patient care perspectives

Depression and Diabetes: Exploring the Neurobiological Overlap

by Roger McIntyre, MD


The spotlight continues to shine on what appears to be the overlapping neurobiology of mood disorders and metabolic disorders such as type 2 diabetes (T2DM), spurring interest and prompting questions about treatment. Evidence suggests that metabolic pathways are highly relevant in cognition – a crucial domain for all patients, and perhaps especially so for patients with major depressive disorder (MDD) and/or diabetes.

Cognition is considered a core domain of the psychopathology of MDD. However, antidepressant medications have not generally been shown to improve measures of cognitive control and executive function. Vortioxetine, a novel antidepressant with multimodal activity, is a notable exception, since it has been reported to improve performance in objective measures of cognition. In patients with MDD, cognitive impairment is recognized as a principle mediator of psychosocial impairment.

Expert Commentary

Roger McIntyre, MD

Professor of Psychiatry and Pharmacology
University of Toronto
Head, Mood Disorders Psychopharmacology Unit
University Health Network
Toronto, Ontario

“The overlap between depression and T2DM is particularly interesting, and we just finished a study with nearly 3800 workers across the nation of Canada in which we examined depression, but we also examined diabetes.”

Roger McIntyre, MD

T2DM is recognized as a risk factor for cognitive decline in older adults; however, less is known about the effect of diabetes on cognitive function in younger populations. Cognitive impairment affects about 20% of the patients of age 60 years or younger with T2DM. In this younger group, impairment is only weakly related to glycosylated hemoglobin levels, according to a study by Roy and colleagues. Cognitive function has been studied in the larger set of patients (of varying ages) with metabolic disorders (ie, impaired glucose metabolism, visceral adiposity, and dyslipidemia), and links between these metabolic disorders and cognitive impairment have been reported.

Pathophysiologic convergence, or overlap, between mood disorders, metabolic disorders, and chronic inflammation may be relevant. This convergence seems to involve a complex milieu of abnormal levels of endocrine-inflammatory markers. For instance, higher C-reactive protein (CRP) levels, indicative of inflammation, have been observed among diabetic patients with MDD. Mechanisms mediated by glucagon-like peptide 1 (GLP-1) and its agonists may also be involved. GLP-1 receptor (GLP-1R) agonists are commercially available for the treatment of T2DM and obesity. In the pilot study by Mansur and colleagues, the GLP-1R agonist liraglutide promoted weight loss and improved metabolic parameters in nondiabetic individuals with mood disorders, with increases in subcortical structures and frontal gray matter volumes that were associated with the weight loss. What is more, cognitive improvement was correlated with these regional brain volume changes in a subsequent analysis from this same study.

The notion that an individual that is impaired – in large part, because of a core, persisting disturbance in cognition – is certainly not confined to depression. There might be an influence from so many different medical conditions and disorders.

The overlap between depression and T2DM is particularly interesting, and we just finished a study with nearly 3800 workers across the nation of Canada in which we examined depression, but we also examined diabetes. Not only is diabetes a very common, chronic medical disorder, but it is also a disorder characterized by cognitive impairment. What we found was that there was more than an additive effect, there was a multiplicative effect on a variety of measures at the workplace because of the depression. Diabetes was associated with its own impairments, largely because of the chronic illness. And what was so interesting was that, the reason why patients with diabetes had such a difficult time in the workplace was also because of cognitive problems.

If patients had both diabetes and MDD, then the proverbial psychiatric calculation was “1 + 1 = 5” (ie, a multiplicative effect on cognitive impairment could be observed), and I think that speaks to the convergent phenomenology of cognition.

We did that study for a host of reasons, including the presence of some speculative mechanistic substrates, but cognition seems to be a convergent mediator that likely is a final common pathway for many other mental and medical disorders.


Alvarez A, Faccioli J, Guinzbourg M, et al. Endocrine and inflammatory profiles in type 2 diabetic patients with and without major depressive disorder. BMC Res Notes. 2013;6:61.

Chen B, Zheng T, Qin L, et al. Strong association between plasma dipeptidyl peptidase-4 activity and impaired cognitive function in elderly population with normal glucose tolerance. Front Aging Neurosci. 2017;9:247.

Jha MK, Minhajuddin A, Gadad BS, et al. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017;78:105-113.

Mansur RB, Zugman A, Ahmed J, et al. Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders. Eur Neuropsychopharmacol. August 31, 2017. pii: S0924-977X(17)30900-8. doi: 10.1016/j.euroneuro.2017.08.433. [Epub ahead of print].

Mansur RB, Ahmed J, Cha DS, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. J Affect Disord. 2017;207:114-120. doi: 10.1016/j.jad.2016.09.056.

McIntyre, RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo- controlled study of vortioxetine on cognitive function in depressed adults. Int. J. Neuropsychopharmacol 2014;17(10):1557-1567.

McIntyre RS, Powell AM, Kaidanovich-Beilin O, et al. The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders. Behav Brain Res. 2013;237:164-171.

Rosenblat JD, Kakar R, McIntyre RS. The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychopharmacol. 2016;19(2):pyv082.

Roy S, Kim N, Desai A, et al. Cognitive function and control of type 2 diabetes mellitus in young adults. N Am J Med Sci. 2015;7(5):220-226.

Yogi-Morren D, Galioto R, Strandjord SE, et al. Duration of type 2 diabetes and very low density lipoprotein levels are associated with cognitive dysfunction in metabolic syndrome. Cardiovasc Psychiatry Neurol. 2014;2014:656341.

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