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PTSD nightmares: Prazosin and atypical antipsychotics
Author(s)
Rebecca L. Graham, PharmD

 

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 levelMedicationEvidence
Recommended for treating PTSD-associated nightmares
1, 4PrazosinIn 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
1VenlafaxineNo 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
4ClonidineReduced 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
4TrazodoneAlthough 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
4OlanzapineAdjunctive olanzapine (10 to 20 mg) rapidly improved sleep in a case series of combat-related PTSD patients resistant to SSRIs and benzodiazepines (N = 5)
4RisperidoneIn 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)
4AripiprazoleIn 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
4TopiramateTopiramate reduced nightmares in 79% of civilians with PTSD and fully suppressed nightmares in 50% of patients in a case series (N = 35)
4Low-dose cortisolSignificant decrease in frequency but not intensity of nightmares with low-dose cortisol (10 mg/d) in civilians with PTSD (N = 3)
4FluvoxamineIn 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)
2Triazolam/nitrazepamLimited 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
4PhenelzineOne 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
4GabapentinAdjunctive 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
4CyproheptadineConflicting data ranges from eliminating nightmares to no changes in the presence or intensity of nightmares
4TCAsAmong 10 Cambodian concentration camp survivors treated with TCAs, 4 reported their nightmares ceased and 4 reported improvement after 1-year follow-up
4NefazodoneReduced 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
2ClonazepamClonazepam (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

 

Clinical Point

Prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo

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

 

StudyDesignPatientsResults
Raskind et al, 20032020-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 nightmaresPrazosin 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, 2007218-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 disturbancePrazosin 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, 2008227-week, randomized, placebo-controlled, crossover trial (mean dose 3.1 ± 1.3 mg)13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbancePrazosin 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

 

StudyDesignPatients/dosageResults
Aripiprazole
Lambert, 2006 aCase report4 veterans with combat-related PTSD (3 male, 1 female; age 22 to 24); dose: 15 to 30 mg; concurrent treatment sertraline or CBTDecreased frequency of weekly nightmares and agitated sleep by at least 50%
Olanzapine
Stein et al, 2002 b8-week, double-blind, placebo-controlled study19 male veterans with combat-related PTSD (olanzapine group mean age: 55.2 ± 6.6; placebo group 51.1 ± 8.1); mean dose: 15 mg/dSignificantly 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 cCase reports5 veterans with combat-related PTSD for 6 to 7 years (age: 28 to 50); dose: 10 to 20 mg; adjunct treatmentDecreased frequency of nightmares within 3 days
Labbate et al, 2000 dCase report1 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
Quetiapine
Ahearn et al, 2006 e8-week, open-label trial15 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 f6-week, open-label trial19 combat veterans; mean dose: 100 ± 70 mg/d (25 to 300 mg/d); adjunct treatmentSignificantly 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 gRetrospective chart review68 male Vietnam War combat veterans (mean age: 55 ± 3.5); mean dose: 155 ± 130 mg (25 to 700 mg); adjunct treatmentImproved sleep disturbances in 62% and nightmares in 25% of patients
Ahearn et al, 2003 hCase report2 male patients with combat-related PTSD (age 53, 72); dose: 25 to 50 mg; adjunct to SSRI therapyDecreased frequency of nightmares with increased sleep duration
Risperidone
David et al, 2006 i6-week, open-label trial17 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 jCase reports3 male patients (age 43 to 46); dose: 1 to 3 mg; adjunct therapyDecreased occurrence of nightmares
Ziprasidone
Siddiqui et al, 2005 kCase report1 male veteran with chronic combat-related PTSD (age 55); dose: 80 to 120 mg/d; adjunct with trazodone (100 mg) and topiramateImproved 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.
 

 

 

Clinical Point

Evidence supporting atypical antipsychotics to reduce nightmares in PTSD is considered to be low quality

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).23 Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.23 Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.24 This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).25 Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).26 The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.27

 

Clinical Point

The benefits of using atypical antipsychotics for PTSD nightmares may be outweighed by metabolic issues

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

 

  • American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
  • Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

 

  • Prazosin • Minipress
  • Quetiapine • Seroquel
  • Sertraline • Zoloft
  • Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

 

1. Dohrenwend BP, Turner JB, Turse NA, et al. The psychological risks of Vietnam for U.S. veterans: a revisit with new data and methods. Science. 2006;313(5789):979-982.

2. Tanielian T, Jaycox L. eds. Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. Santa Monica, CA: RAND Corporation; 2008.

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

4. Wittmann L, Schredl M, Kramer M. Dreaming in posttraumatic stress disorder: a critical review of phenomenology psychophysiology and treatment. Psychother Psychosom. 2007;76(1):25-39.

5. Clum GA, Nishith P, Resick PA. Trauma-related sleep disturbance and self-reported physical health symptoms in treatment-seeking female rape victims. J Nerv Ment Dis. 2001;189(9):618-622.

6. Kramer TL, Booth BM, Han X, et al. Service utilization and outcomes in medically ill veterans with posttraumatic stress and depressive disorders. J Trauma Stress. 2003;16(3):211-219.

7. Neylan TC, Marmar CR, Metzler TJ, et al. Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry. 1998;155(7):929-933.

8. Nappi CM, Drummond SP, Hall JM. Treating nightmares and insomnia in posttraumatic stress disorder: a review of current evidence. Neuropharmacology. 2012;62(2):576-585.

9. Maher MJ, Rego SA, Asnis GM. Sleep disturbances in patients with post-traumatic stress disorder: epidemiology impact and approaches to management. CNS Drugs. 2006;20(7):567-590.

10. van Liempt S, Vermetten E, Geuze E, et al. Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. Int Clin Psychopharmacol. 2006;21(4):193-202.

11. 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.

12. Boehnlein JK, Kinzie JD. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin. J Psychiatr Pract. 2007;13(2):72-78.

13. Strawn JR, Geracioti TD, Jr. Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety. 2008;25(3):260-271.

14. Calohan J, Peterson K, Peskind ER, et al. Prazosin treatment of trauma nightmares and sleep disturbance in soldiers deployed in Iraq. J Trauma Stress. 2010;23(5):645-648.

15. Daly CM, Doyle ME, Radkind M, et al. Clinical case series: the use of Prazosin for combat-related recurrent nightmares among Operation Iraqi Freedom combat veterans. Mil Med. 2005;170(6):513-515.

16. Peskind ER, Bonner LT, Hoff DJ, et al. Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol. 2003;16(3):165-171.

17. Raskind MA, Dobie DJ, Kanter ED, et al. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry. 2000;61(2):129-133.

18. Taylor F, Raskind MA. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol. 2002;22(1):82-85.

19. Raskind MA, Thompson C, Petrie EC, et al. Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin Psychiatry. 2002;63(7):565-568.

20. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003;160(2):371-373.

21. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007;61(8):928-934.

22. Taylor FB, Martin P, Thompson C, et al. Prazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol Psychiatry. 2008;63(6):629-632.

23. Byers MG, Allison KM, Wendel CS, et al. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety. J Clin Psychopharmacol. 2010;30(3):225-229.

24. Jin H, Lanouette NM, Mudaliar S, et al. Association of posttraumatic stress disorder with increased prevalence of metabolic syndrome. J Clin Psychopharmacol. 2009;29(3):210-215.

25. Cates ME, Jackson CW, Feldman JM, et al. Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients. Community Ment Health J. 2009;45(4):251-254.

26. Williams SG, Alinejad NA, Williams JA, et al. Statistically significant increase in weight caused by low-dose quetiapine. Pharmacotherapy. 2010;30(10):1011-1015.

27. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-272.

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Rebecca L. Graham, PharmD
Dr. Graham is a Second-Year Psychiatric Pharmacy Resident, Veterans Affairs San Diego Healthcare System (VASDHS)
Susan G. Leckband, RPh, BCPP
Ms. Leckband is a Clinical Psychiatric Pharmacist Specialist, VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Psychiatry, University of California, San Diego
Rene A. Endow-Eyer, PharmD, BCPP
Dr. Endow-Eyer is Psychiatric Clinical Pharmacy Specialist, VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Psychiatry, University of California, San Diego, San Diego, CA

Vicki L. Ellingrod, PharmD, BCPP, FCCP
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Rebecca L. Graham, PharmD
Dr. Graham is a Second-Year Psychiatric Pharmacy Resident, Veterans Affairs San Diego Healthcare System (VASDHS)
Susan G. Leckband, RPh, BCPP
Ms. Leckband is a Clinical Psychiatric Pharmacist Specialist, VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Psychiatry, University of California, San Diego
Rene A. Endow-Eyer, PharmD, BCPP
Dr. Endow-Eyer is Psychiatric Clinical Pharmacy Specialist, VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Psychiatry, University of California, San Diego, San Diego, CA

Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor

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Rebecca L. Graham, PharmD
Dr. Graham is a Second-Year Psychiatric Pharmacy Resident, Veterans Affairs San Diego Healthcare System (VASDHS)
Susan G. Leckband, RPh, BCPP
Ms. Leckband is a Clinical Psychiatric Pharmacist Specialist, VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Psychiatry, University of California, San Diego
Rene A. Endow-Eyer, PharmD, BCPP
Dr. Endow-Eyer is Psychiatric Clinical Pharmacy Specialist, VASDHS, and Assistant Clinical Professor through Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Psychiatry, University of California, San Diego, San Diego, CA

Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor

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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 levelMedicationEvidence
Recommended for treating PTSD-associated nightmares
1, 4PrazosinIn 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
1VenlafaxineNo 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
4ClonidineReduced 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
4TrazodoneAlthough 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
4OlanzapineAdjunctive olanzapine (10 to 20 mg) rapidly improved sleep in a case series of combat-related PTSD patients resistant to SSRIs and benzodiazepines (N = 5)
4RisperidoneIn 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)
4AripiprazoleIn 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
4TopiramateTopiramate reduced nightmares in 79% of civilians with PTSD and fully suppressed nightmares in 50% of patients in a case series (N = 35)
4Low-dose cortisolSignificant decrease in frequency but not intensity of nightmares with low-dose cortisol (10 mg/d) in civilians with PTSD (N = 3)
4FluvoxamineIn 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)
2Triazolam/nitrazepamLimited 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
4PhenelzineOne 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
4GabapentinAdjunctive 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
4CyproheptadineConflicting data ranges from eliminating nightmares to no changes in the presence or intensity of nightmares
4TCAsAmong 10 Cambodian concentration camp survivors treated with TCAs, 4 reported their nightmares ceased and 4 reported improvement after 1-year follow-up
4NefazodoneReduced 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
2ClonazepamClonazepam (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

 

Clinical Point

Prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo

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

 

StudyDesignPatientsResults
Raskind et al, 20032020-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 nightmaresPrazosin 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, 2007218-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 disturbancePrazosin 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, 2008227-week, randomized, placebo-controlled, crossover trial (mean dose 3.1 ± 1.3 mg)13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbancePrazosin 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

 

StudyDesignPatients/dosageResults
Aripiprazole
Lambert, 2006 aCase report4 veterans with combat-related PTSD (3 male, 1 female; age 22 to 24); dose: 15 to 30 mg; concurrent treatment sertraline or CBTDecreased frequency of weekly nightmares and agitated sleep by at least 50%
Olanzapine
Stein et al, 2002 b8-week, double-blind, placebo-controlled study19 male veterans with combat-related PTSD (olanzapine group mean age: 55.2 ± 6.6; placebo group 51.1 ± 8.1); mean dose: 15 mg/dSignificantly 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 cCase reports5 veterans with combat-related PTSD for 6 to 7 years (age: 28 to 50); dose: 10 to 20 mg; adjunct treatmentDecreased frequency of nightmares within 3 days
Labbate et al, 2000 dCase report1 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
Quetiapine
Ahearn et al, 2006 e8-week, open-label trial15 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 f6-week, open-label trial19 combat veterans; mean dose: 100 ± 70 mg/d (25 to 300 mg/d); adjunct treatmentSignificantly 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 gRetrospective chart review68 male Vietnam War combat veterans (mean age: 55 ± 3.5); mean dose: 155 ± 130 mg (25 to 700 mg); adjunct treatmentImproved sleep disturbances in 62% and nightmares in 25% of patients
Ahearn et al, 2003 hCase report2 male patients with combat-related PTSD (age 53, 72); dose: 25 to 50 mg; adjunct to SSRI therapyDecreased frequency of nightmares with increased sleep duration
Risperidone
David et al, 2006 i6-week, open-label trial17 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 jCase reports3 male patients (age 43 to 46); dose: 1 to 3 mg; adjunct therapyDecreased occurrence of nightmares
Ziprasidone
Siddiqui et al, 2005 kCase report1 male veteran with chronic combat-related PTSD (age 55); dose: 80 to 120 mg/d; adjunct with trazodone (100 mg) and topiramateImproved 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.
 

 

 

Clinical Point

Evidence supporting atypical antipsychotics to reduce nightmares in PTSD is considered to be low quality

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).23 Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.23 Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.24 This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).25 Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).26 The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.27

 

Clinical Point

The benefits of using atypical antipsychotics for PTSD nightmares may be outweighed by metabolic issues

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

 

  • American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
  • Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

 

  • Prazosin • Minipress
  • Quetiapine • Seroquel
  • Sertraline • Zoloft
  • Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

 

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 levelMedicationEvidence
Recommended for treating PTSD-associated nightmares
1, 4PrazosinIn 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
1VenlafaxineNo 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
4ClonidineReduced 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
4TrazodoneAlthough 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
4OlanzapineAdjunctive olanzapine (10 to 20 mg) rapidly improved sleep in a case series of combat-related PTSD patients resistant to SSRIs and benzodiazepines (N = 5)
4RisperidoneIn 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)
4AripiprazoleIn 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
4TopiramateTopiramate reduced nightmares in 79% of civilians with PTSD and fully suppressed nightmares in 50% of patients in a case series (N = 35)
4Low-dose cortisolSignificant decrease in frequency but not intensity of nightmares with low-dose cortisol (10 mg/d) in civilians with PTSD (N = 3)
4FluvoxamineIn 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)
2Triazolam/nitrazepamLimited 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
4PhenelzineOne 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
4GabapentinAdjunctive 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
4CyproheptadineConflicting data ranges from eliminating nightmares to no changes in the presence or intensity of nightmares
4TCAsAmong 10 Cambodian concentration camp survivors treated with TCAs, 4 reported their nightmares ceased and 4 reported improvement after 1-year follow-up
4NefazodoneReduced 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
2ClonazepamClonazepam (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

 

Clinical Point

Prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo

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

 

StudyDesignPatientsResults
Raskind et al, 20032020-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 nightmaresPrazosin 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, 2007218-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 disturbancePrazosin 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, 2008227-week, randomized, placebo-controlled, crossover trial (mean dose 3.1 ± 1.3 mg)13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbancePrazosin 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

 

StudyDesignPatients/dosageResults
Aripiprazole
Lambert, 2006 aCase report4 veterans with combat-related PTSD (3 male, 1 female; age 22 to 24); dose: 15 to 30 mg; concurrent treatment sertraline or CBTDecreased frequency of weekly nightmares and agitated sleep by at least 50%
Olanzapine
Stein et al, 2002 b8-week, double-blind, placebo-controlled study19 male veterans with combat-related PTSD (olanzapine group mean age: 55.2 ± 6.6; placebo group 51.1 ± 8.1); mean dose: 15 mg/dSignificantly 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 cCase reports5 veterans with combat-related PTSD for 6 to 7 years (age: 28 to 50); dose: 10 to 20 mg; adjunct treatmentDecreased frequency of nightmares within 3 days
Labbate et al, 2000 dCase report1 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
Quetiapine
Ahearn et al, 2006 e8-week, open-label trial15 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 f6-week, open-label trial19 combat veterans; mean dose: 100 ± 70 mg/d (25 to 300 mg/d); adjunct treatmentSignificantly 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 gRetrospective chart review68 male Vietnam War combat veterans (mean age: 55 ± 3.5); mean dose: 155 ± 130 mg (25 to 700 mg); adjunct treatmentImproved sleep disturbances in 62% and nightmares in 25% of patients
Ahearn et al, 2003 hCase report2 male patients with combat-related PTSD (age 53, 72); dose: 25 to 50 mg; adjunct to SSRI therapyDecreased frequency of nightmares with increased sleep duration
Risperidone
David et al, 2006 i6-week, open-label trial17 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 jCase reports3 male patients (age 43 to 46); dose: 1 to 3 mg; adjunct therapyDecreased occurrence of nightmares
Ziprasidone
Siddiqui et al, 2005 kCase report1 male veteran with chronic combat-related PTSD (age 55); dose: 80 to 120 mg/d; adjunct with trazodone (100 mg) and topiramateImproved 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.
 

 

 

Clinical Point

Evidence supporting atypical antipsychotics to reduce nightmares in PTSD is considered to be low quality

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).23 Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.23 Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.24 This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).25 Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).26 The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.27

 

Clinical Point

The benefits of using atypical antipsychotics for PTSD nightmares may be outweighed by metabolic issues

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

 

  • American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
  • Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

 

  • Prazosin • Minipress
  • Quetiapine • Seroquel
  • Sertraline • Zoloft
  • Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

 

1. Dohrenwend BP, Turner JB, Turse NA, et al. The psychological risks of Vietnam for U.S. veterans: a revisit with new data and methods. Science. 2006;313(5789):979-982.

2. Tanielian T, Jaycox L. eds. Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. Santa Monica, CA: RAND Corporation; 2008.

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

4. Wittmann L, Schredl M, Kramer M. Dreaming in posttraumatic stress disorder: a critical review of phenomenology psychophysiology and treatment. Psychother Psychosom. 2007;76(1):25-39.

5. Clum GA, Nishith P, Resick PA. Trauma-related sleep disturbance and self-reported physical health symptoms in treatment-seeking female rape victims. J Nerv Ment Dis. 2001;189(9):618-622.

6. Kramer TL, Booth BM, Han X, et al. Service utilization and outcomes in medically ill veterans with posttraumatic stress and depressive disorders. J Trauma Stress. 2003;16(3):211-219.

7. Neylan TC, Marmar CR, Metzler TJ, et al. Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry. 1998;155(7):929-933.

8. Nappi CM, Drummond SP, Hall JM. Treating nightmares and insomnia in posttraumatic stress disorder: a review of current evidence. Neuropharmacology. 2012;62(2):576-585.

9. Maher MJ, Rego SA, Asnis GM. Sleep disturbances in patients with post-traumatic stress disorder: epidemiology impact and approaches to management. CNS Drugs. 2006;20(7):567-590.

10. van Liempt S, Vermetten E, Geuze E, et al. Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. Int Clin Psychopharmacol. 2006;21(4):193-202.

11. 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.

12. Boehnlein JK, Kinzie JD. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin. J Psychiatr Pract. 2007;13(2):72-78.

13. Strawn JR, Geracioti TD, Jr. Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety. 2008;25(3):260-271.

14. Calohan J, Peterson K, Peskind ER, et al. Prazosin treatment of trauma nightmares and sleep disturbance in soldiers deployed in Iraq. J Trauma Stress. 2010;23(5):645-648.

15. Daly CM, Doyle ME, Radkind M, et al. Clinical case series: the use of Prazosin for combat-related recurrent nightmares among Operation Iraqi Freedom combat veterans. Mil Med. 2005;170(6):513-515.

16. Peskind ER, Bonner LT, Hoff DJ, et al. Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol. 2003;16(3):165-171.

17. Raskind MA, Dobie DJ, Kanter ED, et al. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry. 2000;61(2):129-133.

18. Taylor F, Raskind MA. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol. 2002;22(1):82-85.

19. Raskind MA, Thompson C, Petrie EC, et al. Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin Psychiatry. 2002;63(7):565-568.

20. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003;160(2):371-373.

21. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007;61(8):928-934.

22. Taylor FB, Martin P, Thompson C, et al. Prazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol Psychiatry. 2008;63(6):629-632.

23. Byers MG, Allison KM, Wendel CS, et al. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety. J Clin Psychopharmacol. 2010;30(3):225-229.

24. Jin H, Lanouette NM, Mudaliar S, et al. Association of posttraumatic stress disorder with increased prevalence of metabolic syndrome. J Clin Psychopharmacol. 2009;29(3):210-215.

25. Cates ME, Jackson CW, Feldman JM, et al. Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients. Community Ment Health J. 2009;45(4):251-254.

26. Williams SG, Alinejad NA, Williams JA, et al. Statistically significant increase in weight caused by low-dose quetiapine. Pharmacotherapy. 2010;30(10):1011-1015.

27. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-272.

References

 

1. Dohrenwend BP, Turner JB, Turse NA, et al. The psychological risks of Vietnam for U.S. veterans: a revisit with new data and methods. Science. 2006;313(5789):979-982.

2. Tanielian T, Jaycox L. eds. Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. Santa Monica, CA: RAND Corporation; 2008.

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

4. Wittmann L, Schredl M, Kramer M. Dreaming in posttraumatic stress disorder: a critical review of phenomenology psychophysiology and treatment. Psychother Psychosom. 2007;76(1):25-39.

5. Clum GA, Nishith P, Resick PA. Trauma-related sleep disturbance and self-reported physical health symptoms in treatment-seeking female rape victims. J Nerv Ment Dis. 2001;189(9):618-622.

6. Kramer TL, Booth BM, Han X, et al. Service utilization and outcomes in medically ill veterans with posttraumatic stress and depressive disorders. J Trauma Stress. 2003;16(3):211-219.

7. Neylan TC, Marmar CR, Metzler TJ, et al. Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry. 1998;155(7):929-933.

8. Nappi CM, Drummond SP, Hall JM. Treating nightmares and insomnia in posttraumatic stress disorder: a review of current evidence. Neuropharmacology. 2012;62(2):576-585.

9. Maher MJ, Rego SA, Asnis GM. Sleep disturbances in patients with post-traumatic stress disorder: epidemiology impact and approaches to management. CNS Drugs. 2006;20(7):567-590.

10. van Liempt S, Vermetten E, Geuze E, et al. Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. Int Clin Psychopharmacol. 2006;21(4):193-202.

11. 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.

12. Boehnlein JK, Kinzie JD. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin. J Psychiatr Pract. 2007;13(2):72-78.

13. Strawn JR, Geracioti TD, Jr. Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety. 2008;25(3):260-271.

14. Calohan J, Peterson K, Peskind ER, et al. Prazosin treatment of trauma nightmares and sleep disturbance in soldiers deployed in Iraq. J Trauma Stress. 2010;23(5):645-648.

15. Daly CM, Doyle ME, Radkind M, et al. Clinical case series: the use of Prazosin for combat-related recurrent nightmares among Operation Iraqi Freedom combat veterans. Mil Med. 2005;170(6):513-515.

16. Peskind ER, Bonner LT, Hoff DJ, et al. Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol. 2003;16(3):165-171.

17. Raskind MA, Dobie DJ, Kanter ED, et al. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry. 2000;61(2):129-133.

18. Taylor F, Raskind MA. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol. 2002;22(1):82-85.

19. Raskind MA, Thompson C, Petrie EC, et al. Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin Psychiatry. 2002;63(7):565-568.

20. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003;160(2):371-373.

21. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007;61(8):928-934.

22. Taylor FB, Martin P, Thompson C, et al. Prazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol Psychiatry. 2008;63(6):629-632.

23. Byers MG, Allison KM, Wendel CS, et al. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety. J Clin Psychopharmacol. 2010;30(3):225-229.

24. Jin H, Lanouette NM, Mudaliar S, et al. Association of posttraumatic stress disorder with increased prevalence of metabolic syndrome. J Clin Psychopharmacol. 2009;29(3):210-215.

25. Cates ME, Jackson CW, Feldman JM, et al. Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients. Community Ment Health J. 2009;45(4):251-254.

26. Williams SG, Alinejad NA, Williams JA, et al. Statistically significant increase in weight caused by low-dose quetiapine. Pharmacotherapy. 2010;30(10):1011-1015.

27. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-272.

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