Repurposing Anti-Diabetic Agents to Treat Cognitive Impairment in Metabolic and Mood Disorders
By: Yena Lee
While depression is colloquially conceptualized as a mood disturbance, such as “feeling low and down,” affective symptoms are only one part of depression. Cognitive impairment, for instance, is also a criterion item for the diagnosis of a major depressive episode within the Diagnostic and Statistical Manual of Mental Disorders (DSM). Phenomenologically, cognitive dysfunction is pervasive among adults with mood disorders and describes a diminished ability to concentrate, process information, learn, and regulate one’s behaviour and emotions.
In recent years there has been a shift in psychiatry toward characterizing dimensional, transdiagnostic domains of human behaviour and physiology. The Research Domain Criteria (RDoC)—developed by the U.S. National Institute of Mental Health—posits that quantifiable biological substrates subserve various domains of psychopathology (1). These domains of psychopathology have been operationalized as the arousal and regulatory systems (e.g., sleep-wakefulness), cognitive systems (e.g., attention, working memory), negative valence systems (e.g., fear, anxiety), positive valence systems (e.g., motivation, reward-related behaviours), and social processes (e.g., attachment, social communication). Within the RDoC framework, mood disorders can be conceptualized as a multidimensional syndrome that affects multiple transdiagnostic domains.
These domains are transdiagnostic, as they include symptoms observed across multiple psychiatric and non-psychiatric medical diagnoses. Using the example of cognition, patients with diabetes mellitus often exhibit clinically significant deficits in objective and subjective measures of cognitive function. Diabetes and depression are common comorbidities, and a bidirectional association in risk elevation is well documented. Having diabetes increases the risk for depression and, conversely, depression increases the risk for diabetes. More specifically, the odds of having both diabetes and depression are approximately double that which would be expected by adding the odds of having either diabetes or depression (2).
The synergistic effect observed in the incidence of diabetes and depression appears to extend to individual patient health and functional outcomes as well. The co-occurrence of diabetes and depression is associated with significantly worse physical and mental health outcomes. Individuals with diabetes and significant depressive symptoms are more likely to have other medical comorbidities (e.g., cardiovascular disease, obesity), which further compounds to the observed morbidity in patients (e.g., hospital admission length, number of visits to their family doctor). Individuals with diabetes and significant depressive symptoms also report greater difficulties related to work (e.g., unemployment, missed days of work, reduced productivity) and other aspects of life (e.g., social withdrawal, inability to complete household chores) (3).
Emerging evidence suggests that cognitive impairment may be a key mediator of functional outcomes in metabolic and mood disorders. It seems intuitive that cognitive disturbances diminish our ability to engage and contribute meaningfully in a workplace, home, or social setting. The ability to work productively and maintain employment demands that an individual be able to function cognitively. A recent cross-national study of 3,627 working Canadians assessed cognitive and depressive symptoms and work-related impairment in adults with prediabetes or type II diabetes mellitus (as proxied by glycated hemoglobin levels) (4). The investigators noted that self-reported cognitive difficulties (e.g., decreased ability in concentrating, planning, or getting organized) led to lost productivity and work absence among pre-diabetic or diabetic adults exhibiting depressive symptoms. Thus, targeting cognitive disturbance may be one way to improve functional outcomes in metabolic and mood disorders. But, how are they mechanistically related?
One possible explanation involves peripheral and central insulin resistance. Replicated evidence from neuroimaging studies indicate that insulin resistance and poor glycemic control may mediate the effects of default mode network dysregulation on cognitive deficits in diabetic populations (5). The default mode network is comprised of brain regions and connections that are active during resting states and inactive during goal-oriented tasks. Hippocampal insulin resistance has been hypothesized to subserve cognitive dysfunction in diabetes and Alzheimer’s disease (6). Moreover, diabetes is associated with an increased risk for mild cognitive impairment and Alzheimer’s disease, suggesting that the mechanisms subserving cognitive dysfunction in diabetes extends to other diagnostic categories as well. Studies of diffusion tensor imaging and resting-state functional magnetic resonance imaging additionally implicate abnormalities in the default mode network, among other brain circuits, nodes and networks, in cognitive dysfunction. Replicated studies have documented microstructural white matter abnormalities and functional disconnectivity in this network in metabolic and mood disorders.
A recent open-label clinical trial led by Dr. Rodrigo Mansur at the University of Toronto investigated the efficacy of liraglutide—a glucagon-like peptide-1 receptor agonist—on objective measures of cognitive function in 19 non-diabetic adults with mood disorder (7). Glucagon-like peptide-1 belongs to a group of insulin-sensitizing metabolic hormones called incretins, which are released after meal consumption and enhance insulin secretion. Liraglutide significantly improved objective measures of cognition after four weeks of treatment. Interestingly, baseline insulin resistance and body mass index was noted to moderate improvements in cognitive function with liraglutide treatment.
Taken together, cognitive impairment is transdiagnostic and pervasive across metabolic and mood disorders, and is a critical determinant of functional outcomes. Accumulating and convergent evidence implicates central and peripheral metabolic disturbances in cognitive dysfunction. While the mechanisms mediating deficits in cognitive systems are not fully understood, interventional studies that have repurposed existing anti-diabetic agents show promise in improving cognitive function in populations with metabolic and/or mood disorders.
- Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry 2014; 171: 395–397.
- Scott KM, Von Korff M, Alonso J, et al. Mental-physical co-morbidity and its relationship with disability: results from the World Mental Health Surveys. Psychol Med 2009; 39: 33–43.
- Vamos EP, Mucsi I, Keszei A, et al. Comorbid depression is associated with increased healthcare utilization and lost productivity in persons with diabetes: a large nationally representative Hungarian population survey. Psychosom Med 2009; 71: 501–507.
- Lee Y, Smofsky A, Nykoliation P, et al. Cognitive Impairment Mediates Workplace Impairment in Persons with Type 2 Diabetes Mellitus: Results From the Motivaction Study. Can J Diabetes. Epub ahead of print 25 September 2017. DOI: 10.1016/j.jcjd.2017.06.013.
- Reijmer YD, Brundel M, de Bresser J, et al. Microstructural white matter abnormalities and cognitive functioning in type 2 diabetes: a diffusion tensor imaging study. Diabetes Care 2013; 36: 137–144.
- Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 2015; 16: 660–671.
- 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.