Blood d-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine

Introduction

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant effects after a single subanaesthetic infusion (0.5 mg/kg) in a substantial proportion of patients with treatment‑resistant major depressive disorder (MDD) or bipolar disorder (BD), but the biochemical determinants of interindividual response remain unclear. Hashimoto discusses recent data reporting that baseline plasma D‑serine — an endogenous co‑agonist at the NMDA receptor — differed between ketamine responders and non‑responders: responders had mean D‑serine 3.02±0.30 μM (n=8) versus 4.68±0.81 μM (n=13) in non‑responders (p<0.0001). Baseline L‑serine was also lower in responders (66.2±62.8 μM) than non‑responders (242.9±67.2 μM), and baseline concentrations of both D‑ and L‑serine correlated with the percentage change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores at 230 minutes after infusion (D‑serine r=0.77, p<0.001; L‑serine r=0.83, p<0.001). The proportion of D‑serine to total serine was reportedly higher in responders than non‑responders (5.91±1.92% versus 2.11±1.05%, p<0.001), and both groups showed a biphasic decrease in plasma D‑serine after ketamine while L‑serine remained unchanged. Greater acute dissociative effects (higher Clinician‑Administered Dissociative States Scale scores) were present among responders, and baseline D‑serine correlated negatively with dissociative increase at 40 minutes (r=−0.52, p=0.02).