Review of: McCall W et al, J Clin Psychopharmacol 2018;38(6):618–621

Study Type: Randomized single-blind controlled trial (pilot study)

Prazosin has become a mainstay in the pharmacologic treatment of PTSD. A selective antagonist of the noradrenergic alpha-1 receptor, it has modest benefits in sleep and nightmares that are supported by around half a dozen clinical trials. That mainstay of practice was recently rocked by a large trial of twice-daily prazosin in (mainly male) military veterans that found no benefit for distressing dreams or sleep quality (Raskind M et al, NEJM 2018;378(6):507–517). But the study had flaws, particularly in the way that patients were selected to participate, and we discussed those flaws in a recent issue (see TCPR April 2019, “Sleep and PTSD”). Now we have a second report questioning prazosin’s utility in PTSD.

The authors hypothesized that prazosin might reduce suicidality in patients with PTSD, based on prior research suggesting a link between insomnia and suicide. They randomized 20 civilians (17 women, 3 men) with PTSD to prazosin or placebo for 8 weeks. Prazosin was given at night in escalating doses as tolerated (the mean final dose was 5.5 ± 3.5 mg qhs). Prior to randomization, the subjects were stabilized for at least 4 weeks on an SSRI or, if suffering from bipolar depression, at least 4 weeks on an FDA-approved bipolar medication. The primary outcome was suicidality, as measured by the Scale for Suicide Ideation (SSI) and the Columbia-Suicide Severity Rating Scale (C-SSRS). Secondary measures included the Disturbing Dreams and Nightmare Severity Index (DDNSI), the Insomnia Severity Index (ISI), and PTSD as measured by the PTSD-checklist-specific version.

The results were surprising. Contrary to expectations, the placebo group showed greater improvement on all measures, including nightmares and insomnia, but also on measures of depression and PTSD overall. However, the study had significant weaknesses that make it difficult to conclude much from these results. The sample size was small, and only 6 of the 20 subjects completed the full 8 weeks. The placebo response was also very high. Suicidality remitted completely on placebo, as measured by the SSI, but on prazosin it only declined 70%.

TCPR’S TAKE
The placebo response has risen in the last 20 years, and that means we’re seeing more studies like this where an otherwise effective treatment fails to separate from placebo. Transcranial magnetic stimulation, behavioral interventions for PTSD, and now prazosin have all shared this fate. The lesson is to beware of media headlines that proclaim a common therapy ineffective. Sometimes the treatment is flawed; sometimes it’s the study. In this case, we’re not convinced that it’s time to give up on prazosin in PTSD.