Antidiabetic Agent May Ease Chronic Depression

Kenneth Bender

November 18, 2015

Adjunctive use of an antidiabetic agent that increases insulin sensitivity may improve symptoms of chronic depression in nondiabetic patients, new research shows.

Investigators at Stanford University School of Medicine in California found that pioglitazone (multiple brands) had an antidepressant effect in patients who had some degree of insulin resistance at baseline. This effect was most prominent in younger patients.

Principal investigator Natalie Rasgon, MD, PhD, told Medscape Medical News that the study is the result of 20 years of work examining insulin resistance and issues of the central nervous system and is based on the "hypothesis about underlying insulin resistance in patients who have mood disorders and cognitive complaints, as a potential link to neurodegenerative disease."

The investigators set to "identify people who might have insulin resistance in addition to having mood disorder and to see if their brain function and structure differ from those who don't, and then if we treat it, what happens to the brain," said Dr Rasgon.

The researchers note that they also undertook the trial "to disentangle the role of insulin-sensitizing and anti-inflammatory mechanisms" that may underlie what they suspect is a "bidirectional" relationship between insulin resistance and depressive symptoms.

The study was published online October 12 in Psychiatry Research.

Surprise Finding

The 12-week, randomized, placebo-controlled trial compared the course of depressive symptoms in 37 nondiabetic participants aged 23 to 71 years who had unremitting depression at baseline and who received either 30 mg daily of pioglitazone or placebo while continuing their prestudy antidepressant treatment regimen.

The 17-item Hamilton Depression Rating Scale (HDRS) was the primary measure of depressive symptoms. Study participants had scores of 7 or higher.

In addition to confirming the effect of pioglitazone on depressive symptoms compared with placebo, the investigators sought to correlate any potential antidepressant effect via increasing insulin sensitivity by distinguishing participants by insulin response.

The presence of insulin resistance was determined at baseline and at study term through the surrogate measures of fasting plasma glucose of 100 mg/dL or higher, fasting plasma insulin of 15 µIU/mL or higher, and the oral glucose tolerance test results at 120 minutes of 140 mg/dL or higher.

Although the investigators found a comparable decline in symptoms of depression in the active treatment group and the placebo group ― 24% and 23% lower HDRS scores, respectively ― there was a significantly greater effect on depressive symptoms with pioglitazone vs placebo in individuals with insulin resistance vs those who were insulin sensitive.

Among those with insulin resistance, HDRS scores with active treatment were reduced by an average of 7.15 points more than with placebo. Younger patients exhibited a greater decline in symptoms relative to placebo.

In contrast, there was no separation of active agent from placebo in the improvement of symptoms among insulin-sensitive participants.

The current findings combined with results of earlier studies of pioglitazone in depression by these investigators and others suggest that "successful treatment of unremitting depression with pioglitazone is more likely when there is corresponding glucose metabolic dysfunction."

The researchers described the similar reduction in depressive symptoms in both the active and placebo groups and in the active treatment, insulin-resistant participants as a "surprising aspect" of the study.

They suggest that the concomitant individualized treatment within the study protocol benefited participants across groups. However, the lack of improvement among insulin-resistant participants receiving placebo prompted speculation that insulin resistance may present a "biological gating mechanism" that prevents antidepressant response, which was remediated by pioglitazone in the active-treatment group.

"Despite the very fascinating neurobiological interplay, there is a very simple and very easily generalizable impact of the findings, in terms of just educating providers who care for people with prediabetes, diabetes, obesity and who have depression. That there is this interplay between both conditions, and identifying each condition...and treating it aggressively is very important for overall well-being," said Dr Rasgon.

"A greater understanding of the reciprocal links between depression and insulin resistance may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction," the investigators write.

Dr Rasgon also discussed potential implications of earlier work by her team, which showed that younger adults had an advantage in restoring cognitive performance.

"If depression and insulin resistance hit a person at a younger age, they have worse cognitive performance, and as you see [in this current study with active treatment], they fare better, which means the sooner we can identify these conditions in patients who have depression and the sooner we treat it, we have better chance at primary prevention."

Dr Rasgon suggested several possible mechanisms. Insulin has multiple functions within the central nervous system, insulin resistance is inherently a proinflammatory state, and depression and inflammation have been linked.

Although the association of depression with insulin resistance and accompanying risk for cardiovascular illness and type 2 diabetes has been well documented, the researchers found that there have been few studies into causal aspects. They emphasize the increasing importance of elucidating mechanisms underlying the association and identifying effective therapeutic interventions.

"As the current prevalence of Type 2 diabetes mellitus and related diseases grow worldwide and its associated metabolic consequences become more salient, it is increasingly critical to understand the role of IR [insulin resistance] in depressive disorders," they write.

"Exciting Possibilities"

Commenting on the study for Medscape Medical News, David Kemp, MD, who was lead author of a pilot study of pioglitazone for depression in patients with abdominal obesity while he was at Case Western Reserve University, in Cleveland, Ohio, described the results as "intriguing and provide preliminary evidence that mechanisms other than alteration of traditional monoamine neurotransmitters may reduce depression severity in some patients."

He agreed with Dr Rasgon regarding expectations of progress in determining causal mechanisms.

"In addition to assessing the role of lowered insulin resistance on mood, future investigations involving pioglitazone should evaluate whether anti-inflammatory mechanisms or direct activation of PPAR-gamma [peroxisome proliferator-activated receptor gamma] receptors in the brain account for the beneficial effect on depression," he said.

Dr Kemp, who is currently co–medical director of Behavioral Health Service Line, Advocate Health Care, reflected on the implications for clinicians.

"The study raises exciting possibilities, as clinicians may one day routinely assess for the presence or absence of insulin resistance in order to tailor antidepressant treatment regimens."

Funding sources of the study and for individual investigators can be found in the original publication. Dr Kemp reports no relevant financial relationships.

Psychiatry Res. Published online October 12, 2015. Abstract

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