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Savvy Psychopharmacology

PTSD nightmares: Prazosin and atypical antipsychotics

Vol. 11, No. 06 / June 2012

Practice Points

• Prazosin is recommended as a first-line therapy for nighttime PTSD symptoms, such as nightmares or sleep disturbances—especially among veterans—because of superior long-term effectiveness.

Risk of metabolic syndrome, which has been reported with low-dose atypical antipsychotics used for treating insomnia, limits their use for PTSD-related nightmares.

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans1 and 14% of service members returning from Iraq and Afghanistan.2 PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.3 Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.4 Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

  1. The person has been exposed to a traumatic event in which both of the following were present:
    1. The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others
    2. The person’s response involved intense fear, helplessness, or horror
  2. The traumatic event is persistently reexperienced in ≥1 of the following ways:
    1. Recurrent and intrusive distressing recollections of the event
    2. Recurrent distressing dreams of the event
    3. Acting or feeling as if the traumatic event were recurring
    4. Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event
    5. Physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event
  3. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by ≥3 of the following:
    1. Efforts to avoid thoughts, feelings, or conversations associated with the trauma
    2. Efforts to avoid activities, places, or people that arouse recollections of the trauma
    3. Inability to recall an important aspect of the trauma
    4. Markedly diminished interest or participation in significant activities
    5. Feeling of detachment or estrangement from others
    6. Restricted range of affect
    7. Sense of a foreshortened future
  4. Persistent symptoms of increased arousal (not present before the trauma), as indicated by ≥2 of the following:
    1. Difficulty falling or staying asleep
    2. Irritability or outbursts of anger
    3. Difficulty concentrating
    4. Hypervigilance
    5. Exaggerated startle response
  5. Duration of disturbance (symptoms in Criteria B, C, and D) is >1 month
  6. The disturbance causes clinically significant distress or impairment of social, occupational, or other important areas of functioning

Source: Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).8

Table 2

Psychosocial consequences of sleep disruption in PTSD

Increased reactivity to emotional cues

Compromised ability to function in social and occupational roles

Negative psychiatric outcomes, including suicidal ideation or worsening of depression or psychosis

Interference of natural recovery from trauma exposure

Repeated resensitization to trauma cues

Neurocognitive deficits

Neuroendocrine abnormalities

PTSD: posttraumatic stress disorder
Source: Adapted from reference 8

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.11 See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

Evidence level



Recommended for treating PTSD-associated nightmares

1, 4


In 3 level 1 studies, adding prazosin (mean dose 3 mg/d) significantly decreased trauma-related nightmares according to the CAPS “recurrent distressing dreams” item after 3 to 9 weeks of treatment vs placebo in veteran and civilian patients (N = 57)

Not suggested for treating PTSD-associated nightmares



No difference between extended-release venlafaxine (37.5 to 300 mg/d) and placebo in the CAPS-SX17 “distressing dreams” item at 12 weeks in 340 PTSD patients

May be considered for treating PTSD-associated nightmares



Reduced the number of nightmares in 11 of 13 refugees for 2 weeks to 3 months (dose: 0.2 to 0.6 mg/d)

May be considered for treating PTSD-associated nightmares, but data are low grade and sparse



Although trazodone (25 to 600 mg) significantly decreased nightmare frequency in veteran patients during an 8-week hospital stay (N = 60), 19% discontinued therapy because of side effects



Adjunctive olanzapine (10 to 20 mg) rapidly improved sleep in a case series of combat-related PTSD patients resistant to SSRIs and benzodiazepines (N = 5)



In case series, risperidone (0.5 to 3 mg) significantly decreased CAPS scores for recurrent distressing dreams and proportion of traumatic dreams documented in diaries of combat veterans over 6 weeks (N = 17), and improved nightmares in adult burn patients taking pain medications after 1 to 2 days (N = 10)



In a case series, aripiprazole (15 to 30 mg at bedtime) with CBT or sertraline significantly improved nightmares in 4 of 5 combat-related PTSD patients



Topiramate reduced nightmares in 79% of civilians with PTSD and fully suppressed nightmares in 50% of patients in a case series (N = 35)


Low-dose cortisol

Significant decrease in frequency but not intensity of nightmares with low-dose cortisol (10 mg/d) in civilians with PTSD (N = 3)



In 2 case series, fluvoxamine (up to 300 mg/d) significantly decreased the IES-R level of “dreams about combat trauma” but not the SRRS “bad dreams” rating at 10 weeks (N = 21). During 4 to 12 weeks of follow-up there was a qualitative decrease in reported nightmares in veteran patients (n = 12)



Limited data showed triazolam (0.5 mg) and nitrazepam (5 mg) provide equal efficacy in decreasing the number of patients who experience unpleasant dreams over 1 night



One study showed phenelzine monotherapy (30 to 90 mg) resulted in elimination of nightmares within 1 month (N = 5); another reported “moderately reduced traumatic dreams” (N = 21) in veterans. Therapy was discontinued because of short-lived efficacy or plateau effect



Adjunctive gabapentin (300 to 3,600 mg/d) improved insomnia and decreased nightmare frequency and/or intensity over 1 to 36 months in 30 veterans with PTSD



Conflicting data ranges from eliminating nightmares to no changes in the presence or intensity of nightmares



Among 10 Cambodian concentration camp survivors treated with TCAs, 4 reported their nightmares ceased and 4 reported improvement after 1-year follow-up



Reduced nightmare occurrence in 3 open-label studies as monotherapy (386 to 600 mg/d). Not recommended first line because of hepatotoxicity risk

No recommendation because of sparse data



Clonazepam (1 to 2 mg/d) was ineffective in decreasing frequency or intensity of combat-related PTSD nightmares in veterans (N = 6)

Evidence levels:

  1. High-quality randomized clinical trials with narrow confidence intervals
  2. Low-quality randomized clinical trials or high-quality cohort studies
  3. Case-control studies
  4. Case series; poor case-control studies; poor cohort studies; case reports

CAPS: Clinician-Administered PTSD Scale; CAPS-SX17: 17-item Clinician-Administered PTSD Scale; CBT: cognitive-behavioral therapy; IES-R: Impact of Event Scale-Revised; PTSD: posttraumatic stress disorder; SRRS: Stress Response Rating Scale; SSRI: selective serotonin reuptake inhibitor; TCAs: tricyclic antidepressants
Source: Adapted from Aurora RN, Zak RS, Auerbach SH, et al. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med. 2010;6(4):389-401

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.


Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.12,13 In open-label trials,14-18 a chart review,19 and placebo-controlled trials,20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.11

Table 4

RCTs of prazosin for trauma-related nightmares





Raskind et al, 200320

20-week, double-blind, placebo-controlled, crossover study (mean dose 9.5 mg/d at bedtime)

10 Vietnam veterans with chronic PTSD and severe trauma-related nightmares

Prazosin was superior to placebo on scores on the recurrent distressing dreams item and difficulty falling/staying asleep item of the CAPS and change in PTSD severity and functional status on the CGI-C

Raskind et al, 200721

8-week, placebo-controlled, parallel study (mean dose 13.3 ± 3 mg/d in the evening)

40 veterans with chronic PTSD, distressing trauma nightmares, and sleep disturbance

Prazosin was superior to placebo in reducing trauma nightmares and improving sleep quality and global clinical status; prazosin also shifted dream characteristics of trauma-related nightmares to those typical of normal dreams

Taylor et al, 200822

7-week, randomized, placebo-controlled, crossover trial (mean dose 3.1 ± 1.3 mg)

13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbance

Prazosin significantly increased total sleep time and REM sleep time; reduced trauma-related nightmares, distressed awakenings, and total PCL-C scores; improved CGI-I scores; and changed PDRS scores toward normal dreaming

CAPS: Clinician-Administered PTSD Scale; CGI-C: Clinical Global Impression of Change; CGI-I: Clinical Global Impression of Improvement; PCL-C: PTSD Checklist-Civilian; PDRS: PTSD Dream Rating Scale; PTSD: posttraumatic stress disorder; RCTs: randomized controlled trials; REM: rapid eye movement

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.11 Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics






Lambert, 2006 a

Case report

4 veterans with combat-related PTSD (3 male, 1 female; age 22 to 24); dose: 15 to 30 mg; concurrent treatment sertraline or CBT

Decreased frequency of weekly nightmares and agitated sleep by at least 50%


Stein et al, 2002 b

8-week, double-blind, placebo-controlled study

19 male veterans with combat-related PTSD (olanzapine group mean age: 55.2 ± 6.6; placebo group 51.1 ± 8.1); mean dose: 15 mg/d

Significantly greater reduction in sleep disturbances (PSQI: -3.29 vs 1.57; P = .01); significantly higher weight gain (13.2 lbs vs -3 lbs; P = .001)

Jakovljevic et al, 2003 c

Case reports

5 veterans with combat-related PTSD for 6 to 7 years (age: 28 to 50); dose: 10 to 20 mg; adjunct treatment

Decreased frequency of nightmares within 3 days

Labbate et al, 2000 d

Case report

1 male veteran (age: 58) with a 20-year history of combat-related PTSD; dose: 5 mg at bedtime; concurrent treatment with sertraline (200 mg/d), bupropion (150 mg/d), and diazepam (15 mg/d)

Eliminated nightmares after 1 week and improved sleep quality


Ahearn et al, 2006 e

8-week, open-label trial

15 PTSD patients (8 male; 7 female; 5 with combat-related PTSD; mean age: 49); mean dose: 216 mg/d (100 to 400 mg/d)

Significantly improved re-experiencing (CAPS: 10 vs 23; P = .0012) and sleep (PSQI: 17.5 vs 30; P = .0044) at 8 weeks compared with baseline

Robert et al, 2005 f

6-week, open-label trial

19 combat veterans; mean dose: 100 ± 70 mg/d (25 to 300 mg/d); adjunct treatment

Significantly improved sleep quality (PSQI: 1.67 vs 2.41; P = .006), latency (PSQI: 1.5 vs 2.65; P = .002), duration (PSQI: 1.31 vs 2.71; P < .001), and sleep disturbances (PSQI: 1.22 vs 1.71; P = .034) and decreased terror episodes (PSQI-A: 0.73 vs 0.91; P = .040) and acting out dreams (PSQI-A: 1.07 vs 1.35; P = .013); however, no difference in nightmares caused by trauma (PSQI-A: 1.53 vs 2.06)

Sokolski et al, 2003 g

Retrospective chart review

68 male Vietnam War combat veterans (mean age: 55 ± 3.5); mean dose: 155 ± 130 mg (25 to 700 mg); adjunct treatment

Improved sleep disturbances in 62% and nightmares in 25% of patients

Ahearn et al, 2003 h

Case report

2 male patients with combat-related PTSD (age 53, 72); dose: 25 to 50 mg; adjunct to SSRI therapy

Decreased frequency of nightmares with increased sleep duration


David et al, 2006 i

6-week, open-label trial

17 male veterans with combat-related PTSD (mean age: 53.7 ± 3.8); mean maximum dose: 2.3 ± 0.6 mg (range: 1 to 3 mg)

Improved recurrent distressing dreams (CAPS B-2: 3.8 vs 5.4; P = .04), but not with the PSQI subscale (PSQI bad dreams: 2.5 vs 2.7; NS). Decreased nighttime awakenings (1.9 vs 2.8; P = .003) and trauma dreams (19% vs 38%; P = .04)

Leyba et al, 1998 j

Case reports

3 male patients (age 43 to 46); dose: 1 to 3 mg; adjunct therapy

Decreased occurrence of nightmares


Siddiqui et al, 2005 k

Case report

1 male veteran with chronic combat-related PTSD (age 55); dose: 80 to 120 mg/d; adjunct with trazodone (100 mg) and topiramate

Improved occurrence of nightmares up to 4 months

CAPS: Clinician-Administered PTSD Scale; CAPS B-2: Clinician-Administered PTSD Scale B-2 (recurrent distressing dreams of the event); CBT: cognitive-behavioral therapy; PSQI: Pittsburgh Sleep Quality Index; PSQI-A: Pittsburgh Sleep Quality Index Addendum for PTSD; NS: not significant; PTSD: posttraumatic stress disorder; SSRI: selective serotonin reuptake inhibitor References

  1. Lambert MT. Aripiprazole in the management of post-traumatic stress disorder symptoms in returning Global War on Terrorism veterans. Int Clin Psychopharmacol. 2006;21(3):185-187.
  2. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry. 2002;159(10):1777-1779.
  3. Jakovljevic M, Sagud M, Mihaljevic-Peles A. Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports. Acta Psychiatr Scand. 2003;107(5):394-396.
  4. Labbate LA, Douglas S. Olanzapine for nightmares and sleep disturbance in posttraumatic stress disorder (PTSD). Can J Psychiatry. 2000;45(7):667-668.
  5. Ahearn EP, Mussey M, Johnson C, et al. Quetiapine as an adjunctive treatment for post-traumatic stress disorder: an 8-week open-label study. Int Clin Psychopharmacol. 2006;21(1):29-33.
  6. Robert S, Hamner MB, Kose S, et al. Quetiapine improves sleep disturbances in combat veterans with PTSD: sleep data from a prospective, open-label study. J Clin Psychopharmacol. 2005;25(4):387-388.
  7. Sokolski KN, Denson TF, Lee RT, et al. Quetiapine for treatment of refractory symptoms of combat-related post-traumatic stress disorder. Mil Med. 2003;168(6):486-489.
  8. Ahearn EP, Winston E, Mussey M, et al. Atypical antipsychotics, improved intrusive symptoms in patients with posttraumatic stress disorder. Mil Med. 2003;168(9):x-xi.
  9. David D, De Faria L, Mellman TA. Adjunctive risperidone treatment and sleep symptoms in combat veterans with chronic PTSD. Depress Anxiety. 2006;23(8):489-491.
  10. Leyba CM, Wampler TP. Risperidone in PTSD. Psychiatr Serv. 1998;49(2):245-246.
  11. Siddiqui Z, Marcil WA, Bhatia SC, et al. Ziprasidone therapy for post-traumatic stress disorder. J Psychiatry Neurosci. 2005;30(6):430-431.
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