title: Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies.
abstract: The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported.
  
  
  
  Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores ≥24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores ≥18 and <50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAEs).
  
  
  
  Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-2.3, 1.3], P=0.583). The only TEAE reported by >5% of LDX participants at twice the placebo rate in both studies was dry mouth.
  
  
  
  Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response.
  
  
  
  Contrary to expectations, LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy.
authors.affiliation: Formerly of Shire, Lexington, MA, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Richards
authors.affiliation: University of Toronto, Toronto, ON, Canada.
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
authors.affiliation: Duke University Medical Center, Durham, and the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Weisler
authors.affiliation: Atlanta Institute of Medicine & Research, Atlanta, GA, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sambunaris
authors.affiliation: Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Brawman-Mintzer
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gao
authors.affiliation: Formerly of Shire, Lexington, MA, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Geibel
authors.affiliation: Formerly of Shire, Lexington, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dauphin
authors.affiliation: Shire, Lexington, MA, USA. Electronic address: mmadhoo@shire.com.
authors.forename: Manisha
authors.initials: M
authors.lastname: Madhoo
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068736:Duloxetine Hydrochloride / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D000069478:Lisdexamfetamine Dimesylate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020280:Sertraline / Q000627:therapeutic use; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D018765:Dopamine Uptake Inhibitors; D015283:Citalopram; D000069470:Venlafaxine Hydrochloride; D000068736:Duloxetine Hydrochloride; D020280:Sertraline; D000069478:Lisdexamfetamine Dimesylate
keywords: Amphetamine; Augmentation; Lisdexamfetamine dimesylate; Major depressive disorder; Selective serotonin reuptake inhibitors; Serotonin-norepinephrine reuptake inhibitors