A Study of Quetiapine and Mirtazapine for the Treatment of Alcohol Dependency

Alcohol dependence is a debilitating illness affecting almost 8 million people annually and
for which the current FDA approved medications are only modestly effective in reducing
relapse or drinking. Because alcohol dependence is such a common, devastating disease,
researchers continue to search for new treatments that could be more effective and better
tolerated. The development and testing of medications that target brain systems involved in
alcohol dependence is of acute interest to patients, clinicians and researchers.

Studies by our group in animals have suggested that medications with a combination of a weak
dopamine D2 receptor antagonism, a potent norepinephrine alpha 2 receptor antagonism, and
norepinephrine reuptake inhibition decrease alcohol drinking. Quetiapine is a weak D2
antagonist and a moderate alpha 2 receptor antagonist, and its primary metabolite,
desalkylquetiapine, is a norepinephrine reuptake inhibitor, this medication is likely to have
some ability to decrease alcohol drinking. But, when combined with mirtazapine, a potent
alpha 2 antagonist, the combination should potently decrease alcohol drinking. The proposed
study is based on this theoretical formulation, as well as on clinical studies of quetiapine
and mirtazapine used independently.

This is an open-label, sequential design study with one group of approximately 20 subjects
studied under two treatment conditions; quetiapine alone and quetiapine + mirtazapine. The
primary objective is to assess the efficacy of quetiapine fumarate extended-release (XR)
alone vs. quetiapine fumarate XR in combination with mirtazapine in reducing the weekly
percentage of days of heavy drinking (5 or more drinks per drinking day for men, 4 or more
drinks per drinking day for women) in subjects meeting DSM-IV criteria for alcohol
dependency.

Participants will begin with quetiapine fumarate XR up to a target dose of 400 mg and will
receive 16 weeks of treatment with quetiapine. At week 8 subjects will begin 9 weeks of
mirtazapine added to their existing regimen of quetiapine treatment. Participants will also
meet with a medical provider at each visit to encourage compliance with study medication and
attending study visits, review adverse events, and set goals for reduction of drinking.
Analyses will assess whether treatment with quetiapine in combination with mirtazapine
reduces drinking more than treatment with quetiapine alone.

Inclusion Criteria:

1. Age 18-64

2. The subject meets Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
(DSM-IV) criteria for alcohol dependence

3. The subject is seeking treatment for alcohol dependence and desires a reduction or
cessation of drinking

4. The subject is able to verbalize understanding of the consent form, able to provide
written informed consent, and able to verbalize willingness to complete study
procedures?

5. If the subject is female and of child bearing potential, she agrees to use an
acceptable method of birth control.

6. The subject is able to take oral medication, willing to adhere to the medication
regimen, and willing to return for regular visits.

7. The subject is able to understand written and oral instructions in English and able to
complete the questionnaires required by the protocol.

8. The subject has a breath alcohol concentration (BAC) equal to 0.000 on s/he signing
the informed consent document.