Supraphysiological Doses of Levothyroxine as Adjunctive Therapy in Bipolar Depression

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

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.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: Placebo; Drug: L-Thyroxine

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
  • Bochum, Germany
    • Department of Psychiatry, LWL University Hospital, Ruhr University Bochum, Bochum, Germany
  • Dresden, Germany
    • Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  • Göttingen, Germany
    • Department of Psychiatry and Psychotherapy, University of Göttingen, Germany
• United States
  • California
    • Los Angeles, California, United States
      • University of California in Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Pill	Drug: Placebo
Experimental: L-Thyroxine as addon	Drug: L-Thyroxine; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Stanley Medical Research Institute

Publications and helpful links

General Publications

• Pilhatsch M, J Stamm T, Stahl P, Lewitzka U, Berghofer A, Sauer C, Gitlin M, Frye MA, Whybrow PC, Bauer M. Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms. Int J Bipolar Disord. 2019 Oct 4;7(1):21. doi: 10.1186/s40345-019-0155-y.
• Stamm TJ, Lewitzka U, Sauer C, Pilhatsch M, Smolka MN, Koeberle U, Adli M, Ricken R, Scherk H, Frye MA, Juckel G, Assion HJ, Gitlin M, Whybrow PC, Bauer M. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014 Feb;75(2):162-8. doi: 10.4088/JCP.12m08305.

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: February 6, 2012
• First Submitted That Met QC Criteria: February 7, 2012
• First Posted (Estimate): February 8, 2012

Study Record Updates

• Last Update Posted (Estimate): February 8, 2012
• Last Update Submitted That Met QC Criteria: February 7, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: antidepressants; Bipolar disorder; Bipolar depression; Thyroid abnormality; mood stabilizer; currently depressed
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Bipolar and Related Disorders; Depression; Bipolar Disorder
• Other Study ID Numbers: 1908Si267

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No