Ketamine for Depression and Alcohol Dependence

Major depression and alcohol dependence are both within the ten disorders for highest
worldwide disease burden as identified by the World Health Organization (WHO), and these
disorders frequently co-occur, especially in high-service utilizing patients with severe and
persistent mental illness. Currently available treatments are inadequate for both chronic
conditions alone, and the inadequacy is even clearer in people meeting criteria for both
disorders. Ketamine was first reported as a rapidly-acting antidepressant in 2000 via
research occurring at Yale, and, since that time, in several small randomized controlled
trials, a single subanesthetic dose of intravenous ketamine has demonstrated efficacy in
improving mood in unipolar and bipolar depression within only hours after administration.
These effects can last at least a week. Interestingly, ketamine has been demonstrated to
produce a more robust effect in treatment-refractory unipolar depressed subjects with a
family history of alcoholism relative to similarly difficult-to-treat subjects without a
family history of alcohol problems. In addition, recently-detoxified alcoholics have been
safely administered subanesthetic doses of ketamine, and, during these infusions, alcoholics
(and even those with only a family history of alcoholism) displayed a differential response
to ketamine, e.g. blunted psychotic-like and cognitive effects, relative to healthy
controls. Therefore, ketamine may reduce depressive symptoms and alcohol consumption
compared to placebo in patients with comorbid major depression and current alcohol
dependence. Positive results will mark a major advance in the clinical care of those being
treated for both conditions and will open the door for further scientific investigations
into the clinical neuroscience of these highly comorbid and prevalent conditions.

This is a two phase, double-blind, randomized, placebo-controlled, cross-over,
proof-of-concept study designed to determine the effects of a single dose of ketamine,
administered IV, on mood and alcohol consumption, in psychotropic medication-free patients
meeting DSM-IV-TR criteria for a major depressive episode (MDE) and current alcohol
dependence. Participants will be assigned randomly to receive either intravenous ketamine
(0.5mg/kg) or saline solution 2 weeks apart in a cross over design. The ketamine dose was
based on previous studies in patients with depression and bipolar disorder. A team member
experienced with ketamine infusions will administer the study medication over a 40-minute
infusion in a blinded fashion at the Biological Studies Unit at the WHVA.

20 depressed alcohol dependent subjects between the ages of 21-65 will be recruited for this
study through advertising and the West Haven VA clinics. Subjects will complete an informed
consent process and will be thoroughly screened for inclusion and exclusion criteria as
described below. Individuals will be given a post consent test to evaluate their
understanding of the procedure. For subjects who provide incorrect answers to any of the
test items, the research staff will review the correct answers with the subject and show the
subject where the correct answers are found in the consent form. Those who get more than 60%
of the questions wrong and are still unable to understand the procedure after reviewing it
with the research staff will be excluded from the study. They will be referred to
appropriate resources for outpatient treatment of their depression and alcoholism. Before
start of the study all patients will be free of any psychotropic medications.

Inclusion Criteria:

1. Male or female (post-menopausal, surgically sterile or negative pregnancy test at
screening and agreement to utilize a medically-approved birth control method
including complete abstinence during the testing period) between the age of 21 and 65
years old.

2. Able to provide written informed consent according to the WHVA and Yale HIC
guidelines.

3. Medically and neurologically healthy on the basis of medical history, physical
examination, EKG, and screening laboratories (CBC w/ differential, basic metabolic
profile including BUN/creatinine, TSH, fT4, AST, ALT, GGT, total protein, albumin,
vitamin B12, folate, VDRL, HIV, hepatitis B and C, urinalysis, HCG, and urine
toxicology screen). Predefined exclusion criteria are identified, e.g. LFTs > 3x
upper limit of normal. Individuals with stable medical problems that do not have
direct CNS effects, e.g. hypertension and diabetes mellitus, or interfere with
medications administered, e.g. oral hypoglycemics, may be included if their
medications have not been adjusted in the month prior to study enrollment.

4. Current DSM-IV-TR major depressive episode (MDE) by structured clinical interview
(SCID) and a MADRS score ¬>20.

5. Current DSM-IV-TR alcohol dependence with one heavy drinking day (> 4 standard
drinks/session for men and > 3 standard drinks/session for women) in the last 3
weeks.

6. Abstinent from drinking for > 5 days prior to receiving ketamine.

7. No current psychotropic medications (excluding benzodiazepines during alcohol
detoxification if needed) in last 2 weeks (4 weeks for fluoxetine).

8. Individuals who have completed a detoxification program and who are at least 5 days
past their last drink.

Exclusion Criteria:

1. Unstable medical condition or medical problem with known CNS effects, e.g.
uncontrolled hypertension (SBP≥170 and/or DBP≥100) or confirmed history of
alcohol-withdrawal seizures.

2. Active suicidal ideation, intent or plan.

3. Active DSM-IV-TR substance use disorder in past three months (other than an alcohol
or nicotine use disorder).

4. Prior diagnosis of a DSM-IV-TR psychotic spectrum disorder, e.g. schizophrenia,
schizoaffective disorder, bipolar I d/o with psychotic features, MDD with psychotic
features.