originally appeared in:

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This article was published in print April 2016 in Volume:Issue 14:4.