Major depression is a chronic, recurrent mood disorder that causes significant disability and disease burden throughout the world. Not surprisingly, there is an enormous demand for (a) finding appropriate medications and devices for treating the clinical symptoms and (b) identifying the underlying molecular mechanisms of the disease. Currently, most therapeutic treatments of depression indirectly target the serotonin (5-HT) and norepinephrine (NE) systems of the brain, as these neurotransmitters have long been considered promising and mechanistically relevant to the etiology of mood disorders (Manji et al., 2001; Belmaker and Agam, 2008). However, selective 5-HT reuptake inhibitors such as sertraline, fluoxetine and paroxetine do not always substantially improve clinical outcome, and when they do show efficacy, it takes weeks of treatment to achieve an appreciable clinical effect. These observations suggest that a

5-HT and NE hypothesis of major depression is incomplete at best, and that novel, rapid onset therapeutic options for depression must be considered (Box 1).

This essay describes one new pharmacological treatment (ketamine) for chronic melancholia and behavioral despair which targets a particular set of glutamate (GLU) receptors (Leheste et al., 2008). The fact that a pediatric anesthetic produces a relatively sustained and rapid antidepressant effect in patients with major depression, suggests the possibility that anesthetic derivatives of ketamine may be used as novel treatments for mood disorders.

Glutamate is the brain’s most pervasive neurotransmitter as it is heavily involved in almost all excitatory or “go” signaling events between nerve cells that are attuned to it (Moghaddam, 2003). Accordingly, virtually all