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Imagine decreasing depression symptoms in patients by one-third, or achieving large improvements in treatment-resistant bipolar disorder without using antidepressant medications or mood stabilizers. Results like these may be possible by addressing a common co-occurring condition: insulin resistance.

While we often try to relegate the causes of mental health conditions to the brain, research clearly shows that we shouldn’t ignore what is happening in the body. We do, after all, have a neck.

While numerous factors can have an impact on mental health, problems with blood sugar regulation and insulin resistance are quite common. Depression, bipolar disorder, schizophrenia, post-traumatic stress disorder, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder have all been associated with insulin resistance (Fernandes 2022, Calkin 2019, Guest 2019, Rosenbaum 2015, Grassi 2022, Landou 2019).

Treating or reversing insulin resistance raises a crucial question: what impact does this have on a patient’s mental health?

Depression and Insulin Resistance

Insulin resistance often progresses to type 2 diabetes, a chronic condition characterized by high blood sugar levels. Notably, there is a significant association between depression and diabetes. In fact, research suggests that almost one in four patients with diabetes struggles with depression (Khaledi 2019). The reverse association also holds, with depressed patients having a 41% greater risk for developing diabetes (Yu 2015).

Treating insulin resistance appears to directly lower depressive symptoms. In depressed patients with diabetes, one study found that metformin—a standard treatment for insulin resistance—decreased depression symptoms by just over one-third (Guo 2014). The medication reduced severe depression to mild depression on average. The results seemed to be mainly from improvements in cognitive function that coincided with lower blood sugar levels.

Treating insulin resistance may also have a role in preventing depression. In a separate study of elderly patients with diabetes, taking metformin came close to halving the risk for developing depression (Chen 2019).

Bipolar Disorder and Insulin Resistance

While the evidence for the relationship between insulin resistance and depression is fairly robust, there’s been growing interest in its relationship with bipolar disorder as well. One study found that insulin resistance or diabetes tripled the risk for a more chronic course of bipolar symptoms while also tripling the risk for rapid cycling (Calkin 2015). Somewhat shockingly, the same study also found that patients with insulin resistance or diabetes were eight times more likely to be resistant to treatment with lithium.

In response to the results, the same research group decided to treat bipolar patients with insulin resistance who had failed standard bipolar treatment with metformin for six months and track their results (Calkin 2022). Half of patients treated with metformin were able to reverse their insulin resistance. These patients had large statistical improvements in mood, anxiety, bipolar symptoms and overall daily functioning. While the study was small, it hints at profound results in addressing insulin resistance in patients who are also struggling with bipolar disorder.

Another recent study further supports addressing insulin resistance for the prevention of mood disorders (Lake 2023). In the study, the changes in genetic expression from drugs known to work for bipolar disorder were compared to the changes induced by other drugs not typically used for treating mental health conditions. Overlap was significant with a number of different drugs, including metformin. As such, the researchers went on to analyze a group of just over 700 patients, tracking metformin prescriptions and mental health outcomes. Over the course of sixteen years, patients prescribed metformin reduced their risks for developing a mood disorder by 69%.


Insulin resistance is linked to mental health problems, including depression and bipolar disorder. Checking for and treating insulin resistance and blood sugar problems can improve mental health outcomes. In some cases, when insulin resistance is reversed, improvements in mental health can be substantial.

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Calkin CV, Chengappa KNR, Cairns K, et al. Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study): A Randomized, Quadruple-Masked, Placebo-Controlled Clinical Trial. J Clin Psychiatry. 2022;83(2):21m14022. Published 2022 Feb 1. doi:10.4088/JCP.21m14022

Calkin CV. Insulin resistance takes center stage: a new paradigm in the progression of bipolar disorder. Ann Med. 2019;51(5-6):281-293. doi:10.1080/07853890.2019.1659511

Calkin CV, Ruzickova M, Uher R, et al. Insulin resistance and outcome in bipolar disorder. Br J Psychiatry. 2015;206(1):52-57. doi:10.1192/bjp.bp.114.152850

Chen F, Wei G, Wang Y, et al. Risk factors for depression in elderly diabetic patients and the effect of metformin on the condition. BMC Public Health. 2019;19(1):1063. Published 2019 Aug 7. doi:10.1186/s12889-019-7392-y

Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression: A large meta-analysis of metabolic parameters and variation. Neurosci Biobehav Rev. 2022;139:104758. doi:10.1016/j.neubiorev.2022.104758

Grassi G, Figee M, Pozza A, Dell’Osso B. Obsessive-compulsive disorder, insulin signaling and diabetes – A novel form of physical health comorbidity: The sweet compulsive brain. Compr Psychiatry. 2022;117:152329. doi:10.1016/j.comppsych.2022.152329

Guest PC. Insulin Resistance in Schizophrenia. Adv Exp Med Biol. 2019;1134:1-16. doi:10.1007/978-3-030-12668-1_1

Guo M, Mi J, Jiang QM, et al. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol. 2014;41(9):650-656. doi:10.1111/1440-1681.12265

Khaledi M, Haghighatdoost F, Feizi A, Aminorroaya A. The prevalence of comorbid depression in patients with type 2 diabetes: an updated systematic review and meta-analysis on huge number of observational studies. Acta Diabetol. 2019;56(6):631-650. doi:10.1007/s00592-019-01295-9

Lake J, Bortolasci CC, Stuart AL, et al. Metformin is Protective Against the Development of Mood Disorders. Pharmacopsychiatry. 2023;56(1):25-31. doi:10.1055/a-1936-3580

Landau Z, Pinhas-Hamiel O. Attention Deficit/Hyperactivity, the Metabolic Syndrome, and Type 2 Diabetes. Curr Diab Rep. 2019;19(8):46. Published 2019 Jun 27. doi:10.1007/s11892-019-1174-x

Rosenbaum S, Stubbs B, Ward PB, Steel Z, Lederman O, Vancampfort D. The prevalence and risk of metabolic syndrome and its components among people with posttraumatic stress disorder: a systematic review and meta-analysis. Metabolism. 2015;64(8):926-933. doi:10.1016/j.metabol.2015.04.009

Yu M, Zhang X, Lu F, Fang L. Depression and Risk for Diabetes: A Meta-Analysis. Can J Diabetes. 2015;39(4):266-272. doi:10.1016/j.jcjd.2014.11.006