title: Efficacy of dose increase among nonresponders to low-dose aripiprazole augmentation in patients with inadequate response to antidepressant treatment: a randomized, double-blind, placebo-controlled, efficacy trial.
abstract: OBJECTIVE
  To examine the efficacy of a dose increase of aripiprazole to 5 mg/d in subjects with major depressive disorder (MDD) who did not respond to 4 weeks of treatment with aripiprazole 2 mg/d in a randomized, double-blind, placebo-controlled, parent study.
  
  
  METHODS
  221 Subjects with Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition-diagnosed DSM-IV-TR MDD (mean ± SD age, 45 ± 11 years; 64% women) with inadequate antidepressant response were recruited from September 2008-July 2009 and randomized to 60 days of double-blind augmentation with either aripiprazole or placebo in two 30-day phases. The study was performed across 8 academic hospital sites and 14 nonacademic (private clinic) sites throughout the United States. Randomization in a 2:3:3 ratio per sequential parallel comparison design was drug/drug (aripiprazole 2 mg/d in phase 1 and 5 mg/d in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1 and aripiprazole 2 mg/d in phase 2). In phase 2, we examined efficacy of an aripiprazole dose increase to 5 mg/d in nonresponders to 2 mg/d by assessing response rates (≥ 50% reduction in Montgomery-Asberg Depression Rating Scale [MADRS] score [primary outcome measure]) and score changes in MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, 9-item Patient Health Questionnaire (PHQ-9), the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, and patient-rated versions of the CGI-I and CGI-S scales.
  
  
  RESULTS
  Response rate for aripiprazole 2 mg/d in phase 1 was 18.5% (n/n = 10/54). Among 39 nonresponders who increased their dose to 5 mg/d, response rate was 12.8% (95% CI, 4.30%-27.43%), with significant overall mean ± SD reductions in MADRS scores (-9.46 ± 7.83 [95% CI, -12.00 to -6.92]; P < .0001), Symptoms Questionnaire Distress scores (19.51 ± 17.73 [95% CI, 13.60 to 25.43]; P < .0001), PHQ-9 scores (-7.92 ± 5.92 [95% CI, -9.89 to -5.94]; P < .0001), and CGI-S scores (-0.86 ± 0.86 [95% CI, -1.15 to -0.58]; P < .0001). Differences in efficacy between drug and placebo groups were nonsignificant, however. Aripiprazole and placebo were well tolerated.
  
  
  CONCLUSIONS
  Augmentation with aripiprazole 5 mg/d may provide only a modest additional benefit in patients who do not benefit from lower doses.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00683852.
authors.affiliation: Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. dmischoulon@partners.org
authors.forename: David
authors.initials: D
authors.lastname: Mischoulon
authors.forename: Janet
authors.initials: J
authors.lastname: Witte
authors.forename: Michael
authors.initials: M
authors.lastname: Levy
authors.forename: George I
authors.initials: GI
authors.lastname: Papakostas
authors.forename: L Russell
authors.initials: LR
authors.lastname: Pet
authors.forename: Wen-hua
authors.initials: WH
authors.lastname: Hsieh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pencina
authors.forename: Sean
authors.initials: S
authors.lastname: Ward
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pollack
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D000068180:Aripiprazole; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D015363:Quinolones / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole