Bipolar Disorder
Conditions
Brief summary
The purpose of this study is to determine whether treating sleep difficulties in patients with bipolar disorder also improves their mood stability.
Detailed description
Patients with euthymic bipolar disorder, although free of significant mood symptoms, often have continued sleep disturbances. Improving patients' sleep by also normalizing the circadian rhythm will lead to fewer mood exacerbations. Ramelteon offers a new and more pharmacologically exact mechanism to re-synchronize the SCN. The administration of ramelteon for bipolar patients will improve sleep and will cause fewer mood exacerbations. Patients with bipolar disorder often experience frequent mood alterations that are attempted to be controlled by mood stabilizing agents and anti-psychotic agents. Both classes of medications have numerous significant side effects. Establishing that ramelteon is helpful in the sleep of patients with bipolar disorder and helpful in mood stability will increase the number of treatment options for bipolar patients.
Interventions
DRUGRamelteon
one 8 mg tablet at bedtime for up to 6 months
DRUGPlacebo
one tablet at bedtime for up to 6 months
Sponsors
Takeda
Lehigh Valley Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent before initiation of any study-related procedures 2. Men and women aged 18 to 65 years. 3. A documented clinical diagnosis according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) meeting criteria 296.4x Bipolar I disorder, most recent episode manic, 296.6x Bipolar I disorder, most recent episode mixed, or 296.5x Bipolar I disorder, most recent episode depressed. 4. PSQI total score of \>=5. 5. MADRS total score of \<=12. 6. YMRS total score of \<= 12 7. Female patients of childbearing potential must have a negative urine pregnancy test at enrollment and be willing to use a reliable method of birth control, i.e., double-barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device or tubal ligation, during the study. 8. Be able to understand and comply with the requirements of the study, as judged by the investigator. 9. Outpatient status at enrollment.
Exclusion criteria
1. Patients with a diagnosis of DSM-IV Axis II disorder which has a major impact on the patient's current psychiatric status. 2. Presence of prohibited medications of antidepressants (including MAOI's) and systemic corticosteroids. 3. Patients with a diagnosis of primary insomnia disorders 4. Patients with a diagnosis of severe chronic obstructive pulmonary disease 5. A clinical finding that is untreated (eg, hypertension, poorly controlled diabetes, angina) or that, in the opinion of the investigator, would be negatively affected by the study medication or that would affect the study medication. 6. Patients with active substance abuse diagnoses (except tobacco abuse). 7. Known history of intolerance or hypersensitivity to ramelteon or to any other component in the tablet.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pittsburgh Sleep Quality Index (PSQI) Global Score | Monthly for 6 months | Self-rated scale to measure quality of sleep via questions regarding sleep latency, duration, efficiency, disturbances, use of sleep medication, and daytime dysfunction. Scores range from 0-21, higher scores represent more significant sleep disturbance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Monthly for 6 months | 10-item, standardized, well-validated scale used to measure severity of depressive symptoms; sensitive to treatment effects in depressed outpatients. Scores range from 0-60, higher scores represent more severe depressive symptoms. |
| Young Mania Rating Scale (YMRS) Total Score | Monthly for 6 months | 11-item standardized, well-validated scale used to measure manic symptoms; sensitive to treatment effects in manic patients. Scores range from 0-60, higher scores represent more severe manic symptoms. |
| Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Monthly for 6 months | 3-part (mania, depression, overall bipolar illness), physician-administered scale used to assess global illness severity; used to measure change. Each part is rated from 1-7, higher scores represent more severe mental illness. Only overall bipolar rating was used. |
| Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Monthly for 6 months | Survival analysis techniques, including Kaplan Meier curves, were used to evaluate group differences in time to relapse. Relapse was defined as a medication initiation or change for manic/depressed/mixed symptoms, a hospitalization for manic/depressed/mixed symptoms, MADRS score \>= 16, YMRS score \> 14, and suicide risk or imminent risk of suicide. Time to relapse was measured discretely in terms of the number of assessment visits until discontinued from the study. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in October 2007 and was completed by August 2009. Participants, who at the time were receiving outpatient psychiatric services through Lehigh Valley Hospital, were recruited via referral through the department of psychiatry, and also through print advertisement. Participants received a $20 travel stipend for each appointment.
Pre-assignment details
90 participants signed the informed consent document, 7 were screen failures, and 83 were randomized to receive either Ramelteon or placebo. During the study, both groups were maintained on their usual medications for bipolar disorder and were not allowed to have any meds changed, as this would signify a manic or depressed event.
Participants by arm
| Arm | Count |
|---|---|
| Ramelteon one 8 mg tablet at bedtime for up to 6 months | 42 |
| Placebo one tablet at bedtime for up to 6 months | 41 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 5 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Medical Condition | 1 | 1 |
| Overall Study | Medication Change | 1 | 0 |
| Overall Study | Non-compliance | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Relapsed- Depressed Event | 10 | 16 |
| Overall Study | Relapsed- Mixed Event | 3 | 5 |
| Overall Study | Relapse- Manic Event | 3 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo | Ramelteon | 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 | 41 Participants | 42 Participants | 83 Participants |
| Age, Continuous | 45.2 years STANDARD_DEVIATION 10.8 | 46.6 years STANDARD_DEVIATION 11 | 45.9 years STANDARD_DEVIATION 10.9 |
| Region of Enrollment United States | 41 participants | 42 participants | 83 participants |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 42 | 12 / 41 |
| serious Total, serious adverse events | 0 / 42 | 0 / 41 |
Outcome results
Primary
Pittsburgh Sleep Quality Index (PSQI) Global Score
Self-rated scale to measure quality of sleep via questions regarding sleep latency, duration, efficiency, disturbances, use of sleep medication, and daytime dysfunction. Scores range from 0-21, higher scores represent more significant sleep disturbance.
Time frame: Monthly for 6 months
Population: Intent to Treat Analysis; excludes 7 screen failures.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 2 | 7.93 units on scale | Standard Error 0.63 |
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 4 | 7.21 units on scale | Standard Error 0.62 |
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 1 | 8.16 units on scale | Standard Error 0.56 |
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 5 | 6.62 units on scale | Standard Error 0.59 |
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 3 | 7.89 units on scale | Standard Error 0.68 |
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 6 | 6.90 units on scale | Standard Error 0.72 |
| Ramelteon | Pittsburgh Sleep Quality Index (PSQI) Global Score | Baseline | 10.17 units on scale | Standard Error 0.53 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 6 | 8.76 units on scale | Standard Error 0.98 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Baseline | 10.88 units on scale | Standard Error 0.53 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 1 | 9.28 units on scale | Standard Error 0.57 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 2 | 9.71 units on scale | Standard Error 0.64 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 3 | 10.38 units on scale | Standard Error 0.78 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 4 | 9.03 units on scale | Standard Error 0.75 |
| Placebo | Pittsburgh Sleep Quality Index (PSQI) Global Score | Month 5 | 8.66 units on scale | Standard Error 0.77 |
Secondary
Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score
3-part (mania, depression, overall bipolar illness), physician-administered scale used to assess global illness severity; used to measure change. Each part is rated from 1-7, higher scores represent more severe mental illness. Only overall bipolar rating was used.
Time frame: Monthly for 6 months
Population: Intent to Treat Analysis; excludes 7 screen failures
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 2 | 2.24 units on scale | Standard Error 0.18 |
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 4 | 2.36 units on scale | Standard Error 0.21 |
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 1 | 2.29 units on scale | Standard Error 0.15 |
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 5 | 2.46 units on scale | Standard Error 0.23 |
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 3 | 2.53 units on scale | Standard Error 0.22 |
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 6 | 2.54 units on scale | Standard Error 0.23 |
| Ramelteon | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Baseline | 2.14 units on scale | Standard Error 0.13 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 6 | 2.41 units on scale | Standard Error 0.34 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Baseline | 2.15 units on scale | Standard Error 0.13 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 1 | 2.25 units on scale | Standard Error 0.15 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 2 | 2.90 units on scale | Standard Error 0.19 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 3 | 2.93 units on scale | Standard Error 0.27 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 4 | 2.98 units on scale | Standard Error 0.29 |
| Placebo | Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score | Month 5 | 2.99 units on scale | Standard Error 0.34 |
Secondary
Cumulative Proportion of Participants in Each Arm Surviving Without Relapse
Survival analysis techniques, including Kaplan Meier curves, were used to evaluate group differences in time to relapse. Relapse was defined as a medication initiation or change for manic/depressed/mixed symptoms, a hospitalization for manic/depressed/mixed symptoms, MADRS score \>= 16, YMRS score \> 14, and suicide risk or imminent risk of suicide. Time to relapse was measured discretely in terms of the number of assessment visits until discontinued from the study.
Time frame: Monthly for 6 months
Population: Intent to Treat Analysis; excludes 7 screen failures.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 2 | 0.849 Cumulative proportion of participants |
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 4 | 0.661 Cumulative proportion of participants |
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 1 | 0.929 Cumulative proportion of participants |
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 5 | 0.632 Cumulative proportion of participants |
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 3 | 0.716 Cumulative proportion of participants |
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 6 | 0.566 Cumulative proportion of participants |
| Ramelteon | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Baseline | 1.00 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 6 | 0.320 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Baseline | 1.00 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 1 | 0.951 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 2 | 0.588 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 3 | 0.448 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 4 | 0.384 Cumulative proportion of participants |
| Placebo | Cumulative Proportion of Participants in Each Arm Surviving Without Relapse | Month 5 | 0.320 Cumulative proportion of participants |
Secondary
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
10-item, standardized, well-validated scale used to measure severity of depressive symptoms; sensitive to treatment effects in depressed outpatients. Scores range from 0-60, higher scores represent more severe depressive symptoms.
Time frame: Monthly for 6 months
Population: Intent to Treat Analysis; excludes 7 screen failures
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 2 | 7.23 units on scale | Standard Error 0.84 |
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 4 | 8.45 units on scale | Standard Error 1.05 |
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 1 | 8.34 units on scale | Standard Error 0.67 |
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 5 | 8.56 units on scale | Standard Error 1.24 |
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 3 | 9.17 units on scale | Standard Error 1 |
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 6 | 10.40 units on scale | Standard Error 1.48 |
| Ramelteon | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Baseline | 7.79 units on scale | Standard Error 0.42 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 6 | 10.46 units on scale | Standard Error 2.18 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Baseline | 8.27 units on scale | Standard Error 0.43 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 1 | 8.90 units on scale | Standard Error 0.68 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 2 | 11.13 units on scale | Standard Error 0.85 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 3 | 11.85 units on scale | Standard Error 1.24 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 4 | 13.03 units on scale | Standard Error 1.39 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Month 5 | 11.59 units on scale | Standard Error 1.73 |
Secondary
Young Mania Rating Scale (YMRS) Total Score
11-item standardized, well-validated scale used to measure manic symptoms; sensitive to treatment effects in manic patients. Scores range from 0-60, higher scores represent more severe manic symptoms.
Time frame: Monthly for 6 months
Population: Intent to Treat Analysis; excludes 7 screen failures
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Month 2 | 5.91 units on scale | Standard Error 0.8 |
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Month 4 | 5.93 units on scale | Standard Error 0.7 |
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Month 1 | 5.89 units on scale | Standard Error 0.51 |
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Month 5 | 5.18 units on scale | Standard Error 0.65 |
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Month 3 | 6.60 units on scale | Standard Error 0.84 |
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Month 6 | 6.51 units on scale | Standard Error 1 |
| Ramelteon | Young Mania Rating Scale (YMRS) Total Score | Baseline | 7.02 units on scale | Standard Error 0.43 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Month 6 | 6.72 units on scale | Standard Error 1.35 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Baseline | 6.59 units on scale | Standard Error 0.44 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Month 1 | 6.46 units on scale | Standard Error 0.52 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Month 2 | 7.75 units on scale | Standard Error 0.82 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Month 3 | 8.09 units on scale | Standard Error 1 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Month 4 | 4.95 units on scale | Standard Error 0.93 |
| Placebo | Young Mania Rating Scale (YMRS) Total Score | Month 5 | 5.71 units on scale | Standard Error 0.88 |