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Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function

Molecular Psychiatry volume 24, pages 1816–1832 (2019)Cite this article

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Abstract

Efforts to develop efficacious antidepressant agents with novel mechanisms have been largely unsuccessful since the 1950’s until the discovery of ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist that produces rapid and sustained antidepressant actions even in treatment-resistant patients. This finding has ushered in a new era for the development of novel rapid-acting antidepressants that act at the NMDA receptor complex, but without dissociative and psychotomimetic side effects of ketamine. Here, we review the current state of rapid-acting antidepressant drug development, including NMDA channel blockers, glycine site agents, and allosteric modulators, as well as ketamine stereoisomers and metabolites. In addition, we focus on the neurobiological mechanisms underlying the actions of these diverse agents and discuss evidence of convergent mechanisms including increased brain-derived neurotrophic factor signaling, increased synthesis of synaptic proteins, and most notably increased GluR1 and synaptic connectivity in the medial prefrontal cortex. These convergent mechanisms provide insight for potential additional novel targets for drug development (e.g., agents that increase synaptic protein synthesis and plasticity). Importantly, the convergent effects on synapse formation and plasticity also reverse the well-documented neuronal and synaptic deficits associated with stress and depression, and thereby target the underlying pathophysiology of major depressive disorder.

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Acknowledgements

This research was supported by NIMH Grants MH045481 and MH093897 and the State of CT.

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  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Ronald S. Duman, Ryota Shinohara, Manoela V. Fogaça & Brendan Hare

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Dr. Duman has received consulting fees from Taisho, Johnson & Johnson, and Naurex, and grant support from Taisho, Johnson & Johnson, Naurex, Allergan, Navitor, Lundbeck, Relmada, and Lilly.

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Duman, R.S., Shinohara, R., Fogaça, M.V. et al. Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry 24, 1816–1832 (2019). https://doi.org/10.1038/s41380-019-0400-x

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