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”

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.

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.

Intervention(s) in this Clinical Trial

• 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
• Drug: paroxetine
  • 20 mg taken at 10a for duration of the study
• Drug: Placebo
  • Placebo

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Prazosin
• Active Comparator: 2
  • Paroxetine
• Placebo Comparator: 3
  • Placebo

Primary Measures

• Change in combat trauma-related nightmares will be assessed by the Clinician Administered PTSD Scale (CAPS) recurrent distressing dreams item at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No
• Change in sleep will be assessed by the Pittsburgh Sleep Quality Index at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No
• Change in global trauma-related symptom severity and functioning will be assessed by the Clinical Global Impression of Change at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No

Secondary Measures

• Change in combat trauma-related symptoms severity will be assessed by the total CAPS score and total PTSD checklist scores at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No
• Additional data on change in nightmares will be assessed by the PTSD Dream Rating Scale and Nightmare Frequency Questionnaire at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No
• Change in depressive symptoms will be assessed by the Hamilton Depression Rating Scale at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No
• Change in quality of life will be assessed by the Quality of Life Inventory at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No
• Study days completed as an indicator of medication tolerability at weeks 6 & 12
  • Time Frame: 6 and 12 weeks
    Safety Issue?: No

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).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Seattle Institute for Biomedical and Clinical Research Other

Overall Clinical Trial Officials and Contacts

Murray Raskind, MD Principal Investigator Director, Mental Health Services and Director, Mental Illness Research, Education, and Clinical Center VA Puget Sound Health Care System  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00202449

Study ID Number: Raskind 0046

ClinicalTrials.gov Identifier: NCT00202449

Health Authority: United States: Institutional Review Board