Melancholic Symptoms in Bipolar Depression and Responsiveness to Lamotrigine

Study Overview
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Brief Summary
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The purpose of this study is to determine if patients with melancholic bipolar II depression are more responsive to lamotrigine than patients with non-melancholic bipolar II depression. To do this, the investigators will re-analyze a previous clinical trial that evaluated lamotrigine as a treatment for bipolar II depression (GSK-SCA100223; NCT00274677).

Detailed Description
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Patients suffering from depression with melancholic symptoms (i.e., anhedonia, flat affect, diurnal mood variation, terminal insomnia, psychomotor disturbances, decreased weight/appetite, and excessive guilt) respond better to certain antidepressants. Melancholic symptoms also occur in bipolar depression, although they have received less research. Lamotrigine has been shown to alter some of the biological processes that are known to occur in melancholic depression. The purpose of this study is to determine if patients with melancholic bipolar II depression are more responsive to lamotrigine than patients with non-melancholic bipolar II depression. This study will re-analyze data from a previous 8-week, randomized, placebo-controlled trial that evaluated lamotrigine as a treatment for bipolar II depression (GSK-SCA100223; NCT00274677). The original study data was made available by GlaxoSmithKline as part of an initiative to make clinical trials data available for research use. Access was applied for via https://www.clinicalstudydatarequest.com. The analysis strategy will be comparable to the original study, although the investigators will first classify participants as suffering from either melancholic or non-melancholic depression. The diagnosis of melancholic depression was established according to baseline responses to the Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Åsberg Depression Rating Scale (MADRS), according to the DSM-IV-TR diagnostic criteria. HAMD-17 and MADRS change scores will be compared between the treatment and placebo groups using Analysis of Variance (ANOVA). Both ANOVA models will include a test for an interaction between treatment group (lamotrigine vs. placebo) and melancholic depression (melancholic depression vs. non-melancholic depression). To handle missing data, each ANOVA model will be computed with only complete-case data first and subsequently using inverse probability weights that account for the probability of drop out. Inverse probability weights will be created based on covariates that predict missing responses. HAMD-17 and MADRS response rates between the treatment and placebo groups will be evaluated with a Cox proportional hazard regression analysis. There will be two separate analyses, one including participants with melancholic depression, and one including participants with non-melancholic depression. Statistical models will also adjust for baseline depression severity, if participants with melancholic depression are found to have more severe depressive symptoms at baseline. Given the delay between antidepressant initiation and response, trial-and-error prescribing is an inevitably lengthy process. The investigators hope the results of this study will enable more timely and effective treatment for patients with bipolar depression.

Official Title
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Melancholic Symptoms in Bipolar Depression and Responsiveness to Lamotrigine: Results From an 8-week, Multicenter, Double-blind, Placebo-controlled Trial

Conditions
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Depression, Bipolar Disorder, Bipolar Depression, Melancholia, Lamotrigine

Intervention / Treatment
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* Drug: Lamotrigine
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must provide written and informed consent. Diagnosis of Bipolar II Disorder and currently depressed for minimum of the last 8 weeks, with a HAMD-17 score of at least 18 with scores of 3 or more on Items 1 or 7. For females, be of non-childbearing potential, or of childbearing potential with a negative pregnancy test at screening and agrees to one of (a) abstinence from sex two weeks prior and five days after drug continuation/discontinuation, (b) personal or partner sterilization, (c) one method of hormonal contraception, or (d) two barrier methods of contraception. Acceptable results (within two times the normal limit) on laboratory screening tests (e.g., thyroid function). Exclusion Criteria: Active suicidality. History of non-response to antidepressant treatment, or any previous treatment with lamotrigine. History of substance dependence in the past year, or abuse within the 4 weeks prior to study entry. Rapid cycling bipolar disorder. Receiving additional psychoactive medication (not including lorazepam for agitation), or has started a new course of psychotherapy within the last month. Received treatment for an anxiety or eating disorder within the last 12 months. Investigational drug use within the last month. History of epilepsy.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Lamotrigine - melancholic depression<br>Participants with melancholic depression who were randomly assigned to receive lamotrigine tablets escalated to a target dose of 200mg/day. | Drug: Lamotrigine<br>* Lamotrigine tablets at dosages of 25mg/day for Week 1 and Week 2, 50mg/day for Week 3 and Week 4, 100mg/day for Week 5, and 200mg/day for Week 6, Week 7, and Week 8.<br>* Other names: Lamictal;|
| Placebo Comparator: Placebo - melancholic depression<br>Participants with melancholic depression who were randomly assigned to receive a placebo comparator. | Drug: Placebos<br>* Placebo tablets<br>* Other names: Placebo;|
| Experimental: Lamotrigine - nonmelancholic depression<br>Participants not meeting DSM-IV-TR diagnostic criteria for melancholic depression who were randomly assigned to receive lamotrigine tablets escalated to a target dose of 200mg/day. | Drug: Lamotrigine<br>* Lamotrigine tablets at dosages of 25mg/day for Week 1 and Week 2, 50mg/day for Week 3 and Week 4, 100mg/day for Week 5, and 200mg/day for Week 6, Week 7, and Week 8.<br>* Other names: Lamictal;|
| Placebo Comparator: Placebo - nonmelancholic depression<br>Participants not meeting DSM-IV-TR diagnostic criteria for melancholic depression who were randomly assigned to receive a placebo comparator. | Drug: Placebos<br>* Placebo tablets<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) Change Scores | Scale scores range from 0 to 60. This outcome is a change score calculated by subtracting Baseline from Week 8 scores. Lower scores indicate greater improvement of depressive symptoms. | Eight weeks | 
| Hamilton Depression Rating Scale (HAMD-17) Change Scores | Scale scores range from 0 to 52. This outcome is a change score calculated by subtracting Baseline from Week 8 scores. Lower scores indicate greater improvement of depressive symptoms. | Eight weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Eight weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Seven weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Six weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Five weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Four weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Three weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | Two weeks | 
| Number of Participants With 50% Reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) | Scale scores range from 0 to 60. A response is defined as a score reduction from baseline of at least 50%. | One week | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Eight weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Seven weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Six weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Five weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Four weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Three weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | Two weeks | 
| Number of Participants With 50% Reduction in the Hamilton Depression Rating Scale (HAMD-17) | Scale scores range from 0 to 52. A response is defined as a score reduction from baseline of at least 50%. | One week |