Clinical Predictors of Extrapyramidal Symptoms Associated With Aripiprazole Augmentation for the Treatment of Late-Life Depression in a Randomized Controlled Trial

J Clin Psychiatry. 2018 Jun 19;79(4):17m11764. doi: 10.4088/JCP.17m11764.


Objective: Augmentation with aripiprazole is an effective pharmacotherapy for treatment-resistant late-life depression (LLD). However, aripiprazole can cause extrapyramidal symptoms (EPS) such as akathisia and parkinsonism; these symptoms are distressing and can contribute to treatment discontinuation. We investigated the clinical trajectories and predictors of akathisia and parkinsonism in older patients receiving aripiprazole augmentation for treatment-resistant LLD.

Methods: Between 2009 and 2013, depressed older adults who did not remit with venlafaxine were randomized to aripiprazole or placebo in a 12-week trial. Participants were 60 years or older and met DSM-IV-TR criteria for major depressive episode with at least moderate symptoms. The presence of akathisia and parkinsonism was measured at each visit using the Barnes Akathisia Scale (BAS) and Simpson-Angus Scale (SAS), respectively. In an exploratory analysis, we examined a broad set of potential clinical predictors and correlates: age, sex, ethnicity, weight, medical comorbidity, baseline anxiety severity, depression severity, concomitant medications including rescue medications, and aripiprazole dosage.

Results: Twenty-four (26.7%) of 90 participants randomized to aripiprazole and who had akathisia scores available developed akathisia compared to 11 (12.2%) of 90 randomized to placebo. Greater depression severity was the main predictor of treatment-emergent akathisia. Most participants who developed akathisia improved over time, especially with reductions in dosage. Fifteen (16.5%) of 91 participants taking aripiprazole and who had parkinsonism scores available developed parkinsonism, but no clinical predictors or correlates were identified.

Conclusions: Akathisia is a common side effect of aripiprazole, but it is typically mild and responds to dose reduction. Patients with greater baseline depression may warrant closer monitoring for akathisia. More research is needed to understand the course and predictors of treatment-emergent EPS with antipsychotic augmentation for treatment-resistant LLD.

Trial registration: identifier: NCT00892047.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Akathisia, Drug-Induced / complications
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / therapeutic use
  • Aripiprazole / adverse effects*
  • Aripiprazole / therapeutic use
  • Depressive Disorder, Treatment-Resistant / complications
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Female
  • Humans
  • Late Onset Disorders / complications
  • Late Onset Disorders / drug therapy*
  • Male
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / complications
  • Risk Factors
  • Time Factors


  • Antidepressive Agents
  • Aripiprazole

Associated data