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.
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.
Preskorn
Sheldon H
SH
Clinical Research Institute, Wichita, KS 67204, USA. spreskorn@cri-research.net
Baker
Bryan
B
Kolluri
Sheela
S
Menniti
Frank S
FS
Krams
Michael
M
Landen
Jaren W
JW
D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D004351:Drug Resistance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000008:administration & dosage / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012107:Research Design; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013997:Time Factors; D017211:Treatment Failure; D055815:Young Adult
D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D017374:Paroxetine; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; C121001:NR2B NMDA receptor; C095106:traxoprodil mesylate