Effects of Discontinuation of Drugs Used for Augmentation Therapy on Treatment Outcomes in Depression: A Systematic Review and Meta-analysis

Pharmacopsychiatry. 2021 May;54(3):106-116. doi: 10.1055/a-1330-8587. Epub 2020 Dec 23.


Introduction: There has been no consensus on whether and how long add-on drugs for augmentation therapy should be continued in the treatment of depression.

Methods: Double-blind randomized controlled trials that examined the effects of discontinuation of drugs used for augmentation on treatment outcomes in patients with depression were identified. Meta-analyses were performed to compare rates of study withdrawal due to any reason, study-defined relapse, and adverse events between patients who continued augmentation therapy and those who discontinued it.

Results: Seven studies were included (n=841 for continuing augmentation therapy; n=831 for discontinuing augmentation therapy). The rate of study withdrawal due to any reason was not significantly different between the 2 groups (risk ratio [RR]=0.86, 95% confidence interval [CI]=0.69-1.08, p=0.20). Study withdrawal due to relapse was less frequent in the continuation group than in the discontinuation group (RR=0.61, 95% CI=0.40-0.92, p=0.02); however, this statistical significance disappeared when one study using esketamine as augmentation was excluded. Analysis of the data from 5 studies that included a stabilization period before randomization found less frequent relapse in the continuation group than in the discontinuation group (RR=0.47, 95% CI=0.36-0.60, p<0.01). This finding was repeated when the esketamine study was excluded.

Discussion: No firm conclusions could be drawn in light of the small number of studies included. Currently available evidence suggests that add-on drugs, other than esketamine, used for augmentation therapy for depression may be discontinued. This may not be the case for patients who are maintained with augmentation therapy after remission.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Depression*
  • Double-Blind Method
  • Humans
  • Pharmaceutical Preparations*
  • Randomized Controlled Trials as Topic
  • Recurrence
  • Treatment Outcome


  • Pharmaceutical Preparations