Agrowing body of preclinical research implicates the N-methyl-d-aspartate (NMDA) class of glutamate receptors in the pathophysiology of major depression and the mechanism of action of antidepressant treatments (Skolnick et al 1996). NMDA receptor antagonists have been shown to be effective in animal models of depression and models that predict antidepressant activity in many Layer et al 1995, Meloni et al 1993, Moryl et al 1993, Papp and Moryl 1994, Papp and Moryl 1996, Przegalinski et al 1997, Trullas and Skolnick 1990 but not all (Panconi et al 1993) studies. Conversely, antidepressant administration has been shown to affect NMDA receptor function (Mjellem et al 1993) and receptor binding profiles (Paul et al 1994). Chronic, but not acute, administration of antidepressant medications consistently decreases the potency of glycine to inhibit [3H]-5,7-dichlorkynurenic acid binding to the strychnine-insensitive glycine sites. These adaptations were found in 16 of 17 tested antidepressant treatments (Paul et al 1994), thereby making this a more sensitive predictor of antidepressant activity than the forced swim test or downregulation of beta-adrenergic receptors. A transcriptional mechanism for this phenomenon is suggested by recent evidence showing that repeated antidepressant administration regionally alters expression of mRNA that encodes multiple NMDA receptor subunits (Boyer et al 1998).

Although these compelling findings suggest that NMDA receptor antagonists have antidepressant activity, this hypothesis has received relatively little clinical evaluation. Preliminary studies with amantadine (Vale et al 1971), a weak NMDA antagonist, and the strychnine-insensitive glycine site partial agonist D-cycloserine Crane 1959, Crane 1961 have provided support for this hypothesis. Nevertheless, design issues and other limitations of these agents complicate the interpretation of these early investigations. Clinical investigation of NMDA receptor function in depression is currently limited by availability of selective compounds. Ketamine hydrochloride is a potent NMDA antagonist. The purpose of this study was to determine whether ketamine had antidepressant effects in patients with depression.