SEATTLE–For years, prazosin has appeared to be one of the most effective medications for treating the nightmares associated with post-traumatic stress disorder, but that treatment is being called into questions by findings from two recent studies that patients with PTSD who received a placebo did as well or better than those who received prazosin.
While the results were discouraging to researchers, they likely demonstrate the need for greater personalization, rather than the futility of treatment, explained Rebecca Hendrickson, MD, PhD, of the VA Puget Sound Health Care System and the University of Washington School of Medicine in Seattle.
More than half of Vietnam combat veterans with PTSD report experiencing chronic nightmares, as do nearly three-quarters of all PTSD patients, according to the VA. And the frightening dreams do more than disturb sleep.
“Nightmares double the odds of suicide,” pointed out William McCall, MD, of the Department of Psychiatry and Health Behavior at the Medical College of Georgia Augusta University in Augusta, GA.
Several small studies over the last 15 years by Murray Raskind, MD, of the VA Puget Sound Health Care System in Seattle, and colleagues indicated that twice daily doses of prazosin reduced nightmares in U.S. veterans with combat trauma.1,2,3 One of those studies found prazosin so beneficial that the Madigan Army Medical Center Institutional Review Board discontinued enrollment because of demonstrated efficacy.
Based on that research, McCall and his colleagues at Augusta University and Wake Forest School of Medicine, Winston-Salem, NC, figured the drug should also reduce suicidality, so they structured a placebo-controlled, randomized pilot trial to see whether targeted treatment of nightmare symptoms with just a bedtime dose of prazosin would help suicidal patients.
While all 20 patients in the study experienced improvement over the eight-week study period, “nighttime measures of nightmares and insomnia showed significantly less improvement in the prazosin group” and “no significant change in daytime measures of suicidal ideation and daytime-only PTSD symptoms, according to the published report in the Journal of Clinical Psychopharmacology.4
While all psychometric measures improved over eight weeks, according to the results, nighttime measures of nightmares and insomnia showed significantly less improvement in the prazosin group and no significant change in daytime measures of suicidal ideation and daytime-only PTSD symptoms were found. In fact, two patients required emergency psychiatric hospitalization, although there were no suicide attempts and no deaths.
“Surprisingly, the effect was in the direction opposite of what we expected,” study authors wrote.
“It almost looked like prazosin was holding some of them back,” McCall told U.S. Medicine, adding that “prazosin likely helps some people but not everyone. We need to better understand who would benefit and personalize the treatment more.”
In the case of his study, McCall noted two factors that might have affected his results, the high dropout rate and the choice to give just one nighttime dose. Because all of the study participants were suicidal, the researchers asked them to come in every week for eight weeks for an evaluation. The time commitment and low payment rate, combined with a high level of illness, may have led many to discontinue participation. Two patients required hospitalization for worsening suicidal ideation. Just six patients completed the full eight weeks of follow-up.
Patients also might have dropped out because of the short-term effect of prazosin, Hendrickson told U.S. Medicine.
“When we are starting to restore normal sleep structure but aren’t yet at a full dose, patients may stay in REM state long enough to have more vivid dreams or nightmares and sometimes have a brief worsening of symptoms,” she said. “We have seen this issue much more frequently in women, maybe because people tend to titrate more slowly with women.” Once patients reach a therapeutic dose, they sleep better and have fewer nightmares. Of the 20 patients in McCall’s study, 17 were female.
McCall and his colleagues also noted that adding a daytime dose might make a difference in the results. Prazosin is an alpha-adrenergic antagonist with a two to three hour half-life. “It is still possible that daytime doses of prazosin might reduce suicidal thinking in PTSD patients,” they noted.
The most recent study by Raskind and his colleagues did provide two doses of prazosin to more than 300 participants. Like McCall’s, it “failed to show a benefit of prazosin over placebo in reducing the frequency and intensity of trauma-related nightmares,” the authors noted in their analysis, which appeared in the New England Journal of Medicine. About half as many participants in the prazosin arm experienced new or worsening suicidal ideation, however, 8% vs 15%.5
The authors suggested that the failure to reduce nightmares in the study might be attributed to selection bias, as the study required patients to be clinically stable, which would reduce the benefit of antiadrenergic treatment. Previous trials had not excluded patients with psychosocial instability.
Hendrickson initiated a study last May to determine which patients with PTSD might benefit most from prazosin. In the study that “halted early because it was so positive, two-thirds of those in treatment had significant or marked improvement compared to about one-quarter of those in the placebo arm,” she said. “What’s going on with the one-third who did not see an improvement with prazosin?”
“We have a strong suspicion that PTSD may be heterogenous in underlying pathophysiology; it could have at least two different causes,” she explained.
A study in the 1990s suggested that, in some individuals, PTSD is exacerbated by increased noradrenergic signaling, while changes in the serotonin system may be the dominant factor in others.5
Hendrickson’s study is exploring the hypothesis that patients with PTSD with increased noradrenergic sensitivity respond more to prazosin than those without this kind of increased noradregenic signaling. Normally, noradrenergic signaling maintains blood pressure when patients go from sitting to standing, so patients who see a rise in blood pressure two minutes after standing rather than maintaining a steady level might be individuals who have a noradrenergic issue and could benefit from prazosin. Pupil dilation, which is also driven by the noradrenergic system, could be another way to identify patients likely to respond to prazosin, Hendrickson said. The study will gather baseline data on both biomarkers.
The aggregated N-of-1 study will enroll 70 veterans, all of whom will start on prazosin for eight weeks, followed by a four-week “blinded discontinuation” period, during which they will at some undisclosed point switch to placebo. In the final phase, patients will be randomized to four weeks of prazosin, followed by four weeks of placebo or the reverse, four weeks of placebo, then four weeks of prazosin.
Patients will track their symptoms in a daily log. While results will be aggregated, the design will allow participants and researchers to know how prazosin works for each individual.
The study design is “really appealing to participants,” Hendrickson said. “Traditionally those with placebo have no idea if prazosin would have worked for them. If in the prazosin arm, do you need to continue to take prazosin for 40 years? Was the response specific to prazosin or a placebo effect?”
With this trial, “everyone in the trial will know clearly whether prazosin works for them and if they need to stay on the medication to maintain the response as well as which symptoms respond,” she said.
And researchers may finally know whether and for whom prazosin provides relief from nightmares.
1. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry 2003;160:371-373.
2. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry 2007;61:928-934.
3. 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;170:1003-1010.
4. McCall WV, Pillai A, Case D, et al. A Pilot, Randomized Clinical Trial of Bedtime Doses of Prazosin Versus Placebo in Suicidal Posttraumatic Stress Disorder Patients With Nightmares. J Clin Psychopharmacol. 2018 Dec;38(6):618-621.
5. Raskind MA, Peskind ER, Chow B, et al. Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. N Engl J Med. 2018 Feb 8;378(6):507-517.
6. Southwick SM, Krystal JH, Bremner JD, et al. Noradrenergic and Serotonergic Function in Posttraumatic Stress Disorder. Arch Gen Psychiatry. 1997;54:749-758.