Atypical Antipsychotics for Continuation and Maintenance Treatment After an Acute Manic Episode

Study Overview
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Brief Summary
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Hypothesis: Continuation of an atypical antipsychotic medication in combination with a Mood Stabilizer, following remission from an acute manic episode, lowers the rates of relapse and recurrence of mood episodes compared to discontinuing the antipsychotics within days of resolution of manic symptoms.

Detailed Description
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This is a randomised, double-blind, placebo controlled trial over 52 weeks. Patients will be on one of four combinations of medications at the time of entry into the study: a) lithium and risperidone, b) lithium and olanzapine, c) valproate and risperidone, or d) valproate and olanzapine. After obtaining informed consent, patients will be randomised to one of three groups 1)0 week group: patients will receive lithium or valproate plus placebo for 52 weeks (risperidone or olanzapine tapering will begin on the day of randomisation with discontinuation of the drug within 2 weeks), 2) continuation of the same atypical antipsychotic, risperidone or olanzapine, plus lithium or valproate for 24 weeks (tapering of the antipsychotic begins at the end of 24 weeks and completed within 2 weeks) followed by the same mood stabilizer plus placebo for another 28 weeks, and 3) continuation of the atypical antipsychotic, risperidone or olanzapine, plus lithium or valproate for 52 weeks. The duration of the double-blind phase of the study will be 52 weeks and all patients will continue on the mood stabilizer, lithium or valproate, they had been on during the acute mania for the full duration of the study. The serum level of the mood stabilizer will be maintained within the therapeutic range (0.6 to 1.2 mmol/L for lithium and 50 to 125 ug/L for valproate) throughout the 52 weeks as determined by blood tests. The dose and the type of atypical antipsychotic (ie risperidone or olanzapine) each patient will receive during the double-blind period will be the same that the patient had been on at the time of entry into the double-blind phase. All patients, irrespective of which treatment arm they are in, will receive active psychoeducation and counselling regarding sleep hygiene, healthy daily routines and rhythms, alcohol and substance abuse, anxiety management, conflict resolution and problem solving as clinically indicated in routine clinical practice. Patients who withdraw from or meet a primary end point of the study will be treated actively as done in regular clinical practice. Patients will not be allowed to receive any other psychotropic medication with the exception of benzodiazepines for sedation and anti-parkinsonian medication for extrapyramidal side effects. The doses of these will be recorded.

Official Title
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Atypical Antipsychotics for Continuation and Maintenance Treatment After an Acute Manic Episode

Conditions
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Bipolar I Disorder

Intervention / Treatment
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* Drug: Valproate
* Drug: Lithium
* Drug: Risperidone
* Drug: Olanzapine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who were recently (within the last 12 weeks) commenced on treatment for a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) manic or mixed episode with a combination of lithium and risperidone, lithium and olanzapine, valproate and risperidone, or valproate and olanzapine; Patients on 1 to 6 mg of risperidone or 5 to 25 mg of olanzapine Patients who are in remission from mania for at least 2 weeks but no more than 6 weeks and have maintained remission for 2 consecutive weeks; Patients must not be taking any other psychotropic medication (with the exception of benzodiazepines) or treatments including bromocriptine, omega 3 fatty acids, Axid or EMPower; Patients aged 17 and above. Exclusion Criteria: Any subjects who do not meet the above inclusion criteria will be excluded from the study. In order for the findings to be generalizable to clinically representative patients with bipolar disorder, any patients with a history of co-morbid substance abuse or medical illnesses will not be excluded.

Ages Eligible for Study
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Minimum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Mood stabilizer & Placebo<br>Patients will receive lithium or valproate plus placebo for 52 weeks (risperidone or olanzapine tapering will begin on the day of randomization with discontinuation of the drug within 2 weeks). | Drug: Valproate<br>* serum level of 50 to 125 ug/L<br>* Other names: Valproic Acid;Drug: Lithium<br>* serum levels of 0.6 to 1.2 mmol/L<br>* Other names: Lithium Carbonate;Other: Placebo<br>* manufactured to mimic risperidone and olanzapine<br>* Other names: Sugar Pill;|
| Experimental: '24 week  arm<br>Continuation of the lithium or valproate plus risperidone or olanzapine for 24 weeks followed by mood stabilizer plus placebo for another 28 weeks. Dosages: 1 to 6 mg of risperidone, 5 to 20 mg olanzapine. | Drug: Valproate<br>* serum level of 50 to 125 ug/L<br>* Other names: Valproic Acid;Drug: Lithium<br>* serum levels of 0.6 to 1.2 mmol/L<br>* Other names: Lithium Carbonate;Drug: Risperidone<br>* 1 to 6 mg/day<br>* Other names: Risperdal;Drug: Olanzapine<br>* 5 to 25 mg/day<br>* Other names: Zyprexa;Other: Placebo<br>* manufactured to mimic risperidone and olanzapine<br>* Other names: Sugar Pill;|
| Active Comparator: 52 week arm<br>Continuation of the atypical antipsychotic, risperidone or olanzapine, plus lithium or valproate for 52 weeks. | Drug: Valproate<br>* serum level of 50 to 125 ug/L<br>* Other names: Valproic Acid;Drug: Lithium<br>* serum levels of 0.6 to 1.2 mmol/L<br>* Other names: Lithium Carbonate;Drug: Risperidone<br>* 1 to 6 mg/day<br>* Other names: Risperdal;Drug: Olanzapine<br>* 5 to 25 mg/day<br>* Other names: Zyprexa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome measure is the time to any mood episode (depressive or manic episode). | A mood episode is defined as 1) Young Mania Rating Scale (YMRS) score of 15 or greater 2)Hamilton Rating Scale for Depression (HAM-D) 21-item score of 15 or greater or a HAM-D suicide item score of 3 or greater 3)A Clinical Global Impression -Severity (CGI-S) score of 3 or greater 4) a patient requiring hospitalization for treatment of mood symptoms or 5) a patient who makes a suicide attempt or commits suicide during the study. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to manic episode. | Time to occurrence of a manic episode measured by Young Mania Rating Scale (YMRS) score of 15 or greater . | 52 weeks | 
| Time to depressive episode | Time to occurrence of a depressive episode measured by Hamilton Rating Scale for Depression (HAM-D) 21-item score of 15 or greater or a HAM-D suicide item score of 3 or greater. | 52 weeks |