Am J Psychiatry 160:2, February 2003
Reduction of Nightmares and Other PTSD Symptoms
in Combat Veterans by Prazosin: A Placebo-Controlled Study
Murray A. Raskind, M.D.
Elaine R. Peskind, M.D.
Evan D. Kanter, M.D.
Eric C. Petrie, M.D.
Allen Radant, M.D.
Charles E. Thompson, M.D.
Dorcas J. Dobie, M.D.
David Hoff, PA-C
Rebekah J. Rein, J.D.
Kristy Straits-Tröster, Ph.D.
Ronald G. Thomas, Ph.D.
Miles M. McFall, Ph.D.
Objective: Prazosin is a centrally active α1 adrenergic antago-
nist. The authors’ goal was to evaluate prazosin efficacy for
nightmares, sleep disturbance, and overall posttraumatic stress
disorder (PTSD) in combat veterans.
Method: Ten Vietnam combat veterans with chronic PTSD and
severe trauma-related nightmares each received prazosin and
placebo in a 20-week double-blind crossover protocol.
Results: Prazosin (mean dose=9.5 mg/day at bedtime, SD=0.5)
was superior to placebo for the three primary outcome mea-
sures: scores on the 1) recurrent distressing dreams item and the
2) difficulty falling/staying asleep item of the Clinician-Adminis-
tered PTSD Scale and 3) change in overall PTSD severity and func-
tional status according to the Clinical Global Impression of
change. Total score and symptom cluster scores for reexperienc-
ing, avoidance/numbing, and hyperarousal on the Clinician-Ad-
ministered PTSD Scale also were significantly more improved in
the prazosin condition, and prazosin was well tolerated.
Conclusions: These data support the efficacy of prazosin for
nightmares, sleep disturbance, and other PTSD symptoms.
(Am J Psychiatry 2003; 160:371–373)
P razosin substantially reduced trauma-related night-
mares and globally rated severity of posttraumatic stress
disorder (PTSD) in open-label studies (1–3). Prazosin is a
centrally active α1 adrenergic antagonist long available for
treating hypertension (4) that should counteract in part the
excessive brain noradrenergic activity reported in PTSD (5).
Ten male Vietnam combat veteran outpatients (mean age=53
years, SD=3) provided signed informed consent for participation
in this study, which was approved by the University of Washing-
ton institutional review board. All of the patients met DSM-IV cri-
teria for PTSD and had experienced PTSD symptoms since their
return from Vietnam at least 25 years earlier. Five patients met
criteria for alcohol abuse in the past, but all had been free of alco-
hol or other substance abuse for at least 6 months. All had fre-
quent and severe combat-trauma-related nightmares, as defined
by a score of 6 or higher on the Clinician-Administered PTSD
Scale (6) recurrent distressing dreams item (maximum score=8),
despite trials of psychoactive medications. Nine were receiving
disability compensation for PTSD. Seven were receiving one or
more of the following medications for PTSD: selective serotonin
Am J Psychiatry 160:2, February 2003
reuptake inhibitors (N=5), trazodone (N=2), benzodiazepines (N=
4), anticonvulsants (N=2), hydroxyzine (N=2), and risperidone
(N=1). Medications and psychotherapy were maintained un-
changed during the study.
Each subject participated in a 20-week, two-period, two-treat-
ment (prazosin and placebo) crossover study. Characteristics of
prazosin and of the study group satisfied criteria for a classic
crossover design (7). First, veterans responsive to open-label pra-
zosin almost always returned to their pretreatment nightmare in-
tensity 1 or 2 days after prazosin discontinuation (i.e., there was
no “carryover” therapeutic effect). Second, PTSD symptoms in
these chronic patients were generally stable.
Following behavioral ratings (baseline 1), the patients were
randomly assigned to prazosin first (N=5) or placebo first (N=5).
Three-week dose titration was followed by 6-week maintenance
treatment at the maximum achieved dose. At the end of week 9
(endpoint 1), the patients entered a 2-week no-study-drug wash-
out period. At the end of week 11 (baseline 2), the patients were
“crossed over” to the other treatment condition. The second drug
then was titrated upward for 3 weeks, followed by a 6-week main-
tenance treatment period terminated at week 20 (endpoint 2).
Capsules contained prazosin 1 mg or placebo. To avoid possible
“first-dose” orthostatic syncope, prazosin should be initiated at a
1-mg dose and then increased (8). One mg/day (or equivalent pla-
cebo) at bedtime for 3 days was followed by 2 mg/day for 4 days. If
nightmares were not markedly improved and adverse effects were
clinically acceptable (as determined by a research psychiatrist
blind to treatment condition), the dose was increased to 4 mg/day
at bedtime for 7 days. Using the same titration guidelines, we in-
creased the dose to 6 mg/day at bedtime for 7 days and then to 6
mg/day at bedtime plus 4 mg/day at 3:00 p.m.
The Clinician-Administered PTSD Scale was completed at
baselines and endpoints. The Clinical Global Impression (CGI) of
change (9) was administered at endpoints. For those few patients
who did not complete a treatment phase (see Results), endpoint
ratings were obtained at study discontinuation; these last obser-
vations were carried forward as imputed endpoints.
The Clinician-Administered PTSD Scale and CGI of change
were administered by a research psychiatrist (E.D.K., E.R.P., or
D.J.D.) or clinical psychologist (M.M.M. or K.S.-T.) blind to medi-
cation condition and blood pressure. These raters had estab-
lished excellent interrater reliability on both instruments. Each
subject had the same rater throughout. Primary outcome mea-
sures were the Clinician-Administered PTSD Scale recurrent dis-
tressing dreams item and difficulty falling or staying asleep item
and the CGI of change for overall PTSD severity and functional
status. Secondary outcome measures were Clinician-Adminis-
tered PTSD Scale total score (17 symptom items) and three symp-
tom cluster scores (reexperiencing/intrusion, avoidance/numb-
ing, and hyperarousal). Differences between baseline and
endpoint (change scores) for all outcome measures (except for
CGI of change) were calculated for each treatment condition re-
gardless of treatment order and compared between treatment
conditions by two-tailed paired t test. Effect sizes were calculated
as mean posttreatment prazosin score minus mean posttreat-
ment placebo score divided by the standard deviation of the
mean posttreatment placebo score (10).
Subjects were more improved when they were taking
prazosin than when they were taking placebo on the pri-
mary outcome measures of nightmares, sleep distur-
bance, and global change in PTSD severity and functional
status (Table 1). Moreover, prazosin was more effective for
reexperiencing/intrusion, numbing/avoidance, and hy-
perarousal symptom cluster scores as well as total scores
on the Clinician-Administered PTSD Scale. Effect size
analyses for dependent variables showed robust and clin-
ically meaningful reductions in symptoms across all out-
comes measured (10).
Prazosin was very well tolerated. Two patients experi-
enced mild orthostatic systolic blood pressure decreases
(10 to 20 mm Hg) and dizziness early during prazosin titra-
tion, which resolved as the dose was increased. At pra-
zosin endpoint, mean systolic blood pressure was 135 mm
Hg (SD=12) supine and 129 mm Hg (SD=12) standing; di-
TABLE 1. Effect of Crossover Treatment With Prazosin and Placebo on Symptom Measures for 10 Combat Veterans With
Clinician-Administered PTSD Scale
Recurrent distressing dreams
Difficulty falling/staying asleep
Clinical Global Impression of changea (overall PTSD
severity and function) at endpoint 2.0
a1=markedly improved, 2=moderately improved, 3=minimally improved, 4=unchanged, 5=minimally worse, 6=moderately worse, 7=mark-
Placebo Analysis of Change Scores
t (df=9) SDMeanSDp Effect Size
Am J Psychiatry 160:2, February 2003 Download full-text
astolic was 89 mm Hg (SD=8) supine and 84 mm Hg (SD=
All patients completed all conditions except for those in
the second placebo condition. Five patients experienced a
rapid return of distressing nightmares during postpra-
zosin washout. Four experienced no benefit from their
second placebo treatment and insisted on discontinuing
the study so they could be given open-label prazosin;
these patients rapidly improved after receiving the active
drug. Last observation carried forward analysis was se-
lected to impute conservative endpoint 2 values for these
subjects. Empirically, the change scores for these early ter-
mination patients were very similar to those for the five
first-period placebo subjects.
PTSD nightmares appear to arise from light sleep and/
or disrupted REM sleep (11). Prazosin reduces light sleep
and normalizes REM sleep (12). Prazosin reduces secre-
tion of corticotropin-releasing hormone (13), a neuropep-
tide elevated in PTSD (14). The high CNS noradrenergic
outflow in PTSD (5) likely stimulates α1 adrenergic regula-
tion of the prefrontal cerebral cortex, disrupting cognitive
processing and increasing fear responses (15). This is cor-
rected by prazosin (15).
These results support the efficacy and safety of prazosin
for trauma-related nightmares, sleep disturbance, and
overall PTSD severity and function in previously treat-
ment-resistant combat veterans. Prazosin offers a novel
and inexpensive approach to nightmare reduction and
other PTSD symptom relief for combat veterans. Further
studies are necessary to replicate these findings and to de-
termine if prazosin is effective in civilian trauma PTSD.
Received Feb. 5, 2002; revision received June 25, 2002; accepted
July 28, 2002. From the Northwest Network VISN 20 Mental Illness
Research, Education, and Clinical Center, VA Puget Sound Health Care
System; the Department of Psychiatry and Behavioral Sciences, Uni-
versity of Washington, Seattle; and the Division of Biostatistics, De-
partment of Family Medicine and Neurosciences, University of Cali-
fornia, San Diego. Address reprint requests to Dr. Raskind, VA Puget
Sound Health Care System (116 MIRECC), 1660 S. Columbian Way, Se-
attle, WA 98108; firstname.lastname@example.org (e-mail).
Supported by the Department of Veterans Affairs and the National
Alliance for Research on Schizophrenia and Depression (Dr. Kanter).
The authors thank Susan Martin for help in preparing this report.
1. Raskind MA, Dobie DJ, Kanter ED, Petrie EC, Thompson CE, Pes-
kind ER: The alpha-1 adrenergic antagonist prazosin amelio-
rates combat trauma nightmares in veterans with posttrau-
matic stress disorder. J Clin Psychiatry 2000; 61:129–133
2. Taylor F, Raskind MA: The alpha-1 adrenergic antagonist pra-
zosin improves sleep and nightmares in civilian trauma post-
traumatic stress disorder. J Clin Psychopharmacol 2002; 22:82–
3. Raskind MA, Thompson C, Petrie EC, Dobie DJ, Rein RJ, Hoff DJ,
McFall ME, Peskind ER: Prazosin reduces nightmares in combat
veterans with posttraumatic stress disorder. J Clin Psychiatry
4. Hieble JP, Ruffulo RR Jr: The use of alpha-adrenoreceptor an-
tagonists in the pharmacological management of benign pros-
tatic hypertrophy: an overview. Pharmacol Res 1996; 33:145–
5. Geracioti TD Jr, Baker DG, Ekhator NN, West SA, Hill KK, Bruce
AB, Schmidt D, Rounds-Kugler B, Yehuda R, Keck PE Jr, Kasckow
JW: CSF norepinephrine concentrations in posttraumatic stress
disorder. Am J Psychiatry 2001; 158:1227–1230
6. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD,
Charney DS, Keane TM: The development of a Clinician-Admin-
istered PTSD Scale. J Trauma Stress 1995; 8:75–90
7. Laska EM, Klein DF, Lavori PW, Levine J, Robinson DS: Design is-
sues for the clinical evaluation of psychotropic drugs, in Clini-
cal Evaluation of Psychotropic Drugs: Principles and Guide-
lines. Edited by Prien RF, Robinson DS. New York, Raven Press,
1994, pp 29–68
8. Physicians’ Desk Reference, 56th ed. Montvale, NJ, Medical
Economics, 2002, pp 2699–2700
9. Guy W (ed): ECDEU Assessment Manual for Psychopharmacol-
ogy: Publication ADM 76-338. Washington, DC, US Department
of Health, Education, and Welfare, 1976, pp 218–222
10. Penava SJ, Otto MW, Pollack MH, Rosenbaum JF: Current status
of pharmacotherapy for PTSD: an effect size analysis of con-
trolled studies. Depress Anxiety 1997; 4:240–242
11. Woodward SH, Arsenault NJ, Murray C, Bliwise DL: Laboratory
sleep correlates of nightmare complaint in PTSD inpatients.
Biol Psychiatry 2000; 48:1081–1087
12. Pickworth WB, Sharpe LG, Nozaki M, Martin WR: Sleep suppres-
sion induced by intravenous and intraventricular infusions of
methoxamine in the dog. Exp Neurol 1977; 57:999–1011
13. Vynthilingam M, Anderson GM, Owens MJ, Halaszynski TM,
Bremner JD, Carpenter LL, Heninger GR, Nemeroff CB, Charney
DS: Cerebrospinal fluid corticotropin-releasing hormone in
healthy humans: effects of yohimbine and naloxone. J Clin En-
docrinol Metab 2000; 85:4138–4145
14. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, South-
wick SM, Nemeroff CB, Charney DS: Elevated CSF corticotropin-
releasing factor concentrations in posttraumatic stress disor-
der. Am J Psychiatry 1997; 154:624–629
15. Arnsten AF, Mathew R, Ubrian R, Taylor JR, Li BM: Alpha-1 nor-
adrenergic receptor stimulation impairs prefrontal cortical
cognitive function. Biol Psychiatry 1999; 45:26–31