Adjunctive Risperidone Treatment for Antidepressant-Resistant Symptoms of Chronic Military Service-Related PTSD A Randomized Trial

Clinical Neuroscience Division, Department of Veterans Affairs National Center for PTSD, VA Connecticut Healthcare System, West Haven, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 08/2011; 306(5):493-502. DOI: 10.1001/jama.2011.1080
Source: PubMed


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. Identifier: NCT00099983.

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    • "In contrast to extensive clinical trials conducted among civilians and veterans with chronic PTSD, little research has been conducted on the treatment of PTSD in active duty military personnel from any combat era. Recent double-blind, placebo-controlled randomized clinical trials (RCTs) of PTSD in military veterans have not found benefits of active medications over placebo, and have suggested that medications may be of limited benefit for combat-related PTSD (Friedman , Marmar, Baker, Sikes, & Farfel, 2007; Krystal et al., 2011). There has been limited PTSD psychotherapy research conducted with active military samples. "

    Cognitive and Behavioral Practice 09/2015; DOI:10.1016/j.cbpra.2015.08.007 · 1.33 Impact Factor
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    • "Adjunctive use of several second-generation antipsychotic medications (olanzapine, risperidone, quetiapine , aripiprazole) has shown efficacy in the treatment of PTSD in a number of small studies (Stein et al., 2002; Hamner et al., 2003; Monnelly et al., 2003; Reich et al., 2004; Bartzokis et al., 2005; Ahearn et al., 2006; Rothbaum et al., 2008; Robert et al., 2009). However, a randomized controlled trial of adjunctive risperidone for PTSD was largely (but not entirely) negative (Krystal et al., 2011). "
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    ABSTRACT: Many individuals with post-traumatic stress disorder (PTSD) experience persistent symptoms despite pharmacological treatment with antidepressants. Several open-label monotherapy and adjunctive studies have suggested that aripiprazole (a second-generation antipsychotic) may have clinical utility in PTSD. However, there have been no randomized placebo-controlled trials of aripiprazole use for PTSD. We thus conducted a pilot randomized controlled trial of adjunctive aripiprazole versus placebo among Veterans with chronic PTSD serving in the US military since 11 September 2001 to assess the feasibility, safety, tolerability, and therapeutic potential of aripiprazole. Sixteen Veterans were randomized, and 14 completed at least 4 weeks of the study; 12 completed the entire 8-week trial. Outcome measures included the Clinician-Administered PTSD Scale (CAPS), PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores. Aripiprazole was well-tolerated in this cohort, and improvements in CAPS, PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores were as hypothesized. Although CAPS change scores did not reach statistical significance, aripiprazole outperformed placebo by 9 points on the CAPS in the last observation carried forward analysis compared with the placebo group (n=7 per group), and by 20 points in the group randomized to aripiprazole that completed the entire study (n=5) compared with the placebo group (n=7). Results suggest promise for aripiprazole as an adjunctive strategy for the treatment of PTSD.
    International Clinical Psychopharmacology 02/2015; 30(3). DOI:10.1097/YIC.0000000000000061 · 2.46 Impact Factor
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    • "As a counterpoint, drug therapies for PTSD did not face similar obstacles, nor did financial considerations produce an equivalent translational gap. The drug risperidone was initially advocated as a treatment for PTSD until a 2011 controlled trial found it no more effective than placebo treatment (Krystal et al., 2011 "
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    ABSTRACT: Clear and transparent standards are required to establish whether a therapeutic method is "evidence based." Even when research demonstrates a method to be efficacious, it may not become available to patients who could benefit from it, a phenomenon known as the "translational gap." Only 30% of therapies cross the gap, and the lag between empirical validation and clinical implementation averages 17 years. To address these problems, Division 12 of the American Psychological Association published a set of standards for "empirically supported treatments" in the mid-1990s that allows the assessment of clinical modalities. This article reviews these criteria, identifies their strengths, and discusses their impact on the translational gap, using the development of a clinical innovation called Emotional Freedom Techniques (EFT) as a case study. Twelve specific recommendations for updates of the Division 12 criteria are made based on lessons garnered from the adoption of EFT within the clinical community. These recommendations would shorten the cycle from the research setting to clinical practice, increase transparency, incorporate recent scientific advances, and enhance the capacity for succinct comparisons among treatments.
    Journal of Nervous & Mental Disease 10/2014; 202(10):699-709. DOI:10.1097/NMD.0000000000000188 · 1.69 Impact Factor
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