Effects of levomilnacipran ER on noradrenergic symptoms, anxiety symptoms, and functional impairment in adults with major depressive disorder: Post hoc analysis of 5 clinical trials

Objective: To evaluate the effects of levomilnacipran extended-release (LVM-ER; 40-120 mg/day) on noradrenergic (NA) and anxiety-related symptoms in adults with major depressive disorder (MDD) and explore the relationship between these symptoms and functional impairment. Methods: Data were pooled from 5 randomized, double-blind, placebo-controlled trials (N=2598). Anxiety and NA Cluster scores were developed by adding selected item scores from the Montgomery-Asberg Depression Rating Scale (MADRS) and 17-item Hamilton Depression Rating Scale (HAMD17). A path analysis was conducted to estimate the direct effects of LVM-ER on functional impairment (Sheehan Disability Scale [SDS] total score) and the indirect effects through changes in NA and Anxiety Cluster scores. Results: Mean improvements from baseline in NA and Anxiety Cluster scores were significantly greater with LVM-ER versus placebo (both P < 0.001), as were the response rates (>= 50% score improvement): NA Cluster (44% vs 34%; odds ratio=1.56; P < 0.0001); Anxiety Cluster (39% vs 36%; odds ratio=1.19; P=0.041). Mean improvement in SDS total score was also significantly greater with LVM-ER versus placebo (-7.3 vs 5.6; P < 0.0001). LVM-ER had an indirect effect on change in SDS total score that was mediated more strongly through NA Cluster score change (86%) than Anxiety Cluster score change (18%); the direct effect was negligible. Limitations: NA and Anxiety Cluster scores, developed based on the face validity of individual MADRS and HAMD17 items, were not predefined as efficacy outcomes in any of the studies. Conclusion: In adults with MDD, LVM-ER indirectly improved functional impairment mainly through improvements in NA symptoms and less so via anxiety symptoms.