Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders
Condition: Alcohol Use Disorder; Bipolar Disorder
MeSH terms: Alcoholism; Bipolar Disorder; Alcohol Drinking
Study type: Interventional
Phase: Phase 4

Summary: 
      Preclinical and clinical data as well as mechanistic justification have been presented
      suggesting citicoline and pregnenolone are each promising treatments for alcohol use in BPD.
      Both appear to have favorable side effect profiles and no known drug-drug interactions. Thus,
      they have the potential to be safely used in a dual diagnosis population already taking other
      medications. A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive
      design study of citicoline and pregnenolone is proposed in 199 persons with alcohol use
      disorder and bipolar I or II disorder or schizoaffective disorder (bipolar type). The primary
      aim will be to assess change in alcohol use. Biomarkers of alcohol use, alcohol craving, mood
      and cognition will also be assessed. Relationships between neurosteroid and choline levels
      and the outcome measures will be explored.
    

Detailed description: 
      A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive, Drop The
      Loser (DTL) design clinical trial of citicoline and pregnenolone will be conducted in 199
      outpatients with bipolar I or II disorder or schizoaffective disorder (bipolar type) and
      current alcohol use disorder. Potential participants will be identified and an appointment
      will be arranged. At this appointment, informed consent will be obtained, and assessment
      procedures, including a review of inclusion and exclusion criteria, will be performed.

      A structured clinical interview for Diagnostic Statistical Manual (DSM-5), Structured
      Clinical Interview for Disorders (SCID) will be performed to establish the diagnoses of
      bipolar I or II disorder and alcohol use disorder. Recent alcohol use (and, if present, other
      substance use) will be assessed using the Timeline Followback (TLFB) method. Drinking
      severity and withdrawal symptoms will be assessed through a variety of measures (e.g.,
      Clinical Institute Withdrawal Assessment of Alcohol Use-Revised (CIWA-Ar), Penn Alcohol
      Craving Scale (PACS), Short Index of Problems (SIP)). Length of problem alcohol use will be
      assessed by asking "When did alcohol first start causing you problems?" Blood will be drawn
      for laboratory analyses including a complete blood count (CBC) and Comprehensive Metabolic
      Panel (includes a liver panel with AST, ALT as well as lipids and electrolytes), and GGT and
      carbohydrate-deficient transferrin (CDT) will be added at baseline (week 0) and weeks 6 and
      12. Cognition, including the domains of memory, decision making, impulsivity, attention, and
      executive functioning will also be assessed at baseline and week 12 using the World Health
      Organization/University of California at Los Angeles Auditory-Verbal Learning Test (WHO-UCLA
      AVLT), Trail Making Test (TMT), and the Golden Stroop Color Word Test. Women of childbearing
      potential will receive a urine pregnancy test at baseline, week 6, and week 12 and will be
      counseled about effective contraceptive methods. A psychiatrist (PI or Co-I) will assess
      participants at baseline and weekly follow-up visits and will participate in the informed
      consent process. The active medication or placebo capsules will be initiated at baseline and
      increased weekly in weeks 1, 2 and 3 to achieve the target doses for citicoline (2000 mg/day)
      or pregnenolone (500 mg/day). Side effects will be managed in a blinded fashion. Safety and
      side effects will be assessed with the Systematic Assessment for Treatment Emergent Events
      (SAFTEE). At weekly visits, mood and suicidality will be assessed through various measures
      (e.g. Hamilton Rating Scale for Depression (HRSD17), Columbia Suicide Severity Rating Scale
      (CSSRS) and assessment of alcohol use will again be evaluated. All participants will receive
      Medical Monitoring (MM) as a psychosocial platform. After study completion, participants will
      be provided standard psychiatric care until outside referral is arranged.
    

Intervention name(s): Placebo; Citicoline; Pregnenolone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Inactive ingredient matching the active comparators in appearance.; Citicoline is an over-the-counter nutritional supplement that is used for neuroprotective effects. It is a naturally occurring neurochemical in the human body.; Pregnenolone is a naturally occurring neurosteroid that is synthesized from cholesterol in the adrenal glands and also in the brain. Pregnenolone produces other neuroactive steroids.
Other intervention name(s): Sugar pill; CDP-Choline; cytidine diphosphate-choline
Intervention MeSH terms: Choline; Cytidine Diphosphate Choline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Alcohol Use Disorder; Bipolar Disorder; Mood; Alcohol craving; Pregnenolone; Citicoline