Back to results

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

Primary Purpose

Bipolar Disorder

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Placebo

Metformin

About this trial

This is an interventional treatment trial for Bipolar Disorder focused on measuring insulin resistance

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

18 years of age or older
diagnosis of BD I or II
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
HOMA-IR ≥ 1.8, indicating IR (subjects will have FPG and FSI testing done to determine whether they have IR or T2D)
current episode of depression 4 weeks or longer in duration
on a stable optimal dose of mood stabilizing treatment for at least 4 weeks prior to study entry

Exclusion Criteria:

Diagnoses of organic mood disorder, mood disorder not otherwise specified, alcohol dependence, T1D or T2D
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])
patient receiving metformin < 2 weeks prior to study entry
metformin allergy or sensitivity
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
pregnancy or breastfeeding
lactose intolerance, diagnosed by a physician
chronic use of narcotic medications
patient lacks full capacity to consent to study participation.

Sites / Locations

Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh
Nova Scotia Health Authority - Dept. of Psychiatry

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Metformin

Arm Description

Placebo comparator to be given twice daily, once with breakfast and once with supper

Metformin 2000 mg daily to be given as follows: 1000 mg with breakfast and 1000 mg with supper

Outcomes

Primary Outcome Measures

Montgomery-Ǻsberg Depression Rating Scale (MADRS)

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).

Secondary Outcome Measures

Montgomery-Ǻsberg Depression Rating Scale (MADRS)

Using this scale, we will assess whether the effect of treating IR on bipolar depression symptoms is sustained up to 26 weeks.

Montgomery-Ǻsberg Depression Rating Scale (MADRS)

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.

Inventory of Depressive Symptomatology-Self Rating (IDS-SR)

We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.

Young Mania Rating Scale (YMRS)

We will examine the effect of treating IR on mania symptoms using this rating scale.

Hamilton Anxiety Rating Scale (HAM-A)

We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.

Clinical Global Impression modified for use in Bipolar Disorder (CGI-BP)

We will use this scale to assess the effect of treating IR on overall psychiatric morbidity and severity of illness.

Global Assessment of Functioning (GAF)

We will use this scale to assess the effect of treating IR on overall psychiatric morbidity and severity of illness.

Full Information

NCT ID

NCT02519543

First Posted

August 3, 2015

Last Updated

January 12, 2021

Sponsor

Cynthia Calkin

Collaborators

Stanley Medical Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT02519543

Brief Title

Treating Insulin Resistance as a Strategy to Improve Outcome in Refractory Bipolar Disorder

Acronym

TRIO-BD

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Completed

Study Start Date

September 2015 (undefined)

Primary Completion Date

September 2020 (Actual)

Study Completion Date

September 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Cynthia Calkin

Collaborators

Stanley Medical Research Institute

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bipolar Disorder

Keywords

insulin resistance

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo comparator to be given twice daily, once with breakfast and once with supper

Arm Title

Metformin

Arm Type

Experimental

Arm Description

Metformin 2000 mg daily to be given as follows: 1000 mg with breakfast and 1000 mg with supper

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

sugar pill

Intervention Description

Placebo to be given twice daily, once with breakfast and once with supper

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Metformin Hydrochloride

Intervention Description

Active experimental drug to be given twice a day, 1000 mg with breakfast and 1000 mg with supper

Primary Outcome Measure Information:

Title

Montgomery-Ǻsberg Depression Rating Scale (MADRS)

Description

Time Frame

14 weeks

Secondary Outcome Measure Information:

Title

Montgomery-Ǻsberg Depression Rating Scale (MADRS)

Description

Using this scale, we will assess whether the effect of treating IR on bipolar depression symptoms is sustained up to 26 weeks.

Time Frame

26 weeks

Title

Montgomery-Ǻsberg Depression Rating Scale (MADRS)

Description

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.

Time Frame

14 and 26 weeks

Title

Inventory of Depressive Symptomatology-Self Rating (IDS-SR)

Description

We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.

Time Frame

14 and 26 weeks

Title

Young Mania Rating Scale (YMRS)

Description

We will examine the effect of treating IR on mania symptoms using this rating scale.

Time Frame

14 and 26 weeks

Title

Hamilton Anxiety Rating Scale (HAM-A)

Description

We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.

Time Frame

14 and 26 weeks

Title

Clinical Global Impression modified for use in Bipolar Disorder (CGI-BP)

Description

We will use this scale to assess the effect of treating IR on overall psychiatric morbidity and severity of illness.

Time Frame

14 and 26 weeks

Title

Global Assessment of Functioning (GAF)

Description

We will use this scale to assess the effect of treating IR on overall psychiatric morbidity and severity of illness.

Time Frame

14 and 26 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 18 years of age or older diagnosis of BD I or II 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 HOMA-IR ≥ 1.8, indicating IR (subjects will have FPG and FSI testing done to determine whether they have IR or T2D) current episode of depression 4 weeks or longer in duration on a stable optimal dose of mood stabilizing treatment for at least 4 weeks prior to study entry Exclusion Criteria: Diagnoses of organic mood disorder, mood disorder not otherwise specified, alcohol dependence, T1D or T2D 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]) patient receiving metformin < 2 weeks prior to study entry metformin allergy or sensitivity 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 pregnancy or breastfeeding lactose intolerance, diagnosed by a physician chronic use of narcotic medications patient lacks full capacity to consent to study participation.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Cynthia Calkin, MD FRCPC

Organizational Affiliation

Nova Scotia Health Authority

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Roy Chengappa, MD FRCPC

Organizational Affiliation

Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213-2593

Country

United States

Facility Name

Nova Scotia Health Authority - Dept. of Psychiatry

City

Halifax

State/Province

Nova Scotia

ZIP/Postal Code

B3H 2E2

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

25323142

Citation

Calkin CV, Ruzickova M, Uher R, Hajek T, Slaney CM, Garnham JS, O'Donovan MC, Alda M. Insulin resistance and outcome in bipolar disorder. Br J Psychiatry. 2015 Jan;206(1):52-7. doi: 10.1192/bjp.bp.114.152850. Epub 2014 Oct 16.

Results Reference

background

PubMed Identifier

12971015

Citation

Ruzickova M, Slaney C, Garnham J, Alda M. Clinical features of bipolar disorder with and without comorbid diabetes mellitus. Can J Psychiatry. 2003 Aug;48(7):458-61. doi: 10.1177/070674370304800705.

Results Reference

background

PubMed Identifier

22621171

Citation

Calkin CV, Gardner DM, Ransom T, Alda M. The relationship between bipolar disorder and type 2 diabetes: more than just co-morbid disorders. Ann Med. 2013 Mar;45(2):171-81. doi: 10.3109/07853890.2012.687835. Epub 2012 May 24.

Results Reference

background

PubMed Identifier

35120288

Citation

Calkin CV, Chengappa KNR, Cairns K, Cookey J, Gannon J, Alda M, O'Donovan C, Reardon C, Sanches M, Ruzickova M. Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study): A Randomized, Quadruple-Masked, Placebo-Controlled Clinical Trial. J Clin Psychiatry. 2022 Feb 1;83(2):21m14022. doi: 10.4088/JCP.21m14022.

Results Reference

derived

Links:

URL

https://apps.webofknowledge.com/full_record.do?product=UA&search_mode=GeneralSearch&qid=1&SID=2CRUvkzBT6AQyUenrvK&page=2&doc=11

Description

The risk of insulin resistance and type 2 diabetes mellitus in bipolar disorder

URL

http://ac.els-cdn.com.ezproxy.library.dal.ca/S0924977X13705789/1-s2.0-S0924977X13705789-main.pdf?_tid=234a7e9a-3c2e-11e5-ace4-00000aab0f01&acdnat=1438860636_5aecad769a45feae96b677c0ccb908cc

Description

Are comorbid insulin resistance and type II diabetes risk factors for refractory bipolar illness?

Learn more about this trial

Treating Insulin Resistance as a Strategy to Improve Outcome in Refractory Bipolar Disorder

We'll reach out to this number within 24 hrs