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

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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.

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Acknowledgments

This work was supported in part by the Intramural Research Programs of the National Institute on Aging (IWW) and National Institute of Mental Health (CAZ) of the National Institutes of Health (NIH) and the Spanish Ministry of Science and Technology (MCIT) grant CTQ2011-23562 (CB). A. V. acknowledges her fellowship provided by EADS CASA.

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Authors and Affiliations

  1. Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD, USA

    Ruin Moaddel, Ying Xie, Anuradha Ramamoorthy, Michel Bernier & Irving W. Wainer

  2. Experimental Therapeutics & Pathophysiology Branch Intramural Research Program, National Institute of Mental Health (NIMH), NIH, Bethesda, MD, USA

    David A. Luckenbaugh, Nancy E. Brutsche, Rodrigo Machado-Vieira & Carlos A. Zarate Jr.

  3. Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Campus Montepríncipe, Madrid, Spain

    Alma Villaseñor, Maria Paz Lorenzo, Antonia Garcia & Coral Barbas

  4. Department of Anesthesiology, Cooper Medical School of Rowan University, Camden, NJ, USA

    Marc C. Torjman & Irving W. Wainer

  5. Bioanalytical and Drug Discovery Unit, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Suite 100, Biomedical Research Center, 251 Bayview Boul., Baltimore, MD, 21224-6825, USA

    Irving W. Wainer

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  1. Ruin Moaddel
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  2. David A. Luckenbaugh
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  3. Ying Xie
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  4. Alma Villaseñor
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  5. Nancy E. Brutsche
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  6. Rodrigo Machado-Vieira
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  7. Anuradha Ramamoorthy
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  8. Maria Paz Lorenzo
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  9. Antonia Garcia
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  10. Michel Bernier
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  11. Marc C. Torjman
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  13. Carlos A. Zarate Jr.
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  14. Irving W. Wainer
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Correspondence to Irving W. Wainer.

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Moaddel, R., Luckenbaugh, D.A., Xie, Y. et al. D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression. Psychopharmacology 232, 399–409 (2015). https://doi.org/10.1007/s00213-014-3669-0

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  • DOI: https://doi.org/10.1007/s00213-014-3669-0

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