Does mismatch negativity have utility for NMDA receptor drug development in depression?

Abstract

Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery.

Identification of an optimal dose of intravenous ketamine for late-life treatment-resistant depression: a Bayesian adaptive randomization trial

“…Study procedures on day of infusion were in a hospital room dedicated to research. Following an overnight fast, on the morning of infusion, clinical ratings (MADRS; QIDS-SR; CGI-S), adverse events scales (Columbia-Suicide Severity Rating Scale [C-SSRS] [ 29 ], Clinician Administered Dissociation Symptom Scale [CADSS] [ 30 ]; four-item Brief Psychiatric Rating Scale [BPRS+] [ 31 ]; Patient Reported Inventory of Side Effects [PRISE] [ 32 ]), 64-channel EEG (resting eyes open and eyes closed two minutes each reported here; auditory mismatch negativity paradigm with duration deviants reported in [ 33 ]), and a blood draw for BDNF were administered before the infusion. CADSS, BPRS+ and PRISE were repeated at 40 minutes (end of infusion), 120 minutes, and 240 minutes after start of infusion.…”