Zonisamide for Heavy Drinkers With Bipolar Disorder
Condition: Alcohol Use Disorders; Bipolar Disorder
MeSH terms: Alcoholism; Alcoholic Intoxication; Bipolar Disorder; Alcohol Drinking
Intervention: Zonisamide; Placebo
Intervention description: titration of dose to 500mg oral, daily, over 8 weeks, then 6 weeks of treatment at that dose; placebo
Intervention MeSH terms: Zonisamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: alcoholism; alcohol use disorder; alcohol dependence; alcohol abuse; bipolar; anticonvulsant; zonisamide

Summary:

      This is a randomized, double blind, placebo controlled trial of the medication zonisamide for
      the purpose of reducing heavy drinking and drinking, as well as reducing mood symptoms, in
      bipolar subjects that drink excessively and heavily.

      Hypotheses: (Primary aims); Add-on zonisamide compared to placebo will result in:

        1. significant reduction in heavy drinking days, drinks per week and per drinking day, and
           significantly greater increase in abstinent days, ii) greater rates of abstinence and
           abstinence to heavy drinking, greater reduction in biomarkers of heavy alcohol use such
           as gamma-glutamyl transferase (GGT), and greater reduction in alcohol urge or "craving",

        2. Significant reduction in prevalent mood symptoms on the BRMS and BRMeS, CARS, HAMD, or
           no worsening of euthymic mood, and significant improvement on the Clinical Global
           Impressions Scale-Severity.

        3. (Secondary aims) Add-on zonisamide compared to placebo will result in significant
           reduction in weight (kilograms) and other secondary weight-related metabolic factors
           such as fasting glucose, lipid profile, and blood pressure.

        4. (Secondary aims) Add-on zonisamide compared to placebo will result in improved clinical
           global impression, overall functioning, quality of life, and reduced medical symptoms.

      5.) (Exploratory Aims) To will examine interactions between genotype and medication on
      treatment response for allelic variation in genetic loci related to the major
      neurotransmitter and neurophysiologic pathways that are relevant to bipolar disorder,
      alcoholism, and zonisamide mechanism of action.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Female/male aged 18-65 years

          -  Ability to provide informed consent to participate

          -  Presence of Axis I diagnosis of BD (either type I, Type II, or NOS), in manic,
             hypomanic, depressive, mixed, or euthymic states plus presence of Axis I diagnosis of
             a current AUD and/or "at risk" regular heavy drinking (must average >2 heavy drinking
             days per week) with the goal of reducing or stopping drinking

          -  treatment with a standard mood stabilizer medication and or other medications with
             known psychotropic effects on mood state but not alcohol use; Lithium, and/or atypical
             antipsychotic medications will be the preferred medications,

          -  Subjects not on any primary acceptable mood stabilizer as described above must be
             willing to begin treatment with Lithium in open label fashion,

          -  English speaking, Able to read at the eighth grade or higher level and show no
             evidence of significant cognitive impairment;

          -  Women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or
             tubal ligation or <2 years postmenopausal), must be non-lactating, practicing a
             reliable method of birth control, and have a negative serum pregnancy test prior to
             initiation of treatment;

          -  Must continue to have at least 2 heavy drinking days per week (averaged per month,
             with heavy drinking defined as having >4 standard drinks per day for males, and >3
             standard drinks per day for females) up to the screening appointment

        Exclusion Criteria:

          -  Presence of another major Axis I disorder such as Schizophrenia or Schizoaffective
             disorder, Delusional disorder, or other severe psychiatric disorder. A history of
             suicidal or violent behavior which, in the opinion of the study physician, puts the
             patient at significant risk of suicide or homicide during the study.

          -  Past history of drug abuse or dependence will be allowed, but active drug dependence
             (with the exception of nicotine dependence) in the last 30 days will be disqualifying.

          -  Serious neurological, or endocrine disorder,

          -  Evidence of potentially serious or as yet undiagnosed medical problems,

          -  Neurocognitive cognitive or language limitations, or other incapacity with providing
             informed consent;

          -  Known adverse reaction to zonisamide, sulfa-drug allergy, penicillin allergy, other
             severe adverse drug reaction or allergy, or any serious systemic autoimmune illness,

          -  Patients currently undergoing ECT treatment.

          -  Also patients with a history of seizures (other than febrile seizures), renal calculi,
             or currently taking medications that could either significantly increase the risk of
             seizures (e.g., tricyclic antidepressant agents, Bupropion, clozaril), or that could
             potentially theoretically significantly influence drinking behavior such as
             benzodiazepines, stimulants, opioid painkillers, sedative-hypnotics, etc.).

          -  Subjects on the following anticonvulsant medications will also be excluded as they may
             increase the risk of similar side-effects (similar to zonisamide) such as rash,
             cognitive impairment, or potentially could confound the study of drinking behavior;
             topiramate, tiagabine, oxcarbazepine, carbamezapine, valproic acid, lamotrigine

          -  Patients who, on clinical examination by a physician, are deemed to be too severely
             alcohol dependent to permit them to participate in an outpatient level of care
             medication trial. We have, over the years, developed methods for reliably and safely
             assessing patients for alcohol treatment and dual diagnosis studies.