Clinical trial NCT01566370: Zonisamide for Heavy Drinkers With Bipolar Disorder
Official title: Zonisamide for Heavy Drinkers With Bipolar Disorder
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alcohol Use Disorders
Bipolar Disorder
Keywords: alcoholism
alcohol use disorder
alcohol dependence
alcohol abuse
bipolar
anticonvulsant
zonisamide
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2012-03-29
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percentage of Total Heavy Drinking Days
timeFrame: from week 11 through 14 (over 4 weeks)
measure: Change on Hamilton Depression Rating Scale
timeFrame: 14 weeks
measure: Change in Clinician Assisted Rating Scale for Mania (CARS-M) Scores
timeFrame: 14 weeks
Secondary outcomes:
measure: Percentage of Abstinent Days
timeFrame: over four weeks, from week 11 through 14
measure: Change in Alcohol Urge Questionnaire Score
timeFrame: from baseline to endpoint, 14 weeks
measure: Change in Gamma Glutamyl Transferase (GGT)
timeFrame: 14 weeks
measure: Change in Beck Depression Inventory (BDI) Scores
timeFrame: 14 weeks
measure: Percentage of Total Drinking Days
timeFrame: 4 weeks
measure: Change in Number of Heavy Drinking Days Per Week by Time
timeFrame: 14 weeks (baseline to endpoint)
measure: Change in Number of Drinks Per Week by Time
timeFrame: 14 weeks (baseline to endpoint)
Other outcomes:
Locations:
city: West Haven
country: United States
facility: VA Connecticut Healthcare System
state: Connecticut
Study officials:
affiliation: Yale University, VA CT Health System
name: Albert J Arias, MD
role: PRINCIPAL_INVESTIGATOR
References: