But does norepinephrine selectivity mean anything clinically? Some researchers have hypothesized that there is a “norepinephrine deficit depression,” associated with poor concentration, inattention, low motivation, lack of energy, and cognitive impairment. This might be distinct from a “serotonin deficit depression,” more associated with anxiety, appetite disturbances, and suicidality (Moret C et al, Neuropsychiatr Dis Treat 2011;7Suppl1:9–13; Nutt DJ, J Clin Psychiatry 2008;69SupplE1:4–7). It would be nice if we could someday identify depressive subtypes that respond to specific medications, but the evidence for this norepinephrine/ serotonin division is still indirect and preliminary.
Nonetheless, these speculations provide promotional talking points for reps, who may argue that their drug has a special norepinephrine-based power to improve impaired daily functioning. Let’s look at the data.
Evidence on improving functioning
According to a recent meta-analysis, 4 out of 5 double-blind, placebo-controlled, short-term studies found that levomilnacipran was more effective than placebo for overall depressive symptoms (Montgomery SA et al, CNS Spectr 2014;5:1–9). The average response rate was 46% for levomilnacipran (vs. 36% on placebo) and the average remission rate was 28% (vs. 22% on placebo).
These studies also assessed change in functionality as a secondary measure. This was done using the Sheehan Disability Scale (SDS), a self-rating scale which asks about work/school, social life, and family life to measure functionality. Each of the three domains is scored from 0 (unimpaired) to 10 (extremely impaired). Any domain with a score of 5 or higher means significant functional impairment. So an SDS score of <12 total and <4 on all subscales indicates functional responders. An SDS score of <6 total and <2 on all subscales means functional remitters.
The meta-analysis reported a mean change in SDS score that was significantly greater with levomilnacipran compared to placebo but the actual difference in score was small, only a mean of 2.2 points better than placebo, (Sambunaris A et al, Int Clin Psychopharmacol 2014;29(4):197–205). The pooled response rate—that is, the percent of patients who functioned better at the end of the trial—was 39% for levomilnacipran vs. 29% on placebo, and the pooled remission rate was 22% vs. 15% on placebo.
Of course, the skeptic in us points out that any medication that eases depression is likely to also improve functioning. It may be that all antidepressants, regardless of their mechanisms of action, are just as effective as levomilnacipran for impaired functioning. Unfortunately, the company has not compared its drug with anything more robust than placebo, so we don’t know the answer yet.
An interesting secondary, post-hoc analysis of 1 of the 10-week placebo-controlled levomilnacipran studies looked at individual items in the major depression scales. The results didn’t support that levomilnacipran was better at any particular neurotransmitter profile of symptoms. Instead, the drug improved the same types of symptoms targeted by other antidepressants. So it’s unclear whether the higher selectivity for norepinephrine truly relates with any significant clinical outcome (Montgomery SA et al, Int Clin Psychopharmacol 2014;29(1):26–35).
TCPR Verdict: Levomilnacipran is an SNRI with especially strong reuptake inhibition of norepinephrine as opposed to serotonin. But whether it has any clear efficacy advantages over its competitors is not clear.
Vortioxetine was approved by the FDA in September of 2013 for major depression. It’s considered a “multimodal agent,” meaning that it acts not only as a serotonin reuptake inhibitor but also affects several other serotonin receptors. It is an agonist of 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3 and 5-HT7 receptors.
How well does vortioxetine work? A recent review of published and unpublished trials of the medication found 14 short-term randomized trials (6 to 12 weeks); eight of which were positive, five were negative, and one was considered “failed” because neither vortioxetine nor the active control, duloxetine, showed symptomatic improvement over placebo (Kelliny M et al, Ther Clin Risk Management 2015;11:1192–1212). Some studies compared vortioxetine to placebo, others to duloxetine or venlafaxine. Vortioxetine showed no clear superiority over active controls in measures of response or remission. So while vortioxetine has a distinctive pharmacological profile (Citrome L, Int J Clin Pract 2014;68(1):60–82), it is no more effective for core depressive symptoms than standard antidepressants.
The approved dose of vortioxetine is 10–20 mg/day. Sexual dysfunction has been reported to be minimal, but most premarketing trials relied solely on spontaneous reporting of adverse effects, which is known to underestimate their frequency (Cosgrove L et al, Account Res 2016 [Epub ahead of print]), and in one of the few trials that used a scale to measure effects on sexual performance, the authors concluded that “the sample number is too small to draw any conclusions” (Mahableshwarkar AR et al, J Clin Psychiatry 2015;76(5):583–591).
Is vortioxetine a smart pill?
As we know, “diminished ability to think or concentrate” is one of the DSM-5 criteria for major depression. Specific domains such as executive function, processing speed, attention, and learning and memory, have been found to be deficient during acute major depressive disorder (MDD) (Hammar A and Ardal G, Front Hum Neurosci 2009;3:26).
In an effort to get a leg up on its competitors, the manufacturer has done studies showing that vortioxetine improves patients’ performance on experimental cognitive tasks. Preclinical trials found that subjects on vortioxetine did better than those on duloxetine on the Digit Symbol Substitution Task (DSST), a measure of psychomotor speed (Gonzalez-Blanch C et al, Arch Clin Neuropsychol 2011;26(1):48–58). They then used the same outcome in 2 larger studies, each with 602 subjects. After 8 weeks, subjects on vortioxetine had higher scores on the DSST compared to those on placebo or those taking duloxetine, but by only 1.5%–3.0% (2 to 4 points on a 133-point scale) compared to placebo, and <0.5% (0.5 points) compared to duloxetine. On the strength of these studies, the company is applying for a new “cognitive dysfunction in MDD” indication. An FDA expert advisory panel recommended the approval in February, but just as we were sending this issue to press, the agency announced it would deny an expanded indication for cognitive dysfunction (http://www.biopharmadive.com/news/in-reversalfda-denies-cognitive-dysfunction-labelexpansion-for-brintelli/416536/).
We assume that the FDA’s skepticism was related to a couple of important questions: First, do improvements on the DSST score translate into functional improvements that we (or our patients) would recognize clinically? Second, is vortioxetine any better than other antidepressants for improving cognition in depression?