Modulators of the Glutamatergic System: Implications for the Development of Improved Therapeutics in Mood Disorders

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system volume as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. One neurotransmitter system implicated in regulating neuronal plasticity and cellular resilience in a variety of neuropsychiatric disorders is the glutamatergic system. Recent preclinical studies have shown that the glutamatergic system often represents indirect targets for the actions of antidepressants and mood stabilizers. For many refractory patients, new drugs that simply mimic traditional drugs, which directly or indirectly alter monoamine levels, may be of limited benefit. This article reviews the growing body of data suggesting that agents which modulate the glutamatergic system may have utility in the long-term treatment of severe, recurrent mood disorders. Such strategies may serve to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. There are a number of glutamatergic “plasticity-enhancing” strategies that may be of considerable utility in the treatment of mood disorders. Among the most immediate are N-methyl-D-aspartate antagonists, glutamate release–reducing agents, and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid potentiators. This research progress holds much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders. Psychopharmacology Bulletin. 2002;36(4):35-83