Comorbid PTSD: Update on the Role of Prazosin

BIPOLAR UPDATE

Posttraumatic stress disorder (PTSD) is often found to be a comorbidity in patients with bipolar disorder. In fact, sometimes it is the primary problem.

Irritable mood is a regular feature of PTSD. Triggers include events or thoughts related to the original trauma, which elicit an immediate adrenalized fight-or-flight response. Patients with PTSD will almost always present with sleep disturbance, including nightmares, disturbed awakenings without nightmare recollection, and night terrors observed by bed partners but not remembered.¹ Although mania can present with irritable (rather than elevated) mood during manic episodes, the irritability in mania tends to occur when others disagree with the unrealistic plans or problematic behaviors of the individual with mania. In DSM-5 mania, the patient must present with 4 rather than 3 of the additional [hypo]manic symptoms during manic episodes if the mood is irritable.

The best medication for PTSD-related sleep disturbances, and perhaps other symptoms as well, is prazosin, which is an α-1 adrenergic antagonist antihypertensive agent. There have been 9 randomized, placebo-controlled trials of prazosin for PTSD, 6 of which have reported positive results. Some of these study results were strongly positive, with effect sizes compared with placebo in the neighborhood of 1.0 for all symptoms.^2-4

However, the largest randomized trial, which was published in 2018 and included 304 veterans from 13 medical centers, found no efficacy with prazosin.⁵ Doses were raised over 5 weeks, to up to 20 mg in men and 12 mg in women (higher than previous studies for the women). Some guidelines (including the latest Veterans Affairs PTSD practice guidelines) concluded that the medication had little value. The authors and others tried to explain these negative results, noting issues such as clinicians’ reluctance to refer very distressed and unstable patients to the study. If patients were receiving trazodone, they could not participate unless they were willing to stop taking it. Trazodone helps many patients with PTSD fall asleep, even if it has not demonstrated efficacy for staying asleep and preventing nightmares. Prazosin (a nonsedative), on the other hand, is not particularly helpful for initial insomnia. Prazosin had also been prescribed in study hospitals for many years, and perhaps the best patient candidates had already been treated.

This study made it clear that there are many patients who do not respond to prazosin and that research is needed to determine whether there are predictors of response.

Already we know that high blood pressure, which is a common medical comorbidity in PTSD, is a predictor.⁶ Raskind has termed these patients the “adrenergic subtype” of PTSD. In their 2013 study,³ which reported positive results overall, the authors found that patients with a baseline systolic blood pressure of 110 mm Hg or less did not respond to prazosin better than to placebo.⁶ Benefits rose sharply with each increase of baseline systolic blood pressure of 10 mm Hg.

Another predictor of poor response could be active drinking in patients who have an alcohol use disorder (AUD) and are actively drinking. Results of a study in veterans (N = 96) with comorbid AUD who were actively drinking during treatment with prazosin showed no efficacy for sleep or other PTSD symptoms. In another negative study, veterans (N= 20) with nightmares and mild to moderate suicidal ideation were given prazosin at night.⁷ Nightmares improved more with placebo than with prazosin, and there was no difference in suicidal ideation or daytime PTSD symptoms. Thus, it may be that suicidal ideation predicts poor response; a larger study is needed to better understand this link. Notably, among the 3 trials reporting negative results for prazosin, the only positive finding for prazosin was a lower rate of suicidal ideation in the prazosin group (8%) compared with placebo (15%) in the large 2018 study.⁵ However, this was a secondary outcome measure.

In an 8-week study comparing prazosin, hydroxyzine, and placebo in 100 patients with nightmares associated with PTSD (28% women), investigators found prazosin was superior to both hydroxyzine and placebo in reducing nightmares and improving other measures of sleep quality.⁸ Hydroxyzine was also more effective than placebo on these measures in this study, which is the only controlled study of hydroxyzine in PTSD to date.

In conclusion, prazosin appears to be effective and perhaps the best medication for properly selected patients with PTSD, especially for their sleep disturbances. It might also address daytime symptoms, including irritability. Prazosin generally does not interact with medications for bipolar disorder. It is not particularly sedating, so another medication is often needed to address initial insomnia. Hydroxyzine and trazodone are good options.^1,8 Clinicians should be aware that there is a rare risk of priapism with prazosin, so, theoretically, there may be a greater than usual risk when combining trazodone and prazosin. Patients should be warned to pay attention to this possible side effect.

The effective doses of prazosin (after slow titration over several weeks) in the studies supporting its use clustered around a mean of 15 mg at bedtime for men and about half that for women. However, patient sensitivity to the medication is highly variable, with some patients only needing 1 mg and some needing and tolerating more than 20 mg.¹ The highest dose mentioned in the literature was 45 mg at bedtime in a case report.⁹

Dr Osser is associate professor of psychiatry, Harvard Medical School, and colead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. He also serves as a member of the Editorial Board of Psychiatric Times^TM. Dr Osser has no financial disclosures regarding this article.

References

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2. Germain A, Richardson R, Moul DE, et al. Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US military veterans. J Psychosom Res. 2012;72(2):89-96.

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(9):1003-1010.

4. Ahmadpanah M, Sabzeiee P, Hosseini SM, et al. Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder. Neuropsychobiology. 2014;69(4)235-242.

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;378(6):507-517.

6. Raskind MA, Millard SP, Petrie EC, et al. Higher pretreatment blood pressure is associated with greater posttraumatic stress disorder symptom reduction in soldiers treated with prazosin. Biol Psychiatry. 2016;80(10):736-742.

7. Petrakis IL, Desai N, Gueorguieva R, et al. Prazosin for veterans with posttraumatic stress disorder and comorbid alcohol dependence: a clinical trial. Alcohol Clin Exp Res. 2016;40(1):178-186.

8. 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;38(6):618-621.

9. Koola MM, Varghese SP, Fawcett JA. High-dose prazosin for the treatment of post-traumatic stress disorder. Ther Adv Psychopharmacol. 2014;4(1):43-47. ❒