Alcohol Use Disorder, Bipolar Disorder, Dual Diagnosis
Conditions
Keywords
Bipolar Disorder, BPD, Alcohol Use Disorder, Alcohol Abuse, Alcohol Dependence, Ondansetron, Cognition, Mood
Brief summary
The purpose of the study is to determine if ondansetron, as an add-on therapy, is associated with reduced depressive symptoms and alcohol use in outpatients with bipolar disorder (BPD), cyclothymic disorder, schizoaffective disorder (bipolar type) and major depressive disorder (MDD) with mixed features. The investigators will also use blood samples to determine if the genotype for the serotonin transporter gene is associated with response to ondansetron.
Detailed description
A total of 70 outpatients with alcohol use disorder and BPD, cyclothymic disorder, schizoaffective disorder (bipolar type), or MDD with mixed features will be enrolled in a 12-week, randomized, double-blind, parallel-group, placebo-controlled study of ondansetron. Participant will receive either ondansetron or a placebo for 12 weeks. He or she has an equal chance of receiving ondansetron or placebo. Randomization will be stratified based on \> 4 or ≤ 4 drinking days per week at start of the study. Ondansetron or placebo will be given at 0.5 milligrams twice a day for the first 4 weeks. At weeks 4, 8 and 10 the dose may be increased to 1.0, 2.0 or 4.0 milligrams twice a day, respectively, if significant reductions in depression and alcohol use are not observed and the participant is not experiencing any side effects. Blood will be drawn for routine laboratory analyses including a complete blood count (CBC), liver panel, and Carbohydrate-deficient Transferrin (CDT) at baseline and weeks 4, 8 and 12. Each participant will return for weekly follow-up visits and repeat outcome measures. Pill counts will be conducted, and a list of current medications and doses will be recorded at each visit. Participants will be compensated at each appointment with a bus pass, gift cards, and a monetary incentive for compliance. Participants will be evaluated by both the research assistant (RA) and principal investigator (PI) at each visit. The Hamilton Rating Scale for Depression (HAMD) and Timeline Followback (TLFB) will be given at each visit as the primary outcome measures. Cognitive assessments will be performed at baseline and week 12.
Interventions
DRUGOndansetron
Ondansetron is a serotonin receptor antagonist that is FDA-approved to treat nausea and vomiting caused by cancer therapy and surgery.
DRUGPlacebo
Inactive ingredient matching the active medication in appearance
Sponsors
Stanley Medical Research Institute
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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, II, or Not Otherwise Specified (NOS) disorders, schizoaffective disorder (bipolar type), cyclothymic disorder, or major depressive disorder with mixed features * Current diagnosis of alcohol use disorder (DSM V terminology) with onset ≤ age 25 * Alcohol use (by self-report) of at least 15 drinks in the 7 days prior to intake * IF diagnosis of Bipolar I, II, or NOS Disorder: Current mood stabilizer therapy (lithium, anticonvulsant, atypical antipsychotic) with stable dose for at least 14 days prior to randomization * IF diagnosis of Schizoaffective disorder (bipolar type): Current atypical antipsychotic therapy with stable dose for at least 14 days prior to randomization * IF diagnosis of Major Depressive Disorder with mixed features: Current antidepressant therapy with stable dose for at least 14 days prior to randomization
Exclusion criteria
* Baseline Young Mania Rating Scale (YMRS) or Hamilton Rating Scale for Depression (HAMD) scores ≥ 35 to exclude those with very severe mood symptoms * Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar (Clinical Institute Withdrawal Assessment of Alcohol Use-Revised) score of ≥ 10 * Therapy in past 14 days with naltrexone, acamprosate, disulfiram, or topiramate * Vulnerable populations (e.g. pregnant, breastfeeding, incarcerated, cognitively impaired (e.g. dementia, mentally challenged)) * High risk of 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 or life-threatening medical condition (e.g., hepatic cirrhosis) or laboratory or physical examination findings consistent with serious medical illness (e.g., dangerously abnormal electrolytes) * AST (aspartate aminotransferase ) or ALT (alanine transaminase) \> 3 times the upper limit of normal * History of severe side effects or allergic reaction with prior ondansetron therapy (e.g. for vomiting) or use of medications with significant drug-drug interactions with ondansetron (phenytoin, carbamazepine, and rifampicin, apomorphine, tramadol)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Rating Scale for Depression (HAMD) | Baseline and Week 12 | The Hamilton Rating Scale for Depression (HAMD) is a 17-item observer-rated measure of depressive symptomatology. HAMD is scored between 0 and 4 points, with the total score ranging from 0 to 52. Scoring is based on the 17-item scale and scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. The higher scores are associated with greater depressive symptom severity and poorer outcome. |
| Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB) | Baseline and Week 12 | The Timeline Followback (TLFB) will be used to assess the change in the number of standard alcoholic drinks per week. The TLFB is interviewer-administered and asks participants to retrospectively estimate their alcohol use between each visit. The reported drinks are then converted to standard drinks based on the drink's alcohol by volume (ABV). The higher number is associated with more standard drinks and worse outcome. Values are corrected for the number of days covered in the assessment period. |
| Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB) | Baseline and Week 12 | The Timeline Followback (TLFB) will be used to assess the change in the number of standard alcoholic drinks per week. The TLFB involves asking participants to retrospectively estimate their alcohol between each research visit. The reported drinks are then converted to heavy drinking days based on the drink's alcohol by volume (ABV) and participant's sex (male/female) - 5 drinks per day for males and 4 for females. Each day during which 4-5 drinks are consumed is counted as a heavy drinking day within a given assessment period. The reported values are corrected for days covered (divided by the number of days between each visit). The higher number is associated with more heavy drinking days and worse outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ondansetron Ondansetron will be given 0.5 mg/ BID. The dose may be increased from 0.5 mg/BID to 1.0 mg/BID at week 4 for participants with less than 30% reduction in HAMD and/or alcohol use. An additional dose increase to 2.0 mg/BID and 4.0 mg/BID is allowed at weeks 8 and 10, respectively, for participants with less than a 50% reduction in HAMD scores and/or alcohol use.
Ondansetron: Ondansetron is a serotonin receptor antagonist that is FDA-approved to treat nausea and vomiting caused by cancer therapy and surgery. | 35 |
| Placebo Placebo will be given 0.5 mg/ BID. The dose may be increased from 0.5 mg/BID to 1.0 mg/BID at week 4 for participants with less than 30% reduction in HAMD and/or alcohol use. An additional dose increase to 2.0 mg/BID and 4.0 mg/BID is allowed at weeks 8 and 10, respectively, for participants with less than a 50% reduction in HAMD scores and/or alcohol use.
Placebo: Inactive ingredient matching the active medication in appearance | 35 |
| Total | 70 |
Baseline characteristics
| Characteristic | Ondansetron | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 35 Participants | 70 Participants |
| Age, Continuous | 46.54 years STANDARD_DEVIATION 8.6 | 43.29 years STANDARD_DEVIATION 10.01 | 44.91429 years STANDARD_DEVIATION 9.41128 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 18 Participants | 36 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 13 Participants | 27 Participants |
| Sex: Female, Male Female | 11 Participants | 17 Participants | 28 Participants |
| Sex: Female, Male Male | 24 Participants | 18 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 35 | 0 / 35 |
| other Total, other adverse events | 7 / 35 | 4 / 35 |
| serious Total, serious adverse events | 10 / 35 | 4 / 35 |
Outcome results
Primary
Hamilton Rating Scale for Depression (HAMD)
The Hamilton Rating Scale for Depression (HAMD) is a 17-item observer-rated measure of depressive symptomatology. HAMD is scored between 0 and 4 points, with the total score ranging from 0 to 52. Scoring is based on the 17-item scale and scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. The higher scores are associated with greater depressive symptom severity and poorer outcome.
Time frame: Baseline and Week 12
Population: 11 participants from Ondansetron group and 13 from the Placebo group did not complete this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ondansetron | Hamilton Rating Scale for Depression (HAMD) | Baseline | 13.77 score on a scale | Standard Deviation 5.39 |
| Ondansetron | Hamilton Rating Scale for Depression (HAMD) | Week 12 | 8.52 score on a scale | Standard Deviation 6.02 |
| Placebo | Hamilton Rating Scale for Depression (HAMD) | Baseline | 14.23 score on a scale | Standard Deviation 7.25 |
| Placebo | Hamilton Rating Scale for Depression (HAMD) | Week 12 | 8.86 score on a scale | Standard Deviation 5.77 |
Primary
Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB)
The Timeline Followback (TLFB) will be used to assess the change in the number of standard alcoholic drinks per week. The TLFB involves asking participants to retrospectively estimate their alcohol between each research visit. The reported drinks are then converted to heavy drinking days based on the drink's alcohol by volume (ABV) and participant's sex (male/female) - 5 drinks per day for males and 4 for females. Each day during which 4-5 drinks are consumed is counted as a heavy drinking day within a given assessment period. The reported values are corrected for days covered (divided by the number of days between each visit). The higher number is associated with more heavy drinking days and worse outcome.
Time frame: Baseline and Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ondansetron | Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB) | Baseline | 0.34 heavy drinking days (corrected) | Standard Deviation 0.33 |
| Ondansetron | Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB) | Week 12 | 0.17 heavy drinking days (corrected) | Standard Deviation 0.28 |
| Placebo | Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB) | Baseline | 0.45 heavy drinking days (corrected) | Standard Deviation 0.37 |
| Placebo | Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB) | Week 12 | 0.20 heavy drinking days (corrected) | Standard Deviation 0.28 |
Primary
Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB)
The Timeline Followback (TLFB) will be used to assess the change in the number of standard alcoholic drinks per week. The TLFB is interviewer-administered and asks participants to retrospectively estimate their alcohol use between each visit. The reported drinks are then converted to standard drinks based on the drink's alcohol by volume (ABV). The higher number is associated with more standard drinks and worse outcome. Values are corrected for the number of days covered in the assessment period.
Time frame: Baseline and Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ondansetron | Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB) | Baseline | 4.06 mean number of standard drinks per week | Standard Deviation 4.07 |
| Ondansetron | Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB) | Week 12 | 2.50 mean number of standard drinks per week | Standard Deviation 3.73 |
| Placebo | Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB) | Baseline | 4.92 mean number of standard drinks per week | Standard Deviation 4.09 |
| Placebo | Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB) | Week 12 | 2.92 mean number of standard drinks per week | Standard Deviation 2.68 |