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.
- SourceAvailable from: Rodrigo Machado-Vieira
[Show abstract] [Hide abstract]
- "Moreover, the antidepressant effects of Ro 25-6981 were negated by pretreatment with rapamycin [Li et al. 2010]. A randomized, double-blind, placebo-controlled study of the intravenous NR2B-selective receptor antagonist CP-101,606 in TRD (n = 30) displayed a 60% response rate (compared with 20% in the placebo group) [Preskorn et al. 2008]. Additionally, 78% of treatment responders maintained their ND Iadarola, MJ Niciu et al. http://taj.sagepub.com "
ABSTRACT: Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.05/2015; 6(3). DOI:10.1177/2040622315579059
[Show abstract] [Hide abstract]
- "All rights reserved. and generally well tolerated agent, capable of producing an antidepressant response in patients with treatment-refractory major depressive disorder . Memantine, an uncompetitive open channel NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease, seemed to be effective in several subjects with major depression  ; however, the scores of the 8-week double-blind placebo-controlled clinical trial revealed no effect of therapy with memantine . "
ABSTRACT: Background According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2–4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10 mg/kg) on the activity of antidepressant agents from diverse pharmacological groups. Methods The antidepressant-like effect was assessed by the forced swim test in mice. Results Ifenprodil potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (5 mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5 mg/kg) or tianeptine (15 mg/kg). Conclusion The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.Pharmacological reports: PR 12/2014; 66(6):1031–1036. DOI:10.1016/j.pharep.2014.06.016 · 2.17 Impact Factor
[Show abstract] [Hide abstract]
- "More selective NMDA antagonists that lack the dissociative side effects of ketamine are being pursued for treatment-resistant depression. Antagonists to the NR2B subunit of the NMDA receptor such as MK-0657 (Ibrahim et al., 2012) and CP-101,606 (Preskorn et al., 2008) have shown promising results in treating resistant patients. 3.4.4. "
ABSTRACT: Major depression is a prevalent and debilitating disorder and a substantial proportion of patients fail to reach remission following standard antidepressant pharmacological treatment. Limited efficacy with currently available antidepressant drugs highlights the need to develop more effective medications for treatment resistant patients and emphasizes the importance of developing better preclinical models that focus on treatment resistant populations. This review discusses methods to adapt and refine rodent behavioral models that are predictive of antidepressant efficacy to identify populations that show reduced responsiveness or are resistant to traditional antidepressants. Methods include separating antidepressant responders from non-responders, administering treatments that render animals resistant to traditional pharmacological treatments, and identifying genetic models that show antidepressant resistance. This review also examines pharmacological and non-pharmacological treatments regimes that have been effective in refractory patients and how some of these approaches have been used to validate animal models of treatment-resistant depression. The goals in developing rodent models of treatment- resistant depression are to understand the neurobiological mechanisms involved in antidepressant resistance and to develop valid models to test novel therapies that would be effective in patients that do not respond to traditional monoaminergic antidepressants. Copyright © 2014. Published by Elsevier B.V.European Journal of Pharmacology 11/2014; 753. DOI:10.1016/j.ejphar.2014.10.063 · 2.68 Impact Factor