Clinical trial NCT00202449: Prazosin vs Paroxetine in Combat Stress-Related Post-Traumatic Stress Disorder (PTSD) Nightmares & Sleep Disturbance
Official title: A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Related PTSD Nightmares and Sleep Disturbance
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Stress Disorders, Post-Traumatic
Sleep Disorders
Keywords: Prazosin
Paroxetine
Stress Disorders, Post-Traumatic
Sleep Disorders
Lead sponsor: Seattle Institute for Biomedical and Clinical Research
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
name: VA Puget Sound Health Care System
First posted: 2005-09-20
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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).

Primary outcomes:
measure: Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12
timeFrame: Baseline and Week 12
measure: Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12
timeFrame: Baseline to Week 12
measure: Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12
timeFrame: Baseline to Week 12
Secondary outcomes:
Other outcomes:
Locations:
city: Washington
country: United States
facility: Walter Reed Army Medical Center
state: District of Columbia
city: Fort Lewis
country: United States
facility: Madigan Army Medical Center
state: Washington
Study officials:
affiliation: Director, Mental Health Services and Director, Mental Illness Research, Education, and Clinical Center VA Puget Sound Health Care System
name: Murray Raskind, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1176/appi.ajp.160.2.371.
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. doi: 10.4088/jcp.v63n0705.
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. doi: 10.4088/jcp.v61n0208.
citation: 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. doi: 10.1177/0891988703256050.