A Randomized Controlled Trial of Doxazosin for Nightmares, Sleep Disturbance, and Non-Nightmare Clinical Symptoms in PTSD

This study will involve a randomized, double-blind, placebo-controlled, flexible dose trial
of doxazosin (1-16mg) for PTSD nightmares, sleep disturbance and overall PTSD symptoms. The
target sample will consist of 60 male and female subjects with chronic PTSD symptoms and
prominent nightmares randomly assigned to receive doxazosin (n=30) or placebo (n=30).
Participants will be enrolled at the San Francisco VA Medical Center. Following baseline
consent procedures, eligibility assessments, and 1-week of baseline assessments including
self-report surveys, actigraphy, and at-home EEG (Sleep Profiler), all subjects will initiate
doxazosin or equivalently marked placebo at 1mg at bedtime. Subjects will undergo a 4-week
titration phase during which doxazosin or placebo may be increased to a maximum dose of 16mg
(or equivalently marked placebo) at bedtime based on symptoms and tolerability. After the
4-week titration phase, subjects will continue at stable dose of study medication for a
4-week stable dose phase. Subjects will be asked to complete sleep diaries daily during their
participation in the study. In the last week of the stable dose phase, participants will
undergo an additional week of at-home sleep monitoring using actigraphy, complete end of
treatment surveys, and undergo end-of-treatment clinical assessments and discontinuation of
study medication. After discontinuation of study medication, participants will complete three
additional days of sleep diaries.

Inclusion Criteria:

- U.S. military veteran;

- age 18-75 and

- current full syndromal PTS as indexed by the CAPS-5 (Clinician-administered PTSD
scale) or partial syndromal PTS of at least 3 months duration with a CAPS-5 score >20,
and CAPS-IV recurrent distressing dreams item of >/= 3.

Exclusion Criteria:

- DSM-5 current moderate to severe alcohol or drug use disorder in the last 3 months;

- lifetime history of any psychiatric disorder with psychotic features, bipolar
disorder, obsessive-compulsive disorder;

- exposure to trauma within the last 3 months;

- prominent suicidal or homicidal ideation;

- pre-existing sleep apnea diagnosis in the absence of adherence to effective treatment
(such as Continuous Positive Airway Pressure (CPAP) or oral device) or positive screen
for sleep apnea by type III device;

- neurologic disorder or systemic illness affecting central nervous system function;

- chronic or unstable medical illness including unstable angina, myocardial infarction
within the past 6 months, congestive heart failure, preexisting hypotension or
baseline standing systolic blood pressure < 110 mmHg; orthostatic hypotension defined
as orthostatic systolic decrease after 3 minutes standing >20 mmHg or any BP decrease
accompanied by lightheadedness; heart block or arrhythmia on ECG; chronic renal or
hepatic failure, and pancreatitis;

- history of priapism;

- pregnancy, breastfeeding and/or refusal to use effective birth control (female
participants);

- previous adverse reaction to an alpha-1-antagonist;

- current use of trazodone, sedative-hypnotics or benzodiazepines, atypical
antipsychotics, alpha-1 antagonists, alpha-2-agonists, boceprevir, midodrine; and

- use of yohimbine, Ma huang or other non-FDA approved substances or herbal remedies
that the investigators consider pose a risk to participation