Prazosin vs Paroxetine in Combat Stress-Related Post-Traumatic Stress Disorder (PTSD) Nightmares & Sleep Disturbance

Stress Disorders, Post-Traumatic Clinical Trial

Official title:

A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Related PTSD Nightmares and Sleep Disturbance

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00202449
• Other study ID #: Raskind 0046
• Secondary ID: DoD #PR054292UW
• Status: Terminated
• Phase: N/A
• Start date: July 2004
• Est. completion date: February 2008

Study information

• Verified date: June 2018
• Source: Seattle Institute for Biomedical and Clinical Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purposes of this study are:

• to evaluate the efficacy and tolerability of the drug prazosin compared to placebo for combat stress-related nightmares, sleep disturbance and overall function in recently combat-exposed returnees from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF).

• to evaluate the effects of the selective serotonin reuptake inhibitor (SSRI) paroxetine on behavioral symptoms and overall function in this population.

Description:

Trauma-related nightmares and sleep disruption that follow combat exposure are distressing and frequently treatment resistant symptoms that impair quality of life and overall function. These symptoms closely resemble core nighttime symptoms of posttraumatic stress disorder (PTSD), and are increasingly recognized in returnees from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Prazosin, a generically available brain active alpha-1 adrenergic receptor antagonist, markedly reduced or eliminated combat trauma-related nightmares and sleep disruption in 23 of 25 combat-exposed returnees from OIF at Madigan Army Medical Center (MAMC). The use of prazosin in OIF returnees was based on clinical efficacy of prazosin for trauma-related nightmares, sleep disturbance, and overall function in Vietnam combat veterans with chronic PTSD. The only drugs FDA approved for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. However, SSRI effectiveness in combat trauma PTSD, especially for nighttime symptoms, remains questionable.

This is a placebo-controlled clinical trial of prazosin vs. the SSRI paroxetine for combat trauma-related nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) clinical severity in OIF/OEF returnees. Both neurobiologic considerations and our preliminary clinical treatment data provide support for the proposed trial. Preclinical and clinical studies suggest a role for increased central nervous system (CNS) adrenergic outflow and/or responsiveness in PTSD pathophysiology. Possible mechanisms include alpha-1 adrenergic receptor-mediated effects on sleep physiology, corticotropin releasing hormone secretion, and disruption of cognitive processing.

Here we propose a double-blind, placebo-controlled parallel group 12 week clinical trial of prazosin vs. paroxetine to test the following hypotheses:

Hypothesis 1. Prazosin will be more effective than paroxetine or placebo for reducing frequency and intensity of combat trauma-related nightmares (as measured by the "distressing dreams" item of the Clinician Administered PTSD Scale [CAPS]).

Hypothesis 2. Prazosin will be more effective than paroxetine or placebo for improving sleep quality (as measured by the Pittsburgh Sleep Quality Index [PSQI]).

Hypothesis 3. Prazosin will be more effective than paroxetine or placebo for improving overall clinical status (as measured by the Clinical Global Impression of Change [CGIC]).

Hypothesis 4. Prazosin will be better tolerated than paroxetine as measured by days retained in the study and frequency of adverse events.

Primary outcome measures will assess trauma-related nightmares, sleep disturbance and change in global clinical status: these will include the CAPS [59] Recurrent Distressing Dreams item, the PSQI (60) and the CGIC (58) score. Secondary outcome measures will include total CAPS score, the CAPS subscale scores (Reexperiencing/ Intrusions, Avoidance/Numbing, and Hyperarousal), the Nightmare Frequency Questionnaire (NFQ), Insomnia Severity Index, and measures of depressive signs and symptoms, quality of life, and number of study days completed.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 59
• Est. completion date: February 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Hazardous duty in Iraq or Afghanistan with the US Armed Forces during Operations Iraqi Freedom and Operation Enduring Freedom

• Exposure to at least a moderate level of combat (>5 on Revised Combat Exposure Scale)

• Good general medical health

• Stable dose of non-excluded medications for at least 4 weeks prior to randomization

• >5 on CAPS recurrent distressing dreams item

• >5 on CAPS difficulty falling or staying asleep item

Exclusion Criteria:

• Acute or significant chronic medical illness, preexisting hypotension or orthostatic hypotension, pancreatitis, gout, Ménière's disease, benign positional vertigo, narcolepsy, or any other unstable medical condition.

• Women of childbearing potential with either positive pregnancy test or refusal to use effective birth control method will be excluded.

• Lifetime schizophrenia, schizoaffective disorder, bipolar disorder, psychotic disorder or any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) cognitive disorder, current delirium, substance dependence disorder within 3 months of the study, severe psychiatric instability or severe situational life crises, including evidence of being actively suicidal or homicidal, or any behavior which poses an immediate danger to patient or others.

• Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist or paroxetine or any other SSRI, no concurrent use of another alpha-1 antagonist agent, no concurrent use of an antidepressant (other than trazodone prescribed for sleep).

Related Conditions & MeSH terms

• Disease
• Dyssomnias
• Parasomnias
• Sleep Disorders
• Sleep Wake Disorders
• Stress Disorders, Post-Traumatic
• Stress Disorders, Traumatic

Intervention

Drug:
• prazosin
taken by mouth, twice daily, titrated up to efficacy or a maximum of 5 mg at 10a and 25 mg at bedtime for duration of study
• paroxetine
20 mg taken at 10a for duration of the study
• Placebo
Placebo

Locations

Country	Name	City	State
United States	Madigan Army Medical Center	Fort Lewis	Washington
United States	Walter Reed Army Medical Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Seattle Institute for Biomedical and Clinical Research	United States Department of Defense, VA Puget Sound Health Care System

Country where clinical trial is conducted

United States, 

References & Publications (4)

Peskind ER, Bonner LT, Hoff DJ, Raskind MA. Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol. 2003 Sep;16(3):165-71. — View Citation

Raskind MA, Dobie DJ, Kanter ED, Petrie EC, Thompson CE, Peskind ER. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry. 2000 Feb;61(2):129-33. — View Citation

Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, Dobie DJ, Hoff D, Rein RJ, Straits-Tröster K, Thomas RG, McFall MM. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003 Feb;160(2):371-3. — View Citation

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. 2002 Jul;63(7):565-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12	Item B-2 "recurrent distressing dreams of the event" is a single item from the Clinician Administered PTSD Scale. The rating consists of two parts: Frequency and Intensity. Symptom frequency rated 0 to 4. Symptom intensity rated 0 to 4. Frequency plus Intensity ratings equal the total score. A higher score is worse; a lower score is better. This outcome measure evaluates the change in score from Baseline to Week 12. Minimum = 0 Maximum = 8	Baseline and Week 12
Primary	Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12	Pittsburgh Sleep Quality Index is a self-report questionnaire assessing sleep quality and disturbances over a 1-month time interval. A global score is obtained by summing the seven component subscales (total score range: 0-21). A score of 5 or less indicates good sleep quality. A score of more than 5 indicates poor sleep quality. Change is measured from Baseline to Week 12.	Baseline to Week 12
Primary	Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12	The Clinical Global Impression of Change is a 7-point scale that rates global change compared to baseline (1=markedly improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=moderately worse, 7=markedly worse). The CGIC is used to determine the impact of treatment effects on meaningful and distinct change in overall sense of well-being and functioning. This outcome measure evaluates change from baseline to Week 12.	Baseline to Week 12