Roger S McIntyre
Identifying innovative mechanisms that translate into improved therapeutics when compared to the extant options is a strategic imperative in mood disorders. More specifically, there is a need for treatments with greater efficacy, shorter time-to-peak efficacy, greater durability of effect, and improved tolerability profiles. Moreover, priority has also shifted toward identifying mood disorder therapeutics capable of targeting domains of psychopathology that are most pervasive, debilitating, and inadequately treated by conventional pharmacology (e.g., anhedonia and cognitive impairment). Available preclinical, translational, observational, and clinical data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) hold promise as potentially mechanistically informed therapeutics for people with mood disorders. Although metabolic effectors are implicated as a putative mechanism of action of GLP-1RAs, nonmutually exclusive targets also include direct effects on neuroplasticity, neurogenesis, neurodifferentiation, neuroprotection, antiapoptotic, and autophagy mechanisms. Available evidence supports the initiation of adequate and well-controlled clinical studies in both major depressive disorder and bipolar disorder as acute and/or maintenance treatments. Although associations between suicidality and GLP-1RAs have been reported, causality has not been established. Moreover, preliminary evidence suggests that GLP-1RAs may benefit aspects of mood disorder psychopathology (e.g., reward) that may be predictive of potential beneficial effects on aspects of suicidality.