Chapter 3 - Novel Targets in the Glutamate and Nitric Oxide Neurotransmitter Systems for the Treatment of Depression

Abstract

The N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine has repeatedly shown rapid and sustained antidepressant effects following a single dose in a number of clinical studies. Since the adverse effects associated with ketamine limit its wider use in the clinic, investigations are instead aimed at developing “cleaner” ketamine compounds that could demonstrate a fast onset of action and sustained efficacy without incurring adverse effects. In this regard, targets located downstream of the NMDA-R, such as nitric oxide synthase (NOS), may represent novel avenues for treating neuropsychiatric disorders. Since nNOS couples to the NMDA-R via the postsynaptic protein PSD-95, strategies that target the PSD-95/nNOS interaction may also represent an interesting locus for the treatment of neuropsychiatric disorders. Here, we review the rationale for the development of glutamate and nitric oxide (NO)-modulating drugs for treating depression and highlight findings in the field, which provide a basis for ongoing drug development.