Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders

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.

Inclusion Criteria:

- Outpatient men and women age 18-70 years old with bipolar I or II disorder or
schizoaffective disorder (bipolar type)

- English or Spanish speaking

- Current diagnosis of alcohol use disorder with at least moderate severity (DSM-5
terminology)

- Alcohol use of at least 28 drinks a week if male or an average of 21 drinks per week
if female and 3 drinking days a week in the 28 days prior to intake

- Current mood stabilizer therapy (defined as lithium, lamotrigine, carbamazepine,
oxcarbazepine or an atypical antipsychotic) with stable dose for ≥ 28 days prior to
randomization or valproate/divalproex at a stable dose for ≥ 90 days (longer period
due to data suggesting valproate may decrease alcohol use in BPD)

- Diagnosis of substance use disorder other than alcohol, caffeine or nicotine is
allowed if 1) alcohol is the self-identified substance of choice and 2) severity of
other substance use disorder is ≤ moderate

Exclusion Criteria:

- Mood disorders other than bipolar I or II disorders or schizoaffective disorder
bipolar type (e.g. bipolar NOS, cyclothymic disorders, schizophrenia, schizoaffective
disorder depressive type, or unipolar depression based on the SCID); other disorders
(e.g. anxiety, will be allowed)

- Baseline HRSD17 or YMRS scores ≥ 35 to exclude those with very severe mood symptoms at
baseline

- Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar
score of ≥ 10

- Current (last 28 days) treatment with naltrexone, acamprosate, disulfiram, topiramate
or as these may also decrease alcohol use

- Oral contraceptives and hormone replacement therapy. This exclusion is due to a
possible interaction with pregnenolone.

- Women with hormone sensitive conditions such as breast cancer, uterine cancer, ovarian
cancer, endometriosis, uterine fibroids. These persons are excluded because
pregnenolone is converted to estrogens.

- Vulnerable populations (e.g. pregnant, nursing, cognitively impaired, incarcerated)

- High risk for suicide defined as > 1 attempt in past 12 months that required medical
attention, any attempt in the past 3 months or current suicidal ideation with plan and
intent such that outpatient care is precluded

- Intensive outpatient treatment (defined as ≥3 visits each week) for substance abuse
(AA, NA meetings, or less intensive counseling at baseline will be allowed)

- Severe/unstable condition (e.g. cirrhosis, poorly controlled hypertension) or
laboratory/physical exam findings consistent with serious illness (e.g. abnormal
electrolytes) or AST or ALT >3 times normal