Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics (CECDRAAD)
|First Received Date ICMJE||July 23, 2012|
|Last Updated Date||November 8, 2013|
|Start Date ICMJE||January 2014|
|Estimated Primary Completion Date||December 2016 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Craving for alcohol in type B alcohol dependence with citalopram compared to placebo [ Time Frame: 2-3 years ] [ Designated as safety issue: No ]
To assess whether craving for alcohol in type B alcohol dependence is affected by iv citalopram, compared to placebo.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01657760 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Striatal dopamine receptor availability in type B alcohol dependence with citalopram, compared to placebo [ Time Frame: 2-3 years ] [ Designated as safety issue: No ]
To assess whether striatal dopamine receptor availability in type B alcohol dependence is affected by iv citalopram, compared to placebo.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics|
|Official Title ICMJE||Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics|
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.
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 (Calhoun et al, 2008). 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 (Kampman et al., 2007).
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; Kampman et al., 2007). 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 (Kampman et al., 2007). 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 (Smith et al, 2009). 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; Smith et al., 2009). The subjective experience of craving for alcohol in alcohol-dependent individuals has been associated with decreased dopamine receptor availability in the striatum via PET (Heinz et al., 2004).
B. 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 (Calhoun et al, 2008). While FDA-approved medications are available to treat alcohol dependence, their overall efficacy is low compared to available psychosocial treatments (Soyka, et al., 2008). 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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
|Condition ICMJE||Alcohol Dependence|
|Intervention ICMJE||Drug: citalopram
citalopram, 40 mg IV, vs. saline control, each to be administered in a double-blinded, within-subjects design.
|Study Arm (s)||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Not yet recruiting|
|Estimated Enrollment ICMJE||60|
|Estimated Completion Date||December 2016|
|Estimated Primary Completion Date||December 2016 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Exclusion criteria for Alcohol Dependence:
Exclusion criteria for Healthy Controls:
Exclusion criteria for all subjects:
|Ages||21 Years to 55 Years|
|Accepts Healthy Volunteers||Yes|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01657760|
|Other Study ID Numbers ICMJE||NURA-022-11F, 8331171|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Department of Veterans Affairs|
|Study Sponsor ICMJE||Department of Veterans Affairs|
|Collaborators ICMJE||Not Provided|
|Information Provided By||Department of Veterans Affairs|
|Verification Date||November 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP