Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists?

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Abstract

Major depressive disorder and bipolar disorder are highly prevalent and disabling conditions. Cognition is considered a core domain of their psychopathology and a principle mediator of psychosocial impairment, disproportionately accounting for overall illness-associated costs. There are few interventions with replicated evidence of efficacy in treating cognitive deficits in mood disorders. Evidence also indicates that cognitive deficits are associated with obesity and involve significant impairment across multiple domains. Conversely, weight-loss interventions, such as physical exercise and bariatric surgery, have been shown to beneficially affect cognitive function. This convergent phenomenology suggests that currently available agents that target metabolic systems may also be capable of mitigating deficits in cognitive functions, and are, therefore, candidates for repurposing. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors (GLP-1R) are widely expressed in the central nervous system. Activation of GLP-1R leads to facilitation of glucose utilization and antiapoptotic effects in various organs. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1, including protection from cell death, promotion of neuronal differentiation and proliferation; and facilitation of long-term potentiation. Liraglutide is a GLP-1R agonist that has been approved for the treatment of type 2 diabetes mellitus and obesity. Convergent preclinical and clinical evidence, including a proof-of-concept pilot study from group, has suggested that liraglutide may improve objective measures of cognitive function in adults with mood disorders. The safety and availability of GLP-1R agonists indicate that they are promising candidates for repurposing, and that they may be viable therapeutic options for mood disorders.

This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’

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