CAP: Doxazosin in the Treatment of Co-Occurring PTSD and Alcohol Use Disorders

Due to sustained military conflicts in Afghanistan and Iraq over the past decade, there are
an increasing number of U.S. military personnel and Veterans returning home with
posttraumatic stress disorder (PTSD) and comorbid alcohol use disorders (AUD) and substance
use disorders (SUD). If left untreated, Veterans with co-occurring PTSD and substance use
disorders are at increased risk for developing other mental health problems (e.g.,
depression, anxiety), suicidal ideation and attempts, physical health problems, reduced
resiliency and military readiness, employment problems, violence, and family/relationship
impairment. While mental health services are in place for U.S. service members, substantial
gaps in the treatment of co-occurring PTSD and SUD exist and there is little scientific
evidence available to guide the provision of care. As part of the Consortium to Alleviate
PTSD (CAP), the proposed study directly addresses this critical knowledge gap by testing the
efficacy of doxazosin, a long-acting and selective alpha-1 adrenergic antagonist, as compared
to placebo in reducing PTSD and AUD/SUD severity among U.S. military personnel. The
medication to be investigated (doxazosin) represents a novel treatment approach for PTSD and
AUD/SUD. While prazosin, also an alpha-1 adrenergic antagonist, has been shown to improve
sleep and nightmares in military personnel with PTSD and may help reduce substance use
severity, it has a short half-life of 2-3 hours and requires multiple doses each day, which
is a significant limitation. In several pilot studies, doxazosin has shown promise in
significantly reducing symptoms of PTSD and AUD/SUD and, in contrast to prazosin, it requires
once per day dosing which confers a significant advantage in terms of translating positive
findings into routine clinical practice. In this Stage II study, the investigators will (1)
employ a two-arm randomized, double-blind, between-groups experimental design that will
consist of 12 weeks of treatment with doxazosin or placebo medication; (2) use standardized,
repeated dependent measures to rigorously assess PTSD symptomatology and AUD/SUD severity;
(3) measure impairment in associated mental and behavioral health problems (e.g., depression,
anxiety, sleep, risky behaviors, family/social functioning); and (4) use functional magnetic
resonance imaging (fMRI) to investigate the underlying pathophysiology of comorbid PTSD/AUD
and identify prognostic indicators of treatment outcome. To achieve these aims, the
investigators have assembled a multidisciplinary team of investigators with
nationally-recognized expertise in combat-related PTSD, substance use disorders and
neuroimaging who have successfully collaborated in the past and are uniquely qualified to
implement this type of investigation. The investigators represent a collaboration of faculty
at the Ralph H. Johnson Veterans Affairs (VA) Medical Center and the Medical University of
South Carolina (MUSC) in Charleston, SC.

Inclusion Criteria:

1. Male or female; any race or ethnicity.

2. Served in U.S. Military - any branch or operation.

3. Subjects must be able to comprehend English.

4. Meet criteria for current (i.e., last 6 months) Substance Use Disorder (SUD) using a
modified version of the MINI 7.0 (i.e., must meet DSM-5 criteria for SUD in the past 6
months instead of 12 months).

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

6. Subjects taking psychotropic medications will be required to be maintained on a stable
dose for at least four weeks before treatment initiation. This is because initiation
or change of medications during the course of the trial may interfere with
interpretation of results.

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

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

Exclusion Criteria:

1. Subjects meeting DSM-5 criteria for current bipolar affective disorders, as the study
protocol may be therapeutically insufficient.

2. 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.

3. Individuals considered an immediate suicide risk or who are likely to require
hospitalization during the course of the study.

4. Previous treatment with doxazosin.

5. 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 may be
discontinued from the treatment trial.

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

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

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

9. 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).

10. Individuals currently taking alpha blockers (terazosin, prazosin),
hypnotics/benzodiazepines, atypical antipsychotics (olanzapine, quetiapine,
risperidone, clozapine), alpha-2-agonists (Clonidine, methyldopa, tizanidine,
guanfacine), conivaptan, boceprevir, idelalisib, PDE-5 inhibitors or
alpha-1-antagonists, protease inhibitors (treatment of HIV), oral antifungals,
alfuzosin, pazopanib, silodosin, tadalafil, or tamulosin.

11. MRI exclusions: Claustrophobia; tattoos above the shoulders after evaluation by MRI
technician; permanent eyeliner or permanent artificial 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; lifetime 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.