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

- Patients with major depressive disorder often experience functional impairment.
- Noradrenergic (NA) symptoms such as fatigue may contribute to functional deficits.
- In Phase 2/3 clinical trials, levomilnacipran ER improved functional impairment.
- This post hoc analysis shows that levomilnacipran ER also improved NA symptoms.
- The treatment effect on function was largely mediated though NA symptom improvement.

ObjectiveTo 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.MethodsData 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-Åsberg 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.ResultsMean 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.LimitationsNA 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.ConclusionIn adults with MDD, LVM-ER indirectly improved functional impairment mainly through improvements in NA symptoms and less so via anxiety symptoms.