Bipolar Disorder, Metabolic Syndrome, Obesity, Schizoaffective Disorder, Schizophrenia
Conditions
Keywords
schizophrenia, schizoaffective disorder, bipolar disorder, olanzapine, melatonin, obesity, metabolic syndrome
Brief summary
Atypical antipsychotic medications, such as olanzapine, cause metabolic side effects, including weight gain, extra fat around the middle of the body, high blood sugar, and high cholesterol. One of the mechanisms by which these medications may cause these effects is by reducing plasma melatonin. This study is a pilot project to evaluate 1) the effect of olanzapine on melatonin secretion levels and 2) the effect of melatonin on olanzapine-induced changes in melatonin secretion in patients with schizophrenia, schizoaffective, or bipolar disorder.
Detailed description
To investigate the relationship between olanzapine, melatonin, and metabolic functioning, this pilot study is evaluating 20 patients with schizophrenia, schizoaffective disorder, or bipolar disorder over 15 weeks under three experimental conditions: 1) baseline (two weeks treatment with already established antipsychotic medication other than olanzapine or clozapine), 2) six weeks treatment with olanzapine only, and 3) six weeks treatment with olanzapine and melatonin. Half of the patients will receive 0.3 mg of oral melatonin and half will receive 3.0 mg of melatonin. Nocturnal melatonin production, as estimated by assay of urinary 6-sulfatoxymelatonin(aMT6s) adjusted for creatinine, will be measured weekly. In addition, weekly measurements of weight and other metabolic indices, including waist and hip measurements, fasting glucose, serum insulin, cholesterol, triglycerides, and leptin will be taken. It is anticipated that there will be an olanzapine-induced decrease in melatonin production. Furthermore, it is expected that the decrease in melatonin production associated with olanzapine treatment will be reversed by administration of melatonin with olanzapine.
Interventions
DRUGolanzapine and melatonin
In treatment phase I, all subjects will receive olanzapine, 10-25 mg/day. In treatment phase II, all subjects will receive olanzapine (10-25 mg/day) plus melatonin. Subjects will be randomized at a ratio of 1:1 to receive melatonin, 0.3 mg/day or 3.0 mg/day. Group IIA will receive 0.3mg day melatonin. Group IIB will receive 3.0 mg/day melatonin.
Sponsors
Eli Lilly and Company
Seattle Institute for Biomedical and Clinical Research
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 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-65; 2. DSM-IV-TR diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder; 3. Patients who, in the clinical judgment of the investigator, may benefit from a switch to olanzapine; 4. Females must be of non-child bearing potential (i.e., surgically sterilized, or at least one year post-menopausal) or on an appropriate dose of oral/depot contraceptives or using barrier protection and not breast-feeding. Females must have a urine pregnancy test at screening; 5. Willingness and ability to take medications nightly at 10:00 p.m.; and 6. The subject or his/her legal representative must provide informed, written consent.
Exclusion criteria
1. Females who are pregnant or lactating; 2. Concurrent participation or participation within the prior 30 days in any study involving investigational medications; 3. Current (within the prior 30 days) diagnosis of substance abuse or dependence; 4. Use of olanzapine within the prior three months; 5. History of allergy or intolerable side-effects to olanzapine in the past; 6. History of significant head trauma, defined as head trauma resulting in loss of consciousness for more than five minutes and/or neurological or cognitive sequelae; 7. Evidence of any clinically relevant disease (e.g., renal or hepatic impairment, significant coronary artery disease, cerebrovascular disease, or cancer) or any clinical finding that in the opinion of the investigator could potentially be negatively affected by study participation or that could potentially affect study participation is criterion for exclusion from the study; 8. Use of fluvoxamine, nifedipine, or warfarin for 30 days prior to Baseline Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nocturnal Melatonin Production | 6 and 12 weeks | Nocturnal melatonin production as estimated by assay of urinary 6-sulfatoxymelatonin (aMT6s) adjusted for creatinine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weight | 6 weeks & 12 weeks | weight (measured in kilograms) |
| Total Cholesterol | 6 weeks & 12 weeks | Total cholesterol on metabolic blood panel |
Countries
United States
Participant flow
Pre-assignment details
Of the 40 participants who were initially consented, 5 were screen fails, 13 were lost to follow up and 5 were withdrawals prior to beginning Phase I of being prescribed olanzapine. 17 participants began Phase I and 4 were lost to follow up during that phase. 13 participants went on to Phase II to be randomized to one of two melatonin groups, however 3 were not able to collect data, leaving 10 participants in Phase II.
Participants by arm
| Arm | Count |
|---|---|
| IIA (0.3mg Day Melatonin) 0.3mg day melatonin
olanzapine and melatonin: In treatment phase I, all subjects will receive olanzapine, 10-25 mg/day. In treatment phase II, all subjects will receive olanzapine (10-25 mg/day) plus melatonin. Subjects will be randomized at a ratio of 1:1 to receive melatonin, 0.3 mg/day or 3.0 mg/day. Group IIA will receive 0.3mg day melatonin. Group IIB will receive 3.0 mg/day melatonin. | 4 |
| IIB (3.0 mg/Day Melatonin) 3.0 mg/day melatonin
olanzapine and melatonin: In treatment phase I, all subjects will receive olanzapine, 10-25 mg/day. In treatment phase II, all subjects will receive olanzapine (10-25 mg/day) plus melatonin. Subjects will be randomized at a ratio of 1:1 to receive melatonin, 0.3 mg/day or 3.0 mg/day. Group IIA will receive 0.3mg day melatonin. Group IIB will receive 3.0 mg/day melatonin. | 6 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase II - Randomization to Melatonin | Data unable to be collected | 0 | 2 | 1 |
| Phase I - Olanzapine Only | Lost to Follow-up | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | IIB (3.0 mg/Day Melatonin) | IIA (0.3mg Day Melatonin) | 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 | 6 Participants | 4 Participants | 10 Participants |
| Age, Continuous | 47.33 years STANDARD_DEVIATION 12.58 | 55.5 years STANDARD_DEVIATION 6.61 | 50.6 years STANDARD_DEVIATION 10.97 |
| Region of Enrollment United States | 6 participants | 4 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 6 | 0 / 17 |
| other Total, other adverse events | 3 / 4 | 3 / 6 | 11 / 17 |
| serious Total, serious adverse events | 1 / 4 | 0 / 6 | 1 / 17 |
Outcome results
Primary
Nocturnal Melatonin Production
Nocturnal melatonin production as estimated by assay of urinary 6-sulfatoxymelatonin (aMT6s) adjusted for creatinine
Time frame: 6 and 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IIA (0.3mg Day Melatonin) | Nocturnal Melatonin Production | Baseline | 11.19 mg/dL | Standard Deviation 9.69 |
| IIA (0.3mg Day Melatonin) | Nocturnal Melatonin Production | Week 6 | 10.39 mg/dL | Standard Deviation 8.51 |
| IIA (0.3mg Day Melatonin) | Nocturnal Melatonin Production | Week 12 | 197.7 mg/dL | Standard Deviation 163.83 |
| IIB (3.0 mg/Day Melatonin) | Nocturnal Melatonin Production | Baseline | 19.09 mg/dL | Standard Deviation 10.12 |
| IIB (3.0 mg/Day Melatonin) | Nocturnal Melatonin Production | Week 6 | 15.18 mg/dL | Standard Deviation 12.49 |
| IIB (3.0 mg/Day Melatonin) | Nocturnal Melatonin Production | Week 12 | 2,137.12 mg/dL | — |
Secondary
Total Cholesterol
Total cholesterol on metabolic blood panel
Time frame: 6 weeks & 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IIA (0.3mg Day Melatonin) | Total Cholesterol | Baseline | 185.25 mg/dL | Standard Deviation 35.68 |
| IIA (0.3mg Day Melatonin) | Total Cholesterol | Week 6 | 207 mg/dL | Standard Deviation 19.29 |
| IIA (0.3mg Day Melatonin) | Total Cholesterol | Week 12 | 205.5 mg/dL | Standard Deviation 26.01 |
| IIB (3.0 mg/Day Melatonin) | Total Cholesterol | Baseline | 204.43 mg/dL | Standard Deviation 31.04 |
| IIB (3.0 mg/Day Melatonin) | Total Cholesterol | Week 6 | 220.43 mg/dL | Standard Deviation 29.56 |
| IIB (3.0 mg/Day Melatonin) | Total Cholesterol | Week 12 | 221.71 mg/dL | Standard Deviation 36.07 |
Secondary
Weight
weight (measured in kilograms)
Time frame: 6 weeks & 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IIA (0.3mg Day Melatonin) | Weight | Baseline | 87.10 kilograms | Standard Deviation 3.76 |
| IIA (0.3mg Day Melatonin) | Weight | Week 6 | 90.71 kilograms | Standard Deviation 3.65 |
| IIA (0.3mg Day Melatonin) | Weight | Week 12 | 93.45 kilograms | Standard Deviation 4.9 |
| IIB (3.0 mg/Day Melatonin) | Weight | Baseline | 88.53 kilograms | Standard Deviation 24.99 |
| IIB (3.0 mg/Day Melatonin) | Weight | Week 6 | 93.20 kilograms | Standard Deviation 28.68 |
| IIB (3.0 mg/Day Melatonin) | Weight | Week 12 | 95.14 kilograms | Standard Deviation 28.71 |