Comparative Efficacy and Acceptability of Antimanic Drugs in Acute Mania

Study Overview
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Brief Summary
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Background: Bipolar disorder is one of the most common mental illnesses affecting 1%-4% of the population, and one of the leading causes of worldwide disability. Mania is a condition of excessively elevated mood, characterizes bipolar disorder, and usually is a main cause of hospitalization. Mood stabilisers and antipsychotic drugs have long been the maintenance treatment of acute mania with and without psychotic symptoms. Though clinical trails have been demonstrated that these drugs are individually more effective than placebo in the relatively long term (e.g 4, 8 weeks). However, in the pragmatic practice, patient at acute mania urgently want to see the effectiveness, and psychiatrist under great pressure and are in great need to evaluate the very short-term effectiveness (e.g one week). If the first attempted antimanic drug fails, psychiatrist need the evidence that which medication should be to added on or switch to. Objectives: one main aim is to rank the short-term ( e.g.one and two week) effectiveness and acceptability of the common anti-mania drugs, including Lithium, Valproate, Oxcarbazepine, Quetiapine, Olanzapine, or Ziprasidone. Secondary aim is to investigate which medication to add on for non-responders or switch to. Methods: The study setting: it is expected that 120 subjects with a diagnose of DSM-IV bipolar I disorder will be recruited from Guangzhou Psychiatric Hospital, the earliest psychiatric hospital in the history of China established by Dr.J. G. Kerr in 1898. Design:This study is a randomized, controlled trial. Participants with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of bipolar I disorder, manic or mixed episode will be randomly assigned to a treatment of Lithium, Valproate, Oxcarbazepine, Quetiapine, Olanzapine, or Ziprasidone. In the following conditions, participants will take another antimanic drug as a combination medication: 1) those who have a reduction in YMRS scores less than 25% after one week of treatment; 2) those who have a reduction in YMRS scores less than 50% after two weeks of treatment; or 3) those who have a increase in YMRS more than 30% at day 4. An antipsychotic (Quetiapine, Olanzapine, and Ziprasidone) will be added on for those who use lithium, Valproate or Oxcarbazepine as a first attempted medication; while Lithium, Valproate, or Oxcarbazepine will be added on for those who use an antipsychotic as a first attempted medication. Those participants who are recognized as non-response/partial response to two combined medications after 6 weeks of treatment will switch to Modified Electroconvulsive Therapy (MECT). Measures: Primary outcome measures are change scores on the Young Mania Rating Scale (YMRS) and dropout rates. Secondary outcome measures include Clinical Global Impressions (CGI) Scale, Global Assessment Scale (GAS), Treatment Emergent Symptom Scale (TESS), and Brief Psychiatric Rating Scale (BPRS). Response criteria: <25% reduction in YMRS scores or >=4 scores of CGI is defined as non-response. 25-49% reduction in YMRS scores from baseline as well as <=3 scores of Clinical General Impression (CGI) is recognized as partial response.>= 50% reduction in YMRS as well as 1 (very much improved) or 2 scores (much improved) of CGI is recognized as response. Remission is defined as a YMRS score <=12 and CGI score equal to 1 or 2.

Detailed Description
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Background: Bipolar disorder is one of the most common mental illnesses affecting 1%-4% of the population, and one of the leading causes of worldwide disability. Mania is a condition of excessively elevated mood, characterizes bipolar disorder, and usually is a main cause of hospitalization. Mood stabilisers and antipsychotic drugs have long been the maintenance treatment of acute mania with and without psychotic symptoms. Though clinical trails have been demonstrated that these drugs are individually more effective than placebo.However, in the pragmatic practice, patient at acute mania urgently want to see the effectiveness, and psychiatrist under great pressure and are in great need to evaluate the very short-term effectiveness (e.g one week). If the first attempted antimanic drug fails, psychiatrist need the evidence that which medication should be to added on or switch to. Objectives: one main aim is to rank the short-term ( e.g.one and two week) effectiveness and acceptability of the common anti-mania drugs, including Lithium, Valproate, Oxcarbazepine, Quetiapine, Olanzapine, or Ziprasidone. Secondary aim is to investigate which medication to add on for non-responders or switch to. Methods: The study setting: it is expected that 120 subjects with a diagnose of DSM-IV bipolar disorder will be recruited from Guangzhou Psychiatric Hospital, the earliest psychiatric hospital in the history of China established by Dr.J. G. Kerr in 1898. Design:This study is a randomized, controlled trial, consisting two phase. 120 participants with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of bipolar I disorder, manic or mixed phase will be randomly assigned to a treatment of Lithium, Valproate, Oxcarbazepine, Quetiapine, Olanzapine, or Ziprasidone. The period from starting dose to effective dose for each drug is within 2 days, and the effective doses for these drugs are described as follow: Lithium, 750mg-2000mg/d, serum Li level: 0.6mmol-1.2mmol/L; Valproate, 800mg-- 1200mg/d, serum Valproate level: 70-120ug/ml; Oxcarbazepine, 600-1200mg/d; Quetiapine, 600mg--800mg/d; Olanzapine, 10mg-- 20mg/d; Ziprasidone, 80mg-160mmg/d. In the following conditions, participants will take a another antimanic drug as a combination medication: 1) those who have a reduction in YMRS scores less than 25% after one week of treatment; 2) those who have a reduction in YMRS scores less than 50% after two weeks of treatment; or 3) those who have a increase in YMRS more than 30% at day 4. An antipsychotic (Quetiapine, Olanzapine, and Ziprasidone) will be added on for those who use lithium, Valproate or Oxcarbazepine as a first attempted medication; while Lithium, Valproate, or Oxcarbazepine will be added on for those who use an antipsychotic as a first attempted medication. Those participants who are recognized as non-response/partial response to two combined medications after 6 weeks of treatment will switch to Modified Electroconvulsive Therapy (MECT). Measures: Primary outcome measures are change scores on the Young Mania Rating Scale (YMRS) and dropout rates. Secondary outcome measures include Clinical Global Impressions (CGI) Scale, Global Assessment Scale (GAS), Treatment Emergent Symptom Scale (TESS), and Brief Psychiatric Rating Scale (BPRS). Response criteria: <25% reduction in YMRS scores or >=4 scores of CGI is defined as non-response. 25-49% reduction in YMRS scores from baseline as well as <=3 scores of Clinical General Impression (CGI) is recognized as partial response.>= 50% reduction in YMRS as well as 1 (very much improved) or 2 scores (much improved) of CGI is recognized as response. Remission is defined as a YMRS score <=12 and CGI score equal to 1 or 2.

Official Title
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Comparative Efficacy and Acceptability of Lithium, Valproate, Oxcarbazepine, Quetiapine, Olanzapine, and Ziprasidone in Bipolar I Disorder, Manic or Mixed Phase

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Lithium
* Drug: Valproate
* Drug: Oxcarbazepine
* Drug: Quetiapine
* Drug: Olanzapine
* Drug: Ziprasidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: with a diagnosis of bipolar I disorder, manic or mixed phase equal or more than 18 scores in Young Mania Rating Scale (YMRS) Exclusion Criteria: Serious general medical illness pregnancy and lactation given long-acting antipsychotic drug within the last two month endocrine disease( e.g.Diabetes and thyrotoxicosis) given thyroxine therapy within the last three months or is being given hormone therapy sexually active and not using contraceptives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valproate<br>Name: Valproate; dosage form: tablet, 250mg; dosage and frequency: 800mg-- 1200mg/d; duration: 6 weeks. | Drug: Valproate<br>* Valproate is used as a mood stabiliser<br>* Other names: Depakote;|
| Experimental: Oxcarbazepine<br>Name: Oxcarbazepine, dosage form: 300mg, tablet; dosage and frequency: 600-1200mg/d; duration: 6 weeks | Drug: Oxcarbazepine<br>* Oxcarbazepine is used as a mood stabiliser<br>* Other names: Trileptal;|
| Experimental: Quetiapine<br>name: Quetiapine, dosage form: 200mg,tablet; dosage and frequency: 600mg-- 800mg/d; duration: 6 weeks | Drug: Quetiapine<br>* Quetiapine is used as a mood stabiliser<br>* Other names: SEROquel;|
| Experimental: Olanzapine<br>Name: Olanzapine, dosage form: 5mg tablet; dosage and frequency: 10mg--20mg/d; duration: 6 weeks | Drug: Olanzapine<br>* Olanzapine is used as a mood stabiliser.<br>* Other names: Zyprexa；;|
| Experimental: Ziprasidone<br>Name: Ziprasidone, dosage form: 10mg tablet; dosage and frequency: 80mg-160mmg/d; duration: 6 weeks | Drug: Ziprasidone<br>* Ziprasidone is used as a mood stabiliser<br>* Other names: Geodon;|
| Experimental: Lithium<br>name: lithium; dosage form: 250mg Tablet; dosage and frequency: 750mg-2000mg/d;serum Li level: 0.6mmol-1.2mmol/L; duration: 6 weeks | Drug: Lithium<br>* Lithium is used as a mood stabiliser<br>* Other names: lithium Carbonate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Young Mania Rating Scale at 2 weeks and 6 weeks | Young Mania Rating Scale is used to assess hypomania/mania symptoms | Baseline, 2 weeks and 6 weeks | 
| rate of dropout (treatment discontinuation) | to compare the rates of treatment discontinuation of different drugs because of side effect or effectiveness | 1,2,4,6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions (CGI) Scale | Clinical Global Impressions (CGI) Scale is used to assess the patient's global functioning prior to and after initiating a study medication. The CGI provides an overall clinician-determined summary measure, taking into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function | baseline, 2 weeks, 4 weeks, and 6 weeks | 
| Brief Psychiatric Rating Scale | Brief Psychiatric Rating Scale is used to assess psychotic symptoms. | baseline, 2, 3, 4 and 6 weeks | 
| Global Assessment Scale | Global Assessment Scale is a numeric scale (1 through 100) used by mental health clinicians to rate the general functioning. | baseline, 2, 3, 4 and 6 weeks | 
| Treatment Emergent Symptom Scale | Treatment Emergent Symptom Scale is used to assess the adverse event of the drug. | 2, 3, 4 and 6 weeks | 
| Hamilton Anxiety Rating Scale | Hamilton Anxiety Rating Scale is used to assess anxious symptoms | baseline, 2, 3, 4, and 6 weeks | 
| Hamilton Depression Rating Scale | Hamilton Depression Rating Scale is used to assess the depressive symptoms | baseline, 2, 3, 4, and 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar disorder, Comparative Effectiveness Research, Therapeutics, Patient Dropouts