title: 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.
authors.affiliation: Clinical Neuroscience Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sanacora
authors.affiliation: AstraZeneca Pharmaceuticals LP, R&D, Wilmington, DE, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: AstraZeneca Pharmaceuticals LP, R&D, Wilmington, DE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pathak
authors.affiliation: AstraZeneca Pharmaceuticals LP, R&D, Wilmington, DE, USA.
authors.forename: H-L
authors.initials: HL
authors.lastname: Su
authors.affiliation: FORENAP, Rouffach, France.
authors.forename: P H
authors.initials: PH
authors.lastname: Boeijinga
authors.affiliation: AstraZeneca Pharmaceuticals LP, R&D, Wilmington, DE, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: McCarthy
authors.affiliation: AstraZeneca R&D, Boston, MA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Quirk
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D018592:Cross-Over Studies; D003865:Major Depressive Disorder / Q000188:drug therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010627:Phenethylamines / Q000009:adverse effects / Q000494:pharmacology*; D011569:Psychiatric Status Rating Scales; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C585977:AZD6765; D000928:Antidepressive Agents; D010627:Phenethylamines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine