Individuals experiencing a current episode of major depressive disorder (MDD) are significantly more likely to have insulin resistance (IR), new research shows.
Investigators found patients with MDD were 51% more likely to have IR compared with their counterparts without the depressive disorder. In addition, in individuals experiencing current depression, IR was also associated with depression severity and depression chronicity.
“We learned two things from this study — first, that insulin resistance was associated with being in a depressive episode and with the severity of that episode,” Kathleen Watson, PhD, a postdoctoral research fellow in the department of psychiatry, Stanford University, California, told Medscape Medical News. “Second, we learned that we can estimate insulin resistance using a surrogate measure that is clinically accessible — the triglyceride/HDL ratio.”
The study was published online December 2 in JAMA Psychiatry.
Targeted Approach
Many studies have linked MDD and IR. However, said Watson, “We did not have much description of the nature of this relationship.” She added that her team wanted to gain a better understanding of how IR relates to depression characteristics, such as remission status, severity, and chronicity.
Characterizing these associations will “represent a critical step at better phenotyping, a prelude to longitudinal studies, and a more targeted approach to the treatment of MDD,” the authors note.
For the study, the researchers drew on data from the Netherlands Study of Depression and Anxiety, a longitudinal Dutch study of adults that “describes the course and consequences of depressive and anxiety disorders.”
The study included 1269 study participants with current MDD (n = 536), remitted MDD (n = 394), and control participants without a history of MDD (n = 339).
In addition to investigating the association between MDD and IR, the researchers also wanted to understand “whether using different surrogate IR measures has consistent association with MDD.”
IR was determined using two surrogate markers — the quantitative insulin sensitivity check index (QUICKI) and the triglyceride to high-density lipoprotein (HDL) ratio.
Participants in the bottom quartile of the QUICKI were categorized as IR, while all other participants were categorized as being “insulin sensitive.”
The second surrogate IR measure — the triglyceride-HDL ratio — is an index based on fasting blood sample measurements, in which the determination of IR was based on sex-specific cut points (female ratio: IR > 1.9; male ratio: IR > 2.8).
Depression was determined based on the Composite International Diagnostic Interview (version 2.1), while depression severity was based on the Inventory of Depression Symptomatology. “Chronicity” was defined as depression during the preceding 4 years and was measured using the life chart review.
State vs Trait
Insulin resistance was associated with current, but not with remitted, MDD (OR, 1.51 [95% CI, 1.08 – 2.12]; and OR, 1.14 [95% CI, 0.79 – 1.64], respectively).
In a model adjusted for age, sex, education, partner status, smoking status, and alcohol consumption, IR, as assessed by both measures, was linked to depression severity — but only the triglyceride-HDL ratio yielded an association between IR and depression chronicity.
IR was not associated with depression severity or chronicity in remitted MDD on either measure.
The findings — specifically the association between current, but not remitted, MDD — suggest that “IR is a state, rather than a trait, biomarker of depression,” the authors note.
“There are many plausible mechanisms between IR and MDD,” said Watson. “Some hypotheses for the link include inflammations, alterations to the hypothalamic-pituitary-adrenal axis, and changes in health behavior.
“Understanding these nuances helped us to lay the foundation for future research, including asking whether IR can lead to the development of MDD,” she added.
Finally, Watson noted that her team is collaborating with neuroscientists to better identify the brain mechanisms at the genetic, molecular, and cellular level that link IR and MDD and how to target them with potential treatments or interventions.
Shared Biological Mechanisms?
Commenting on the study for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit, said the results “suggest that a subpopulation of people with depression have what might be referred to as ‘metabolic syndrome type II’ — the depression is a consequence of abnormal metabolic processes.”
The results also suggest “maybe metabolic markers can be used as biomarkers of disease presence vs absence,” said McIntyre, who is also the chairman and executive director of the Brain and Cognition Discovery Foundation, Toronto, and was not involved with the study.
Also commenting on the study for Medscape Medical News, Andrea Fagiolini, MD, professor of psychiatry, University of Siena School of Medicine, Italy, said depression, metabolic, and inflammatory diseases “likely share some common biological mechanism, as they share risk factors such as unhealthy diet, unhealthy lifestyles, and frequent exposure to physical and psychological distress.”
It is “possible that treatment of depression improves IR; conversely, it is possible that lifestyle programs or medications that are able to improve IR may improve depressive symptoms,” suggested Fagiolini, who was not involved with the study.
“It remains to be established which symptoms of depression are most involved in this correlation and whether their improvement precedes or follows the improvement in IR,” he noted.
The Netherlands Study of Depression and Anxiety is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development and is supported by several participating universities and mental healthcare organizations. Watson has disclosed no relevant financial relationships. The other authors’ disclosures are listed on the original paper. McIntyre reported research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva,Intra-Cellular, and Abbvie. McIntyre is also CEO of AltMed. Fagiolini has served or is currently serving as consultant or speaker or is a research grant recipient from Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo, Doc Generici, Glaxo Smith Kline, Italfarmaco, Lundbeck,Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, and Vifor.
JAMA Psychiatry. Published online December 2, 2020. Abstract
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