Metabolomic correlates of intravenous racemic ketamine in treatment-resistant major depressive disorder: the Bio-K/NNDC multicenter trial.

OBJECTIVE: Ketamine is a rapid-acting antidepressant with an incompletely understood mechanism of action. Pharmacometabolomics can identify pathways underlying its effects and response variability. Using data from the Bio-K trial (NCT03156504), a multisite open-label study, we characterised metabolomic signatures of intravenous (IV) racemic ketamine in adults with treatment-resistant depression (TRD). METHODS: Sixty-nine adults with TRD and major depressive disorder received three ketamine infusions (0.5 mg/kg). Remission was defined as MADRS ≤9 at 24 h post-third infusion. Metabolomic profiling used the Biocrates MxP® Q500 kit (>600 metabolites). Mixed-effects models assessed changes across time points (pre-dose, post-infusion 1, post-infusion 3), adjusting for age, sex, infusion length (first), and body mass index, with false discovery rate correction. RESULTS: Mean MADRS improved from 27.8 ± 5.8 to 11.1 ± 9.1 post-third infusion (p < 0.001); 54% achieved remission. Post-infusion 1, ketamine was associated with increased acylcarnitines, cortisol, amino acids (glutamine, glycine, BCAAs), and biogenic amines (GABA, putrescine), with reduced medium-chain acylcarnitines and glutamate. Post-infusion 3, C16, serotonin, and GABA elevations persisted while cortisol normalised. Remitters showed greater GABA synthesis increases, however, no metabolite change correlated with MADRS improvement after correction for multiple testing. CONCLUSIONS: Ketamine exposure was correlated with broad metabolic alterations spanning mitochondrial activation, neurotransmitter modulation, and neuroendocrine signalling. These findings represent metabolic correlates of ketamine exposure and remission, rather than validated predictors or established mechanistic drivers of antidepressant response. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03156504.