Allopurinol Add-on Treatment for Refractory Mania
Study Details
Study Description
Brief Summary
The purpose of this study is to investigate the efficacy of allopurinol as an augmentation agent for treatment resistant mania and mixed mania.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
Bipolar disorder is a severe mental disorder with episodes of mania and depression. Current medications for mania can have significant side effects, high costs and the need for blood monitoring. The purpose of this research study is to study the effectiveness of allopurinol, in combination with lithium or valproic acid or carbamazepine, for treatment-resistant bipolar mania and mixed mania. This research study is designed to test the safety and/or effectiveness of allopurinol that has been approved by the U.S. Food and Drug Administration (FDA) for recurrent calcium renal calculus, gout, hyperuricemia (cancer and tumor lysis syndrome), but it is not approved for use in treatment-resistant bipolar mania or mixed mania.
Participants in this double-blind study will be randomly assigned to one of two study groups. The first group will receive the study medication of allopurinol while the second group will receive a placebo. These will be taken in conjunction with current medications and doses. The study will last for 7 weeks (an initial screening, a baseline visit and 4 follow-up visits at weeks 1,2,4, and 6). The initial screening visit will be used to determine whether or not the subject is able to participate in the study. The following will be conducted during the screening visit: Review of medical and psychiatric history along with standard psychiatric assessment exams; Physical examination, including review of prior and current medications and adverse drug effects; An electrocardiogram (ECG) - a painless test which is done by attaching straps or pads to your limbs and chest and recording the electrical pattern of your heart, will be done to record your heart rhythm; About 5 tablespoons of blood will be drawn to assess basic laboratory values that show if you are healthy enough to participate in the study; Blood levels of lithium, valproic acid, and/or carbamazepine will be measured; A urine sample will be collected to test for the presence of illegal drugs and for pregnancy test (if you are a female of child-bearing potential); Collection of demographic data (e.g., age, gender, marital status, social and vocational status) and other information including health beliefs, and knowledge of illness. At the baseline visit the participant will be given questionnaires related to mood, quality of life, disability, medications, and side effects. The participant's vitals (temperature, weight, heart rate, and blood pressure) will be measured. The participant will be randomized to treatment (300 mg of allopurinol/day) or placebo. After week one at the Week 1 visit, those that have tolerated the dosage of allopurinol will get an increased dosage. The participant will also complete a set of questionnaires. Vitals will be taken. The remaining follow-up visits will be similar to visit one except that there will be no more increases in dosage; Week 2 will include a blood draw to measure levels of lithium, valproic acid, and/or carbamazepine in the participant's blood, and the final visit at Week 6 will in addition include a blood draw, and exit physical exam, and a urine sample will be collected.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Allopurinol Subjects will be randomized to allopurinol at a fixed dose of 300 mg/day for the first week and then 600mg/day while continuing their current medications during the 7-week study. A battery of assessments will be administered at baseline and weeks 1, 2, 4, 6 after baseline. At each assessment, subjects will also be asked about side effects including potential side effects of allopurinol. Side effects will be assessed by the Treatment Emergent Side Effects Scale. Serum levels of lithium, valproic acid, carbamazepine, atypical antipsychotics or atypical antipsychotic metabolite, uric acid blood levels will be drawn at screen and at week 6 after baseline. Subjects taking only lithium, valproic acid, and/or carbamazepine will also have their serum levels drawn at week 2. |
Drug: Allopurinol
300-600 mg/day over a 6 week period
Other Names:
|
| Placebo Comparator: Placebo Subjects will be randomized to placebo and will follow the same protocol as the allopurinol group. |
Other: Placebo
Inactive substance
|
Outcome Measures
Primary Outcome Measures
- Young Mania Rating Scale (YMRS) [7 weeks (Baseline and 6 weeks (or last visit date) after baseline]
The YMRS is an 11-item, clinician-administered rating scale to assess the severity of manic symptoms before, during and after treatment. There are four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. A score of 0 indicates the behavior is absent, whereas a score of 4 or 8 indicates the behavior is present and severe. The change in score between Baseline and the Completion Visit will be reported. Ideally, the two time points will be Baseline and 6 Weeks after Baseline, but, if a subject terminates early, his/her last YMRS score will be carried forward to the final visit. The scores from each question are added together to form a total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms. A score of 0-12 indicates the absence of mania or a very mild manic state, a score of 13-20 or higher indicates a mild man
Secondary Outcome Measures
- Hamilton Depression Scale (HAM-D) [7 weeks]
The Hamilton Depression Rating Scale (HAM-D) is a clinician-administered tool used to determine a patient's level of depression before, during, and after treatment. A 28-item HAM-D form was used but only the first 17 questions are used in the assessment for depression. Of the first 17 questions, eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. The sum of the scores from the first 17 questions is: 0-7 = normal, 8-13 = mild depression, 14-18 = moderate depression, 19-22=severe depression and ≥ 23=very severe depression. Questions 18-28 are scored similarly and assess sleep disorders, paranoid behavior, motor dysfunction, psychosis, and weight gain, etc.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Subjects must be between ages 18 and 70.
-
Subjects must meet DSM-IV criteria for bipolar disorder, most recent episode manic or mixed, at the time of screening confirmed by the Mini International Neuropsychiatric Interview (MINI).
-
Subjects must be taking at least one medication for mania (lithium, valproic acid, carbamazepine) at a therapeutic dose for at least 4 weeks.
-
Subjects must have non-response or partial response to medications as evidenced by Young Mania Rating Scale (YMRS) score greater than or equal to 14 at screening and at baseline.
-
Female subjects must be either postmenopausal for at least 1 year, surgically sterile, abstinent or practicing an effective method of birth control if sexually active. Female subjects must also have a negative urine pregnancy test at screening, baseline and other time points throughout the study.
-
Subjects must be able and willing to comply with self-administration of medication or have consistent help/support available.
-
Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
-
Subjects must be able and willing to meet or perform study requirements (e.g. answer self-administered questionnaires).
-
Subjects must be willing to allow study staff to contact subject's regular psychiatrist while the subject is in the study.
Exclusion Criteria:
-
Subjects who are unable to provide informed consent.
-
Subjects with a serious, unstable medical illness (such as cardiovascular, respiratory, neurologic, hematologic, renal, hepatic, endocrine, immunologic, or other systemic illness), a history of cerebrovascular disease, uncontrolled diabetes mellitus or AIDS. Subjects with chronic illness must be stable and otherwise physically healthy on the basis of a physical examination, medical history, electrocardiogram and the results of blood biochemistry, hematology tests and a urinalysis.
-
Subjects with a history of substance abuse or dependence (excluding nicotine and caffeine) according to DSM-IV criteria within last 4 weeks.
-
Subjects taking azathioprine, mercaptopurine, apalcillin, and/or amoxicillin.
-
Subjects taking dopamine agonists and/or anti-psychotics.
-
Subjects who have been intoxicated with alcohol or illicit drugs within 3 days prior to baseline.
-
Subjects with a history of severe pre-existing gastrointestinal narrowing or inability to swallow oral study medication whole with the aid of water.
-
Female subjects who are pregnant or nursing.
-
Subjects who have previously participated in this study.
-
Subjects with an anticipated life expectancy of 6 months or less.
-
Subjects who have received an experimental drug or used an experimental medical device within 1 month of screening.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cedars-Sinai Medical Center | Los Angeles | California | United States | 90048 |
Sponsors and Collaborators
- Cedars-Sinai Medical Center
- National Alliance for Research on Schizophrenia and Depression
Investigators
- Study Chair: Itai Danovitch, M.D., Cedars-Sinai Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB8981
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 8 subjects screen failed; 5 subjects did not qualify at Baseline. 13 total subjects were not randomized |
| Arm/Group Title | Allopurinol | Placebo |
|---|---|---|
| Arm/Group Description | Allopurinol: 300-600 mg/day over a 6 week period | Placebo: Inactive substance |
| Period Title: Overall Study | ||
| STARTED | 15 | 12 |
| COMPLETED | 10 | 11 |
| NOT COMPLETED | 5 | 1 |
Baseline Characteristics
| Arm/Group Title | Allopurinol | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Allopurinol: 300-600 mg/day over a 6 week period | Placebo: Inactive substance | Total of all reporting groups |
| Overall Participants | 15 | 12 | 27 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
15
100%
|
12
100%
|
27
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
8
53.3%
|
5
41.7%
|
13
48.1%
|
| Male |
7
46.7%
|
7
58.3%
|
14
51.9%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Caucasian |
9
60%
|
8
66.7%
|
17
63%
|
| African-American |
3
20%
|
4
33.3%
|
7
25.9%
|
| Hispanic |
3
20%
|
0
0%
|
3
11.1%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
15
100%
|
12
100%
|
27
100%
|
| Marital Status (Count of Participants) | |||
| Never Married |
8
53.3%
|
6
50%
|
14
51.9%
|
| Married |
1
6.7%
|
3
25%
|
4
14.8%
|
| Divorced |
4
26.7%
|
3
25%
|
7
25.9%
|
| Not Reported |
2
13.3%
|
0
0%
|
2
7.4%
|
| Employment Status (Count of Participants) | |||
| Employed |
4
26.7%
|
4
33.3%
|
8
29.6%
|
| Unemployed |
9
60%
|
6
50%
|
15
55.6%
|
| Disabled |
1
6.7%
|
2
16.7%
|
3
11.1%
|
| Student |
1
6.7%
|
0
0%
|
1
3.7%
|
Outcome Measures
| Title | Young Mania Rating Scale (YMRS) |
|---|---|
| Description | The YMRS is an 11-item, clinician-administered rating scale to assess the severity of manic symptoms before, during and after treatment. There are four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. A score of 0 indicates the behavior is absent, whereas a score of 4 or 8 indicates the behavior is present and severe. The change in score between Baseline and the Completion Visit will be reported. Ideally, the two time points will be Baseline and 6 Weeks after Baseline, but, if a subject terminates early, his/her last YMRS score will be carried forward to the final visit. The scores from each question are added together to form a total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms. A score of 0-12 indicates the absence of mania or a very mild manic state, a score of 13-20 or higher indicates a mild man |
| Time Frame | 7 weeks (Baseline and 6 weeks (or last visit date) after baseline |
Outcome Measure Data
| Analysis Population Description |
|---|
| 27 subjects were randomized but 4 (3 from the Treatment group and 1 from the Control group) withdrew from the study immediately following the baseline visit. Therefore, a second time point was unavailable for these subjects. |
| Arm/Group Title | Allopurinol | Placebo |
|---|---|---|
| Arm/Group Description | Allopurinol: 300-600 mg/day over a 6 week period | Placebo: Inactive substance |
| Measure Participants | 12 | 11 |
| Mean (Standard Error) [units on a scale] |
-12.3
(1.9)
|
-9.6
(2.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Allopurinol, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | .45 |
| Comments | ||
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 2.9 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.3 |
|
| Estimation Comments | ||
| Title | Hamilton Depression Scale (HAM-D) |
|---|---|
| Description | The Hamilton Depression Rating Scale (HAM-D) is a clinician-administered tool used to determine a patient's level of depression before, during, and after treatment. A 28-item HAM-D form was used but only the first 17 questions are used in the assessment for depression. Of the first 17 questions, eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. The sum of the scores from the first 17 questions is: 0-7 = normal, 8-13 = mild depression, 14-18 = moderate depression, 19-22=severe depression and ≥ 23=very severe depression. Questions 18-28 are scored similarly and assess sleep disorders, paranoid behavior, motor dysfunction, psychosis, and weight gain, etc. |
| Time Frame | 7 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| No data displayed because no data was collected prior to closing of the research unit. |
| Arm/Group Title | Allopurinol | Placebo |
|---|---|---|
| Arm/Group Description | Allopurinol: 300-600 mg/day over a 6 week period | Placebo: Inactive substance |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | 5 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Placebo | Allopurinol | ||
| Arm/Group Description | Placebo: Inactive substance | Allopurinol: 300-600 mg/day over a 6 week period | ||
All Cause Mortality |
||||
| Placebo | Allopurinol | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/15 (0%) | ||
Serious Adverse Events |
||||
| Placebo | Allopurinol | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/15 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Placebo | Allopurinol | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/12 (8.3%) | 2/15 (13.3%) | ||
| Psychiatric disorders | ||||
| Suicidal thoughts and plan | 0/12 (0%) | 0 | 1/15 (6.7%) | 1 |
| Medication non-compliance | 0/12 (0%) | 0 | 1/15 (6.7%) | 1 |
| Reproductive system and breast disorders | ||||
| Inflamed prostate | 1/12 (8.3%) | 1 | 0/15 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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.
Results Point of Contact
| Name/Title | Felicia Mayes |
|---|---|
| Organization | Cedars Sinai Medical Center |
| Phone | 310-423-0825 |
| mayesf@cshs.org |
- IRB8981