Ondansetron for Bipolar Disorder and Alcohol Use Disorders

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02082678
• Collaborator: Stanley Medical Research Institute (Other)
• Enrollment: 70
• Location: 1
• Arms: 2
• Actual Duration (Months): 50.9
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder; Alcohol Use Disorder; Dual Diagnosis	Drug: Ondansetron; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Ondansetron for Bipolar Disorder and Alcohol Use Disorders
• Actual Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ondansetron Ondansetron will be given 0.5 mg twice a day (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.	Drug: Ondansetron; Ondansetron is a serotonin receptor antagonist that is FDA-approved to treat nausea and vomiting caused by cancer therapy and surgery.; Other Names: Zofran Zuplenz
Placebo Comparator: 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.	Drug: Placebo; Inactive ingredient matching the active medication in appearance; Other Names: Sugar-pill

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• Stanley Medical Research Institute

Investigators

• Principal Investigator: E. Sherwood Brown, MD, PhD, UT Southwestern Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 18, 2017

More Information

Publications

None provided.

• Responsible Party: Sherwood Brown, MD, PhD, PROFESSOR, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02082678
• Other Study ID Numbers: 112013-075
• First Posted: Mar 10, 2014
• Last Update Posted: Aug 24, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by Sherwood Brown, MD, PhD, PROFESSOR, University of Texas Southwestern Medical Center: Bipolar Disorder; BPD; Alcohol Use Disorder; Alcohol Abuse; Alcohol Dependence; Ondansetron; Cognition; Mood
• Additional relevant MeSH terms: Disease; Alcoholism; Bipolar Disorder; Alcohol Drinking; Ondansetron

Study Results

Participant Flow

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	Ondansetron will be given at the dose of 0.5 mg twice a day. The dose may be increased from 0.5 mg twice a day to 1.0 mg twice a day at week 4 for participants with less than 30% reduction in the Hamilton Depression Rating Scale (HAMD) and/or alcohol use based on Timeline Followback (TLFB) assessment of alcohol use. An additional dose increase to 2.0 mg twice a day and 4.0 mg twice a day is allowed at weeks 8 and 10, respectively, for participants with less than a 50% reduction in HAMD scores and/or TLFB.	Placebo that matches the active medication in appearance will be started at 0.5 mg capsule twice day. The dose may be increased from 0.5 mg twice day to 1.0 mg twice a day at week 4 for participants with less than 30% reduction in the Hamilton Depression Rating Scale (HAMD) and/or alcohol use per Timeline Followback (TLFB) assessment score. An additional dose increase to 2.0 mg twice a day and 4.0 mg twice a day is allowed at weeks 8 and 10, respectively, for participants with less than a 50% reduction in HAMD scores and/or alcohol use per TLFB.
Period Title: Overall Study
STARTED	35	35
COMPLETED	23	21
NOT COMPLETED	12	14

Baseline Characteristics

Arm/Group Title	Ondansetron	Placebo	Total
Arm/Group Description	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.	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	Total of all reporting groups
Overall Participants	35	35	70
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	35 100%	35 100%	70 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	11 31.4%	17 48.6%	28 40%
Male	24 68.6%	18 51.4%	42 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 2.9%	1 1.4%
Asian	3 8.6%	3 8.6%	6 8.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	18 51.4%	18 51.4%	36 51.4%
White	14 40%	13 37.1%	27 38.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.54 (8.60)	43.29 (10.01)	44.91429 (9.41128)

Outcome Measures

1. Primary Outcome

Title	Hamilton Rating Scale for Depression (HAMD)
Description	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

Outcome Measure Data

Analysis Population Description

11 participants from Ondansetron group and 13 from the Placebo group did not complete this study.

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	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.	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
Measure Participants	35	35
Baseline	13.77 (5.39)	14.23 (7.25)
Week 12	8.52 (6.02)	8.86 (5.77)

2. Primary Outcome

Title	Number of Standard Drinks Per Assessment Period on Timeline Followback (TLFB)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	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.	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
Measure Participants	35	35
Baseline	4.06 (4.07)	4.92 (4.09)
Week 12	2.50 (3.73)	2.92 (2.68)

3. Primary Outcome

Title	Number of Heavy Drinking Days Per Assessment Period on Timeline Followback (TLFB)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	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.	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
Measure Participants	35	35
Baseline	0.34 (0.33)	0.45 (0.37)
Week 12	0.17 (0.28)	0.20 (0.28)

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	Adverse events were assessed by a weekly questionnaire at each appointment.
Arm/Group Title	Ondansetron		Placebo
Arm/Group Description	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.		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
All Cause Mortality
	Ondansetron		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/35 (2.9%)		0/35 (0%)
Serious Adverse Events
	Ondansetron		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/35 (28.6%)		4/35 (11.4%)
Blood and lymphatic system disorders
Leg swelling	1/35 (2.9%)	1	0/35 (0%)	0
Cardiac disorders
Prolonged QTc interval	1/35 (2.9%)	1	0/35 (0%)	0
Hypertension	1/35 (2.9%)	1	0/35 (0%)	0
General disorders
Death	1/35 (2.9%)	1	0/35 (0%)	0
Infections and infestations
UTI	1/35 (2.9%)	1	0/35 (0%)	0
Bacterial parasite in gut	1/35 (2.9%)	1	0/35 (0%)	0
Sepsis	1/35 (2.9%)	1	0/35 (0%)	0
Corneal ulcer	1/35 (2.9%)	1	0/35 (0%)	0
Cellulitis	0/35 (0%)	0	1/35 (2.9%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/35 (2.9%)	1	2/35 (5.7%)	2
Nervous system disorders
Spinal disk degeneration	1/35 (2.9%)	1	0/35 (0%)	0
Psychiatric disorders
Manic episode	1/35 (2.9%)	1	0/35 (0%)	0
Social circumstances
Detoxification	1/35 (2.9%)	1	0/35 (0%)	0
Suicide attempt	1/35 (2.9%)	1	1/35 (2.9%)	1
Suicide ideation	1/35 (2.9%)	1	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Ondansetron		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/35 (20%)		4/35 (11.4%)
Cardiac disorders
Hypertension	1/35 (2.9%)	1	0/35 (0%)	0
Eye disorders
Glaucoma	1/35 (2.9%)	1	0/35 (0%)	0
Gastrointestinal disorders
Indigestion	1/35 (2.9%)	1	0/35 (0%)	0
GERD	1/35 (2.9%)	1	0/35 (0%)	0
Nausea	1/35 (2.9%)	1	0/35 (0%)	0
Cramping	1/35 (2.9%)	1	0/35 (0%)	0
General disorders
Hot flashes	1/35 (2.9%)	1	0/35 (0%)	0
Drowsiness	0/35 (0%)	0	1/35 (2.9%)	1
Headache	0/35 (0%)	0	1/35 (2.9%)	1
Sedation	0/35 (0%)	0	1/35 (2.9%)	1
Swollen feet	1/35 (2.9%)	1	1/35 (2.9%)	1
Dehydration	0/35 (0%)	0	1/35 (2.9%)	1
Injury, poisoning and procedural complications
Pain in finger and foot	0/35 (0%)	0	1/35 (2.9%)	1
Psychiatric disorders
Auditory hallucinations	0/35 (0%)	0	2/35 (5.7%)	2
Skin and subcutaneous tissue disorders
Rash	1/35 (2.9%)	1	0/35 (0%)	0
Social circumstances
Suicidal ideation	1/35 (2.9%)	1	1/35 (2.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.