Levomilnacipran: A Brief Overview

Michael E. Thase, MD


July 26, 2013


Levomilnacipran is an active enantiomer of the racemic drug milnacipran (Savella®). Like milnacipran, levomilnacipran is a relatively selective and potent inhibitor of neuronal serotonin and norepinephrine uptake transporters and, as such, is classified as a serotonin norepinephrine reuptake inhibitor (SNRI). Although milnacipran was approved for the treatment of depression in France in 1996 (only a few years after venlafaxine was introduced), it was not systematically studied as an antidepressant in the United States. Indeed, milnacipran came relatively late to the US market as a Food and Drug Administration (FDA)-approved treatment of fibromyalgia. By contrast, a full clinical development program was undertaken for an extended-release formulation of levomilnacipran (Fetzima®). This research, which includes 3 pivotal, phase 3 randomized controlled trials , formed the basis for review by the FDA, culminating in an approval for the treatment of major depressive disorder (MDD).

Levomilnacipran is thus the fourth member of the SNRI class to receive the MDD indication in the United States. Along with the selective serotonin reuptake inhibitors (SSRIs), these modern-generation selective reuptake inhibitors are among the world's most commonly prescribed medications and are the cornerstones of contemporary medical treatment of depression.

On the basis of in vitro studies, levomilnacipran is the most noradrenergically active of the SNRI class of antidepressant drugs.[1] In one study, levomilnacipran was found to have twofold greater potency for norepinephrine relative to serotonin reuptake inhibition, and 17 and 27 times higher selectivity for norepinephrine reuptake inhibition compared with venlafaxine and duloxetine, respectively.[1] Studies using PET scans to image receptor occupancy, which have recently been undertaken with milnacipran,[2,3] would be helpful to establish differences in vivo. Nevertheless, it is plausible that levomilnacipran will show a dose-response relationship that is the mirror image of venlafaxine, with greater noradrenergic selectivity at low doses and increasing effect on serotoninergic neurotransmission with upward dose escalation. Because there currently are no modern selective norepinephrine reuptake inhibitors approved for the treatment of depression in the United States, this characteristic may represent a novel contribution for levomilnacipran.

Efficacy, Safety, and Therapeutic Role

The efficacy of extended-release levomilnacipran has been established (versus placebo) in doses ranging from 40 mg/day to 120 mg/day.[4,5] Principal side effects in clinical trials include nausea, constipation, and sweating. Approximately 1%-3% of patients will report a significant increase in blood pressure and up to 6% will report a significant elevation of pulse. Like its racemate, levomilnacipran is neither a substrate for nor potent inhibitor of cytochrome P450 isoenzymes. Because levomilnacipran is primarily excreted by the kidneys, it is not recommended for treatment of patients with end-stage renal disease.

To date, none of the controlled studies of levomilnacipran have included an active comparator. Drawing on the numerous comparative studies of milnacipran, meta-analyses have reported comparable efficacy and more favorable tolerability in early studies using imipramine as the comparator[6] and efficacy and tolerability comparable to that with the SSRIs.[7]

The studies conducted as part of the phase 3 development program for levomilnacipran have established its efficacy in MDD. This conclusion is, of course, buttressed by the more numerous studies of the racemate, milnacipran, which have been conducted over the past 2 decades worldwide. As with drugs within any therapeutic class, the various SNRIs are not interchangeable, and as such, it is likely that some patients who have either not benefitted from or have not been able to tolerate other SNRIs, including generic formulations of venlafaxine or duloxetine, may do well on levomilnacipran. The cynically minded might suggest that, with milnacipran already on the market, there was little need for levomilnacipran. Nevertheless, it is true that without FDA approval for MDD, the therapeutic potential of this more noradrenergically active SNRI has not been available for most of the depressed patients treated in the United States. Whether levomilnacipran will show particular promise among subsets of depressed patients, such as those with prominent fatigue, anergia, more pronounced functional impairments, or treatment-emergent sexual dysfunction, remains to be seen.