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

This will be a 26-week randomized, double-blind, parallel group prospective study of the
efficacy of metformin as add-on treatment in patients with insulin resistance ( IR) and
non-remitting bipolar illness, conducted over three years. The investigators will compare the
effects of metformin versus placebo on outcome in each patient, while their 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) remains
unchanged for a period of at least 8 weeks prior to and throughout the study. Patients will
undergo a baseline assessment and then be randomized to treatment with placebo or metformin
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). The investigators will
compare response to metformin versus placebo (measured by Montgomery-Ǻsberg Depression Rating
Scale [MADRS] as the primary outcome).

Subjects: Enrolment of 110 subjects with IR and non-remitting bipolar depression will be
recruited over three years from 2 sites, the primary site in Halifax, Nova Scotia, Canada and
a second site in Pittsburgh, Pennsylvania, USA.

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 and

4. HOMA-IR > 1.8, indicating IR (subjects will haveFasting PLasma Glucose (FPG) and
Fasting Serum Insulin (FSI) testing done to determine whether they have Insulin
Resistance (IR) or Type II Diabetes (T2D).

Exclusion Criteria:

1. Diagnoses of organic mood disorder, mood disorder not otherwise specified, alcohol
dependence or T2D

2. presence of rapid cycling (by the Diagnostic and Statistical Manual of Mental
Disorders (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. patients receiving metformin < 3 months prior to study entry

4. metformin allergy or sensitivity

5. metformin contraindicated where liver function tests > three times the upper limit of
normal (alanine transaminase (ALT) > 162 U/L, aspartate transaminase (AST) > 69 U/L at
NSHA), estimated glomerular filtration rate (eGFR) < 30, complete blood count (CBC)
revealing megaloblastic anemia or pre-existing untreated B12 deficiency

6. pregnancy or breastfeeding

7. lactose intolerance, or 8) patient lacks full capacity to consent to study
participation -