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

Clinical Research Institute, Wichita, KS 67204, USA.
Journal of clinical psychopharmacology (Impact Factor: 3.24). 12/2008; 28(6):631-7. DOI: 10.1097/JCP.0b013e31818a6cea
Source: PubMed


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.

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    • "A second aim of the present study was to begin to explore the underlying mechanisms using a comparative pharmacological approach. A negative allosteric modulator (NAM) of the NR2B subtype of NMDA receptor, CP-101,606 (Menniti et al, 1997; 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). "
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    ABSTRACT: Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely-moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5 to 30 min (Drug-On) and 5 to 6 h (Drug-Off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the Drug-Off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma band power during the Drug-On period. While both drugs affected delta power, these did not correlate with increase in AEPs in the Drug-Off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.Neuropsychopharmacology accepted article preview online, 25 September 2015. doi:10.1038/npp.2015.298.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2015; DOI:10.1038/npp.2015.298 · 7.05 Impact Factor
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    • "Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats. Neuroscience (2015), 1 NSC 16338 No. of Pages 12 52 2012), while a NR2B receptor antagonist was effective for 53 treatment-resistant depression patients (Preskorn et al., 54 2008). "
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    ABSTRACT: Chronic stress during critical periods of human fetal brain development is associated with cognitive, behavioral, and mood disorders in later life. Altered glutamate receptor (GluR) expression has been implicated in the pathogenesis of stress-dependent disorders. To test whether prenatal chronic mild stress (PCMS) enhances offspring's vulnerability to stress-induced behavioral and neurobiological abnormalities and if this enhanced vulnerability is sex-dependent, we measured depression-like behavior in the forced swimming test (FST) and regional changes in GluR subunit expression in PCMS-exposed adult male and female rats. Both male and female PCMS-exposed rats exhibited stronger depression-like behavior than controls. Males and females exhibited unique regional changes in GluR expression in response to PCMS alone, FST alone (CON-FST), and PCMS with FST (PCMS-FST). In females, PCMS alone did not alter NMDAR or mGluR expression, while in PCMS males, higher mGluR2/3, mGluR5, and NR1 expression levels were observed in the prefrontal cortex. In addition, PCMS altered the change in glutamate receptor expression induced by acute stress (the FST test), and this too was sex-specific. Male PCMS-FST rats expressed significantly lower mGluR5 levels in hippocampus, lower mGluR5, NR1, PSD95, and higher mGluR2/3 in prefrontal cortex, and higher mGluR5 and PSD95 in amygdala than male CON-FST rats. Female PCMS-FST rats expressed lower NR1 in hippocampus, lower NR2B and PSD95 in prefrontal cortex, lower mGluR2/3 in amygdala, and higher PSD95 in amygdala than female CON-FST rats. PCMS may increase offspring's vulnerability to depression by altering sex-specific stress-induced changes in glutamatergic signaling. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 06/2015; 301. DOI:10.1016/j.neuroscience.2015.06.008 · 3.36 Impact Factor
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    • "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. "
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    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.
    Therapeutic Advances in Chronic Disease 05/2015; 6(3). DOI:10.1177/2040622315579059
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