Open Label Study of Lithium Plus Extended-Release Carbamazepine (ERC-CBZ) for Rapid Cycling Bipolar Disorder

Study Overview
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Brief Summary
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This is an open label design using Lithium plus extended release carbamazepine (Equetro) in combination for 6 months. Rapid cycling bipolar disorder is frequently treatment refractory and associated with repeated hospitalizations and complications. The results of this study will offer a promising approach to treat this complex disorder. The primary efficacy measure will be the time to relapse. Relapse will determined by the investigator based on the following: Need for additional pharmacotherapy for mood-related symptoms, hospitalization for an mood episode, increase of more than 50% in HAM-D and YMRS scores from the baseline visit.

Detailed Description
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Open label Design with Lithium plus Extended release carbamazepine combination for 6 months. Extended release carbamazepine at doses of 1600 mg/day will be utilized. Lithium dosage will be adjusted to maintain therapeutic blood levels. Patient Population: N = 20. Primary and Secondary Efficacy Endpoints: The primary efficacy measure will be the time to relapse. Relapse will determined by the investigator based on the following Need for additional pharmacotherapy for affective symptoms Hospitalization for an affective episode Increase of more than 50% in HAM-D and YMRS scores from baseline The differences in the frequency of affective episodes in the 6-month prior to the treatment with ERC-CBZ and 6 months after treatment initiation will also be measured. Secondary efficacy measures will include; changes in the 17- Item Hamilton Depression Scale (HAM-D), Young Mania Rating Scale (YMRS), Clinical Global Severity Scale (CGI -S), Clinical Global Improvement Scale (CGI-I) scores at baseline and scores during treatment with ERC-CBZ. Inclusion Criteria: Subjects, 19 years and older with DSM-IV defined Bipolar Disorder with a history of the rapid cycling within the past 12 months. Subjects may be either in a manic, mixed or depressive phase at time of study entry. Subjects must be on lithium therapy for 6 months or longer. Stable lithium therapy will be defined as: No changes in lithium dosage for at least 2 weeks prior to study entry and a therapeutic lithium level (0.6 to 1.2 mEq) prior to study entry. Exclusion Criteria: Subjects with a lifetime history of Schizophrenia or Schizoaffective Disorder If patients are on thyroid replacement therapy they have to on stable doses for the past 3 months at study enrollment. Presence of active suicide ideations or score of > 3 on the suicide subscale of the 17 - item HAM-D. Current substance dependence (excluding nicotine) defined as no dependence criteria for 30 days prior to study enrollment Subjects with a history of non-response to carbamazepine or lithium Subjects who are pregnant or planning to become pregnant Subjects with a history of allergic/idiosyncratic reaction or intolerability to carbamazepine or lithium. Study Procedures: Preliminary Phase: The Structured Clinical Interview Diagnostic Schedule (SCID), medical & psychiatric history and baseline laboratory testing, EKG; pregnancy test will be obtained to ensure study eligibility. Eligible subjects will receive ERC-CBZ at starting doses ranging from 100 to 200 mg b.i.d. depending on clinical presentation and further titration up to a maximum dose of 1600 mg/day will be done at the discretion of the investigator. This titration phase will not extend beyond 2 weeks during which changes in concomitant medications will be allowed. Next, all psychotropics excluding lithium, ERC-CBZ and benzodiazepines will be tapered over a 2-week period. During the preliminary phase subjects will be seen weekly and assessments will be made using the HAM-D, YMRS, CGI -S, CGI-I, AE, and Concomitant medications Open Label Phase: Subjects on lithium and ERC-CBZ therapy will enter this phase for 6 months. Changes to both lithium and ERC-CBZ will be permitted during this phase with serum levels to guide titration. Use of lorazepam, as a rescue medication will be permitted. Study visits will be every biweekly for 6 months. The HAM-D, YMRS and CGI-S, CGI-I, AE, concomitant medications will be assessed at each visit. Compliance will be assessed by pill counts at each study visit.

Official Title
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Open Label Prophylaxis Study of Lithium Plus Extended- Release Carbamazepine (Equetro®) Combination for Rapid Cycling Bipolar Disorder

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Lithium Plus Extended- Release Carbamazepine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects, 19 years and older with DSM-IV defined Bipolar Disorder with a history of the rapid cycling within the past 12 months. Subjects may be either in a manic, mixed or depressive phase at time of study entry. Subjects must be on lithium therapy for 6 months or longer. Stable lithium therapy will be defined as: No changes in lithium dosage for at least 2 weeks prior to study entry and a therapeutic lithium level (0.6 to 1.2 mEq) prior to study entry. Exclusion Criteria: Subjects with a lifetime history of Schizophrenia or Schizoaffective Disorder If patients are on thyroid replacement therapy they have to on stable doses for the past 3 months at study enrollment. Presence of active suicide ideations or score of > 3 on the suicide subscale of the 17 - item HAM-D. Current substance dependence (excluding nicotine) defined as no dependence criteria for 30 days prior to study enrollment Subjects with a history of non-response to carbamazepine or lithium Subjects who are pregnant or planning to become pregnant Subjects with a history of allergic/idiosyncratic reaction or intolerability to carbamazepine or lithium.

Ages Eligible for Study
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Minimum Age: 19 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Treatment with lithium and extended release carbamazepine | Drug: Lithium Plus Extended- Release Carbamazepine<br>* Preliminary phase subjects receive ERC-CBZ starting dose range from 100 to 200 mg b.i.d. and further titration up to a maximum dose of 1600 mg/day done at the discretion of the investigator. Titration phase will not extend beyond 2 weeks.Open label phase subjects stabilized on lithium and ERC-CBZ therapy will enter this phase for 6 months<br>* Other names: Epitol, Tegretol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary efficacy measure will be the time to relapse. Relapse will determined by; need for additional pharmacotherapy, hospitalization for an affective episode, increase of >/= 50% in HAM-D and YMRS scores. |  | Patients will be seen weekly during preliminary phase and biweekly during the open label phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The differences in the frequency of affective episodes in the 6-month prior to the treatment with ERC-CBZ and 6 months after treatment initiation will also be measured. Secondary efficacy measures will include; changes in the 17- Item Hamilton Depression |  | Patients will be seen weekly during the preliminary phase and biweekly during the open label phase |