N-Methyl-D-Aspartate (NMDA) antagonists for the treatment of depression

Abstract

Depression is a major public health concern that affects ∼5% of the population in industrialized societies in any given year. Drugs that increase the synaptic availability of biogenic amines (norepinephrine, serotonin, and/or dopamine) have been used to treat depression for over five decades. While the most widely used antidepressants (serotonin and/or norepinephrine selective reuptake inhibitors) are generally safe and effective for many individuals, these drugs are far from ideal. For example, controlled clinical studies have repeatedly demonstrated that ≥2–4 weeks of treatment are required to provide palpable symptom relief. In addition, between 30 and 40% of patients do not respond to a first course of therapy with these biogenic amine-based agents. By contrast, N-methyl-d-aspartate (NMDA) receptor antagonists have been reported to produce rapid and robust antidepressant effects in patients unresponsive to conventional antidepressants. The use of these agents as antidepressants is grounded on a corpus of preclinical evidence, first published 20 years ago, demonstrating the antidepressant-like properties of NMDA antagonists and that chronic treatment with conventional antidepressants attenuates NMDA receptor function. In this chapter, we describe evidence that NMDA antagonists represent an effective alternative to biogenic amine-based agents for treating depression and provide perspective on the hurdles that could impede the development and commercialization of these agents in the face of this remarkable clinical data.