Alcohol Use Disorder, Bipolar Disorder, Schizoaffective Disorder Bipolar Type
Conditions
Keywords
Alcohol Use Disorder, Bipolar Disorder, Mood, Alcohol craving, Pregnenolone, Citicoline
Brief 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.
Interventions
DRUGPlacebo
Inactive ingredient matching the active comparators in appearance.
DIETARY_SUPPLEMENTCiticoline
Citicoline is an over-the-counter nutritional supplement that is used for neuroprotective effects. It is a naturally occurring neurochemical in the human body.
DRUGPregnenolone
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.
Sponsors
University of Miami
University of Texas Rio Grande Valley
Sherwood Brown, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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 an average of 28 drinks a week if male or an average of 21 drinks per week if female and an average of 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, or topiramate 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB) | 12 weeks | The Timeline Follow Back (TLFB) - Alcohol is a clinician-completed assessment calendar that allows for an estimate of an individual's daily drinking habits over time (i.e., prior 30 days at baseline and since last visit during the study). Drinks per drinking day is calculated as the average number of standard drinks consumed, per each day indicated as a day during which alcohol was consumed, adjusted for the period of time being assessed (e.g., 30 days at baseline). Baseline-to-Exit Change in Drinks per Drinking Day (TLFB) was calculated as Drinks/Drinking Day (Exit) - Drinks/Drinking Day (Baseline), with negative scores indicating a decrease in the number of drinks per drinking day. The TLFB (Timeline Followback) is a method of assessment of alcohol consumption and is not a scale with minimum and maximum values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Examine the Use of an Adaptive Design in a Clinical Trial for Alcohol Use Disorder. | Study Month 30 | A two-phase adaptive drop-the-loser (DTL) design was incorporated. A planned interim analysis was to be conducted after 50% of participants (n = 99) had been enrolled (phase 1), in which both treatments were to be compared to placebo. Predetermined decision rules were to be applied for dropping a treatment failing to show clinically meaningful efficacy over placebo: (1) The trial will be stopped if neither active treatment appears to be effective (Cohen's d \< 0.25) and (2) The trial will continue to phase 2 (re-randomization) if there is evidence that at least one treatment is more effective than placebo. If both treatments were more effective, the trial was to continue with three arms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo given beginning at 1 capsule twice daily (BID) increasing to 2 capsules BID at week 1, 3 capsules BID at week 2, and 4 capsules BID at weeks 3-12.
Placebo: Inactive ingredient matching the active comparators in appearance. | 29 |
| Citicoline Citicoline will be given beginning at 250 mg BID with an increase to 500 mg BID at week 1, 750 mg BID at week 2, and 1000 mg BID at weeks 3-12.
Citicoline: Citicoline is an over-the-counter nutritional supplement that is used for neuroprotective effects. It is a naturally occurring neurochemical in the human body. | 30 |
| Pregnenolone Pregnenolone will be given beginning at 50 mg BID with an increase to 100 mg BID at week 1, 150 mg BID at week 2, and 250 mg BID at weeks 3-12.
Pregnenolone: 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. | 37 |
| Total | 96 |
Baseline characteristics
| Characteristic | Placebo | Citicoline | Pregnenolone | Total |
|---|---|---|---|---|
| Age, Continuous | 48.00 years STANDARD_DEVIATION 8.98 | 49.40 years STANDARD_DEVIATION 10.07 | 47.35 years STANDARD_DEVIATION 10.11 | 48.19 years STANDARD_DEVIATION 9.71 |
| CIWA-Ar | 3.64 units on a scale STANDARD_DEVIATION 3.84 | 3.40 units on a scale STANDARD_DEVIATION 2.85 | 2.97 units on a scale STANDARD_DEVIATION 3.47 | 3.31 units on a scale STANDARD_DEVIATION 3.38 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 26 Participants | 32 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| HRSA | 13.07 units on a scale STANDARD_DEVIATION 7.27 | 13.80 units on a scale STANDARD_DEVIATION 6.67 | 14.19 units on a scale STANDARD_DEVIATION 8.51 | 13.73 units on a scale STANDARD_DEVIATION 7.54 |
| HRSD | 14.62 units on a scale STANDARD_DEVIATION 6.14 | 15.50 units on a scale STANDARD_DEVIATION 7.13 | 13.46 units on a scale STANDARD_DEVIATION 6.91 | 14.45 units on a scale STANDARD_DEVIATION 6.74 |
| IDS-SR | 26.00 units on a scale STANDARD_DEVIATION 14.38 | 30.07 units on a scale STANDARD_DEVIATION 16.57 | 26.92 units on a scale STANDARD_DEVIATION 14.46 | 27.60 units on a scale STANDARD_DEVIATION 15.05 |
| Metabolic Panel (ALT) | 22.96 U/L STANDARD_DEVIATION 14.99 | 22.27 U/L STANDARD_DEVIATION 9.15 | 24.51 U/L STANDARD_DEVIATION 24.71 | 23.40 U/L STANDARD_DEVIATION 18.33 |
| Metabolic Panel (AST) | 23.82 U/L STANDARD_DEVIATION 10.59 | 23.00 U/L STANDARD_DEVIATION 8.39 | 24.38 U/L STANDARD_DEVIATION 13.73 | 23.81 U/L STANDARD_DEVIATION 11.35 |
| Metabolic Panel (CDT) | 57.39 mg/L STANDARD_DEVIATION 17.15 | 58.04 mg/L STANDARD_DEVIATION 27.06 | 58.72 mg/L STANDARD_DEVIATION 24.18 | 58.12 mg/L STANDARD_DEVIATION 22.97 |
| Metabolic Panel (GGT) | 52.85 U/L STANDARD_DEVIATION 73.46 | 36.50 U/L STANDARD_DEVIATION 26.22 | 37.46 U/L STANDARD_DEVIATION 27.07 | 41.80 U/L STANDARD_DEVIATION 46.03 |
| PACS | 19.72 units on a scale STANDARD_DEVIATION 6.6 | 19.31 units on a scale STANDARD_DEVIATION 7.9 | 17.65 units on a scale STANDARD_DEVIATION 7.47 | 18.79 units on a scale STANDARD_DEVIATION 7.33 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 15 Participants | 13 Participants | 40 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 16 Participants | 15 Participants | 21 Participants | 52 Participants |
| Sex: Female, Male Female | 12 Participants | 13 Participants | 18 Participants | 43 Participants |
| Sex: Female, Male Male | 17 Participants | 17 Participants | 19 Participants | 53 Participants |
| TLFB (Drinks per Drinking Day) | 9.15 Standard Drinks per Drinking Day STANDARD_DEVIATION 5.22 | 8.01 Standard Drinks per Drinking Day STANDARD_DEVIATION 3.61 | 7.35 Standard Drinks per Drinking Day STANDARD_DEVIATION 3.6 | 8.11 Standard Drinks per Drinking Day STANDARD_DEVIATION 4.17 |
| YMRS | 10.76 units on a scale STANDARD_DEVIATION 8.23 | 10.20 units on a scale STANDARD_DEVIATION 7.01 | 11.14 units on a scale STANDARD_DEVIATION 7.33 | 10.73 units on a scale STANDARD_DEVIATION 7.45 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 30 | 0 / 37 |
| other Total, other adverse events | 11 / 29 | 9 / 30 | 7 / 37 |
| serious Total, serious adverse events | 3 / 29 | 2 / 30 | 4 / 37 |
Outcome results
Primary
Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB)
The Timeline Follow Back (TLFB) - Alcohol is a clinician-completed assessment calendar that allows for an estimate of an individual's daily drinking habits over time (i.e., prior 30 days at baseline and since last visit during the study). Drinks per drinking day is calculated as the average number of standard drinks consumed, per each day indicated as a day during which alcohol was consumed, adjusted for the period of time being assessed (e.g., 30 days at baseline). Baseline-to-Exit Change in Drinks per Drinking Day (TLFB) was calculated as Drinks/Drinking Day (Exit) - Drinks/Drinking Day (Baseline), with negative scores indicating a decrease in the number of drinks per drinking day. The TLFB (Timeline Followback) is a method of assessment of alcohol consumption and is not a scale with minimum and maximum values.
Time frame: 12 weeks
Population: Participants having at least one post-baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB) | -1.98 Standard Drinks per Drinking Day | Standard Deviation 4.68 |
| Citicoline | Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB) | -2.82 Standard Drinks per Drinking Day | Standard Deviation 3.84 |
| Pregnenolone | Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB) | -1.22 Standard Drinks per Drinking Day | Standard Deviation 3.45 |
Secondary
Examine the Use of an Adaptive Design in a Clinical Trial for Alcohol Use Disorder.
A two-phase adaptive drop-the-loser (DTL) design was incorporated. A planned interim analysis was to be conducted after 50% of participants (n = 99) had been enrolled (phase 1), in which both treatments were to be compared to placebo. Predetermined decision rules were to be applied for dropping a treatment failing to show clinically meaningful efficacy over placebo: (1) The trial will be stopped if neither active treatment appears to be effective (Cohen's d \< 0.25) and (2) The trial will continue to phase 2 (re-randomization) if there is evidence that at least one treatment is more effective than placebo. If both treatments were more effective, the trial was to continue with three arms.
Time frame: Study Month 30
Population: Planned interim analyses were to be conducted after 50% of participants (n = 99) were enrolled (phase 1) to determine whether to proceed with a two-arm trial in phase 2 (i.e., drop-the-loser). Only upon proceeding to phase 2 could this aim be tested. Due to low enrollment (total enrolled: n=96), the required data necessary to test this aim was not obtained. As such, the study remained in phase 1 (with three arms), and the adaptive drop-the-loser design was untested.