Anxiety and Depression

Can anxiety and depression unexpectedly improve when treating insulin resistance with metformin? I am an interventional pain physician in the urban core. More than 90% of my patients with chronic unrelenting pain also have metabolic syndrome with insulin resistance, and more than 90% also have significant anxiety and depression. I had always assumed that the anxiety and depression were related to socioeconomic conditions or comorbidity of chronic pain — until I started aggressively treating their insulin resistance.

Undertreatment, I found that lifestyle modification and interventional techniques certainly improved their pain, but their anxiety seemed to persist. However, when I added metformin to treat insulin resistance and metabolic syndrome, the anxiety and depression seemed to immediately improve, unexpectedly. A recent mouse study sheds light on why this might be.

People with diabetes are known to have an increased risk for mood disorders such as depression and anxiety; the underlying mechanisms may be the neurotransmitter serotonin, or it may be an issue of gut-induced vagal signaling with reduced heart rate variability. Tryptophan is a necessary precursor for serotonin, and if tryptophan’s entry into the brain is reduced, it also reduces serotonin production. This mouse study demonstrated that metformin reduced the amino acids that impair the entry of tryptophan into the brain, increasing tryptophan entry and subsequently increasing serotonin. Additionally, metformin’s antidepressant-like effects were accompanied by improved neurotransmission in the hippocampus.

J Zemdegs, et al. The Journal of Neuroscience, 2019; 2904-18.

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