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Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics (CECDRAAD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01657760
First received: July 23, 2012
Last updated: September 9, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Alcohol Dependence
Drug: citalopram
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Citalopram Effects on Craving and Dopamine Receptor Availability in Alcoholics

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 60
Study Start Date: April 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Arm 1
Intravenous citalopram, 40 mg vs. saline control, in a double-blind, crossover study, with infusion days at least 2 weeks apart.
Active Comparator: citalopram infusion
40 mg citalopram in 250 ml saline infused over 1 hour, in a double-blind, crossover study, with infusion days at least 2 weeks apart.
Drug: citalopram
citalopram, 40 mg IV, vs. saline control, each to be administered in a double-blinded, within-subjects design.

  Hide Detailed Description

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 (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.

  Eligibility

Ages Eligible for Study:   21 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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 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, ALT, 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 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 acquis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01657760

Contacts
Contact: Todd S Zorick, MD PhD Todd.Zorick@va.gov
Contact: Arthur L Brody, MD arthur.brody@va.gov

Locations
United States, California
VA Greater Los Angeles Healthcare System, West Los Angeles, CA Recruiting
West Los Angeles, California, United States, 90073
Contact: Todd S Zorick, MD PhD       Todd.Zorick@va.gov   
Contact: Arthur L Brody, MD       arthur.brody@va.gov   
Principal Investigator: Todd S. Zorick, MD PhD         
Sponsors and Collaborators
Investigators
Principal Investigator: Todd S. Zorick, MD PhD VA Greater Los Angeles Healthcare System, West Los Angeles, CA
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01657760     History of Changes
Other Study ID Numbers: NURA-022-11F, 8331171
Study First Received: July 23, 2012
Last Updated: September 9, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
craving
dopamine
citalopram
ssri

Additional relevant MeSH terms:
Alcoholism
Alcohol-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Citalopram
Dexetimide
Dopamine
Dopamine Agents
Anti-Dyskinesia Agents
Antidepressive Agents
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Autonomic Agents
Cardiotonic Agents
Cardiovascular Agents
Central Nervous System Agents
Cholinergic Agents
Cholinergic Antagonists
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Parasympatholytics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Psychotropic Drugs
Serotonin Agents

ClinicalTrials.gov processed this record on November 25, 2014