• John H Krystal, Robert A Rosenheck, Joyce A Cramer, Jennifer C Vessicchio, Karen M Jones, Julia E Vertrees, Rebecca A Horney, Grant D Huang, Christopher Stock, and Veterans Affairs Cooperative Study No. 504 Group.
• Clinical Neuroscience Division, Department of Veterans Affairs National Center for PTSD, VA Connecticut Healthcare System, West Haven, USA. john.krystal@yale.edu
• JAMA. 2011 Aug 3; 306 (5): 493-502.

ContextSerotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).ObjectiveTo determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD.Design, Setting, And ParticipantsA 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure.InterventionRisperidone (up to 4 mg once daily) or placebo.Main Outcome MeasuresThe Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V).ResultsChange in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively.ConclusionAmong patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms.Trial Registrationclinicaltrials.gov Identifier: NCT00099983.

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