Thousands of people with post-traumatic stress disorder (PTSD) have taken the drug prazosin to ease the nightmares and disturbances that stalk their sleep, but a team of researchers from the US Department of Veterans Affairs found that it was no better than a placebo.
Numerous studies have shown the drug to be effective at controlling those episodes. But a team of researchers from the US Department of Veterans Affairs, seeking to collect more evidence, set out to study the sustained effectiveness of the treatment. They organised a large, lengthy, multi-site trial — the most rigorous type of trial.
The drug was no better than a placebo.
The trial “seemed like a good idea, but you know, live and learn,” said Dr Murray Raskind, a lead researcher on the trial.
Some researchers not involved with the study were quick to say that clinicians should still prescribe prazosin for some patients; Raskind, director of the VA Northwest Network Mental Illness Research, Education, and Clinical Centre, agreed. There are few other treatment options and there is evidence supporting the use of the drug, a generic that was originally approved to treat high blood pressure but is prescribed off label to control nightmares and improve sleep quality in patients with PTSD.
“I don’t think it should change clinical practice – there are six positive studies and one negative study,” said Raskind, who described the research team as “humbled” by the results. He estimated that 15% to 20% of veterans in the VA system with PTSD are currently prescribed prazosin, and said he did not expect that to change.
But the study has already had some reverberations. Last year, citing the then-unpublished results of the new study, the VA and US Department of Defence wrote that there was “insufficient evidence to recommend for or against the use of prazosin as … therapy for nightmares or sleep disturbances associated with PTSD.” It should be up to clinicians and their patients to decide whether to stop or continue the use of prazosin, the officials said, noting that patients who stop taking it and whose symptoms return might need to restart the therapy.
For some people with PTSD, the trouble isn’t so much getting to sleep, it’s staying that way. Nightmares and other disturbances are common symptoms. Prazosin is thought to help by blocking the alpha1 receptor for norepinephrine, a chemical that boosts the body’s arousal in response to stimuli. The receptors may become more sensitive in combat settings, which can prove lifesaving there, but “just because you come home doesn’t mean this upregulation of the alpha1 receptor goes away,” Raskind said.
The new study was run over six months at 12 VA medical centres with about 300 participants, half of whom were given a placebo and half of whom were give prazosin. Patients in both arms of the study saw mild improvements in sleep quality and in the frequency and severity of nightmares, but there was no significant difference between the improvements in the different study groups.
Enrolment was limited to people who were clinically stable, meaning they were not drinking heavily, facing family conflicts, or experiencing suicidal or violent thoughts, Raskind said. Because of the long duration of the study, researchers didn’t want to risk exposing such patients to a placebo; some psychiatrists didn’t want their patients enrolled in the study at all for that reason.
But by focusing on stable patients, Raskind and his colleagues may have set themselves up for a negative result, he said. Perhaps, they speculated, only patients experiencing some distress respond to prazosin.
The trial participants had, on average, low blood pressure, which could also help explain why they did not see significant improvement in their sleep. In a separate 2016 study, Raskind and colleagues found that people with high blood pressure were more likely to respond to prazosin, perhaps because higher blood pressure serves as a proxy for how active the adrenaline and arousal system is.
Even though it was a negative trial, the new study still offers insights as researchers try to understand the full complexity of PTSD, said Dr Matthew Friedman, who led the National Centre for PTSD for more than two decades and who was not involved in the new study.
“I really think that we are beginning to recognise that sweeping everything under one PTSD rug may be more than one rug can cover, or should cover,” said Friedman, a psychiatry professor at Dartmouth’s Geisel School of Medicine. “By better defining what the syndrome is that we’re treating, we can better identify medications that could be helpful.”
PTSD was traditionally thought of as an anxiety disorder, but it can also manifest as depression or disassociation or reckless behaviour, experts said. The different presentations of the condition that will likely require different treatments.
“I do hope that this trial doesn’t necessarily prevent clinicians from using prazosin as one of the tools in their arsenals,” said Anne Germain, the director of the Military Sleep Tactics and Resilience Research Team at the University of Pittsburgh School of Medicine, who was not involved with the study. “I still think that some people can benefit from it, but we just need to do a much better job of having personalised, predictive treatment algorithms to help people in the end.”
Background: In randomized trials, prazosin, an α1-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans.
Methods: We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 (“recurrent distressing dreams”; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change).
Results: A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], −0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, −0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, −0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.
Conclusions: In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality.
Murray A Raskind, Elaine R Peskind, Bruce Chow, Crystal Harris, Anne Davis-Karim, Hollie A Holmes, Kimberly L Hart, Miles McFall, Thomas A Mellman, Christopher Reist, Jennifer Romesser, Robert Rosenheck, Mei-Chiung Shih, Murray B Stein, Robert Swift, Theresa Gleason, Ying Lu, Grant D Huang