Stanford Medicine scientists have linked insulin resistance to an increased risk of developing major depressive disorder (MDD). The researchers’ analysis of data from more than 600 participants in a major longitudinal study in the Netherlands demonstrated that three surrogate measures of insulin resistance positively predicted major depressive disorder developing over a nine-year period among adults with no prior history of depression or anxiety disorder.

“If you’re insulin-resistant, your risk of developing major depressive disorder is double that of someone who’s not insulin-resistant, even if you’ve never experienced depression before,” said research lead Natalie Rasgon, MD, PhD, professor of psychiatry and behavioral sciences. Rasgon is a member of the Wu Tsai Neurosciences Institute at Stanford, Stanford Cardiovascular Institute, and the Stanford Maternal and Child Health Research Institute.

The researchers’ findings are described in a study in the American Journal of Psychiatry, which is titled “Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study.” Rasgon shares senior authorship with Brenda Penninx, MD, PhD, professor of psychiatric epidemiology at the University of Amsterdam Medical Center. The study’s lead author is Kathleen Watson, PhD, a postdoctoral scholar in Rasgon’s group.

MDD is the leading cause of disability worldwide, the authors noted. Upward of 1 in 5 Americans will experience major depressive disorder sometime during their lives. Symptoms include unremitting sadness, despair, sluggishness, sleep disturbances, and loss of appetite.” Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder,” they continued. “An important first step in this process is identifying risk factors for the incidence of major depressive disorder.” Some factors contributing to MDD, such as childhood traumas, loss of a loved one, or the stresses of the COVID-19 pandemic, for example, are things that can’t be prevented.

But accumulating biological evidence has also linked insulin resistance with the development of depressive disorders, the team pointed out. And unlike some contributory factors, insulin resistance is preventable, and can be reduced or eliminated by diet, exercise and, if need be, drugs. Studies in animal models of insulin resistance have shown increased risk of depression-like behaviors and factors such as neuroinflammation, which are hypothesized to be relevant to human depression. “In addition, studies show that treatment for insulin resistance in animals can reverse depression-like behavior.”

Studies have confirmed that at least 1 in 3 of us may have insulin resistance—often without knowing it. The condition does not arise from a deficiency in the ability of the pancreas to secrete insulin into the bloodstream—as occurs in type 1 diabetes—but develops because of the decreased ability of cells throughout the body to respond to the hormone.

Insulin effectively instructs cells to process glucose in the bloodstream. Every cell in the body uses glucose as fuel, and each of those cells has receptors on its surface that, on binding to insulin, signal the cell to ingest this glucose energy source. But an increasing proportion of the world’s population is insulin-resistant. For various reasons—including excessive caloric intake, lack of exercise, stress, and not getting enough sleep—their cells’ insulin receptors fail to bind to insulin properly. Eventually, their blood sugar levels become chronically high. Once those levels stay above a certain threshold, the diagnosis is type 2 diabetes. While treatable, type 2 diabetes can lead to cardiovascular and cerebrovascular disorders, neuropathy, kidney disease, limb amputations, and other detrimental health outcomes.

Associations between insulin resistance and several mental disorders have already been established, the authors pointed out. For example, it’s been shown that about 40% of patients suffering from mood disorders are insulin-resistant, Rasgon said. But these assessments have been based on cross-sectional studies—snapshots of populations at a single point in time. The question of whether one event was the cause or the result of the other or whether both were results of some other causal factor—are best resolved by longitudinal studies, which typically track people over years or even decades and can determine which event came first.

As a part of a multi-institutional collaboration within a research network Rasgon established in 2015, the scientists obtained data from the Netherlands Study of Depression and Anxiety (NESDA). This is an ongoing longitudinal study monitoring more than 3,000 participants in scrupulous detail to learn about the causes and consequences of depression. Rasgon is the Stanford principal investigator, and Penninx is the overall principal investigator of the study.

“NESDA presents a unique opportunity to address the question of insulin resistance and incident major depressive disorder because it is among the few studies that have extensively assessed behavioral and psychosocial risk factors, metabolic function, and the incidence of major depression in a longitudinal design,” the investigators wrote. Watson added, “The Dutch study, with its meticulous monitoring of a large subject population for nine years and still climbing, presented a great opportunity for us.”

The Stanford team analyzed data from 601 men and women, average age 41 years, who served as control subjects for the Netherlands study. At the time of their enrollment, they’d never been troubled by depression or anxiety. The team measured multiple proxies of insulin resistance. First, the ratio of circulating triglyceride levels to those of circulating high-density lipoprotein (HDL), commonly referred to as “good” cholesterol. “This measure has been well correlated with the gold standard for insulin resistance and is often used in a clinical context,” the team noted. They also looked at two other surrogate measures. “To evaluate the consistency of our findings, we also tested whether two related surrogate metabolic measures, fasting plasma glucose levels and waist circumference, were associated with incident major depression.”

The scientists probed the data to see if the subjects found to be insulin-resistant had a heightened nine-year risk of developing MDD. By all three measures, the answer was yes. A moderate increase in insulin resistance, as measured by the triglyceride-to-HDL ratio, was linked to an 89% increase in the rate of new cases of MDD. Similarly, every 5 cm increase in abdominal fat was related to an 11% higher rate of depression, and an increase in fasting plasma glucose of 18 milligrams per deciliter of blood was associated with a 37% higher rate of depression.

“Some subjects were already insulin-resistant at the study’s start—there was no way to know when they’d first become insulin-resistant,” Watson said. “We wanted to more carefully determine how soon the connection kicks in.” So, theresearchers restricted the next phase of their analysis to the roughly 400 subjects who, in addition to never having experienced major depression, also showed no sign of insulin resistance at the study’s onset. Within the first two years of the study, nearly 100 of these participants became insulin-resistant. The researchers compared this group’s likelihood of developing MDD in the next seven years with that of the participants who hadn’t yet become insulin-resistant at the two-year point.

While the number of participants was too small to establish statistical significance for waist circumference and the triglyceride-to-HDL ratio, the results for fasting glucose were not only statistically significant—meaning unlikely to have arisen by chance—but clinically meaningful—that is, important enough to worry about. They indicated that individuals developing prediabetes within the first two years of the study had 2.66 times the risk for major depression by nine-year follow-up, compared with those who had normal fasting-glucose test results at the two-year point. “If replicated, these findings may have utility for physicians and researchers evaluating the risk for the development of major depression, as well as implications for our understanding of major depressive disorder pathogenesis.”

While the authors acknowledged several limitations of their study, they concluded, “In spite of these issues, the ability to predict an increased risk in major depressive disorder incidence using standard clinical tests of metabolic status can be deployed as an important tool for treatment and prevention.” The investigators also pointed out that their own work has suggested that certain treatments that decrease insulin resistance can aid in the treatment of major depression in some patients. “It will be especially important to ascertain in future studies whether reversing insulin resistance is able to decrease the risk of future clinical depression,” they noted.

Rasgon commented, “It’s time for providers to consider the metabolic status of those suffering from mood disorders and vice versa, by assessing mood in patients with metabolic diseases such as obesity and hypertension. To prevent depression, physicians should be checking their patients’ insulin sensitivity. These tests are readily available in labs around the world, and they’re not expensive. In the end, we can mitigate the development of lifelong debilitating diseases.”

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