Insulin-sensitizing drug relieves symptoms of chronic depression in some people

Pioglitazone, available generically for treating Type 2 diabetes, improved symptoms of long-term depression in patients also suffering from insulin resistance.

- By Bruce Goldman

Natalie Rasgon

A drug that makes the body more sensitive to insulin helped to relieve symptoms of chronic depression in people resistant to the hormone, according to a study by researchers at the Stanford University School of Medicine.

The 12-week, randomized, placebo-controlled study, published Nov. 18 in Psychiatry Research, involved patients whose symptoms of depression had failed to improve substantially, despite treatment, for at least six months leading up to the study’s onset.

“This is the first placebo-controlled study to show the antidepressant benefits of treating unremittingly depressed patients with an insulin-sensitizing drug,” said the study’s senior author, Natalie Rasgon, MD, PhD, professor of psychiatry and behavioral sciences.

“The study is important,” Rasgon said, “because it bears out a hypothesis we first advanced over a decade ago about the connection between insulin resistance — the body’s inability to efficiently process glucose, even with adequate insulin production in the pancreas — and mood disorders.”

Insulin is released by the pancreas in response to food intake. It alerts cells throughout the body to the presence in the blood of glucose, the body’s primary energy source. The cells of people with insulin resistance fail to take up glucose adequately, eventually resulting in high blood levels of the sugar, which is deleterious to multiple tissues in the body.

Insulin resistance — a precursor to Type 2 diabetes — and major depression are common conditions. Close to one in five Americans are diagnosed with depressive illness at some point in their lives, Rasgon said, while about one in three otherwise healthy Americans — and an even greater share of people with depression — are insulin-resistant.

“While insulin resistance is more prevalent among people who are overweight or obese, significant numbers  of people with normal weight are insulin-resistant, too,” she said. “But most don’t find out about it until they’re diagnosed with Type 2 diabetes, hypertension or cardiovascular disease.”

Insulin resistance is associated with higher likelihoods of many chronic diseases, among them Alzheimer’s disease and depression.

Mirroring earlier results

The insulin-sensitizing drug pioglitazone is approved by the U.S. Food and Drug Administration for treatment of Type 2 diabetes. Marketed for many years under the trade name Actos, it is now available generically. In a pilot study published in 2010, Rasgon and her associates found that administering a similar drug, rosiglitazone, to depressed patients who were insulin-resistant alleviated their depression. However, no placebo was used, and both the researchers and participants knew which treatment was being administered.

It bears out a hypothesis we first advanced over a decade ago about the connection between insulin resistance ... and mood disorders.

“I wanted to replicate that study’s findings in a controlled experimental design,” Rasgon said. The new trial was placebo-controlled, and researchers were blinded as to which patients were receiving pioglitazone versus a placebo. The patients didn’t know which they were getting, either. Furthermore, not only insulin-resistant but also insulin-sensitive patients, all between the ages of 23 and 71, participated.

All the patients had been experiencing episodes of depression lasting, on average, more than one year. Their symptoms had failed to remit under standard treatment regimens. They remained on these regimens for the duration of the Stanford study and, in addition, were given either pioglitazone or a placebo.

The patients were tested for depression severity and insulin resistance at the study’s outset and then roughly every two weeks from the beginning of the trial to the end. A total of 37 patients — 29 women and eight men — completed the study.

The insulin-sensitive subjects showed a decline in severity of depression regardless of whether they received pioglitazone or a placebo, the researchers found, and the difference in the degree of those two groups’ improvement was statistically insignificant.

But among the insulin-resistant group, those given pioglitazone showed a much greater improvement than those who got a placebo. They also showed more improvement than insulin-sensitive patients did.

“The people who didn’t get better are the people who are insulin-resistant and didn’t get pioglitazone,” said Kathleen Lin, a graduate student in Rasgon’s group who shared lead authorship with Tonita Wroolie, PhD, clinical associate professor of psychiatry and behavioral sciences.

The more insulin-resistant a participant was at the beginning of the study, the better the drug’s antidepressant effect, the researchers said. In addition, insulin sensitivity improved in insulin-resistant patients treated with pioglitazone — not a surprising result, given that the drug was designed for that purpose.

The role of insulin resistance

Equally intriguing is what did not happen. Unlike members of the control group, insulin-resistant patients’ depression was not relieved by the placebo. This suggests, Rasgon and Lin said, that whatever it is that allows insulin-sensitive patients’ depression symptoms to diminish over time doesn’t seem to work for insulin-resistant patients. It could be, they speculated, that for some patients, insulin resistance is a barrier to the effectiveness of standard antidepressant therapies, which may kick into gear only once the patients’ insulin resistance is reduced.

This finding may help us to determine which therapies are best for which person.

Rasgon cautioned that the study was small and short-term and needs to be replicated on a large-scale, longer-term basis. But, she said, insulin’s importance in brain function is well-documented. The brain, in fact, is a glucose glutton, accounting for one-fifth of all glucose consumption in an active human being. So it stands to reason that impaired glucose uptake due to insulin resistance would affect many pivotal processes in the brain, including regulation of emotion and cognition, and that the effect could become detrimental.

The research reflects Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

“There’s enough evidence now to say that insulin-sensitizing drugs may have a place in treating chronic mood disorders in insulin-resistant subjects,” Rasgon said.

“This finding may help us to determine which therapies are best for which person,” said Lin. “We’re trying to get a little better at that.”

Thalia Robakis, MD, PhD, clinical assistant professor of psychiatry and behavioral sciences at Stanford, also contributed to the study.

The study was funded by a grant from the National Institutes of Health (grant R21MH093948).

Stanford’s Department of Psychiatry and Behavioral Sciences also supported the work.

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