ine 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 which may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are N-methyl-D-aspartate antagonists, glutamate release-reducing agents, and a-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.