Effects of Sulfasalazine on BOLD Response to Alcohol Cues
Condition: Alcohol Dependence
MeSH terms: Alcoholism
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Sulfasalazine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 500mg capsules of Sulfasalazine x 3 doses 12 hours apart.; Placebo capsule x 3 doses 12 hours apart
Intervention MeSH terms: Sulfasalazine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Alcohol; Sulfasalazine