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Searching for Rational Anti–N-methyl-D-aspartate Treatment for Depression
Guochuan E. Tsai, MD, PhD
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Zarate et al1 demonstrated a rapid antidepressant effect from ketamine hydrochloride, an antagonist at the N-methyl-D-aspartate (NMDA) ionophore. The proof-of-principle study needs to be addressed in the context of drug development and a risk and benefit assessment. Interestingly, they also reported memantine, another NMDA antagonist, does not improve depressive symptoms.2 High doses of D-cycloserine, a weak antagonist on the glycine coagonist site, also failed to improve depression.3 Taken together, high-affinity, strong open-channel blockers with a slow off-rate, like ketamine, possess antidepressant effects whereas low-affinity, weak open-channel blockers with a fast off-rate, like memantine, or antagonists on the competitive site, like D-cycloserine, are ineffective.
Repeated administration of ketamine or other noncompetitive NMDA antagonists induce unacceptable clinical adverse effects. Accordingly, many NMDA receptor antagonists have failed advanced clinical trials for neuroprotection. Exceptionally, memantine, which does not accumulate in the NMDA channel to . . . [Full Text of this Article]
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RELATED LETTER
Searching for Rational Anti–N-methyl-D-aspartate Treatment for Depression—Reply
Carlos A. Zarate, Jr, Dennis S. Charney, and Husseini K. Manji
Arch Gen Psychiatry. 2007;64(9):1100-1101.
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RELATED ARTICLE
A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression
Carlos A. Zarate, Jr, Jaskaran B. Singh, Paul J. Carlson, Nancy E. Brutsche, Rezvan Ameli, David A. Luckenbaugh, Dennis S. Charney, and Husseini K. Manji
Arch Gen Psychiatry. 2006;63(8):856-864.
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