Doxazosin for PTSD and Alcohol Use Disorder

As a result of sustained operations in Afghanistan and Iraq, there are an increasing number
of U.S. military personnel and Veterans at risk of developing both posttraumatic stress
disorder (PTSD) and an alcohol use disorder (AUD). If left untreated, individuals with
PTSD/AUD are at risk of developing other mental health problems (e.g., depression, anxiety),
suicidal ideation and attempts, physical health problems, reduced resiliency, vocational
problems, and family/relationship impairment. While mental health services are in place for
U.S. military personnel and Veterans, there are substantial gaps in the evidence base to
guide treatment of co-occurring PTSD/AUD. The proposed study directly addresses this gap by
testing the efficacy of doxazosin, a long-acting and selective alpha-1 adrenergic antagonist,
as compared to placebo in reducing PTSD symptomatology and alcohol use severity among U.S.
military personnel (including National Guard and Reservists) who have served in Operation
Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn (OEF/OIF/OND).

The primary objectives of this stage II study are to evaluate the benefits of doxazosin as
compared to placebo in reducing (1) PTSD symptomatology, (2) AUD severity, and (3) impairment
in associated mental and behavioral health problems (e.g., depression, anxiety, sleep, risky
behaviors) among OEF/OIF/OND Veterans (N=126) with co-occurring PTSD and AUD. Secondary
objectives are to characterize the underlying pathophysiology of comorbid PTSD/AUD and
identify prognostic indicators of treatment outcome using functional magnetic resonance
imaging (fMRI). In order to accomplish this the investigators will (1) employ an
intent-to-treat, double-blind, placebo-controlled randomized clinical trial that will consist
of 12 weeks of treatment with doxazosin or placebo medication; (2) examine standardized,
repeated dependent measures of clinical outcomes at 5 time points (baseline, week 4, week 8,
week 12, and 1-month follow-up); and (3) employ advanced neuroimaging methodology.

Inclusion Criteria:

1. Male or female; any race or ethnicity; age 21 to 65 years old.

2. U.S. military veteran.

3. Score of > 21 on the Mini Mental Status Exam.

4. Subjects must be able to comprehend English.

5. Meet DSM-5 criteria for current (i.e., last 6 months) alcohol use disorder (AUD).

6. Meet DSM-5 criteria for current (i.e., last 6 months) PTSD.

7. Enrolled in the VAMC Substance Abuse Treatment Clinic (SATC) program.

8. Subjects taking psychotropic medications will be required to be maintained on a stable
dose for at least eight weeks before treatment initiation.

9. Must consent to random assignment to doxazosin or placebo.

10. Must consent to complete all treatment and follow-up visits.

11. Must live within 50 miles of the Ralph H. Johnson VAMC in Charleston, SC.

Exclusion Criteria:

1. DSM-5 criteria for a history of or current psychotic or bipolar affective disorders,
current eating disorder, as the study protocol may be therapeutically insufficient.

2. DSM-5 criteria for another substance use disorder, except caffeine or nicotine, within
the past 12 months.

3. Subjects experiencing significant withdrawal symptoms, as evidence by a score of 10 or
above on the Clinical Institute Withdrawal Assessment of Alcohol (CIWA).These subject
will be referred for clinical detoxification and may be re-assessed for study
eligibility after medically supervised detoxification has been completed.

4. Individuals considered an immediate suicide risk based on the Columbia Suicide
Severity rating Scale (C-SSRS) or who are likely to require hospitalization during the
course of the study.

5. Previous treatment with doxazosin.

6. Subjects on maintenance anxiolytic, antidepressant, or mood stabilizing medications
which have been initiated during the past four weeks. If it is determined, based on
clinical criteria, that a subject needs to be started on maintenance medications for
anxiety, mood or psychotic symptoms during the course of the study, they will be
discontinued from the treatment trial.

7. Women who are pregnant, nursing or not practicing an effective form of birth control.

8. Individuals with a history of or current medical illness including unstable angina,
myocardial infarction, congestive heart failure or other cardiac condition,
hypotension or hypertension, renal or hepatic disorders, endocrine disorders, prostate
or other cancer, pancreatitis, or a seizure disorder.

9. Subjects with abnormal liver function test (LFTs) as evidenced by laboratory findings
of SGOT or SGPT greater than two times normal.

10. Subjects with a history of adverse reactions to quinazolines or other
alpha-1-antagonists (such as allergic reactions, priapism, hepatitis, angioedema, or
intraoperative floppy iris syndrome).

11. Individuals currently taking medications to treat hypertension, trazodone,
hypnotics/benzodiazepines, mirtazapine, atypical antipsychotics, alpha-2-agonists,
prazosin, conivaptan, boceprevir, fusidic acid, idelalisib, PDE-5 inhibitors or
alpha-1-antagonists.

12. MRI exclusions: Claustrophobia; tattoos above shoulders; permanent eyeliner or
eyebrows; cardiac pacemaker; metal fragments in eye, skin, or body, including
shrapnel; heart valve replacement; brain clips; venous umbrella; being a sheet-metal
worker or welder; history of aneurysm surgery; intracranial bypass, renal, or aortic
clips; prosthetic devices such as middle ear, eye, joint, or penile implants; joint
replacements; non-removable hearing aid, neurostimulator, or insulin pump;
shunts/stents; metal mesh/coil implants; metal plate/pin/screws/wires; or any other
metal implants.