of Proposed Study Background: Alcohol abuse and dependence represent a spectrum of maladaptive behaviors with enormous public health impact, especially for the U.S. veteran population. Depressive symptoms are frequently comorbid with alcohol use disorders, but despite their frequent use in clinical practice, clinical trials with serotonin reuptake inhibiors (SSRIs) for alcohol use disorders have been unsuccessful. In clinical trials, a divergence in response to treatment with SSRIs among different subtypes of alcoholics is seen (less severe "Type A" vs. more severe "Type B" alcohol dependence). Type A alcoholics show decreased drinking behavior in clinical trials with SSRIs, whereas type B alcoholics show increased drinking. The literature does not offer an explanation for this divergence, and therefore, it is no clear how these research findings can be applied clinically. Alcohol research is well- suited to a veteran population because of the high proportion of veterans with alcohol dependence. Program Objectives: The nominee has a strong background in clinical addiction psychiatry, and he seeks to accomplish two objectives through the proposed training program: 1) to become an expert in the field of human alcohol addiction research, and 2) to learn techniques of PET research. The nominee's work environment at the West Los Angeles Veterans Administration Medical Center, in collaboration with colleagues at UCLA provides an ideal infrastructure for this training. He will be mentored by renowned experts in these areas, Arthur Brody M.D., and Edythe London Ph.D. The mentors have several NIH and VA grant-funded ongoing studies in alcohol and other addictive disorders research with strong ties to the VA PET research infrastructure. The nominee plans to submit an NIH R01 and/or VA Merit Review grant toward the end of the award period. Long term, he plans to found an independent research career studying neuropharmacological approaches to treating and understanding substance use disorders, focusing primarily on alcohol. Design: This project proposes to study 20 individuals in each of 3 groups (Type A alcohol dependence, Type B alcohol dependence, and healthy control subjects) for a double-blinded, placebo- controlled, within-subjects, outpatient study with iv citalopram (40 mg and saline, in counter-balanced order) and [18F]fallypride PET scanning. The project aims: 1) to determine the change in striatal dopamine receptor D2/3 receptor availability (measured as binding potential for the radiotracer) with iv citalopram (40 mg) as compared to iv saline by [18F]fallypride PET scanning;2) To determine whether iv citalopram (40 mg) affects measures of cue-induced craving for alcohol compared to a blinded saline iv control infusion;and 3) to assess whether changes in striatal D2/3 receptor availability with iv citalopram (40 mg, compared to iv saline control) are related to measures of craving for alcohol among subjects. Description of Intervention(s)/Treatment(s): Interested participants will be recruited through phone screening. Qualified participants will be invited to participate in a structural magnetic resonance imaging (sMRI scan) for PET scan registration purposes, and two day-long experimental sessions at WLAVA, where they will undergo infusions with iv citalopram (40 mg and saline, double blinded). After each infusion, participants will undergo assessment of measures of mood and both baseline and cue- induced craving for alcohol. Subsequently, participants will undergo [18F]fallypride PET scanning (~90 min) to assess striatal D2/3 receptor availability. After completion of both infusions and PET scans, participants will be discharged from the study.

Public Health Relevance

Alcohol use disorders (AUDs) are highly prevalent among U.S. civilians, and even more prevalent in the U.S. Veteran population. AUDs are frequently co-morbid with depressive symptoms in psychiatric clinical populations, resulting in an increased severity of both conditions. Indeed, returning OEF/OIF Veterans have extraordinarily high rates of alcohol misuse and co-morbid psychiatric symptoms, indicating that future Veteran clinical populations will be particularly affected by AUDs. While FDA-approved medications are available to treat AUDs, their efficacy is low compared to available psychosocial treatments. Despite the lack of evidence for efficacy from controlled trials, antidepressants are frequently prescribed to clinical populations (including Veterans) with active AUDs. A better understanding of patient-level clinical variables that may confer poor response to treatment with antidepressants would allow clinicians better tools to distinguish those alcohol- dependent Veterans likely to do worse with antidepressant treatment.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2CX000624-02
Application #
8595165
Study Section
Neurobiology A (NURA)
Project Start
2012-10-01
Project End
2017-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Greater Los Angels Healthcare System
Department
Type
DUNS #
066689118
City
Los Angeles
State
CA
Country
United States
Zip Code
90073