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

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.

Trial registration: ClinicalTrials.gov NCT00491686 NCT00781742 NCT01130909.

Figures

Figure 1

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.

Figure 2

Electroencephalography (EEG) effects of lanicemine relative to ketamine in man. Left: Distribution over skull surface of absolute gamma EEG magnitude, theta-cordance and alpha slow-wave index at 1 h of perfusion. Color mapping depicts levels of statistical significance between study drug (lanicemine 75 or 150 mg; ketamine 0.5 mg kg−1) and vehicle at a given electrode location (blue: decrease; red: increase in P-value). Top right: Comparison of lanicemine (75 or 150 mg), ketamine (0.5 mg kg−1), and vehicle for mean (s.e.) change in relative gamma-EEG magnitude over time (eyes closed). Bottom right: Comparison of lanicemine (75 or 150 mg), ketamine (0.5 mg kg−1), and vehicle for mean (s.e.) change in Clinician Administered Dissociative States Scale (CADSS) total score from baseline. CADSS total score was increased significantly with ketamine vs vehicle at 1 h (P<0.01) and across all times (P<0.05). Lanicemine (each dose) did not significantly increase CADSS total score vs vehicle at any time.

Figure 3

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).

Figure 4

Clinical Global Impression of Improvement (CGI-I) response rate (%) 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. Response is defined as CGI-I score⩽2 (much or very much improved) (phase IIB study, study 9).