title: 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.
abstract: To evaluate the effects of levomilnacipran extended-release (LVM-ER; 40-120mg/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.
  
  
  
  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-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.
  
  
  
  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.
  
  
  
  NA and Anxiety Cluster scores, developed based on the face validity of individual MADRS and HAMD17items, were not predefined as efficacy outcomes in any of the studies.
  
  
  
  In adults with MDD, LVM-ER indirectly improved functional impairment mainly through improvements in NA symptoms and less so via anxiety symptoms.
authors.affiliation: Department of Psychiatry, Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: pierre.blier@theroyal.ca.
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
authors.affiliation: Allergan Inc., Jersey City, NJ, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Gommoll
authors.affiliation: Allergan Inc., Jersey City, NJ, USA.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Allergan Inc., Jersey City, NJ, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kramer
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000523:psychology; D016000:Cluster Analysis; D003521:Cyclopropanes / Q000627:therapeutic use*; D003692:Delayed-Action Preparations / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D005221:Fatigue / Q000523:psychology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D016032:Randomized Controlled Trials as Topic; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D003521:Cyclopropanes; D003692:Delayed-Action Preparations; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Anxiety; ClinicalTrials.gov NCT00969709; Depression; EudraCT 2006-002404-34; Functional impairment; Levomilnacipran; NCT00969150; NCT01034462; NCT01377194; Noradrenaline