A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder.

Major depressive disorder (MDD) is a leading cause of global disease burden; by 2030, it is projected that it will be only second to human immunodeficiency virus/acquired immunodeficiency syndrome in worldwide burden of disease.1 Some defining symptoms of MDD are thought to be related to reduced noradrenergic activity exacerbating the depressed mood state.2 These symptoms, which include fatigue, lack of motivation, decreased concentration, and lassitude, complicate the depressive state by impairing social and occupational functioning. An inability to correlate changes in the biological indices that accompany improvement in MDD has restricted the definition of treatment response to a reduction in the number and the severity of symptoms. However, the complex nature of depression is better suited to a multifaceted concept of recovery and wellness that includes broader outcome criteria and improvement in key domains, including both symptomatic and functional improvement.3 Research suggests that changes in symptom severity and improvement in functional impairment may occur asynchronously, with functional improvement often lagging behind changes in symptoms.4,5 As such, symptom improvement may provide an early sign of treatment response, whereas functional improvement may be a better indicator of meaningful change.5 Independent assessments of symptoms and functioning in MDD may improve clinical research by providing greater insight into the relationship between symptoms and functioning. Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI); an extended-release (ER) formulation was developed to allow for once-daily dosing. Levomilnacipran has approximately 2-fold greater potency for norepinephrine than serotonin reuptake inhibition. Compared with duloxetine or venlafaxine, levomilnacipran has more than 10-fold higher selectivity for norepinephrine relative to serotonin reuptake inhibition.6 Studies suggest that antidepressants with a prominent noradrenergic component may be especially effective in improving symptoms related to functioning2,7,8; as such, levomilnacipran ER may be an antidepressant that can provide both symptomatic and functional efficacy. Levomilnacipran is the more active enantiomer of milnacipran, an SNRI that is approved for the treatment of fibromyalgia in the United States (prescribing information: Savella [milnacipran hydrochloride], 2011; Forest Laboratories, Inc, St Louis, MO). Milnacipran is not approved for the treatment of MDD in the United States; it is approved for that use in many countries outside the United States. Milnacipran studies in MDD were conducted more than a decade ago, and no head-to-head trials have been performed; as such, no valid comparison between levomilnacipran ER and milnacipran clinical data can be made. Milnacipran is a racemic mixture of levomilnacipran (1S, 2R-milnacipran) and F2696 (1R, 2S-milnacipran); the 2 enantiomers are not interconvertible.9 Regulatory guidelines in the United States and Europe recommend development of enantiomers over racemic drugs where appropriate,10 for a variety of reasons.11 Levomilnacipran exhibited high affinities for human recombinant transporter proteins for norepinephrine and serotonin (Ki = 92.2 and 11.2 nM, respectively) that were at least 10 times higher than the other enantiomer, F2696.6 Moreover, levomilnacipran was substantially more potent than was F2696 in an animal model of antidepressant activity and in vitro functional assays.6 Levomilnacipran also has pharmacokinetic advantages relative to F2696. When the milnacipran racemate was administered to human subjects, levomilnacipran was eliminated more slowly than was F2696, with higher maximum concentration (Cmax) and area under the curve (AUC) values. The elimination half-life was ∼9 hours for levomilnacipran and 6 hours for F2696. The AUC0-∞ of levomilnacipran was ∼85% greater than that of F2696. Plasma clearance was ∼2 times greater for F2696 than for levomilnacipran. The pharmacokinetic results are consistent with those of a milnacipran human mass balance study, in which the elimination rate for F2696 was higher than for levomilnacipran.9 Given the favorable characteristics of this enantiomer, levomilnacipran was selected for development as an antidepressant. Levomilnacipran ER is approved for the treatment of MDD in adults. Efficacy and safety have been evaluated in 4 additional randomized, double-blind, placebo-controlled studies. In 1 flexible-dose (75-100 mg/d of levomilnacipran ER) study12 and 2 fixed-dose (40, 80, and 120 mg/d of levomilnacipran ER13 and 40 and 80 mg/d of levomilnacipran ER14) studies, differences in scores on the primary efficacy parameter were statistically significant in favor of levomilnacipran ER over placebo. In a second flexible-dose study, 40 to 120 mg/d of levomilnacipran improved depressive symptoms but did not achieve statistically significant separation from placebo.15 Levomilnacipran ER was generally well tolerated in all 4 studies. The objective of this study (NCT01034462) was to evaluate the efficacy, the safety, and the tolerability of 40 to 120 mg/d of flexibly dosed levomilnacipran ER versus placebo in the treatment of patients with MDD.