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

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.

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).