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There are currently no validated pharmacotherapies for posttraumatic stress disorder (PTSD)-related insomnia. The purpose of the National Adaptive Trial for PTSD-Related Insomnia (NAP Study) is to efficiently compare to placebo the effects of three insomnia medications with different mechanisms of action that are already prescribed widely to veterans diagnosed with PTSD within U.S. Department of Veterans Affairs (VA) Medical Centers. This study plans to enroll 1224 patients from 34 VA Medical Centers into a 12- week prospective, randomized placebo-controlled clinical trial comparing trazodone, eszopiclone, and gabapentin. The primary outcome measure is insomnia, assessed with the Insomnia Severity Index. A novel aspect of this study is its adaptive design. At the recruitment midpoint, an interim analysis will be conducted to inform a decision to close recruitment to any "futile" arms (i.e. arms where further recruitment is very unlikely to yield a significant result) while maintaining the overall study recruitment target. This step could result in the enrichment of the remaining study arms, enhancing statistical power for the remaining comparisons to placebo. This study will also explore clinical, actigraphic, and biochemical predictors of treatment response that may guide future biomarker development. Lastly, due to the COVID-19 pandemic, this study will allow the consenting process and follow-up visits to be conducted via video or phone contact if in-person meetings are not possible. Overall, this study aims to identify at least one effective pharmacotherapy for PTSD-related insomnia, and, perhaps, to generate definitive negative data to reduce the use of ineffective insomnia medications. NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT03668041., (Published by Elsevier Inc.)

Background: Posttraumatic stress disorder (PTSD) is a chronic and often difficult-to-treat condition that is prevalent among military veterans. First-line pharmacotherapy for this population typically involves antidepressants; however, veterans who do not improve are sometimes prescribed antipsychotics such as risperidone. A 2011 randomized controlled trial of adjunctive risperidone versus placebo for veterans with chronic, antidepressant-resistant, military service-related PTSD revealed no difference between groups. Hence, there is a need to examine predictors of nonimprovement for chronic, treatment-resistant PTSD., Methods: We examined correlates of nonimprovement and delayed improvement (ie, ≥12 weeks) using data from 267 veterans with chronic, antidepressant-resistant PTSD who were prescribed adjunctive risperidone or a placebo. Veterans received 1 to 4 mg adjunctive risperidone (n = 133; mean dose, 2.74 mg) or a placebo daily (n = 134) in addition to their original treatment regimen over the 24-week trial., Results: Greater severity of PTSD symptoms at baseline, specifically reexperiencing (ie, nightmares) and emotional numbing (ie, sense of foreshortened future), was independently associated with nonimprovement. Of the 194 veterans (72.7%) who did improve, 95 (49.0%) showed delayed improvement, taking 12 weeks or longer to demonstrate a 10-point reduction in Clinician-Administered PTSD Scale scores. Emotional difficulties affecting role functioning, as assessed using the Veterans RAND 36-item Health Survey, independently predicted nonimprovement., Conclusions: While results are indicative of nonspecific pharmacotherapeutic effects, they suggest that specific PTSD symptom clusters and impairment are associated with variable improvement in veterans with antidepressant-resistant PTSD. They underscore the importance of developing more effective and targeted pharmacotherapies for specific symptom clusters in this population.

Objective: Sleep disturbances are common among veterans with chronic military-related posttraumatic stress disorder (PTSD). This article reports the results of a multicenter clinical trial that explored the clinical correlates of reported sleep impairment in these veterans and tested the impact of the second-generation antipsychotic risperidone upon these symptoms., Method: This article reports secondary analyses of a 24-week multicenter randomized placebo-controlled trial of adjunctive risperidone in patients with chronic military-related PTSD symptoms (n = 267, 97% male) who were symptomatic despite treatment with antidepressants and other medications. The study was conducted between February 2007 and February 2010. DSM-IV PTSD diagnoses were made by using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Nonpatient Edition. Sleep disturbances were assessed principally by using the Pittsburgh Sleep Quality Index (PSQI) (primary outcome measure). Analyses were conducted using bivariate correlations and longitudinal mixed model regressions., Results: Eighty-eight percent of the patients in this study had clinically significantly impaired sleep on the PSQI. Severity of sleep disturbances correlated with PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS) and reductions in multiple measures of quality of life (Veterans RAND 36-item Health Survey [SF-36 V] subscales, Boston Life Satisfaction Index). Risperidone produced small but statistically significant effects on total PSQI scores (main effect of drug: F1,228 = 4.57, P = .034; drug-by-time interaction: F2,421 = 4.32, P = .014) and severity of nightmares as assessed by the CAPS (main effect of drug: F1,248 = 4.60, P = .033). The improvements in sleep quality produced by risperidone correlated with reductions in PTSD symptom severity and improvement in the mental health subscale of the SF-36 V., Conclusions: This study highlighted the near universality and significant negative impact of severe disturbances in sleep quality in veterans with chronic military-related PTSD who were partial responders to standard pharmacotherapies. The modest improvements in sleep quality produced by adjunctive risperidone were correlated with limited reductions in PTSD severity and improvements in quality of life., Trial Registration: ClinicalTrials.gov identifier: NCT00099983., (© Copyright 2016 Physicians Postgraduate Press, Inc.)