Major Depressive Disorder
Levomilnacipran hydrochloride is used for the treatment of major depressive disorder in adults. The short-term antidepressant efficacy of levomilnacipran was mainly established in 3 multicenter, randomized, double-blind, placebo-controlled studies of 8 weeks' duration in 1709 adult outpatients who met DSM-IV-TR criteria for major depressive disorder. Two of the studies compared multiple fixed doses of levomilnacipran and the third was flexible dose in design. In all 3 of these studies, levomilnacipran (40-120 mg once daily given as extended-release capsules) was found to be more effective than placebo in improving depressive symptoms as measured by the mean change from baseline to week 8 on the Montgomery-Asberg Depression Rating Scale (MADRS) total score (the primary efficacy end point). Levomilnacipran was also found to be more effective than placebo in improving the Sheehan Disability Scale (SDS) functional impairment total score (the secondary efficacy end point) in these studies. In the flexible-dose study, 21, 34, and 44% of the levomilnacipran-treated patients were receiving 40, 80, or 120 mg once daily of the drug, respectively, at the end of the treatment; the mean daily dosage was approximately 73 mg. No age-, race-, or gender-related differences in efficacy were noted in these studies.
In a long-term (24-week), double-blind relapse prevention study comparing fixed-dose extended-release levomilnacipran (40, 80, or 120 mg daily) with placebo in 345 adults with major depressive disorder, the relapse rate for levomilnacipran (14%) was lower than that for placebo (21%), but the difference did not achieve statistical significance (possibly because of lower than predicted relapse rates). In a longer-term (48-week), multicenter, open-label, flexible-dose study, extended-release levomilnacipran (40-120 mg daily) was found to be generally well tolerated in adults with major depressive disorder. Most of the adverse effects were mild or moderate in severity and similar to those reported in the short-term studies; in addition, levomilnacipran did not appear to be associated with weight gain during long-term use.
The manufacturer states that the efficacy of levomilnacipran for long-term use (i.e., exceeding 8 weeks) has not been established. If the drug is used for extended periods, the need for continued therapy and the appropriate dosage should be reassessed periodically.
The American Psychiatric Association (APA) states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of these medications, including selective serotonin-reuptake inhibitors (SSRIs), serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and other antidepressants (e.g., bupropion, mirtazapine, trazodone). Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost. For most patients, an SSRI, SNRI, mirtazapine, or bupropion is considered optimal based on these considerations. Clinicians may consult APA's Practice Guidelines for the Treatment of Patients with Major Depressive Disorder (at http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx) for additional information.
Levomilnacipran is the more active 1S,2R-enantiomer of racemic milnacipran (Savella), which is labeled by the US Food and Drug Administration (FDA) for the management of fibromyalgia.
(See Description.)However, the manufacturer states that levomilnacipran (Fetzima) is not approved for the management of fibromyalgia, and that the efficacy and safety of the drug for the management of this condition have not been established.