Topiramate and Prolonged Exposure

Objectives. Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently
co-occur, and having one condition worsens the course of the other. Individuals with both
disorders exhibit worse functioning across a number of domains than individuals with either
disorder alone. Prolonged exposure therapy (PE) is among the most effective treatments for
PTSD. PE has been rated as a frontline treatment by multiple guidelines and reviews including
the VA/DoD Clinical Practice Guidelines for the treatment of PTSD. However, in studies of
individuals with PTSD and AUD, changes in alcohol use are only slightly better than in
control or standard care conditions, reductions in PTSD symptoms are sometimes modest
relative to studies of PE in PTSD patients without AUD, and rates of drop out from treatment
are high. Combining PE with medication to curb drinking shows promise to improve upon the
effectiveness of PE for individuals with comorbid AUD and PTSD, although thus far few studies
have examined combining psychotherapy and medication. Topiramate is the single medication
that has shown effectiveness for both AUD and PTSD and shows promise for reducing drinking
among individuals with AUD and PTSD. However, the effect of adding topiramate to PE to treat
comorbid AUD/PTSD has yet to be examined. The critical next step is to test a best practice
PTSD treatment, PE, together with a promising pharmacological agent, topiramate, which has
been found to be effective for both AUD and PTSD. Innovation: This application seeks to shift
current clinical practice paradigms. A refinement to existing interventions is proposed
through integration of two evidence based treatments.

Methodology. The investigators propose to use a randomized, controlled, double blind study
design to examine the effect of adding topiramate (TOP) to a best practice treatment for
PTSD, PE. Participants will be 120 male and female Veterans from all services with AUD and
PTSD. The investigators' primary aims are to determine the relative efficacy of
PE+topiramate, as compared to PE+placebo, in reducing problematic drinking, reducing PTSD
symptoms, and improving functioning and quality of life among Veterans with comorbid AUD/PTSD
at post-treatment and 3- and 6-month post-treatment follow-up. The investigators will explore
the extent to which decreases in drinking and PTSD symptoms lead to improvement in
functioning.

The proposed study has the potential to improve functional and psychological recovery for a
highly prevalent and highly impaired population of Veterans. This study will test a novel and
innovative combination of psychotherapy and medication with the goal of improving the care of
Veterans. The successful completion of this project will help change the practices that drive
treatment for Veterans who have both AUD and PTSD. The fundamental rationale for this study
is to improve the evidence base that informs how patients with AUD and PTSD can attain
sustained recovery from both of these disorders. The investigators will also explore whether
changes in PTSD symptoms in the PE+TOP condition are partially explained by reductions in
alcohol cravings.

Inclusion Criteria:

- Veteran of the U.S. military or and Reserve/National Guard member

- are at least 18 years of age

- have a BMI 18 kg/m2

- are survivors of a psychological trauma meeting DSM-5 criterion A, at least one month
post-trauma

- have current DSM-5 diagnoses of AUD and PTSD based on semi-structured diagnostic
interviews

- have at least 20 days of heavy drinking (>= 5 drinks/day for men and >= 4/drinks per
day for women) in the last 90 days spent in a non-restricted environment and meet
criteria for heavy drinking at least 4 days in the 30 days prior to screening

- are not currently receiving trauma-focused psychotherapy

- are literate in English and intend to stay in the San Diego area during study
participation

- are willing to attend psychotherapy, medication, and assessment sessions

- trying or planning to try to cut down on or abstain from alcohol

- are generally in good health, as confirmed by medical history, physical examination,
laboratory tests, and vital signs

- for females of childbearing potential, agree to use an approved form of contraception
for the duration of the study, including:

- hormonal contraceptives (e.g., oral contraceptives or implantable devices)

- intrauterine device (IUD)

- or double barrier methods (e.g., diaphragm with spermicidal condom)

- are capable of giving informed consent

Exclusion Criteria:

- based on medical history and physical examination conducted by the study physician,
report or show evidence of a clinically significant medical condition including, but
not limited to:

- symptomatic coronary artery or peripheral vascular disease

- malignancy or history of malignancy within the past 5 years (except basal cell
carcinoma)

- clinically significant renal disease and/or impaired renal function as defined by
participants with an estimated creatinine clearance of 60 mL/min

- clinically significant diseases of the gastrointestinal system including active
liver disease

- participants with AST and/or ALT >3 times the upper limit of the normal range
and/or serum bilirubin >2 times the upper limit of normal at screening

- Note: if these values are abnormal they can be retested prior to enrollment.
If the repeat study is within the limits of the protocol, the participant
may be randomized

- pulmonary disorders including participants with active tuberculosis

- endocrinological disorders

- neurological disorders including participants with seizure disorders and
participants with progressive and degenerative neurological disorders (e.g.,
multiple sclerosis)

- any disease or condition that compromises the function of those body systems that
could result in altered absorption, excess accumulation or impaired metabolism or
excretion of topiramate

- participants with myocardial infarction, unstable angina, stroke or other major
cardiovascular event within 6 months of the screening period

- have been treated with topiramate for any reason in the past and discontinued the drug
due to an adverse event or to a hypersensitivity reaction DSM-5 diagnosis of an
uncontrolled psychiatric disorder with psychotic symptoms or cognitive impairment

- in the opinion of the investigator, should not be enrolled because of the precautions,
warnings, or contraindications listed on the topiramate package insert (e.g. history
of kidney stones, glaucoma)

- have a history of nephrolithiasis

- are taking or plan to take during the study period prohibited medications including,
but not limited to

- other anti-relapse medications

- stimulants

- anxiolytics and sedative hypnotics

- herbal preparations

- other antiepileptic agents

- antipsychotics

- carbonic anhydrase inhibitors

- systemic corticosteroids

- or opioid analgesics.

- These medications will be prohibited for a washout period of five serum
half-lives

- are pregnant, lactating, or plan to become pregnant during the period of participation
in the study

- in the judgment of the investigator, represent a significant risk of suicidal or
homicidal behavior