Treating Insulin Resistance as a Strategy to Improve Outcome in Refractory Bipolar Disorder (TRIO-BD)

January 12, 2021 updated by: Cynthia Calkin

Treating Insulin Resistance to Improve Outcome in Refractory Bipolar Disorder: a Randomized, Double-blind, Placebo-control Study of the Efficacy of Metformin in Patients With Insulin Resistance and Non-remitting Bipolar Illness

In a previous study by Dr. Calkin, the principal investigator of this study, persons with bipolar disorder and either type II diabetes or insulin resistance were found to experience more severe symptoms of bipolar illness and a lower response to treatment, compared to persons with bipolar disorder who did not have type II diabetes or insulin resistance. To further explore these findings, the investigators have developed this study to see if treating insulin resistance (using metformin, a drug used to improve the body's use of insulin) may also help improve the symptoms of bipolar illness.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a 26-week randomized, double-blind, parallel group prospective study of the effectiveness of treating insulin resistance (IR) to improve mood in patients with IR and treatment-resistant bipolar depression (TRBD). The investigators will compare the effects of treating IR (with metformin) versus placebo on outcome in each patient. The primary outcome will be change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) scores. Patients' current optimized mood stabilizing treatment as usual (TAU, according to the Canadian Network for Mood and Anxiety Treatments [CANMAT] or American Psychiatric Association [APA] guidelines) must remain unchanged for a period of at least 4 weeks prior to and throughout the study. Patients will undergo a baseline assessment and then be randomized to treatment with metformin or placebo with titration to full dose after 2 weeks. Patients will remain on full treatment for 24 weeks thereafter (total trial duration of 26 weeks for each patient). In those patients with TRBD assigned to treatment with the insulin sensitizer metformin, a significant improvement in depression symptoms will be mediated by the conversion of IR to insulin sensitivity.

Subjects: We aim to enrol 110 subjects with IR and TRBD from 2 sites: the primary site in Halifax, Nova Scotia, Canada, and a second site in Pittsburgh, Pennsylvania, USA.

Study Type

Interventional

Enrollment (Actual)

50

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 2E2
        • Nova Scotia Health Authority - Dept. of Psychiatry
  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213-2593
        • Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. 18 years of age or older
  2. diagnosis of BD I or II
  3. non-remitting BD as defined by the presence of mood symptoms of at least moderate severity, indicated by a MADRS score ≥ 15 despite being on optimal treatment according to the CANMAT/APA guidelines
  4. HOMA-IR ≥ 1.8, indicating IR (subjects will have FPG and FSI testing done to determine whether they have IR or T2D)
  5. current episode of depression 4 weeks or longer in duration
  6. on a stable optimal dose of mood stabilizing treatment for at least 4 weeks prior to study entry

Exclusion Criteria:

  1. Diagnoses of organic mood disorder, mood disorder not otherwise specified, alcohol dependence, T1D or T2D
  2. presence of rapid cycling (by DSM-5 criteria), mania, (indicated by a Young Mania Rating Scale [YMRS] score > 15), or suicide ideation (current score of 5 on the Suicidal Ideation section of the Columbia-Suicide Severity Rating scale [C-SSRS])
  3. patient receiving metformin < 2 weeks prior to study entry
  4. metformin allergy or sensitivity
  5. metformin contraindicated where liver function tests > three times the upper limit of normal, estimated glomerular filtration rate (eGFR) < 30, CBC revealing megaloblastic anemia or pre-existing untreated B12 deficiency
  6. pregnancy or breastfeeding
  7. lactose intolerance, diagnosed by a physician
  8. chronic use of narcotic medications
  9. patient lacks full capacity to consent to study participation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Placebo comparator to be given twice daily, once with breakfast and once with supper
Drug: Placebo
Placebo to be given twice daily, once with breakfast and once with supper
Other Names:
  • sugar pill
Experimental: Metformin
Metformin 2000 mg daily to be given as follows: 1000 mg with breakfast and 1000 mg with supper
Drug: Metformin
Active experimental drug to be given twice a day, 1000 mg with breakfast and 1000 mg with supper
Other Names:
  • Metformin Hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery-Ǻsberg Depression Rating Scale (MADRS)
Time Frame: 14 weeks
Using this scale, we will study the effect of treating insulin resistance (IR) on bipolar depression symptoms after 14 weeks of study drug treatment. We will assess whether the effect of metformin on improvement in MADRS scores at week 14 is mediated by conversion of IR to insulin sensitivity (determined using Homeostatic Model Assessment - Insulin Resistance, i.e. HOMA-IR).
14 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery-Ǻsberg Depression Rating Scale (MADRS)
Time Frame: 26 weeks
Using this scale, we will assess whether the effect of treating IR on bipolar depression symptoms is sustained up to 26 weeks.
26 weeks
Montgomery-Ǻsberg Depression Rating Scale (MADRS)
Time Frame: 14 and 26 weeks
Using this scale, we will assess whether treating IR results in a ≥ 30% improvement in bipolar depression symptoms after 14 weeks and 26 weeks of study drug treatment.
14 and 26 weeks
Inventory of Depressive Symptomatology-Self Rating (IDS-SR)
Time Frame: 14 and 26 weeks
We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.
14 and 26 weeks
Young Mania Rating Scale (YMRS)
Time Frame: 14 and 26 weeks
We will examine the effect of treating IR on mania symptoms using this rating scale.
14 and 26 weeks
Hamilton Anxiety Rating Scale (HAM-A)
Time Frame: 14 and 26 weeks
We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.
14 and 26 weeks
Clinical Global Impression modified for use in Bipolar Disorder (CGI-BP)
Time Frame: 14 and 26 weeks
We will use this scale to assess the effect of treating IR on overall psychiatric morbidity and severity of illness.
14 and 26 weeks
Global Assessment of Functioning (GAF)
Time Frame: 14 and 26 weeks
We will use this scale to assess the effect of treating IR on overall psychiatric morbidity and severity of illness.
14 and 26 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cynthia Calkin

Collaborators

Stanley Medical Research Institute

Investigators

  • Principal Investigator: Cynthia Calkin, MD FRCPC, Nova Scotia Health Authority
  • Principal Investigator: Roy Chengappa, MD FRCPC, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2015

Primary Completion (Actual)

September 1, 2020

Study Completion (Actual)

September 1, 2020

Study Registration Dates

First Submitted

August 3, 2015

First Submitted That Met QC Criteria

August 6, 2015

First Posted (Estimate)

August 11, 2015

Study Record Updates

Last Update Posted (Actual)

January 13, 2021

Last Update Submitted That Met QC Criteria

January 12, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TRIO-BD-100

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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