Concomitant use of prescribed psychotropic medications was similar in the two groups at baseline and over 26 weeks. Changes from baseline in the three primary outcome measures did not differ significantly between the groups at 10 weeks Table 2 or at 26 weeks Figure 1. Linear mixed models were used to analyze the change in scores from baseline to 10 weeks, with adjustment for the two stratification variables antidepressant use [yes vs.
No significant differences between the prazosin group and the placebo group were found for the change from baseline in secondary outcomes at 10 weeks Table 2 or at 26 weeks Fig. S2 and Table S2 in the Supplementary Appendix. See Table 3 for details. There was one death in each group; both deaths involved a combination of an accident and a medical event and were considered by the data and safety monitoring committee to be unrelated to trial participation.
Details about adverse events are provided in Table S4 in the Supplementary Appendix. There were two instances of suicidal ideation in the placebo group that led to hospitalization and none in the prazosin group. This week trial involving military veterans with chronic PTSD failed to show a benefit of prazosin over placebo in reducing the frequency and intensity of trauma-related nightmares. These results contrast with previous smaller randomized trials of prazosin involving a total of active-duty service members, veterans, and civilian participants, which showed efficacy of prazosin with respect to PTSD-related nightmares, sleep disturbance, and overall clinical function.
A possible explanation for these negative results is selection bias resulting from recruitment of patients who were mainly in clinically stable condition, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment. Concern about the increasing incidence of suicide and of violent behavior among veterans led the planning committee to make psychosocial instability an exclusion criterion for participation in the trial.
None of the previous smaller randomized trials of prazosin for PTSD had such an exclusion criterion. Similarly, the concern that the condition of potential participants would deteriorate clinically during 6 months of receiving placebo could have motivated providers to use available open-label prazosin rather than refer patients for trial participation.
It is also possible that the high threshold for frequency and intensity of nightmares in the inclusion criteria selected for patients who would be less likely to have a response. The clinical characteristics of patients recruited in this trial suggest that participants had clinically stable PTSD. For example, the lower-than-expected baseline mean blood-pressure levels in this cohort of veterans among whom the average age was approximately 50 years and who reported high levels of PTSD symptoms suggest low baseline adrenergic activity, which makes unstable PTSD unlikely.
Furthermore, VA clinicians frequently prescribe benzodiazepines for PTSD in patients with distressing anxiety and agitation. The high retention of participants may also suggest that even though the levels of reported PTSD symptoms were high, they were not unacceptable to most participants. The low use of the option to add additional treatments after week 10 may also have been consistent with the chronicity of PTSD.
A further limitation of this trial was that participants were not screened for sleep apnea or sleep-disordered breathing except by means of history taking and chart review. There is a high prevalence of previously undiagnosed sleep apnea among veterans with PTSD.
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Another limitation is that the screening measure for nightmares was derived from the CAPS, which was also an outcome measure. The current trial is not the first instance in which a multicenter, randomized trial involving male military veterans with psychiatric disorders has failed to show efficacy for a treatment that had been effective in initial studies and that was available within the VA health care system.
Other examples include a negative randomized trial of sertraline for PTSD, 29 despite Food and Drug Administration FDA approval of the drug for PTSD and recommendations in VA practice guidelines that it be used as first-line pharmacotherapy for PTSD 30 ; a negative trial of trauma-focused psychotherapy for PTSD, 31 despite its promotion within the VA system as first-line evidence-based psychotherapy; a negative trial of naltrexone for alcoholism, despite FDA approval of the drug for this purpose 32 ; a negative trial of risperidone for PTSD 33 ; and a negative trial of depot risperidone vs.
As with prazosin, each treatment studied in these multicenter, randomized trials was already available throughout the VA health care system. Given the concern about suicide among veterans, it is noteworthy that the specifically solicited adverse event of new or worsening suicidal ideation was less common in the prazosin group than in the placebo group, but the absolute number of events was small; this issue warrants further study. Disclosure forms provided by the authors are available with the full text of this article at NEJM.
Mellman reports receiving grant support, lecture fees, and consulting fees from Merck and consulting fees from Tonix Pharmaceuticals and Jazz Pharmaceuticals; Dr. Swift, receiving grant support from Laboratorio Farmaceutico CT and honoraria and travel support from Lundbeck; and Dr. Lu, receiving fees for serving on a safety monitoring committee for PaxVax, advisory fees from PTC Therapeutics, and lecture fees from Boehringer Ingelheim.
No other potential conflict of interest relevant to this article was reported. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or any U. Address reprint requests to Dr. Crystal Harris is deceased. Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry ; - Sleep disturbance as the hallmark of posttraumatic stress disorder. CSF norepinephrine concentrations in posttraumatic stress disorder.
Abnormal noradrenergic function in posttraumatic stress disorder. Arch Gen Psychiatry ; - Association of posttraumatic stress disorder with reduced in vivo norepinephrine transporter availability in the locus coeruleus. JAMA Psychiatry ; - Biol Psychiatry ; - A role for norepinephrine in stress-induced cognitive deficits: alphaadrenoceptor mediation in the prefrontal cortex.
Little Nightmares #1
Effects of methoxamine, an alpha-1 adrenoceptor agonist, and prazosin, an alpha-1 antagonist, on the stages of the sleep-waking cycle in the cat. Acta Physiol Scand ; - Adrenergic agonists and antagonists. In: Brunton LL, ed. New York : McGraw-Hill , : - Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder.
Prazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study.
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Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US military veterans. J Psychosom Res ; 89 - A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan.
Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder. Neuropsychobiology ; - J Trauma Stress ;8: 75 - Pocock SJ , Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.
Following an historical and theoretical overview and introduction, reports on the direct psychological treatments of nightmares are reviewed. The majority of the reviewed reports are case studies, although there are several controlled and group studies. Advantages and limitations of the different methods, as well as the ways the therapies impact on the anxiety, uncontrollability, perceived importance, or realism of the nightmares, are discussed. The article concludes with suggestions far both the clearer reporting of case studies are for further research.
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