'Remarkable' Response to Diabetes Drug in Resistant Bipolar Depression

Fran Lowry

June 07, 2021

Treating insulin resistance may improve treatment-resistant bipolar depression, early research suggests.

In a randomized, placebo-controlled trial, treatment with the diabetes drug metformin reversed insulin resistance in 50% of patients, and this reversal was associated with significant improvement of depressive symptoms. One patient randomly assigned to placebo also achieved a reversal of insulin resistance and improved depressive symptoms.

Dr Jessica Gannon

"The study needs replication, but this early clinical trial suggests that the mitigation of insulin resistance by metformin significantly improves depressive symptoms in a significant percentage of treatment resistant bipolar patients," presenting author Jessica M. Gannon, MD, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, told Medscape Medical News.

"It looks like in treatment-resistant bipolar depression treating insulin resistance is a way to get people well again, to get out of their depression," principal investigator Cynthia Calkin, MD, from Dalhousie University, Halifax, Canada, added.

The findings were presented at the virtual American Society of Clinical Psychopharmacology 2021 Annual Meeting.

Chronic Inflammation

The study was a joint effort by UPMC and Dalhousie University and was sponsored by the Stanley Medical Research Institute.

Dr Cynthia Calkin

Patients with bipolar disorder (BD) who are obese tend to have more serious illness, with a more chronic course, more rapid cycling, and more morbidity. These patients also fail to respond to lithium, Calkin said.

"Untreated hyperinsulinemia could be contributing to a state of chronic inflammation and be involved in disease progression. So the question for me was, if we treat this insulin resistance, would patients get better?" she said.

Calkin said investigators used metformin because it is already used by psychiatrists for weight management in patients on antipsychotics.

"I wanted to test the drug that would work to reverse insulin resistance and that psychiatrists would be comfortable prescribing," she said.

The 26-week study randomly assigned 20 patients to receive metformin and 25 patients to placebo.

All participants were 18 years and older, had a diagnosis of BD I or II, and had nonremitting BD defined by moderate depressive symptoms as measured on the Montgomery-Asberg Depression Rating Scale (MADRS) score of 15 or greater, despite being on optimal, guideline-compatible treatment.

All patients were stable, were on optimal doses of mood-stabilizing medications for at least 4 weeks prior to study entry, and had insulin resistance as defined by a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥1.8.

Characteristics were similar between the two groups, including baseline MADRS scores, body mass index, fasting glucose and insulin serum levels.

Patients were titrated up to 2000 mg of metformin, which was the full dose, over 2 weeks and then maintained on treatment for a further 24 weeks.

Highly Resistant Population

The study's primary outcome measure was change in MADRS score, with a response defined as a 30% reduction in MADRS from baseline.

By week 14, 10 metformin-treated patients (50%) and one patient in the placebo group (4%) no longer met insulin resistance criteria.

"It was a bit of a surprise to me that 50% of patients converted to being insulin sensitive again. When you use metformin to treat diabetes, people respond to it at more than a 50% rate, so I was expecting more people to respond," Calkin said.

Nevertheless, the 11 patients who did respond and reversed insulin resistance achieved greater reduction in MADRS scores compared with nonconverters.

"Those who reversed their insulin resistance showed a remarkable resolution in their depressive symptoms. The reduction in MADRS scores began at week 6, and were maintained through to the end of the study, and the Cohen's d effect size for MADRS depression scores for converters was 0.52 at week 14 and 0.55 at week 26," Calkin said.

"They were moderately to severely depressed going in, and at the end of the study, they had mild residual depressive symptoms, or they were completely well. These were very treatment-resistant patients.

"All had failed, on average, 8 or 9 trials in their lifetime. When they came to us, nothing else would work. That's one of the remarkable things about our results, just how well they responded when they had not responded to any other psychotropic medications," This approach may be very helpful for some patients," Calkin said.

A Holistic Approach

Commenting on the study for Medscape Medical News, Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, said the findings need to be replicated but provide further support for the broader strategy of taking a holistic approach to the care of patients with difficult-to-treat mood disorders."

"Approximately one half of people with treatment-resistant bipolar depression showed evidence of glucose resistance and that adjunctive treatment with metformin, a medication that enhances insulin sensitivity, was moderately effective in normalizing glucose metabolism, with about a 50% response rate. Among those who experienced improved glucose regulation, there was a significant reduction in depressive symptoms," he noted.

The study was funded by the Stanley Medical Research Institute (SMRI). Calkin and Thase have disclosed no relevant financial relationships.

American Society of Clinical Psychopharmacology (ASCP) 2021: Abstract 3002792 Presented June 2, 2021.

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