Excitatory Amino Acids: Clinical Results with Antagonists

The psychopharmacology of agonists and antagonists of excitatory amino acids is in its infancy relative to the decades of intensive research associated with drugs acting on monoamine neurotransmitter systems. The prototype drug in this class, phencyclidine, and its derivative, ketamine, block the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors with competing with glutamate and without selective for subtypes of NMDA receptors (Yamakura et al., Neuroreport 4:687-690, 1993.). However, these drugs have produced insights into neurobiological mechanisms underlying higher cognitive function as well as a striking diversity of disorders ranging from alcoholism to schizophrenia However, unselective uncompetitive NMDA antagonists are blunt clinical tools, and there has been a great deal of interest in the human psychopharmacology of NMDA antagonists that either compete with glutamate for binding to this receptor or are selective for subtypes of this receptor. Despite intensive research into both areas, relatively little of it has been published in the peer-reviewed literature. Thus, it was with great anticipation that I read Excitatory Amino Acids: Clinical Results with Antagonists, edited by Paul Herrling, of Novartis Pharmaceuticals, an important scientist in excitatory amino acid medications development. Readers of this book are rewarded with important insights into the cognitive and behavioral effects of drugs that have been the subject of intensive scrutiny in the scientific community, and yet have received superficial attention in the published literature. For example, the reviews presented in this book suggest that the competitive NMDA antagonists share the cognitive and perceptual effects associated with the uncompetitive NMDA antagonists. Similarly, the utility of low-affinity uncompetitive NMDA antagonists, such as remacimide, is supported by the relative lack of psychotomimetic effects. In addition, promising data are presented regarding the cognitive and behavioral safety profile of the NMDA subtype-selective agent, eliprodil. However, for the psychopharmacologist, this book has a superficial quality as well. Cognitive and behavioral effects of the drugs under investigation receive limited discussion. Many critical issues related to dose-response, methods of behavioral assessment, and time-course of behavioral effects are not addressed in sufficient depth to accurately guide further clinical research. Also, literature citations designed to provide depth often point the reader to other superficial presentations of this area of research. Thus, the reader is left with the concern that important data about these agents have not yet been released or that rigorous psychopharmacologic study of these agents remains to be conducted. Assuming the latter to be the case, I see this …