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

Bipolar Disorder Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02519543
• Other study ID #: TRIO-BD-100
• Status: Completed
• Phase: Phase 3
• Start date: September 2015
• Est. completion date: September 2020

Study information

• Verified date: January 2021
• Source: Nova Scotia Health Authority
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: September 2020
• Est. primary completion date: September 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bipolar Disorder
• Insulin Resistance

Intervention

Drug:
• Placebo
Placebo to be given twice daily, once with breakfast and once with supper
• Metformin
Active experimental drug to be given twice a day, 1000 mg with breakfast and 1000 mg with supper

Locations

Country	Name	City	State
Canada	Nova Scotia Health Authority - Dept. of Psychiatry	Halifax	Nova Scotia
United States	Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Cynthia Calkin	Stanley Medical Research Institute

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (3)

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. Review. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Montgomery-?sberg 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).	14 weeks
Secondary	Montgomery-?sberg 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.	26 weeks
Secondary	Montgomery-?sberg 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.	14 and 26 weeks
Secondary	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.	14 and 26 weeks
Secondary	Young Mania Rating Scale (YMRS)	We will examine the effect of treating IR on mania symptoms using this rating scale.	14 and 26 weeks
Secondary	Hamilton Anxiety Rating Scale (HAM-A)	We will examine the effect of treating IR on mood and anxiety symptoms using this rating scale.	14 and 26 weeks
Secondary	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.	14 and 26 weeks
Secondary	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.	14 and 26 weeks

External Links

•   Are comorbid insulin resistance and type II diabetes risk factors for refractory bipolar illness?
•   The risk of insulin resistance and type 2 diabetes mellitus in bipolar disorder