Towards the Molecular Foundations of Glutamatergic-targeted Antidepressants

Background: Depression affects over 120 million individuals of all ages and is the leading cause of disability worldwide. The lack of objective diagnostic criteria, together with the heterogeneity of the depressive disorder itself, makes it challenging to develop effective therapies. The accumulation of preclinical data over the past 20 years derived from a multitude of models using many divergent approaches, has fueled the resurgence of interest in targeting glutamatergic neurotransmission for the treatment of major depression. Objective: The emergence of mechanistic studies are advancing our understanding of the molecular underpinnings of depression. While clearly far from complete and conclusive, they offer the potential to lead to the rational design of more specific therapeutic strategies and the development of safer and more effective rapid acting, long lasting antidepressants. Methods: The development of comprehensive omics-based approaches to the dysregulation of synaptic transmission and plasticity that underlies the core pathophysiology of MDD are reviewed to illustrate the fundamental elements. Results: This review frames the rationale for the conceptualization of depression as a “pathway disease”. As such, it culminates in the call for the development of novel state-of-the-art “-omics approaches” and neurosystems biological techniques necessary to advance our understanding of spatiotemporal interactions associated with targeting glutamatergic-triggered signaling in the CNS. Conclusion: These technologies will enable the development of novel psychiatric medications specifically targeted to impact specific, critical intracellular networks in a more focused manner and have the potential to offer new dimensions in the area of translational neuropsychiatry.