Treatment for insulin resistance can improve treatment-resistant bipolar depression, early research suggests.
In a randomized, placebo-controlled study, treatment with the diabetes drug metformin reversed insulin resistance in 50% of patients, and this reversal was associated with a significant improvement in depressive symptoms. One patient who was randomly assigned to a placebo also achieved reversal of insulin resistance and improved depressive symptoms.
Dr. Jessica Gannon
“The study has to be repeated, but this early clinical study suggests that metformin ameliorating insulin resistance significantly improves depressive symptoms in a significant percentage of treatment-resistant bipolar patients,” said author Jessica M. Gannon, MD, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, told Medscape Medical News.
“It looks like treating insulin resistance in treatment-resistant bipolar depression is a way to help people recover and get out of their depression,” added study director Cynthia Calkin, MD, of Dalhousie University, Halifax, Canada .
The results were presented at the American Society of Clinical Psychopharmacology’s 2021 annual virtual 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
Overweight patients with bipolar disorder (BD) tend to have more severe illnesses, a more chronic course, faster cycling and higher morbidity. These patients also don’t respond to lithium, Calkin said.
“Untreated hyperinsulinemia could contribute to a chronic inflammatory condition and be involved in the progression of the disease. So the question for me was whether patients would be better off if we treated this insulin resistance?” She said.
Calkin said investigators used metformin because it is already being used by psychiatrists to control weight in patients taking antipsychotics.
“I wanted to test the drug that reverses insulin resistance and that psychiatrists can conveniently prescribe,” she said.
In the 26-week study, 20 patients were randomly assigned to metformin and 25 to placebo.
All participants were 18 years of age or older, had a diagnosis of BD I or II, and had non-remitting BD as defined by moderate depressive symptoms, as measured on the Montgomery-Asberg Depression Rating Scale (MADRS) score of 15 or higher, though you on optimal, guideline-compliant treatment.
All patients were stable, received optimal doses of mood-stabilizing drugs for at least 4 weeks prior to study entry, and had insulin resistance as defined by a Homeostatic Model Score for Insulin Resistance (HOMA-IR) ≥ 1.8.
The characteristics were similar between the two groups, including baseline MADRS scores, body mass index, fasting glucose, and serum insulin levels.
Patients were titrated up to 2000 mg metformin, the full dose, over 2 weeks and then treated for an additional 24 weeks.
Highly resistant population
The primary endpoint of the study was change in MADRS score, with 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 the criteria for insulin resistance.
“It surprised me a little that 50% of the patients became insulin sensitive again. When you use metformin to treat diabetes, people respond at a rate greater than 50%, so I expected more people to respond, “” said Calkin.
Nevertheless, the 11 patients who responded to insulin resistance and reversed insulin resistance achieved a greater reduction in MADRS scores compared to non-converters.
“Those who reversed their insulin resistance showed a remarkable improvement in their depressive symptoms. The decrease in MADRS scores started at week 6 and was maintained through 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, ”said Calkin .
“You were moderately to severely depressed at the beginning and had mild residual symptoms at the end of the study or were completely healthy. The patients were very resistant to therapy.
“All of them had failed an average of 8 or 9 attempts in their lives. When they came to us, nothing else worked. One of the remarkable things about our results is how well they responded when they hadn’t responded to anyone else.” Psychotropic Drugs “This approach can be very helpful for some patients,” said Calkin.
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 results needed replicating, but continued support for the broader strategy of a holistic approach for the care of patients with difficult-to-treat mood disorders. “
“About half of people with treatment-resistant bipolar depression showed signs of glucose resistance and that concomitant treatment with metformin, a drug that increases insulin sensitivity, was moderately effective in normalizing glucose metabolism, with a response rate of about 50% seen 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 not disclosed any relevant financial relationships.
American Society of Clinical Psychopharmacology (ASCP) 2021: Abstract 3002792 Presented June 2, 2021.
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