The neuroprotective and neuroplastic potential of glutamatergic therapeutic drugs in bipolar disorder

The monoamine hypothesis has dominated research on the pathophysiology of mood disorders as well as the development of therapeutic drugs by over half a century. Nowadays a change of perspective is taking place. The glutamate system is increasingly implicated in the pathophysiology of mood disorders. The evidence spans from animal, post-mortem, imaging, pharmacological and genome-wide association studies. Bipolar disorder has been recently re-conceptualized as a synaptic plasticity-related disorder rather than simply as a result of deficits or excesses in individual neurotransmitters. A paradigm shift from a monoamine hypothesis to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the research for new drugs and therapies. In this review we summarize data from clinical and pre-clinical studies that have addressed gluta-matergic alterations in bipolar disorder. Along with an in-depth discussion of glutamatergic alterations in bipolar disorder, we also report available data on the neuroprotective and neuroplastic potential of the classic mood stabilizers, ketamine, and psychedelics. The glutamatergic mechanisms underlying the efficacy of these drugs are described and discussed.

Automated summary

The monoamine hypothesis, which has been dominating the research on mood disorders and development of therapeutic drugs for over half a century, is now being challenged by the emerging evidence implicating the glutamate system in the pathophysiology of mood disorders. Bipolar disorder is being reconceptualized as a disorder related to synaptic plasticity, and the shift from a monoamine hypothesis to a neuroplasticity hypothesis focused on glutamate may lead to significant advancements in the research for new drugs and therapies.