Does Prazosin Benefit Patients With Posttraumatic Stress Disorder?

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

Murray A. Raskind, MD

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.