Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation

Mark Hyman Rapaport, Georges M. Gharabawi, Carla M. Canuso, Ramy A. Mahmoud, Martin B. Keller, Cynthia A. Bossie, Ibrahim Turkoz, Robert A. Lasser, Amy Loescher, Philippe Bouhours, Fiona Dunbar, Charles B. Nemeroff

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


Approximately one-third of persons with depression do not respond to antidepressant monotherapy. Studies suggest that atypical antipsychotic augmentation may benefit these patients. We investigated the longer-term efficacy of risperidone augmentation of serotonin-selective reuptake inhibitor treatment for resistant depression. In 57 in- and outpatient centers in three countries, we conducted a three-phase study with 4-6 weeks of open-label citalopram monotherapy, 4-6 weeks of open-label risperidone augmentation, and a 24-week double-blind, placebo-controlled discontinuation phase. A total of 489 patients with major depressive disorder and 1-3 documented treatment failures entered the citalopram monotherapy phase (20-60 mg/day). Patients with <50% reduction in HAM-D-17 scores entered the risperidone augmentation phase (0.25-2.0 mg/day). Patients with HAM-D-17≤7 or CGI-S≤2 were randomized to risperidone or placebo augmentation. The primary outcome was time to relapse during the double-blind phase. During citalopram monotherapy, 434 patients had <50% HAM-D-17 reduction; 299 (68.9%) were fully nonresponsive (<25% reduction) and 135 were partially nonresponsive (25-49% reduction). Of the 386 nonresponders who entered the augmentation phase, 243 remitted and 241 entered the double-blind phase. Median time to relapse was 102 days with risperidone augmentation and 85 days with placebo (NS); relapse rates were 53.3 and 54.6%, respectively. In a post hoc analysis of patients fully nonresponsive to citalopram monotherapy, median time to relapse was 97 days with risperidone augmentation and 56 with placebo (p=0.05); relapse rates were 56.1 and 64.1%, respectively (p≤0.05). Open-label risperidone augmentation substantially enhanced response in treatment-resistant patients, but the longer-term benefits of augmentation were not demonstrated in this study.

Original languageEnglish (US)
Pages (from-to)2505-2513
Number of pages9
Issue number11
StatePublished - Nov 7 2006
Externally publishedYes


  • Citalopram
  • Resistant depression
  • Risperidone augmentation

ASJC Scopus subject areas

  • Pharmacology


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