Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics

Description of Proposed Study A. Scientific Basis: 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 the frequent use of serotonin reuptake inhibitors (SSRIs) in clinical practice,
clinical trials with these agents for alcohol use disorders have yielded mixed results
concerning their impact on drinking behavior.

The characterization of alcohol-dependent subjects on the basis of demographic variables,
severity of addiction, and psychiatric symptomatology has revealed a divergence in response
to treatment with SSRIs among different subtypes of alcoholics (less severe "Type A" vs. more
severe "Type B" alcohol dependence. Type A alcoholics have exhibited a trend toward decreased
drinking behavior in clinical trials with SSRIs, whereas type B alcoholics showed a trend in
the opposite direction. The literature does not offer an explanation for this divergence, and
therefore, it is not clear how these research findings can be applied clinically.

As intravenous (iv) citalopram infusion (40 mg) bypasses hepatic metabolism, a single
infusion produces a clinically relevant concentration in human brain, and the brain
concentration remains stable for up to 4 h post-infusion, and is well-tolerated. A single
infusion reduces striatal dopamine receptor binding potential by a magnitude comparable to
the effect of chronic oral citalopram treatment, as measured by positron emission tomography
(PET). The subjective experience of craving for alcohol in alcohol-dependent individuals has
been associated with decreased dopamine receptor availability in the striatum via PET.

Significance of the research: Alcohol abuse and dependence occur at a higher rate in Veterans
than in the overall U.S. population, and the presence of comorbid depressive symptoms
amplifies the health risks to affected Veterans. While FDA-approved medications are available
to treat alcohol dependence, their overall efficacy is low compared to available psychosocial
treatments. Given that SSRIs are frequently utilized in Veteran populations with depressive
symptoms and alcohol use disorders, there is the certainty that many Veterans with Type B
alcohol dependence are receiving a pharmacological intervention that may exacerbate their
drinking behavior, thereby increasing morbidity. A better understanding of patient-level
clinical variables that may confer poor response to treatment with SSRIs would allow
clinicians better tools to distinguish those alcohol-dependent Veterans likely to do worse,
and prevent what was intended to be a beneficial medical intervention from worsening a
Veteran's clinical course. This research is well-suited to a Veteran population because of
the high proportion of Veterans with alcohol dependence.

C. 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 (WLAVA), in collaboration with colleagues at UCLA provides an ideal
infrastructure for this training. He will be mentored by renowned experts in these areas,
Drs. Arthur Brody, and Edythe London. 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. As part of training, the nominee will attend several courses and
workshops at UCLA in foundational neuroimaging topics with relevance to PET (statistics,
neuroimaging, neuroanatomy), as well as courses in the neurobiological bases of addiction. He
will also attend annual conferences in Alcohol Dependence (Research Society on Alcoholism
annual meeting) and neuroimaging (e.g., Society for Nuclear Medicine annual meeting), and
meet with mentors regularly. 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.

D. Project Design and Methods: 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.
Participants should be in good physical health, have no history of complicated alcohol
withdrawal symptoms (e.g., seizures, delirium tremens), be 21-55 years of age, and taking no
psychoactive medications. Typology among alcohol-dependent subjects will be assessed after
Kampman et al. (2007). The project aims: 1) To determine whether iv citalopram (40 mg)
affects measures of craving for alcohol compared to a blinded saline iv control infusion; 2)
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; and 3) to assess whether changes in striatal D2/3 receptor
availability with iv citalopram (40 mg, compared to iv saline control) is related to measures
of craving for alcohol among subjects.

E. Description of Intervention(s)/Treatment(s): Through Internet advertising, interested
participants will be invited to call a phone number for anonymous phone screening, and
individuals who pass phone screening will be invited to the WLAVA for a screening visit.
Potential subjects will meet criteria for alcohol dependence (via SCID; except for control
subjects), will have no current psychotropic medication use, will be in good physical health
(as assessed by clinical history and physical examination and laboratory assay), and have no
current dependence on other substances of abuse (SCID; aside from nicotine). After 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); at least one week will separate infusion days to allow for participants to
return to baseline functioning between sessions. After each infusion, participants will
undergo ~30 min of paper- and computer-based questionnaires designed to assess measures of
mood and other psychiatric symptoms, and ~15 min of assessment of both baseline and
cue-induced craving for alcohol. Subsequently, participants will undergo [18F]fallypride PET
scanning (~2h) to assess striatal D2/3 receptor availability. After completion of both
infusions and PET scans, participants will be discharged from the study. Participants will be
compensated for their participation according to VA research guidelines.

Inclusion Criteria:

Must be U.S. Veteran

Alcohol Dependence:

- Age between 21 and 55;

- Meeting DSM-IV diagnostic criteria for alcohol dependence;

- Report drinking at least 48 standard drinks in a 30-day period, during the 90 days
before enrollment, and

- Must have had at least 2 days of heavy drinking (at least 5 drinks/day for men, 4
drinks/day for women) in the last 30 days

Healthy Control:

- Age between 21 and 55;

- No Axis I DSM-IV diagnosis (except for nicotine dependence);

- Report drinking less than 10 drinks weekly over the past 90 days prior to study entry
by Timeline Followback Method (TLFB).

Exclusion Criteria:

Exclusion criteria for Alcohol Dependence:

- Current treatment for alcohol problems or a history of treatment in the 30 days before
enrollment or are treatment seeking;

- A current (last 12 months) DSM-IV diagnosis of dependence on any psychoactive
substances other than alcohol and nicotine.

Exclusion criteria for Healthy Controls:

- Any history of treatment for alcohol or other substance use disorders;

- Any history of DSM-IV diagnosis of dependence on any psychoactive substances other
than nicotine;

- Any history of DSM-IV diagnosis of Axis I mental illness.

Exclusion criteria for all subjects:

- A current (last 12 months) DSM-IV diagnosis of schizophrenia, bipolar disorder, other
psychotic disorder, eating disorder, panic disorder with or without agoraphobia;

- Current use of psychoactive drugs, other than occasional marijuana use (< 3 uses per
week), as determined by a positive urine screen for narcotics, amphetamines, or
sedative hypnotics;

- Serious alcohol withdrawal symptoms as indicated by a score > 10 on the Clinical
Institute Withdrawal Assessment for Alcohol-Revised (CIWA);

- Clinically significant physical abnormalities as indicated by physical examination,
hematological laboratory assay, or urinalysis, defined as: hematology and chemistry
laboratory tests that are within normal (+/- 10%) limits with the following
exceptions: a) liver function tests (total bilirubin, alanine transaminase [ALT],
aspartate aminotransferase [AST], and alkaline phosphatase) < 3 x the upper limit of
normal, and b) kidney function tests (creatinine and BUN) < 2 x the upper limit of
normal;

- A screening ECG that demonstrates anything other than normal sinus rhythm, normal
conduction, and no clinically significant arrhythmias;

- History of epilepsy, seizures, or severe head trauma;

- History of alcohol intoxication delirium, alcohol withdrawal delirium or seizure,
alcohol-induced persisting dementia, or alcohol-induced psychosis;

- Treatment with any of the following medications within the last 30 days prior to
randomization: antidepressants, anti-convulsants, hypnotics, antipsychotics,
psychomotor stimulants, or anti-anxiety agents;

- Previous treatment with citalopram discontinued due to an adverse event;

- Pregnancy, nursing, or refusal to use reliable barrier method of birth control, if
female;

- Presence of metal fragments, pacemaker, or other ferromagnetic material which would
prevent safe completion of an MRI scan;

- Recent history of radiation exposure which would make exposure to radiation from
serial PET scans contraindicated;

- Non-zero breath-alcohol level on screening. We will exclude participants who present
to study appointments intoxicated, as active alcohol intoxication may interact
unpredictably with citalopram and produce unreliable results in assessments of mood or
alcohol craving (e.g. Ray and Hutchison, 2007; Ray et al., 2011; see preliminary data
C.2. above);

- Resting vital signs on any study visit outside of acceptable parameters: Pulse of
50-105 bpm, Blood pressures of 90-160 mm Hg systolic, 55-100 mm Hg diastolic;

- Any indication of suicidal ideation (i.e. as assessed by question 9 on the Beck
Depression Inventory-II [BDI-II]), or elevated index of depressive symptoms, as
evidenced by BDI-II score of 20;

- Presence in the body of a metal device (e.g., pacemaker, infusion pump, aneurysm clip,
metal prosthesis or plate) that could either interfere with the acquisition of the MRI
scan of the brain or for whom the MRI scan would pose a potential risk will be
excluded.

- Radiation exposure: Participation in any other research study involving exposure to
ionizing radiation in the past year if the total cumulative exposure from the past
research studies and the current research study would exceed the limits described by
the FDA in 21 CFR 361.1. Specifically, the total cumulative dose to the whole body,
active blood-forming organs, lens of the eye, and gonads must remain below 5 rems, and
the cumulated dose to all other organs must remain below 15 rems over the last year.