As with most areas of pharmacotherapeutics, a significant percentage of patients are not fully served by existing medicines in the area of major depressive disorder (MDD) [1, 2]. Only about one third of patients respond to current antidepressants and less than one third display symptom remission. Another third of the patients do not respond to multiple therapeutic interventions (treatment resistant depression or TRD) leaving a huge unmet medical need in a disease area that affects millions of people each year .
A report by Berman and colleagues  and its subsequent replication by Zarate et al.  have inspired new ideas about antidepressant drug action. In patients that did not respond to at least two adequate antidepressant regimens, the dissociative anesthetic, ketamine, produced immediate and relatively long-lasting relief of mood symptoms after a single intravenous dose. The work has been systematically replicated in different cohorts of TRD patients including those suffering with bipolar depression [5, 6]. The idea that blockade of N-methyl-D-asparte (NMDA) receptors by ketamine would be antidepressant was deduced from connections of NMDA receptors, long-term potentiation, and electroconvulsive therapy by Trullas and Skolnick in 1990 . Additional clinical validation came with the finding that an NMDA receptor antagonist selective for NR2B receptors was also effective in TRD patients .
Given the efficacy of ketamine and the difficulties of using ketamine as a prescription drug (it is abused and produces marked central nervous system side effects as do other NMDA receptor antagonists ), finding novel agents that can mimic the antidepressant effects without the safety issues becomes a goal of those seeking improved therapeutic options for TRD patients. A large clue already in hand in the new discovery effort is that ketamine is known to block NMDA receptors. In this vein, other NMDA receptor blockers might be viable treatment agents without the side effects. Zn2+ also blocks NMDA receptors and is antidepressant; work in TRD patients has shown it to be effective as an adjunct with imipramine . Other ways of producing functional dampening of NMDA receptor function are already being explored. GLYX-13, a putative glycine-site functional partial agonist, has preclinical antidepressant-like activity and is being funded now for Phase II clinical investigation .
The vigorous activity in the area of TRD therapeutics is a testament to the mood that shines over many laboratory benches as answers to important questions seem within reach. What are the key biological actions of ketamine that enable relief from TRD? One of the first clues came from the preclinical laboratory. Ketamine and other NMDA receptor antagonists produced effects in the mouse-forced swim test that were comparable to those of other antidepressant drugs; these behavioral effects of ketamine were prevented by an alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) receptor antagonist . Thus, ketamine, by virtue of its glutamate releasing effects, produces activation of AMPA receptors that is responsible for the antidepressant-like signatures observed. Convergent biochemical, neurobiological, and behavioral data implicate AMPA receptor amplification as a core feature of antidepressant drug action . It is not unreasonable to speculate that other methods of increasing AMPA receptor function would also produce fast-acting antidepressant response in TRD patients. What drugs exist that most directly facilitate AMPA receptor function? Positive allosteric modulators of AMPA receptors are one such possibility and display robust antidepressant effects in rodent models [13, 14] but have yet to be put to clinical proof of concept in TRD . Zn2+, with augmenting effects in TRD patients , is also AMPA antagonist sensitive . Antagonists of metabotropic mGlu2/3 receptors also engender antidepressant-like neurochemical and behavioral effects in a host of preclinical models and a number of these effects are prevented by AMPA receptor antagonists [1, 14]....