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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.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.

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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Montgomery Åsberg Depression rating Scale (MADRS) score change at prespecified time points during the 3-week treatment and 5-week follow-up period in lanicemine 100 mg, lanicemine 150 mg and placebo groups (intent-to-treat (ITT), last observation carried forward (LOCF)) (phase IIB study, study 9).
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fig3: Montgomery Åsberg Depression rating Scale (MADRS) score change at prespecified time points during the 3-week treatment and 5-week follow-up period in lanicemine 100 mg, lanicemine 150 mg and placebo groups (intent-to-treat (ITT), last observation carried forward (LOCF)) (phase IIB study, study 9).

Mentions: Patients treated with lanicemine (100 or 150 mg) exhibited a significantly greater change from baseline at week 3 in MADRS total score (the primary efficacy variable) than placebo-treated patients (Figure 3). The LSM difference between lanicemine 100 mg and placebo and between lanicemine 150 mg and placebo was −5.5 (95% confidence interval (CI)=−9.1 to −1.9, P=0.006) and −4.8 (95% CI=−8.5 to −1.2, P=0.019), respectively.


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)

Montgomery Åsberg Depression rating Scale (MADRS) score change at prespecified time points during the 3-week treatment and 5-week follow-up period in lanicemine 100 mg, lanicemine 150 mg and placebo groups (intent-to-treat (ITT), last observation carried forward (LOCF)) (phase IIB study, study 9).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Montgomery Åsberg Depression rating Scale (MADRS) score change at prespecified time points during the 3-week treatment and 5-week follow-up period in lanicemine 100 mg, lanicemine 150 mg and placebo groups (intent-to-treat (ITT), last observation carried forward (LOCF)) (phase IIB study, study 9).
Mentions: Patients treated with lanicemine (100 or 150 mg) exhibited a significantly greater change from baseline at week 3 in MADRS total score (the primary efficacy variable) than placebo-treated patients (Figure 3). The LSM difference between lanicemine 100 mg and placebo and between lanicemine 150 mg and placebo was −5.5 (95% confidence interval (CI)=−9.1 to −1.9, P=0.006) and −4.8 (95% CI=−8.5 to −1.2, P=0.019), respectively.

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.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.

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