Savvy Psychopharmacology PTSD nightmares: Prazosin and atypical antipsychotics Rebecca L. Graham, PharmD, Susan G. Leckband, RPh, BCPP, and Rene A. Endow-Eyer, PharmD, BCPP r. S, a 45-year-old veteran, was diag- PTSD occurs in approximately 19% of nosed with posttraumatic stress disor- Vietnam war combat veterans1 and 14% der (PTSD) 18 years ago after a tour of of service members returning from Iraq M 2 duty in the Persian Gulf. He had combat-related and Afghanistan. PTSD symptoms are flashbacks triggered by the smell of gasoline or classified into clusters: intrusive/re- smoke from a fire, was easily startled, and began experiencing; avoidant/numbing; and to isolate himself socially. However, his symp- hyperarousal.3 Nightmares are part of the Vicki L. Ellingrod, toms improved when he started volunteering at intrusive/re-experiencing cluster, which is PharmD, BCPP, FCCP his local Veterans Affairs Medical Center. After he Criterion B in DSM-IV-TR. See this article Series Editor lost his job 3 years ago, Mr. S started experiencing at CurrentPsychiatry.com for a descrip- flashbacks. He was irritable, easily startled, and tion of DSM-IV-TR PTSD criteria. Among avoided things that reminded him of his time in PTSD patients, 50% to 70% report PTSD- the Persian Gulf. His psychiatrist prescribed ser- associated nightmares.4 Despite adequate traline, titrated to 200 mg/d. The drug reduced treatment targeted to improve PTSD’s core the severity of his avoidance and hyperarousal symptoms, symptoms such as sleep distur- symptoms and improved his mood. bances or nightmares often persist. During a clinic visit, Mr. S says he is doing Nightmares and other sleep disturbanc- well and can fall asleep at night but is having es are associated with significant distress recurring nightmares about traumatic events and daytime impairment and can interfere that occurred during combat. These night- with PTSD recovery4-8 by disrupting sleep- mares wake him up and have become more dependent processing of emotional experi- frequent, occurring once per night for the ences and causing repeated resensitization past month. Mr. S says he has been watch- to trauma cues (Table 1, page 60).8 ing more news programs about conflicts in Few randomized controlled medication Afghanistan and Iraq since the nightmares trials specifically address PTSD-related began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg Practice Points at bedtime, but after 6 weeks Mr. S says his • Prazosin is recommended as a first- nightmares continue. line therapy for nighttime PTSD symptoms, such as nightmares or Dr. Graham is a Second-Year Psychiatric Pharmacy Resident, sleep disturbances—especially among Discuss this article at Veterans Affairs San Diego Healthcare System (VASDHS); veterans—because of superior long-term www.facebook.com/ Ms. Leckband is a Clinical Psychiatric Pharmacist Specialist, effectiveness. CurrentPsychiatry VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and • Risk of metabolic syndrome, which Department of Psychiatry, University of California, San has been reported with low-dose Diego; and Dr. Endow-Eyer is Psychiatric Clinical Pharmacy Specialist, VASDHS, and Assistant Clinical Professor through atypical antipsychotics used for treating Skaggs School of Pharmacy and Pharmaceutical Sciences and insomnia, limits their use for PTSD-related Department of Psychiatry, University of California, San Diego, nightmares. Current Psychiatry San Diego, CA. Vol. 11, No. 6 59 Savvy Psychopharmacology Table 1 with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only Psychosocial consequences agent recommended in the AASM’s Best of sleep disruption in PTSD Practice Guide for treating PTSD-related 11 Increased reactivity to emotional cues nightmares. Compromised ability to function in social and occupational roles Atypical antipsychotics Negative psychiatric outcomes, including Atypical antipsychotics have been used suicidal ideation or worsening of depression to reduce nightmares in PTSD; however, or psychosis most of the evidence from studies evaluat- Interference of natural recovery from trauma ed in the AASM’s Best Practice Guide were exposure considered to be low quality.11 Quetiapine Repeated resensitization to trauma cues and ziprasidone were not included in Neurocognitive deficits the AASM review. Visit this article at Neuroendocrine abnormalities CurrentPsychiatry.com for a table review- PTSD: posttraumatic stress disorder ing the evidence for atypical antipsychot- Source: Adapted from reference 8 Clinical Point ics for treating PTSD nightmares. Prazosin reduced Comparing prazosin and quetiapine. A trauma nightmares nightmares. Most PTSD studies do not historical prospective cohort study of 237 and improved sleep examine sleep outcomes as a primary veterans with PTSD receiving prazosin or quality and global measure, and comprehensive literature re- quetiapine for nighttime PTSD symptoms clinical status more views could not offer evidence-based rec- demonstrated that although the 2 drugs ommendations.9,10 The American Academy have similar efficacy (defined as symp- than placebo of Sleep Medicine (AASM) also noted a tomatic improvement) for short-term, paucity of PTSD studies that identified 6-month treatment (61% vs 62%; P = .54), nightmares as a primary outcome mea- a higher percentage of patients continued sure.11 See this article at CurrentPsychiatry. prazosin long-term (3 to 6 years) than com for a list of recommended medication those taking quetiapine (48% vs 24%; P < options for PTSD-associated nightmares. .001).23 Twenty-five percent of patients tak- ing quetiapine switched to prazosin dur- CASE CONTINUED ing the study, and approximately one-half Medication change, improvement of these patients remained on prazosin After reviewing AASM’s treatment recommen- until the study’s end. Only 8% of prazo- dations, we prescribe prazosin, 1 mg at bedtime sin patients switched to quetiapine, and for 7 nights, then increase by 1 mg at bedtime none continued this therapy until study each week until Mr. S’s nightmares improve. He end.23 Patients in the quetiapine group reports a substantial improvement in nightmare were more likely to discontinue the drug severity and frequency after a few weeks of treat- because of lack of efficacy (13% vs 3%; P = ment with prazosin, 5 mg at bedtime. .03) and adverse effects (35% vs 18%; P = .008), specifically sedation (21% vs 2%; P Prazosin < .001) and metabolic effects (9% vs 0%; P Prazosin is an α1-adrenergic receptor an- = .014), compared with prazosin. Although Visit this article at tagonist with good CNS penetrability. The this trial may be the only published com- CurrentPsychiatry.com rationale for reducing adrenergic activity parison study of prazosin and quetiapine, for a list of medication to address intrusive PTSD symptoms has its methodological quality has been ques- options for PTSD nightmares been well documented.12,13 In open-label tioned, which makes it difficult to draw trials,14-18 a chart review,19 and placebo- definitive conclusions. controlled trials,20-22 prazosin reduced Metabolic syndrome—elevated diastol- trauma nightmares and improved sleep ic blood pressure, increased waist circum- quality and global clinical status more ference, and low high-density lipoprotein than placebo (Table 2). In these studies, cholesterol—is common among PTSD pa- Current Psychiatry 60 June 2012 prazosin doses ranged from 1 to 20 mg/d, tients treated with antipsychotics.24 This Savvy Psychopharmacology Table 2 RCTs of prazosin for trauma-related nightmares Study Design Patients Results Raskind 20-week, double- 10 Vietnam veterans Prazosin was superior to placebo on scores et al, blind, placebo- with chronic PTSD on the recurrent distressing dreams item 200320 controlled, and severe trauma- and difficulty falling/staying asleep item of crossover study related nightmares the CAPS and change in PTSD severity and (mean dose 9.5 functional status on the CGI-C mg/d at bedtime) Raskind 8-week, placebo- 40 veterans with Prazosin was superior to placebo in reducing et al, controlled, parallel chronic PTSD, trauma nightmares and improving sleep 200721 study (mean dose distressing trauma quality and global clinical status; prazosin 13.3 ± 3 mg/d in nightmares, and also shifted dream characteristics of trauma- the evening) sleep disturbance related nightmares to those typical of normal dreams Taylor 7-week, 13 outpatients with Prazosin significantly increased total sleep et al, randomized, chronic civilian time and REM sleep time; reduced trauma- 200822 placebo-controlled, trauma PTSD, related nightmares, distressed awakenings, Clinical Point crossover trial frequent nightmares, and total PCL-C scores; improved CGI-I (mean dose 3.1 ± and sleep scores; and changed PDRS scores toward Evidence 1.3 mg) disturbance normal dreaming CAPS: Clinician-Administered PTSD Scale; CGI-C: Clinical Global Impression of Change; CGI-I: Clinical Global Impression of supporting atypical Improvement; PCL-C: PTSD Checklist-Civilian; PDRS: PTSD Dream Rating Scale; PTSD: posttraumatic stress disorder; RCTs: randomized controlled trials; REM: rapid eye movement antipsychotics to reduce nightmares in PTSD is considered syndrome may be caused by medications, 4. Wittmann L, Schredl M, Kramer M. Dreaming in posttraumatic stress disorder: a critical review of phenomenology, to be low quality lifestyle factors, or long-term overactiva- psychophysiology and treatment.