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JAMA. 2011 Aug 3;306(5):493-502. doi: 10.1001/jama.2011.1080.

Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.

Collaborators (148)

Canive J, Calais L, Smith A, Nye E, Duncan E, Skelton K, Bradley R, Tabb K, Sergent T, Daugherty M, Russ E, Denny N, Arnemann K, Lauren-Rusnack J, Schillac J, Batten S, Dixon L, Santanello A, Bell L, Duncan J, Carney S, Kavanagh G, Parker P, McCall K, Rathmell S, Kaloupek D, Aguayo G, Ryngala D, Collins A, Hamner M, Agbor-Tabi D, Timmerman M, Brown M, Robert S, Coleman S, Fore P, Tepper T, Yount J, Konicki E, Nero V, Smith E, Huhra-Grassel R, Suris A, North C, Whitman J, Wiley E, Hertzberg M, Biddix R, Becker M, Grieder T, Feigel C, Vo T, Wolf P, Garza R, Murphy C, Melton B, Ahearn E, Johnson C, Mussey M, Smith T, David D, Junco-Valladares J, Slone P, Giron A, Westermeyer J, Spring M, Ferrier A, Eakin M, Wolkin A, Woo C, Kramer M, Erhman R, Marquez K, Fornish A, Khan A, Zakai A, Frank H, Kikuchi J, Stock C, Carpenter L, Plumb S, Allen S, Olsen C, Greenwell M, Casada J, Polanco J, Benson T, Baker D, Shah P, Gorman P, Perin T, Kelada A, Cooley J, Pittman J, Madra N, Schoenfeld F, Schmitz M, Coeshott R, Tong H, Davis L, Garner C, Newell J, Hicks P, Justice S, Lippe B, Saunders C, Goldstein D, Ereshefsky S, Melnick A, Urbaitis M, Affleck S, Beam M, Spence E, Briones D, Dixon S, Howell C, Lu X, Conner D, Haakenson C, Grieger T, Blake D, Dickerson K, Thase M, Harvey P, Jones K, Vertrees J, Stein M, Stock C, Hertzberg M, Duncan E, Gelernter J, Ciraulo D, Kaloupek D, Stein M, Bartzokis G, Rasmusson A, Davidson J, Marmar C, Lavori P, Berkowitz S, O'Leary T, Schuster B, Jones K, Collins J, Howell C, Vertrees J, Bradham D, Friedman M.

Author information

Clinical Neuroscience Division, Department of Veterans Affairs National Center for PTSD, VA Connecticut Healthcare System, West Haven, USA.



Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).


To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD.


A 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.


Risperidone (up to 4 mg once daily) or placebo.


The 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).


Change 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.


Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms.

TRIAL REGISTRATION: Identifier: NCT00099983.

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