title: Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047.
  
  
  RESULTS
  From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables.
  
  
  CONCLUSIONS
  In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.
  
  
  BACKGROUND
  National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA. Electronic address: lenzee@psychiatry.wustl.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lenze
authors.affiliation: Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Blumberger
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jordan F
authors.initials: JF
authors.lastname: Karp
authors.affiliation: Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Newcomer
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Anderson
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Mary Amanda
authors.initials: MA
authors.lastname: Dew
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Meryl A
authors.initials: MA
authors.lastname: Butters
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Stack
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Begley
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Reynolds
mesh_terms: D000368:Aged; D017109:Akathisia, Drug-Induced / Q000209:etiology; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000068180:Aripiprazole / Q000008:administration & dosage* / Q000009:adverse effects; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D000068180:Aripiprazole