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.
Tsai GE. Searching for Rational Anti–N-methyl-D-aspartate Treatment for Depression. Arch Gen Psychiatry. 2007;64(9):1099-1100. doi:10.1001/archpsyc.64.9.1099