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

• Published in: Psychopharmacology Vol. 232; no. 2; pp. 399 - 409
• Main Authors: Moaddel, Ruin, Luckenbaugh, David A., Xie, Ying, Villaseñor, Alma, Brutsche, Nancy E., Machado-Vieira, Rodrigo, Ramamoorthy, Anuradha, Lorenzo, Maria Paz, Garcia, Antonia, Bernier, Michel, Torjman, Marc C., Barbas, Coral, Zarate, Carlos A., Wainer, Irving W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2015; Springer; Springer Nature B.V
• Subjects: Adult; Antidepressants; Antidepressive Agents - therapeutic use; Biomarkers; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; Care and treatment; Chromatography, Liquid; Depressive Disorder, Treatment-Resistant - blood; Depressive Disorder, Treatment-Resistant - drug therapy; Dosage and administration; Female; Humans; Infusions, Intravenous; Ketamine - therapeutic use; Liquid chromatography; Major depressive disorder; Male; Mental depression; Middle Aged; N-methyl-D-aspartate; Neurosciences; Original Investigation; Pharmacology/Toxicology; Plasma; Psychiatry; Psychopharmacology; Risk factors; Serine - blood; Tandem Mass Spectrometry; Maryland; Antidepressant; D-serine; ketamine; Plasma response marker; Treatment-resistant depression; (; N-methyl-D-aspartate receptor; Bipolar depression; Serine racemase
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-014-3669-0

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.