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This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Åsberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, −12.3 to −4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.