Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects

Sanacora, Gerard; Ma, Smith; Pathak, Sanjeev; Hl, Su; Ph, Boeijinga; Dj, McCarthy; Mc, Quirk

doi:10.1038/mp.2013.130

Cited by 205 publications

(194 citation statements)

References 32 publications

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“…Indeed, preliminary studies evaluating the antidepressant potential of i.v. infusions of AZD6765 appear consistent with this hypothesis, as AZD6765 showed low potential for dissociative effects, psychotomimetic effects, or cognitive impairment at doses of 100 and 150 mg in patients (Sanacora et al, 2014;Zarate et al, 2013). In the present studies acute treatment with AZD6765 did not impair list-DMS performance at doses of 1 and 3 mg/ kg, achieving plasma drug concentrations of 1 μM-656 nM and 3.7-4.2 μM, respectively, during the testing period.…”

Section: Discussionsupporting

confidence: 75%

“…Preclinical studies have shown that AZD6765 is a modest potency, voltage-dependent, nonselective, NMDA receptor channel blocker (Sanacora et al, 2014). Although this profile is similar to ketamine, the 'low trapping' effects seen in electrophysiology assays are hypothesized to better preserve use-dependent block under conditions of normal synaptic transmission, leading to improved tolerability (Mealing et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…One approach is the development of NMDA receptor channel blockers with low potential to become trapped in the channel pore following repetitive channel activation as exemplified by AZD6765 (lanicemine). Although this agent is still a nonselective NMDA receptor antagonist, AZD6765 shows 'low trapping' in electrophysiology studies and appears to be well tolerated in humans (Sanacora et al, 2014;Zarate et al, 2013). Unfortunately, the antidepressant efficacy of this agent is now uncertain given that the beneficial effects seen in early clinical testing were not observed in a larger clinical trial (Sanacora and Schatzberg, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Weed

Bookbinder

Polino

et al. 2015

Neuropsychopharmacol

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Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a nonspecific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Weed

Bookbinder

Polino

et al. 2015

Neuropsychopharmacol

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“…The present results also raise further questions regarding the relationship of changes in gamma power to psychotomimetic effects. Recent studies of the low-trapping NMDA channel blocker lanicemine showed an enhanced gamma-band power both in rats and humans, but it did not induce psychotomimetic effects in patients (Sanacora et al, 2014). On the other hand, in humans, CP-101,606 was observed to evoke dissociative effects in some patients at higher doses (Nutt et al, 2008;Preskorn et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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

Nagy

Stoiljković

Menniti

et al. 2015

Neuropsychopharmacol

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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 5-30 min (drug-on) and 5-6 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. Although both drugs affected delta power, these changes 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.

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“…AZD6765 had lower response rates, lower remission rates, and a shorter duration of effect . In a subsequent 3-week, placebo-controlled trial, patients with TRD received repeated adjunctive AZD6765 (now renamed lanicemine) infusions at two doses (100 and 150 mg); as hypothesized lanicemine had antidepressant efficacy without ketamine-like side effects [Sanacora et al 2014b]. However, as presented at the 2014 American Society of Clinical Psychopharmacology annual meeting in Hollywood, FL, in a 6-week phase IIb study, adjunctive repeated-dose (50 and 150 mg) AZD6765/lanicemine failed to separate from placebo, potentially due to the large placebo effect (39% placebo response rate at trial end) [Sanacora et al 2014a].…”

Section: Peripheral Measuresmentioning

confidence: 99%

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

Iadarola

Niciu

Richards

et al. 2015

Therapeutic Advances in Chronic Disease

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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.

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Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects

Cited by 205 publications

References 32 publications

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

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

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

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

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