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

Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, Quirk MC - Mol. Psychiatry (2013)

Bottom Line: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients.However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data.Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

View Article: PubMed Central - PubMed

Affiliation: Clinical Neuroscience Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

ABSTRACT
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

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Electroencephalography (EEG) effects of lanicemine relative to ketamine in rodent model. Left: Time course of gamma-band EEG following administration of lanicemine and ketamine (doses: 10 mg kg−1) and respective vehicles. Right: Tolerability of lanicemine vs ketamine, measured by hyper-locomotor activity, at comparable levels of target engagement.
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fig1: Electroencephalography (EEG) effects of lanicemine relative to ketamine in rodent model. Left: Time course of gamma-band EEG following administration of lanicemine and ketamine (doses: 10 mg kg−1) and respective vehicles. Right: Tolerability of lanicemine vs ketamine, measured by hyper-locomotor activity, at comparable levels of target engagement.

Mentions: Previous studies with lanicemine and ketamine demonstrated that both compounds bind with low-to-moderate affinity to sites within the NMDA channel pore, exhibit strong voltage dependence, and have similar lack of NR2A vs NR2B subunit selectivity (Table 1).14, 19, 20, 21, 22 However, at steady-state concentrations, ketamine had a greater propensity to be trapped within the NMDA channel pore following the removal and reapplication of glutamate (trapping: 86% with ketamine vs 54% with lanicemine). Low trapping theoretically preserves use-dependent channel block under conditions of normal, pyramidal cell-driven, synaptic transmission.14 Thus, while NMDARs are ubiquitously expressed within the central nervous system, the low-trapping property of lanicemine may bias channel block to those elements of the brain, such as cortical interneurons, with high levels of tonic activity. Since selective reduction in NMDAR activity on cortical interneurons has been shown to increase spontaneous, high-frequency (gamma-band ∼40 Hz) EEG,23, 24 gamma-band EEG may serve as a useful biomarker for NMDA channel blockers in general and lanicemine in particular. To test this hypothesis, cortical EEG recordings were obtained from rats trained to perform an auditory detection task for food reward. Both ketamine and lanicemine produced pronounced dose-dependent elevations in spontaneous gamma-band EEG (Figure 1, left), but only gamma changes for ketamine were tightly coupled to increases in locomotor activity (Figure 1, right)—suggesting that lanicemine not only engages brain circuits involved in the generation of gamma-EEG, but also influences these networks independent of the broader systems-level disruptions typical of ketamine.


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

Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, Quirk MC - Mol. Psychiatry (2013)

Electroencephalography (EEG) effects of lanicemine relative to ketamine in rodent model. Left: Time course of gamma-band EEG following administration of lanicemine and ketamine (doses: 10 mg kg−1) and respective vehicles. Right: Tolerability of lanicemine vs ketamine, measured by hyper-locomotor activity, at comparable levels of target engagement.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4195977&req=5

fig1: Electroencephalography (EEG) effects of lanicemine relative to ketamine in rodent model. Left: Time course of gamma-band EEG following administration of lanicemine and ketamine (doses: 10 mg kg−1) and respective vehicles. Right: Tolerability of lanicemine vs ketamine, measured by hyper-locomotor activity, at comparable levels of target engagement.
Mentions: Previous studies with lanicemine and ketamine demonstrated that both compounds bind with low-to-moderate affinity to sites within the NMDA channel pore, exhibit strong voltage dependence, and have similar lack of NR2A vs NR2B subunit selectivity (Table 1).14, 19, 20, 21, 22 However, at steady-state concentrations, ketamine had a greater propensity to be trapped within the NMDA channel pore following the removal and reapplication of glutamate (trapping: 86% with ketamine vs 54% with lanicemine). Low trapping theoretically preserves use-dependent channel block under conditions of normal, pyramidal cell-driven, synaptic transmission.14 Thus, while NMDARs are ubiquitously expressed within the central nervous system, the low-trapping property of lanicemine may bias channel block to those elements of the brain, such as cortical interneurons, with high levels of tonic activity. Since selective reduction in NMDAR activity on cortical interneurons has been shown to increase spontaneous, high-frequency (gamma-band ∼40 Hz) EEG,23, 24 gamma-band EEG may serve as a useful biomarker for NMDA channel blockers in general and lanicemine in particular. To test this hypothesis, cortical EEG recordings were obtained from rats trained to perform an auditory detection task for food reward. Both ketamine and lanicemine produced pronounced dose-dependent elevations in spontaneous gamma-band EEG (Figure 1, left), but only gamma changes for ketamine were tightly coupled to increases in locomotor activity (Figure 1, right)—suggesting that lanicemine not only engages brain circuits involved in the generation of gamma-EEG, but also influences these networks independent of the broader systems-level disruptions typical of ketamine.

Bottom Line: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients.However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data.Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

View Article: PubMed Central - PubMed

Affiliation: Clinical Neuroscience Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

ABSTRACT
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

Show MeSH
Related in: MedlinePlus