Effects of Sulfasalazine on BOLD Response to Alcohol Cues

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Kent Hutchison, Ph.D., The Mind Research Network
ClinicalTrials.gov Identifier:
NCT01312129
First received: March 9, 2011
Last updated: September 18, 2014
Last verified: September 2014

March 9, 2011
September 18, 2014
March 2010
September 2011   (final data collection date for primary outcome measure)
% BOLD Response Increase Above Baseline [ Time Frame: Over two weeks ] [ Designated as safety issue: No ]
Test whether Sulfasalazine, as compared to placebo, diminishes blood-oxygen-level dependent (BOLD) response to alcohol cues in the striatum and prefrontal cortex (PFC). BOLD response refers to brain activation in response to the presence of oxygen in a particular part of the brain. To test the hypothesis, we will compare Sulfasalazine treatment with placebo treatment. During the fMRI scan session, participants will be presented with the alcohol cue task. We will compare the difference in BOLD response during the presence of alcohol vs. a novel substance during the alcohol cue task. Outcome data collected during the alcohol cue task will provide us with BOLD response data for each intervention period. We will analyze the outcome data using FSL (Oxford Centre for Functional MRI of the Brain (FMRIB) Software - a collection of functional and structural brain image analysis tools).
Blood-Oxygen-Level Dependent (BOLD) Response [ Time Frame: After each MRI session ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01312129 on ClinicalTrials.gov Archive Site
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Effects of Sulfasalazine on BOLD Response to Alcohol Cues
Effects of Sulfasalazine on BOLD Response to Alcohol Cues

The overarching objective of this pilot study is to apply both neuroimaging and pharmacogenetic tools to the study of alcohol dependence. This proposed research will provide a mechanistic test of the function of the genetic variation. The specific aims and hypotheses are to test whether Sulfasalazine, as compared to placebo, diminishes blood-oxygen-level dependent (BOLD) response to alcohol cues in the striatum and prefrontal cortex (PFC). To test the hypothesis, we will compare Sulfasalazine treatment with placebo treatment on BOLD difference maps for the contrast alcohol minus control. We will also explore whether specific genetic variations influence this effect. A double-blind, placebo-controlled 2 (Medication: Sulfasalazine 1500 mg vs. placebo control) x 2 (Cue: Alcohol Cue vs. Control cue) within-subjects, crossover design will be used to test the hypothesis that Sulfasalazine reduces the BOLD response in the striatum and prefrontal cortex after exposure to alcohol cues. Twenty alcohol-dependent participants will complete two rounds of the study medication followed by an functional magnetic resonance imaging (fMRI) scan, during which they will complete an alcohol cue-exposure task. The order of the medication condition will be counterbalanced such that subjects will be randomly assigned to receive either Sulfasalazine (1500 mg) in the first session and placebo in the second session one week later (or vice versa). This pilot study will help to determine whether NMDA receptors play a role in cue-elicited activation of key areas of the brain implicated in the development and maintenance of substance use disorders. Furthermore, if Sulfasalazine reduces cue-elicited activation of these brain regions, as hypothesized; this study will lay the groundwork for a larger trial on the efficacy of Sulfasalazine as a treatment for substance use disorders.

The overarching objective of this pilot study is to apply both neuroimaging and pharmacogenetic tools to the study of alcohol dependence. This proposed research will provide a mechanistic test of the function of the genetic variation. The specific aims and hypotheses are to test whether Sulfasalazine, as compared to placebo, diminishes blood-oxygen-level dependent (BOLD) response to alcohol cues in the striatum and prefrontal cortex (PFC). To test the hypothesis, we will compare Sulfasalazine treatment with placebo treatment on BOLD difference maps for the contrast alcohol minus control. We will also explore whether specific genetic variations influence this effect.

Several recent studies support the premise that genetic differences may predict treatment outcomes. In an early study, an A to G single nucleotide polymorphism (SNP; rs1799971) of the mu opiate receptor gene (OPRM1) predicted 12 week abstinence after treatment of alcohol dependence with naltrexone (Oslin et al 2003). The relationship was such that individuals with at least one copy of the G allele demonstrated lower relapse rates and longer time to return to heavy drinking when treated with naltrexone (Oslin et al 2003). These observations were recently replicated and extended in the multisite COMBINE study, such that individuals with the G allele demonstrated superior outcomes after treatment with naltrexone, in combination with medication management (Anton et al 2008). Laboratory studies have suggested that clinical effects may be related to a greater reduction in the acute rewarding effects of alcohol among individuals with the G allele (Ray & Hutchison 2007) and suggest that the mechanism may be related to a blunting of dopamine release in the VTA (Ramchandani et al 2009). In addition, recent studies with other medications (e.g., topiramate, olanzapine) have found that genetic variables predict treatment outcomes (e.g., Hutchison et al 2006; Hutchison 2008; Seneviratne et al 2009). It is important to note that these gene by treatment interactions are not limited to pharmacological treatments, as recent studies have also suggested that genetic variation may predict responses to psychosocial interventions as well (Feldstein Ewing et al 2009; Hutchison et al 2006).

We decided to evaluate the clinical effects of Sulfasalazine because our work to date suggests that genetic variations with downstream function implications for glutamate function, specifically cysteine/glutamate exchange and glutamate transport, are strongly associated with BOLD response in the striatum and prefrontal cortex after exposure to alcohol cues. Sulfasalazine is a medication with a well characterized safety profile that has been used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease and several types of arthritis, particularly rheumatoid arthritis for many years. Most recently, it has been suggested that Sulfasalazine may have beneficial effects in the brain, specifically by blocking N-methyl D-aspartate receptor-mediated excitotoxicity resulting in reduced neuronal death (Bo Rum Ryu et al, 2003). This pilot study will help to determine whether NMDA receptors play a role in cue-elicited activation of key areas of the brain implicated in the development and maintenance of substance use disorders. Furthermore, if Sulfasalazine reduces cue-elicited activation of these brain regions, as hypothesized; this study will lay the groundwork for a larger trial on the efficacy of Sulfasalazine as a treatment for substance use disorders.

To that end, a double-blind, placebo-controlled 2 (Medication: Sulfasalazine 1500 mg vs. placebo control) x 2 (Cue: Alcohol Cue vs. Control cue) within-subjects, crossover design will be used to test the hypothesis that Sulfasalazine reduces the BOLD response in the striatum and prefrontal cortex after exposure to alcohol cues. Twenty alcohol-dependent participants will complete two rounds of the study medication followed by an fMRI scan, during which they will complete an alcohol cue-exposure task. The order of the medication condition will be counterbalanced such that subjects will be randomly assigned to receive either Sulfasalazine (1500 mg) in the first session and placebo in the second session one week later (or vice versa).

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Alcohol Dependence
  • Drug: Sulfasalazine
    500mg capsules of Sulfasalazine x 3 doses 12 hours apart.
  • Drug: Placebo
    Placebo capsule x 3 doses 12 hours apart
  • Experimental: Sulfasalazine
    Sulfasalazine 1500 mg
    Intervention: Drug: Sulfasalazine
  • Placebo Comparator: Placebo
    Placebo capsule x 3 doses 12 hours apart
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
23
September 2011
September 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 21-55 years of age with
  • Alcohol Dependence

Exclusion Criteria:

  • Medical or MRI Contraindications
  • Pregnancy
  • Allergy to Sulfa medications
Both
21 Years to 55 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01312129
20-381
No
Kent Hutchison, Ph.D., The Mind Research Network
The Mind Research Network
Not Provided
Principal Investigator: Kent E Hutchison, PhD The Mind Research Network
The Mind Research Network
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP