Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics
Condition: Alcohol Dependence
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 1

Summary: 
      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 Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (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.
    

Detailed description: 
      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.
    

Intervention name(s): citalopram
Intervention type(s): Drug
Intervention description(s): citalopram, 40 mg IV, vs. saline control, each to be administered in a double-blinded, within-subjects design.
Intervention MeSH terms: Citalopram
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: craving; dopamine; citalopram; ssri