Deep Brain Stimulation for Refractory Alcoholism

Objective

The purpose of this pilot clinical study is to test the safety and efficacy of deep brain
stimulation (DBS) of the nucleus accumbens, ventral striatum and ventral capsule in patients
with treatment-resistant alcoholism and to provide critical information for planning
subsequent clinical trials, including additional experience with the safety of this
procedure.

Study Population

Ten patients 21 to 60 years of age with severe, treatment-resistant alcoholism will be
enrolled in this study.

Design

This study is a randomized, sham-controlled trial with open-label extension exploring the
use of DBS of the nucleus accumbens, ventral striatum, and ventral capsule in ten healthy
alcohol dependent men and women who have failed repeated alcoholism treatments.

Neurosurgical implantation of the DBS in the nucleus accumbens, ventral striatum and ventral
capsule will be performed. Following surgery but prior to initiation of the titration phase,
baseline cognitive and behavioral testing will be performed. Approximately four weeks
following placement of the electrodes, a randomized, sham-controlled trial with an
open-label extension will be instituted whereby participants will be randomized and blinded
to undergo either titration for two weeks followed by 24 weeks with the DBS system ON, or
titration followed by 24 weeks with the DBS system OFF.

After 24 weeks with DBS ON or OFF, the open-label extension phase will occur. All
participants will be readmitted to the hospital for the second two-week titration period.
The cognitive and behavioral assessments performed at baseline will be repeated. Following
the inpatient titration phase, they will be discharged from the hospital and followed in the
outpatient clinic for 24 weeks with the DBS ON. Cognitive and behavioral assessments which
were performed at baseline will be repeated at the end of this 24-week period. Participants
will be followed monthly after this time for 9 months, for a total of approximately 24
months of active enrollment.

Outcome Measures

Primary Outcome Measures:

Safety: Risks associated with DBS for alcoholism

Efficacy: Alcohol consumption as measured by Alcohol Timeline Followback (TLFB).

Secondary Outcome Measures:

Secondary outcome measures include: 1) change in processing of rewards and punishments as
measured in decision-making tasks, 3) change in mood as measured by Comprehensive

Psychopathological Rating Scale (CPRS), 4) change in participation in social, physical, and

rehabilitative activities as measured by the Mayo-Portland Adaptability Inventory-4
(MPAI-4), 5) change in overall life satisfaction as measured by the Satisfaction with Life
Scale (SWLS), 6) change in alcohol craving as measured by the Penn Alcohol Craving Scale
(PACS), and (7) number of alcohol relapses and time to alcohol relapse.

- INCLUSION CRITERIA:

1. Enrolled in 05-AA-0121.

2. Age 21-60 years at time of enrollment.

3. Fulfills DSM-IV diagnostic criteria for alcohol dependence.

4. Has no current DSM-IV substance dependence diagnoses except for alcoholism and
nicotine dependence.

5. Has demonstrated greater than 10 years of refractory symptoms of alcohol
dependence.

6. Has failed two or more detoxification and rehabilitation treatment programs
(both inpatient and outpatient).

7. Has failed two or more community and self-help programs.

8. Has failed standard psychotherapeutic and pharmacological treatments.

9. Is unable to remain sober for more than a 6-month period (excluding periods of
incarceration, inpatient treatment programs, or in a closely supervised
therapeutic community) in the last 5 years.

10. Has serious psychological and/or psychosocial consequences of alcohol
dependence.

11. Has a stable living arrangement (e.g., living in proximity to people who will
assist with monitoring subject s behavior, encouraging subjects to attend
clinic visits, and providing contact information) that will provide reasonable
assurance that they will participate in follow-up evaluations following DBS
implantation.

12. Is able to comprehend the consent form and provide informed consent.

13. Is fluent in the English language.

- A physician outside of the intramural NIAAA program, who is an expert in the
treatment of substance abuse, will review each candidate s coded records prior to
enrollment. The purpose of this review is to assure that the candidate has severe,
treatment resistant alcoholism (as defined by criteria 5-10).

EXCLUSION CRITERIA:

1. Has medical problems requiring intensive medical or diagnostic management, including:

1. a diagnosis of acute myocardial infarction or cardiac arrest within the previous
6 months

2. history of a neurosurgical ablation procedure

3. any medical contraindications to undergoing DBS surgery

4. history of hemorrhagic stroke

5. life expectancy of < 3 years

2. Has abnormal coagulation lab studies, defined as INR > 1.4, abnormal PT/PTT.

3. Has liver function tests > 3 times the upper limit of normal (ULN).

4. Has infection with the Human Immunodeficiency Virus (HIV), because of the potential
for CNS involvement which might confound the analysis of study outcomes.

5. Is participating in other clinical trials that would compromise the ability to
determine the safety and efficacy of this study.

6. Has a past or present diagnosis of schizophrenia, bipolar disease, or any psychotic
disorder other than one determined to be substance induced; past or present diagnosis
of dementia or any other disorder which has led to a clinically significant cognitive
impairment.

7. Has manifested behaviors such as violence which, in the investigator s judgment,
could lead to non-compliance with study procedures.

8. Is unable to undergo MR-imaging because of implanted pacemakers, medication pumps,
aneurysm clips, metallic prostheses (including metal pins and rods, heart valves or
cochlear implants), shrapnel fragments, permanent eye liner or small metal fragments
in the eye that welders and other metal workers may have, or if candidates are
uncomfortable in small closed spaces (have claustrophobia), or cannot lie comfortably
on their back for up to one hour

9. Has known destruction and/or damage to the nucleus accumbens, ventral striatum and
ventral capsule region as determined by MRI.

10. Has documentation of an MRI abnormality indicative of a neurological condition that
may jeopardize the subject s safety, the conduct of the study, or confound the
subject s diagnosis or assessments.

11. Has been evaluated and judged by a board certified psychiatrist to be either severely
depressed or an imminent risk for suicide or violent behavior in spite of optimal
medical treatment.

12. Is unlikely or unable to complete the clinical trial because they are likely to be
incarcerated while on the protocol.

13. Is required to receive treatment by a court of law or is involuntarily committed to
treatment.

14. Is pregnant (negative pregnancy test required) or planning to become pregnant.

15. Has a history of seizures (including alcohol withdrawal seizures), other than
documented febrile seizures.