The sustained antidepressant effects of esmethadone [18] and other low-potency NMDAR antagonists that are effective against MDD at non-dissociative doses, such as dextromethorphan [17,19], and potentially arketamine [55], may be determined by a preferential block of tonically and pathologically hyperactive GluN2D subtypes at resting membrane potential. This evidence concerns the gene GRIN2D and major depressive disorder.