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

Condition(s) targeted: Stress Disorders, Post-Traumatic; Sleep Disorders

Intervention: prazosin (Drug); paroxetine (Drug); Placebo (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Seattle Institute for Biomedical and Clinical Research

Official(s) and/or principal investigator(s):
Murray Raskind, MD, Principal Investigator, Affiliation: Director, Mental Health Services and Director, Mental Illness Research, Education, and Clinical Center VA Puget Sound Health Care System

Overall contact:
Hollie A Holmes, BA, Phone: 206-277-6207, Email: hollie.holmes@va.gov

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.

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

Study design: Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Parallel Assignment, Efficacy Study

Primary outcome:

Change in combat trauma-related nightmares will be assessed by the Clinician Administered PTSD Scale (CAPS) recurrent distressing dreams item at weeks 6 & 12

Change in sleep will be assessed by the Pittsburgh Sleep Quality Index at weeks 6 & 12

Change in global trauma-related symptom severity and functioning will be assessed by the Clinical Global Impression of Change at weeks 6 & 12

Secondary outcome:

Change in combat trauma-related symptoms severity will be assessed by the total CAPS score and total PTSD checklist scores at weeks 6 & 12

Additional data on change in nightmares will be assessed by the PTSD Dream Rating Scale and Nightmare Frequency Questionnaire at weeks 6 & 12

Change in depressive symptoms will be assessed by the Hamilton Depression Rating Scale at weeks 6 & 12

Change in quality of life will be assessed by the Quality of Life Inventory at weeks 6 & 12

Study days completed as an indicator of medication tolerability at weeks 6 & 12

Detailed 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.

Minimum age: 18 Years. Maximum age: 50 Years. Gender(s): Both.

Criteria:

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).

Hollie A Holmes, BA, Phone: 206-277-6207, Email: hollie.holmes@va.gov

Walter Reed Army Medical Center, Washington, District of Columbia 20307, United States; Recruiting
Phoebe Kuesters, Phone: 202-356-1012, Ext: 40315, Email: Phoebe.Kuesters@NA.AMEDD.ARMY.MIL
Charles Engel, MD, Principal Investigator

Madigan Army Medical Center, Fort Lewis, Washington 98431, United States; Recruiting
Hollie A Holmes, BA, Phone: 206-277-6207, Email: hollie.holmes@va.gov
Rebekah J Rein, JD, Phone: 206-768-5259, Email: rebekah.rein@va.gov
Kris Peterson, MD, Principal Investigator

Related publications:

Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, Dobie DJ, Hoff D, Rein RJ, Straits-Troster 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.

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.

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.

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.

Starting date: July 2004
Ending date: September 2009
Last updated: January 2, 2008