D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression

Abstract

Rationale: (R,S)-ketamine is a rapid and effective antidepressant drug that produces a response in two thirds of patients with treatment-resistant depression (TRD). The underlying biochemical differences between a (R,S)-ketamine responder (KET-R) and non-responder (KET-NR) have not been definitively identified but may involve serine metabolism.

Objectives: The aim of the study was to examine the relationship between baseline plasma concentrations of D-serine and its precursor L-serine and antidepressant response to (R,S)-ketamine in TRD patients.

Methods: Plasma samples were obtained from 21 TRD patients at baseline, 60 min before initiation of the (R,S)-ketamine infusion. Patients were classified as KET-Rs (n = 8) or KET-NRs (n = 13) based upon the difference in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a ≥50 % decrease in MADRS score. The plasma concentrations of D-serine and L-serine were determined using liquid chromatography-mass spectrometry.

Results: Baseline D-serine plasma concentrations were significantly lower in KET-Rs (3.02 ± 0.21 μM) than in KET-NRs (4.68 ± 0.81 μM), p < 0.001. A significant relationship between baseline D-serine plasma concentrations and percent change in MADRS at 230 min was determined using a Pearson correlation, r = 0.77, p < 0.001, with baseline D-serine explaining 60 % of the variance in (R,S)-ketamine response. The baseline concentrations of L-serine (L-Ser) in KET-Rs were also significantly lower than those measured in KET-NRs (66.2 ± 9.6 μM vs 242.9 ± 5.6 μM, respectively; p < 0.0001).

Conclusions: The results demonstrate that the baseline D-serine plasma concentrations were significantly lower in KET-Rs than in KET-NRs and suggest that this variable can be used to predict an antidepressant response following (R,S)-ketamine administration.

Fig. 1

Baseline plasma levels of D-serine (D-Ser) and L-serine (L-Ser) in TRD patients prior to receiving a 40-min intravenous infusion of 0.5 mg/kg (R,S)-ketamine determined using liquid chromatography with mass spectrometric detection with D-arginine (D-Arg) as the internal standard; see text for details. Patients were classified as responding to (R,S)-ketamine (KET-Rs) or non-responders (KET-NRs) based upon the difference in Montgomery–Åsberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a ≥50 % decrease in MADRS score. a Representative chromatogram from the baseline plasma sample obtained from a KET-R in which the measured plasma concentrations of D-Ser and L-Ser are 2.76 and 34.6 μM, respectively. b Representative chromatogram from the baseline plasma sample obtained from a KET-NR in which the measured plasma concentrations of D-serine and L-serine are 5.44 and 273.6 μM, respectively. c Baseline D-Ser concentration by response group, where squares denote KET-Rs and circles denote KET-NRs

Fig. 2

Relationship between plasma levels of D-serine (μM) and L-serine (μM) at baseline and percent change in MADRS from baseline to 230 min post-(R,S)-ketamine infusion, where squares denote KET-Rs and circles denote KET-NRs. a Relationship between plasma levels of D-serine (μM) and percent change in MADRS; b relationship between plasma levels of L-serine (μM) at baseline and percent change in MADRS

Fig. 3

The effect of a 40-min intravenous infusion of 0.5 mg/kg (R,S)-ketamine on the plasma concentration of D-serine (μM) in MDD patients determined from baseline to 21 days post-infusion. Patients were classified as responding to (R,S)-ketamine (KET-Rs) or non-responders (KET-NRs) based upon the difference in Montgomery–Åsberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a ≥50 % decrease in MADRS score. Linear mixed models with restricted maximum likelihood estimation and compound symmetry covariance structure were used to examine D-serine levels over time by response group, where squares denote KET-Rs and circles denote KET-NRs. The initial model (a) used baseline as a separate time point and the second (b) used baseline as a covariate. Bonferroni post hoc tests were used to compare response groups at individual time points, with ***p<0.005, **p<0.01, and *p<0.05

Fig. 4

Changes in the average Clinician Administered Dissociative States Scale (CADSS) scores over time in MDD patients classified as responding to (R,S)-ketamine (squares) or non-responders (circles) measured before administration of (R,S)-ketamine (−60 min) and up to 21 days post-administration