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Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

  • Alan L. Pehrson (a1) and Connie Sanchez (a1)

Abstract

Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction.

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Copyright

The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence . The written permission of Cambridge University Press must be obtained for commercial re-use.

Corresponding author

*Address for correspondence: Dr. Connie Sanchez, External Sourcing and Scientific Excellence, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652, USA. (Email CS@lundbeck.com)

Footnotes

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The authors thank Dr. Huailing Zhong of U-Pharm Laboratories LLC (Parsippany, NJ) for insightful and very valuable help with writing the manuscript, and Dr. David Simpson for helpful insights and comments.

Footnotes

References

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Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

  • Alan L. Pehrson (a1) and Connie Sanchez (a1)

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