Brain Insulin Resistance and Major Depression

Illustration of an abstract plexus brain.
Researchers believe that data show stress impairs the hypothalamus-pituitary-adrenal axis and sympathetic nervous system, causing inflammation that is the link between type 2 diabetes mellitus and depression.

Patients with type 2 diabetes mellitus are 2 to 3 times more likely to have depression than those without diabetes.1 In addition, 40% to 60% of people with depression exhibit glucoregulatory mechanism disruptions that increase the risk for diabetes.2 This depression-diabetes relationship may hold answers to the treatment of both conditions. However, the exact pathophysiologic and molecular mechanisms underlying the relationship require further exploration, with brain insulin resistance sparking much research.3

Brain Insulin Resistance in Depression

Brain insulin resistance is a failure of brain cells to respond to insulin activity.4 Insulin in the brain is regulated by the central nervous system and is mostly concentrated in the hippocampus, hypothalamus, and cortex regions.5

Evidence suggests 3 pathophysiologic or molecular mechanisms that link brain insulin resistance with major depression: the brain’s reward system, the hypothalamic-pituitary-adrenal (HPA) stress axis, and gray matter volume in certain brain regions.3

Brain Insulin Resistance and the Brain’s Reward System

A convergence has been found between insulin resistance, depression, reward-seeking behavior, obesity, and diabetes.3 Brain insulin plays a role in modulating dopaminergic pathways in the brain and therefore impairments in insulin signaling lead to disruptions in dopamine signaling, further affecting the brain’s reward and motivation mechanisms. This can lead to symptoms of depression.2 For example, people with depression and insulin resistance have shown disruptions in the brain’s ability to signal satiation, exhibiting increased levels of anhedonia (inability to feel pleasure) and food-seeking behavior.

Brain Insulin Resistance and the HPA Stress Axis

Studies suggest that brain insulin resistance could impair the HPA axis, which is responsible for mediating the brain’s response to stress. Specifically, a compromised HPA axis could affect the regulation of glucocorticoid secretion and lead to abnormal responses to stress, contributing to depressive behavior.6

Brain Insulin Resistance and Hippocampal and Anterior Cingulate Cortex (ACC) Volumes

Associations have also been posited between insulin resistance and abnormal structure and functional connectivity in the ACC and hippocampus, 2 regions of the brain that form the neural motivational network. Research suggests that young people with high insulin resistance have reduced volumes in ACC and hippocampal gray matter and more severe depressive symptoms than those with low insulin resistance.7 The ACC is also involved in emotional processing and decision making and the hippocampus is linked with learning and memory; therefore, the reduced volume in these brain regions may explain the cognitive impairments observed in persons with insulin resistance and depression.2

Brain Insulin Resistance as a Target for Treating Depression

Dr Rodrigo Barbachan Mansur, psychiatrist at the University Health Network and Assistant Professor in the Department of Psychiatry at the University of Toronto, has been researching the potential role of therapeutic agents for insulin signaling in major depression treatments. Currently, there are 4 antidiabetic drugs being explored for antidepressant effects3:

1. Intranasal insulin. Clinical studies have shown improvements in mood and memory, as well as in HPA axis response, in people administered intranasal insulin. According to Dr Mansur, “There has been interest on the intranasal approach to drug delivery, as it is a noninvasive, user-friendly delivery method. It also offers rapid absorption and avoids drug degradation in the gastrointestinal tract and subsequent liver metabolism.” However, there remain concerns regarding bioavailability. “Intranasal delivery tends to be more inconsistent than oral or intravenous administration, which [this has an] impact [on] how much of the drug you are getting; and this is one of the main reasons why, until recently, intranasal medications were more in the realm of scientific investigation than regular clinical practice. At this point, we need more research to translate potential into actual empirically supported treatments for depression,” Dr Mansur explains.

2. Liraglutide. Dr Mansur’s team has also been investigating liraglutide, which is an injectable antidiabetic medication that can penetrate the blood-brain barrier and enhance insulin signaling.

3. Metformin. This is a diabetes treatment affecting regulators of cellular energy status such as mitochondrial proteins and the adenosine monophosphate-activated protein kinase, potentially leading to improvements in depressive behavior.

4. Peroxisome proliferator-activated receptor gamma agonists. These are antidiabetic drugs that augment insulin. Examples include rosiglitazone, which has shown antidepressant like effects, and pioglitazone, which has shown higher antidepressant effect in persons with insulin resistance than in those without.

Implications for Clinical Practice

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According to Dr Mansur, the use of brain insulin resistance medicine as a treatment for depression is still experimental. “Treatments for major depressive disorder that involve insulin and/or metabolic targets still need more testing before being used in clinical settings,” he says.

As healthcare providers and patients await further research on this subject, physicians can continue to rely on therapies that are known to be effective in treating depression and diabetes separately. Cognitive behavior therapy is one such solution. According to Dr Thalia Robakis, who is a clinical assistant professor in the Psychiatry and Behavioral Sciences department at Stanford University, “Cognitive behavior therapy is a highly flexible treatment modality, and its form that has demonstrated the most benefit for treating [type 2 diabetes] is focused on promoting treatment adherence and self-care, helping them stick to diet and exercise regimens.” Adherence to healthy behaviors has been shown to reduce insulin sensitivity and moderate depressive symptoms.2 “Although not a treatment in the traditional sense of a medication, physical exercise is repeatedly shown to improve depressive symptoms in multiple populations,” says Dr Mansur. Exercise can therefore be used either as a preventive measure or therapeutic agent for depression.

Enhancing Diagnosis

The relationship between depression and diabetes underscores the need for screening for diabetes in people with depression and screening for depression in those with diabetes. Diagnosing for possible co-occurrence of the 2 conditions is important, as many cases remain undiagnosed, leaving patients to suffer with the burden of 2 diseases without adequate clinical support.1 Indeed, there is a general lack of objective criteria for diagnosing depression. Given the relationship between depression and insulin resistance, however, could diabetes metabolic markers play a role in diagnosing depression?

According to Dr Robakis, people with depression exhibit higher levels of biomarkers that are associated with insulin resistance (eg, lower adiponectin) and inflammation (eg higher C-reactive protein, interleukin-6, tumor necrosis factor-α levels). “However, there is currently no single biomarker that is consistently different enough between individuals with depression and healthy controls that it could be diagnostically useful. The gold standard for diagnosis of depression remains the clinical interview,” she explains. Nonetheless, diabetes biomarkers offer some hope toward improving depression diagnostics. “Identifying markers of variation in metabolic activity between depressed vs healthy individuals may help us better understand the mechanisms that link the mind and body and identify new targets for treatment,” Dr Robakis adds.

Optimizing Existing Diabetes Medications to Treat Depression

Understanding the impact of brain insulin resistance in depression has opened a window into the depression-diabetes relationship, but understanding of the overlapping mechanisms between the 2 conditions is still emerging. What remains clear is that continued research into these mechanisms will be of tremendous value in optimizing existing antidiabetic medicines to treat major depressive disorder.


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3. Lyra e Silva NM, Lam MP, Soares CN, Munoz DP, Milev R, De Felice FG. Insulin resistance as a shared pathogenic mechanism between depression and type 2 diabetes. Front Psychiatry. 2019;10:57.

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6. Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring HU. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev. 2016;96(4):1169-1209.

7. Singh MK, Leslie SM, Packer MM. Brain and behavioral correlates of insulin resistance in youth with depression and obesity. Horm Behav. 2019;108:73-83.