Supraphysiological Doses of Levothyroxine as Adjunctive Therapy in Bipolar Depression

Study Overview
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Brief Summary
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There is growing evidence that thyroid axis dysfunction may contribute to the pathophysiology of bipolar illness. Open-label studies have consistently demonstrated that the behavioral expression of bipolar disorder can be modified by a change in thyroid status, and in many instances the course of illness is improved through the use of adjunct thyroid hormone treatment. Recent evidence emerged from acute intervention studies that add-on treatment with supraphysiological doses of levothyroxine is an effective augmenting agent in patients with a major depressive episode. The primary goal of this international multicenter trial (5 sites) is to determine in a 13-week, randomized, placebo-controlled design (1 week single-blind placebo run-in, 6 week double-blind, 6 week open-label) the efficacy and safety of add-on treatment with levothyroxine (300 mcg/d) in combination with mood stabilizer/antidepressant therapy in the treatment of patients with bipolar depression. The main hypotheses is: treatment with levothyroxine will result in a significantly greater mean reduction of HRSD total score and in a higher number of responders and remitters compared to placebo treatment. This proposal will build on our pilot data and provide evidence for the use of levothyroxine as an effective augmentation strategy in the treatment of bipolar depression.

Official Title
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Supraphysiological Doses of Levothyroxine as Adjunctive Therapy in Bipolar Depression: A Multicenter, Randomized, Double-blind, Placebo-controlled Study.

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: L-Thyroxine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of bipolar I or II disorder, currently depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Hamilton Rating Scale for Depression (HAM-D) 17-item score ≥14, a HAM-D item 1 (depressed mood) score ≥2 at the screening and randomization visits Young Mania Rating Scale (YMRS) score ≤12 at the screening and randomization visits. Pretreatment with a mood stabilizer and/or an antidepressant at standard doses (Bauer et al. 2007a) for at least six weeks since the last dose adjustment, and for at least two weeks before enrollment Serum levels of mood stabilizer were required to be within therapeutic ranges TSH levels in normal range (serum TSH 0.3 - 4.7 mU/l) Exclusion Criteria: Any axis I disorder other than bipolar disorder Recent ultra-rapid cycling course (12 or more episodes in previous year), - - a diagnosis of substance dependence (DSM-IV) or substance use (except for nicotine) within 12 months before the screening visit Clinically significant medical illness, especially severe cardiovascular diseases Organic brain disorder Current serious suicidal or homicidal risk by clinical judgment of the investigator History of previous or current thyroid disease Thyroid hormone treatment

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Pill<br> | Drug: Placebo<br> <br> |
| Experimental: L-Thyroxine as addon<br> | Drug: L-Thyroxine<br>* L-Thyroxine as addon to ongoing stable antidepressant and /or mood stabilizing therapy: week 1: 100 mcg; week 2: 200 mcg: week 3 to week 6: 300 mcg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in Hamilton Rating Scale for Depression (HRSD, 17 items) |  | baseline and six weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change and single items change in the Thyroid Symtom List (TSL) |  | baseline and six weeks | 
| Remission/Response | Rate of Resonders (>50% decline in HRDS) and Remitters (HRDS- score < 9)after l-Thyroxine addon treatment | six weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar disorder, Bipolar depression, Thyroid abnormality, mood stabilizer, antidepressants, currently depressed