Augmentation with Atypical Antipsychotics for Treatment-Resistant Depression

Filippo Cantù, Valentina Ciappolino, Paolo Enrico, Chiara Moltrasio, Giuseppe Delvecchio, Paolo Brambilla

Research output: Contribution to journalReview articlepeer-review


Background: Treatment-resistant depression (TRD) is considered a common clinical condition often associated with relevant suicidal ideation and characterized by a severe functional impairment lifetime. Among the available drugs for the TRD treatment, second-generation antipsychotics (SGAs) have been reported as effective. In this context, the aim of this study was to review the clinical studies evaluating the efficacy of SGAs as add-on therapy in TRD. Methods: A comprehensive search on PubMed, Medline and PsychINFO of all randomized clinical trials (RCTs) assessing the augmentation with antipsychotics in TRD, published from January 2000 until March 2020, was performed. Sixteen RCTs studies met the inclusion criteria. Results: The reviewed studies showed that the add-on therapy with aripiprazole could be beneficial in the treatment of TRD. Furthermore, RCTs on quetiapine augmentation support its use in TRD, especially when comorbid anxiety or insomnia are present. The effects of risperidone and olanzapine as add-on in TRD were less studied, but preliminary data indicated an efficacy respect to placebo, making them a possible therapeutic option in TRD. Limitations: The lack of consistency in the definition of TRD together with the small sample sizes and the heterogeneity of antipsychotics dosages used in the reviewed RCTs may have limited the strength of evidences obtained. Conclusion: Overall, the available RCTs studies seem to support the hypothesis that the augmentation with SGAs, in particular aripiprazole and quetiapine, is a valid therapeutic option for TRD. However, to improve the therapeutic outcome of patients with TRD, larger and more homogeneous RCTs are needed.

Original languageEnglish
Pages (from-to)45-53
Number of pages9
JournalJournal of Affective Disorders
Publication statusPublished - Feb 1 2021


  • Atypical antipsychotic
  • major depressive disorder
  • treatment resistant depression (TRD)

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health


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