Leveraging Biomarkers for Personalized Treatment of Alcohol Use Disorder Comorbid With PTSD

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, and
present a clinical challenge for which existing treatments have limited efficacy. Existing
clinical evidence suggests treatments that simultaneously address symptoms of both PTSD and
AUD should be more efficacious than treating either disorder in isolation. The overlap in the
neurobiological basis of PTSD and AUD (involving alterations in incentive salience,
stress/negative affect, and executive control network functioning) suggests that there could
be treatments that would effectively treat both disorders. However, there is no
pharmacotherapy or psychotherapy treatment that is clearly effective for both disorders.

Topiramate, an FDA-approved anticonvulsant with effects on GABAergic and glutamatergic
signaling, has demonstrated efficacy in the treatment of AUD in several randomized clinical
trials (RCTs), and has also been tested in several open-label and small RCTs for treatment of
PTSD with some evidence of effectiveness. Positive results in one open-label trial and one
small RCT in patients with co-occurring PTSD and AUD suggest that topiramate may have
beneficial effects on symptoms of both PTSD and AUD in this population. Preclinical work also
supports the efficacy of topiramate in ameliorating anxiety-like behavior and altered stress
response in animal models of stress and chronic alcohol exposure. A recent clinical study
demonstrated that the effects of topiramate on alcohol use were moderated by a polymorphism
of the GRIK1 gene (coding for the kainate receptor GluK1 subunit), such that significant
benefit was found only among rs2832407 C-allele homozygotes.

This trial is designed to contrast acute and persisting effects of topiramate to those of
placebo treatment in a sample of 150 participants with comorbid PTSD and moderate to severe
AUD, and to evaluate the moderating effect of rs2832407 genotype on medication effects. Drug
will be titrated over 8 weeks to a maximum dose of 200 mg and continued for 4 more weeks for
a total of 12 weeks of treatment, followed by a 2-week taper. Alcohol and PTSD-related
outcomes will be assessed at multiple time points throughout the study. Plasma biomarkers and
neuropsychological assessments will be obtained at baseline and at week 12. In support of the
overall aims of the center focusing on personalized medicine, the trial will serve as a
platform for studies of topiramate's effects on brain chemistry and function as measured by
fMRI, and EEG . Data from this clinical trial will also contribute to Overall Center Aims
investigating the relationship of plasma biomarkers to neuroimaging markers.

Inclusion Criteria:

- DSM-5 80 diagnosis of moderate or severe AUD;

- endorse desire to cut down or stop drinking;

- At least 10 heavy drinking days in the month prior to screening, as assessed by the
Time Line Follow Back (TLFB) 81,82;

- DSM-5 diagnosis of PTSD;

- Clinician Administered PTSD Scale for DSM-5 (CAPS-5) current symptom score > 25;

- If female of childbearing potential, are willing to use approved form of contraception
for the duration of the trial (Acceptable methods of contraception include oral
contraceptives, barrier with spermicide, IUD, levonorgestrel implant (Norplant ®),
medroxyprogesterone acetate (Depo Provera ®), surgical sterilization, contraceptive
patch, vaginal contraceptive ring, and complete abstinence (not having sex));

- able to provide at least 2 locators;

- able to provide voluntary informed consent.

Exclusion Criteria:

- Current alcohol withdrawal (AW), evidenced by CIWA-Ar scale > 7

- Severe psychiatric conditions, including past or current DSM-5 diagnosis of
schizophrenia, schizoaffective disorder, bipolar disorder, or current suicidality;

- DSM-5 diagnosis of current moderate or severe substance use disorder for a substance
other than alcohol or nicotine;

- Traumatic brain injury involving current concussive symptoms or a Post-Concussion
Syndrome score greater than or equal to 12

- Exposure to trauma in the last 30 days, including police duty or military service;
significantly impaired liver function, defined as a) alanine aminotransferase (ALT)
and/or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN); b) ALT or
AST > 3 × ULN with concomitant total bilirubin > 2.0 × ULN; or c) ALT or AST ≥ 3 × ULN
with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or
tenderness, fever, rash, and/or eosinophilia;

- other medical conditions which would preclude safe participation in the study;

- significant laboratory abnormalities, including significantly impaired hepatic
function, abnormalities in complete blood count or metabolic panel;

- serious ECG abnormalities (e.g., evidence of ischemia, myocardial infarction);

- current use of exclusionary medications, including antidepressants, antipsychotics,
anticonvulsants, psychostimulants, and pharmacologic treatments for addictions
including alcohol use disorder

- pregnancy or lactation,

- current treatment for substance use disorder or PTSD;

- allergy or hypersensitivity to topiramate; and

- active legal problems likely to result in incarceration within 12 weeks of treatment
initiation.