D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression
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 definitiv...
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| Published in | Psychopharmacology Vol. 232; no. 2; pp. 399 - 409 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.01.2015
Springer Springer Nature B.V |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0033-3158 1432-2072 1432-2072 |
| DOI | 10.1007/s00213-014-3669-0 |
Cover
| 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. |
|---|---|
| AbstractList | (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.
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.
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.
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).
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. (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.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.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.OBJECTIVESThe 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.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.METHODSPlasma 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.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).RESULTSBaseline 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).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.CONCLUSIONSThe 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. (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. 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. 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-Asberg 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. Baseline D-serine plasma concentrations were significantly lower in KET-Rs (3.02±0.21 [mu]M) than in KET-NRs (4.68±0.81 [mu]M), 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 [mu]M vs 242.9±5.6 [mu]M, respectively; p<0.0001). 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. 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-Aasberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a greater than or equal to 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 plus or minus 0.21 mu M) than in KET-NRs (4.68 plus or minus 0.81 mu M), 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 plus or minus 9.6 mu M vs 242.9 plus or minus 5.6 mu M, 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. 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. 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-Asberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a [greater than or equal to] 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 [+ or -] 0.21 [micro]M) than in KET-NRs (4.68 [+ or -] 0.81 [micro]M), 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 [+ or -] 9.6 [micro]M vs 242.9 [+ or -] 5.6 [micro]M, 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. Keywords (R,S)-ketamine * Antidepressant * Treatment-resistantdepression * Bipolardepression * D-serine * N-methyl-D-aspartate receptor * Serine racemase * Plasma response marker |
| Audience | Academic |
| Author | Lorenzo, Maria Paz Bernier, Michel Brutsche, Nancy E. Xie, Ying Torjman, Marc C. Luckenbaugh, David A. Villaseñor, Alma Barbas, Coral Machado-Vieira, Rodrigo Ramamoorthy, Anuradha Wainer, Irving W. Moaddel, Ruin Garcia, Antonia Zarate, Carlos A. |
| Author_xml | – sequence: 1 givenname: Ruin surname: Moaddel fullname: Moaddel, Ruin organization: Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) – sequence: 2 givenname: David A. surname: Luckenbaugh fullname: Luckenbaugh, David A. organization: Experimental Therapeutics & Pathophysiology Branch Intramural Research Program, National Institute of Mental Health (NIMH), NIH – sequence: 3 givenname: Ying surname: Xie fullname: Xie, Ying organization: Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) – sequence: 4 givenname: Alma surname: Villaseñor fullname: Villaseñor, Alma organization: Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo – sequence: 5 givenname: Nancy E. surname: Brutsche fullname: Brutsche, Nancy E. organization: Experimental Therapeutics & Pathophysiology Branch Intramural Research Program, National Institute of Mental Health (NIMH), NIH – sequence: 6 givenname: Rodrigo surname: Machado-Vieira fullname: Machado-Vieira, Rodrigo organization: Experimental Therapeutics & Pathophysiology Branch Intramural Research Program, National Institute of Mental Health (NIMH), NIH – sequence: 7 givenname: Anuradha surname: Ramamoorthy fullname: Ramamoorthy, Anuradha organization: Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) – sequence: 8 givenname: Maria Paz surname: Lorenzo fullname: Lorenzo, Maria Paz organization: Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo – sequence: 9 givenname: Antonia surname: Garcia fullname: Garcia, Antonia organization: Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo – sequence: 10 givenname: Michel surname: Bernier fullname: Bernier, Michel organization: Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) – sequence: 11 givenname: Marc C. surname: Torjman fullname: Torjman, Marc C. organization: Department of Anesthesiology, Cooper Medical School of Rowan University – sequence: 12 givenname: Coral surname: Barbas fullname: Barbas, Coral organization: Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo – sequence: 13 givenname: Carlos A. surname: Zarate fullname: Zarate, Carlos A. organization: Experimental Therapeutics & Pathophysiology Branch Intramural Research Program, National Institute of Mental Health (NIMH), NIH – sequence: 14 givenname: Irving W. surname: Wainer fullname: Wainer, Irving W. email: Wainerir@grc.nia.nih.gov organization: Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Department of Anesthesiology, Cooper Medical School of Rowan University, Bioanalytical and Drug Discovery Unit, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25056852$$D View this record in MEDLINE/PubMed |
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)-ketamine is a rapid and effective antidepressant drug that produces a response in two thirds of patients with treatment-resistant depression... (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... Rationale (R,S)-ketamine is a rapid and effective antidepressant drug that produces a response in two thirds of patients with treatment-resistant depression... Rationale: (R,S)-ketamine is a rapid and effective antidepressant drug that produces a response in two thirds of patients with treatment-resistant depression... |
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| SubjectTerms | 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 |
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| Title | D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression |
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