Piogliatazone for Alcohol Craving

Objective: The objective of the present study is to evaluate the role of proinflammatory
signaling in alcohol craving. The peroxisome proliferator-activated receptor y (PPARy)
agonist pioglitazone, which modulates glial activity, will be used as an experimental
treatment. Guided imagery auditory scripts will be used as an established set of stimuli to
induce craving. Low dose lipopolysaccharide (LPS) administration which activates
proinflammatory signaling will be used as a novel challenge, and evaluated for its ability
to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will
allow evaluation of whether pioglitazone can inhibit this response.

Study population: Up to 60 subjects will be recruited for a target accrual of 50 completers.
Subjects will be aged 21-65 years, with alcohol dependence as their primary complaint, and
without other serious medical or psychiatric conditions. They will be admitted to the NIAAA
research inpatient unit at the NIH Clinical Research Center (CRC) through one of the
screening protocols (05-AA-0121 Assessment and Treatment of People with Alcohol Drinking
Problems ) or 14-AA-0181 "Unit and Clinic Evaluations, Screening, Assessment, and
Management") which provides basic assessments and standard withdrawal treatment if needed.

Design: Following inclusion, subjects will undergo interviews for construction of guided
imagery scripts, and these scripts will subsequently be used as stress-, alcohol- or neutral
condition associated stimuli. Subjects will be randomized to pioglitazone (n=25; final dose:
45mg/daily) or identically looking placebo (n=25). Following at least two weeks of
treatment, subjects will undergo three sessions of guided imagery, on separate days and in a
counter-balanced order, exposing them to the personalized stress-, alcohol- or neutral
condition associated auditory scripts, respectively. During the final week, subjects will
undergo two challenge sessions, a minimum of five days apart, with lipopolysaccharide (LPS)
or placebo, in counterbalanced order.

Outcome measures: Subjective ratings of mood, anxiety and craving will be obtained twice
weekly throughout the study. During the challenge sessions that utilize psychological
stimuli or LPS, subjective ratings of craving for alcohol, as well as ratings of negative
emotions will be obtained. Lumbar puncture will be performed and cerebrospinal fluid (CSF)
obtained to determine the effect of pioglitazone on levels of proinflammatory cytokines.
Neuroendocrine, psychological and physiological measures will be collected for exploratory
purposes. An fMRI scan will be obtained to evaluate the effect of pioglitazone on BOLD
signal in response to emotionally salient visual cues.

- INCLUSION CRITERIA:

1. DSM-IV diagnosis of alcohol dependence on Structured Clinical Interview for DSM
Diagnosis alcohol problems as primary complaint among substance use disorders,
and alcohol use within the last month.

2. Age 21 65

3. Right handed

4. For women:

1. post-menopausal or surgically sterile (tubal ligation or hysterectomy); or

2. if sexually active with a male partner and able to get pregnant, documented
agreement to use an effective form of birth control. Acceptable forms of
contraception for this study include: hormonal contraceptives
(birth-control pills, injectable hormones, vaginal-ring hormones); IUD;
diaphragm with spermicide; condom with permicide.

EXCLUSION CRITERIA:

1. Any medical illness that in the view of the investigators would compromise
participation in research, as determined by medical history, physical examination,
laboratory tests (see details under Screening measures below), including, but not
limited to:

1. Diabetes mellitus Type I or Type II

2. Past or current diagnosis of congestive heart failure

3. Signs and symptoms suggestive of congestive heart failure

4. Cardiovascular disease (e.g., history of congenital heart defect, heart disease,
symptomatic coronary-artery disease, heart attack, clinically significant
arrhythmia, etc.)

5. Cerebrovascular disease

6. Infection, autoimmune disease, or fever of unknown origin

7. Unexplained history of syncope

8. History of seizures, except for febrile seizures during childhood

9. History of head injury with loss of consciousness of more than 30 minutes or
with postconcussive sequelae lasting more than two days, regardless of loss of
consciousness

10. Chronic renal failure as estimated by glomerular filtration rate (GFR) < 60
milliliters per minute 1.73 per Square

11. HIV infection

12. Active bladder cancer, history of bladder cancer, or persistent hematuria

13. Allergy, hypersensitivity, or intolerance to pioglitazone, other TZD s, or the
metabolites of any of those drugs (determined by medical history)

14. Pregnancy or breastfeeding (urine pregnancy test; self-report)

15. Diabetes medications (e.g., sulfonylureas, metformin, insulin, etc.)

16. Contraindicated or strongly interacting medications: Gemfibrozil (inhibitor of
CYP2C8) and rifampin (inducer of CYP2C8), atorvastatin, ketoconazole, nifedipine

17. Any ongoing, or regular use of CNS active medications within the last week
(fluoxetine: last 4 weeks), with the exception of withdrawal medication,
obtained according to the NIAAA clinical guidelines if needed

18. Use of DHA dietary supplements, or consumption of oily fish > 3 times per week
(because of effects of DHA on inflammatory parameters)

19. History of Rhabdomyolysis

2. Psychiatric history:

1. Cognitive impairment severe enough to preclude informed consent or valid
responses on questionnaires, as established by clinical exam, in questionable
cases aided by a Mini Mental State Examination (with a score of < 21, indicating
more than mild cognitive impairment, being exclusionary)

2. Current diagnosis of schizophrenia or any other DSM-IV psychotic disorder,
bipolar disorder, or major depressive disorder, in each case as established by
clinical evaluation and SCID.

3. Substance use disorders:

1. Current alcohol intoxication on breathalizer test or positive urine drug screen
on enrollment

2. Current dependence on drugs other than alcohol or nicotine, as established by
SCID interview

4. Inability or unwillingness to participate in an fMRI scan, including

1. Presence of ferromagnetic objects in the body that are contraindicated for MRI
of the head (pacemakers or other implanted electrical devices, brain
stimulators, some types of dental implants, aneurysm clips, metallic prostheses,
permanent eyeliner, implanted delivery pump, or shrapnel fragments) or fear of
enclosed spaces. Eligibility will be determined by a MRI Safety Screening
Questionnaire and verified, if necessary, by a physician.

2. Subjects that cannot lie comfortably flat on their back for up to 2 hours in the
MRI scanner.