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

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).

Hashimoto places these findings in the context of prior work on serine metabolism and NMDA receptor function. He notes earlier observations that patients with schizophrenia had lower serum D‑serine and higher L‑serine compared with healthy controls, interpreting that pattern as supportive of NMDA receptor hypofunction; by contrast, the relatively high D‑serine fraction reported in the treatment‑resistant depression sample may indicate hyperglutamatergic signalling via NMDA receptors in that population. The author highlights key enzymes that regulate serine and glycine pathways — serine racemase (L‑ to D‑serine conversion), D‑amino‑acid oxidase (D‑serine degradation), serine hydroxymethyltransferase (interconversion of glycine and L‑serine) and astrocytic synthesis from 3‑phosphoglycerate — and recommends investigation of enzymatic activity and genetic variation in these pathways among ketamine responders and non‑responders. He also draws attention to stereoisomer effects, citing preclinical work in which R‑ketamine produced more potent and longer‑lasting antidepressant-like effects than S‑ketamine in rodents, and suggests it would be valuable to measure D‑ and L‑serine in blood and cerebrospinal fluid after administration of ketamine stereoisomers. Finally, Hashimoto proposes that baseline plasma D‑serine could serve as a predictive biomarker for antidepressant response to racemic ketamine, its stereoisomers, and other NMDA receptor antagonists in treatment‑resistant MDD or BD, but he emphasises the need for replication in larger samples.