Prazosin was not effective at treating post-traumatic stress disorder (PTSD)-related sleep issues among military veterans, a new trial reported.
The alpha-1-adrenoreceptor antagonist failed to achieve any of the three primary endpoints of the trial, with no significant changes in PTSD symptoms after 10 weeks compared with placebo, according to Murray A. Raskind, MD, of the Veterans Affairs Puget Sound Health Care System in Seattle, and colleagues.
According to the study, published in the New England Journal of Medicine, there were no major improvements seen in mean change from baseline for recurrent distressing dreams measured by the Clinical-Administered PTSD Scale (CAPS) item B2, sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI), or the Clinical Global Impression of Change score (CGIC):
- CAPS: between-group difference 0.2 (95% CI, −0.3 to 0.8, P=0.38)
- PSQI: 0.1 (−0.9 to 1.1, P=0.80)
- CGIC: 0 (−0.3 to 0.3, P=0.96)
Similarly, the trial did not achieve secondary outcomes of improvement of these scores after 26 weeks of prazosin treatment.
“Trauma-related nightmares and sleep disturbance are common symptoms of PTSD. Enhanced central nervous system adrenergic activity and its persistence during sleep provide a rationale for the use of antiadrenergic medications to ameliorate these symptoms,” Raskind’s group explained, adding that of the α1-adrenergic antagonists available, prazosin “most readily enters the central nervous system.”
Recruited from 12 veterans affairs medical centers, 304 military veterans meeting the DSM-IV criteria for PTSD were included in the trial. All participants also had reported combat-related nightmares and a score of 50 or higher on the CAPS assessment. Those with low blood pressure or other medical illnesses were excluded.
Both groups were generally similar at baseline, with nearly all of the participants being male (96.1%; 99.3% placebo). Over a third of both groups reported having major depression at baseline (33.6%; 42.1%) and/or anxiety disorder besides PTSD (23.7%; 21.7%), and a majority of both groups were receiving a maintenance dose of an antidepressant at this time (78.3%; 77.0%).
Participants were randomized to receive either prazosin treatment (n=152) or placebo (n=152). Those receiving prazosin were administered an escalating dose for the initial 5 weeks of the trial, up to a maximum dose of 20 mg for men (5 mg mid-morning, 15 mg bedtime) or 12 mg for women (2 mg mid-morning, 10 mg bedtime).
Throughout the trial, use of psychotropic medications, including antidepressants, benzodiazepines, and non-opioid analgesics, was similar between the two groups.
After 10 weeks of treatment, those receiving prazosin reported a significant drop in both supine and standing blood pressures from baseline, which was not seen in the placebo group.
Light-headedness, dizziness, as well as urinary incontinence, were more commonly reported in the treatment group, although new or worsening suicidal thoughts were also less commonly reported among those on prazosin.
In an accompanying editorial, Kerry J. Ressler, MD, PhD, chief scientific officer and chief of the Division of Depression and Anxiety Disorders at McLean Hospital, a Harvard Medical School affiliate in Belmont, MA, called the findings both “surprising and disappointing.” He pointed out that the trial might have failed to replicate the findings of prior studies assessing prazosin possibly due to the exclusion of patients with social instability, those who were already on trazodone, and an inclusion of those with possible sleep apnea.
“Perhaps the most important lesson from this trial is a reminder that PTSD is a cluster of disorders that share trauma exposure as a cause but that can manifest with different combinations of symptoms,” Ressler continued, adding that “even though rational neuronal system-based therapy, including α1-adrenergic antagonism, may fit neatly with our current understanding of the disorder, only a subgroup of the millions of patients with PTSD may respond to an approach targeting α1-adrenergic receptors.”
Additional studies in this area should be more precisely targeted with “recognized biomarkers” as well as “intermediate phenotypes” to help isolate who is an ideal candidate for this type of treatment, he suggested.
The study was funded by the Department of Veterans Affairs Cooperative Studies Program.
Raskin and co-authors reported financial relationships with Merck, Tonix Pharmaceuticals, Jazz Pharmaceuticals, Actelion Pharmaceuticals, Neurocrine Biosciences, Pfizer, Braeburn Pharmaceuticals, Aptinyx, Janssen, Resilience Therapeutics, Oxeia Biopharmaceuticals, Laboratorio Farmaceutico CT, Lundbeck, PaxVax, PTC Therapeutics, and Boehringer Ingelheim.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner