An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients With Treatment-Refractory Major Depressive Disorder

Abstract

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-Asberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Asberg 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.

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…The NR2B NAM CP-101,606 has been shown to have an antidepressant response in patients similar to that of ketamine, namely, the response developed rapidly after drug infusion and was sustained in responders for days after the drug was presumed to be eliminated (Preskorn et al, 2008). Significantly, in the present study CP-101,606 also induced a robust increase in AEPs in both cortex and hippocampus in rats after the drug was eliminated.…”

“…A negative allosteric modulator (NAM) of the NR2B subtype of NMDA receptor, CP-101,606 Mott et al, 1998), also evidenced an antidepressant response in patients (Preskorn et al, 2008). Compounds of the NR2B NAM class bind at the interface of the NR2B/ NR1 amino terminal domains to allosterically reduce channel-opening probability to inhibit ion flux and functionally inhibit receptor activity (Karakas et al, 2011;Traynelis et al, 2010).…”

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

“…CP101,606 (traxoprodil) is a negative allosteric modulator (NAM), which binds to a site present on the N-terminal domain of the NR2B receptor and prevents channel activation (Menniti et al, 1998). In a small, proof of concept, clinical trial a single IV infusion of CP101,606 produced an antidepressant effect at a dose with low potential to produce dissociative effects in patients (Preskorn et al, 2008).…”

Antidepressant-like Effects of the Gastrodia elata Bl Extract in Mice

“…Furthermore, ketamine (a noncompetitive antagonist of the NMDA receptor complex) and CP-101,606 (a selective antagonist of NR2B subunit of NMDA receptor) is effective in human depression [23][24][25] . In randomized, placebo-controlled, double blind study, robust and rapid antidepressant effects resulted from a single intravenous dose of ketamine.…”