Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system

Introduction

Mood disorders, particularly major depressive disorder (MDD), are highly prevalent and a leading cause of disability. Conventional antidepressants require weeks to take effect and achieve full remission in fewer than 50% of patients; around one third develop treatment-resistant depression (TRD). Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to produce a rapid antidepressant effect, including in TRD, but its psychotomimetic side-effects limit broad clinical use. Earlier mechanistic work has implicated mTORC1 activation, synaptogenesis and, more recently, active ketamine metabolites acting via AMPA receptors. The investigators' prior time-dependent metabolomics work suggested a role for mitochondrial energy metabolism pathways such as glycolysis and the citrate cycle in ketamine's effects. Weckmann and colleagues set out to extend those findings by profiling the hippocampal metabolome and proteome after a single low dose of ketamine in mice, correlating molecular changes with antidepressant-like behaviour in the forced swim test (FST). The study aimed to identify ketamine-affected pathways and biosignatures, with particular attention to mitochondrial oxidative phosphorylation (OXPHOS), cellular energy status (for example ATP/ADP ratio), and antioxidant defence systems that could mediate ketamine's rapid antidepressant-like action.