Elevated peripheral blood glutamate levels in major depressive disorder

Figures & data

Table 1 Characteristics of the included studies

Study	Country	Number of samples (Male, Female)	Mean age (SD)	Mean glutamate concentration (SD)	Unit of measure	Blood sampling	Measureing method	Medication exposure	Fasting information	Diagnosis
Altamura et al,^Citation15 1993	Italy	MDD: 4 (not available) CTRL: 9 (M7F2)	MDD: not available CTRL: 36.6 (8.3)	MDD: 191.86 (272.90) CTRL: 21.58 (7.61)	nmol/mL	Plasma	HPLC	Medication-free MDD for at least 3 weeks	No information (drawn at 9:00)	DSM-III-R
Altamura et al,^Citation20 1995	USA	MDD: 25 (M15F10) CTRL: 22 (M13F9)	MDD: 31.6 (9.4) CTRL: 28.7 (8.3)	MDD: 336 (159) CTRL: 265 (165)	Not available	Plasma	HPLC	Medication-free MDD for at least 8 days	No information (drawn at 9:00)	DSM-III-R
Mauri et al,^Citation16 1998	Italy	MDD: 29 (M15F14) CTRL: 28 (M16F12)	MDD: 47.4 (10.9) CTRL: 42.5 (14.2)	MDD: 86.05 (147.84) CTRL: 21.97 (23.54)	nmol/mL	Plasma	HPLC	Medication-free MDD for at least 4 weeks	Fasting blood	DSM-IV
Maes et al,^Citation12 1998	Belgium	MDD: 35 (M17F18) CTRL: 15 (M10F5)	MDD: 50.7 (14.4) CTRL: 47.5 (15.0)	MDD: 155.66 (57.51) CTRL: 134 (49)	μmol/L	Serum	HPLC	MDD with a washout period of 10 days	No information (drawn at 7:45)	DSM-III-R
Mitani et al,^Citation17 2006	Japan	MDD: 23 (M11F12) CTRL: 31 (M17F14)	MDD: 38.0 (11.3) CTRL: 41.5 (10.3)	MDD: 94.0 (48.1) CTRL: 59.6 (17.7)	nmol/mL	Plasma	HPLC	6 medication-free MDD and 17 medicated MDD	No information	DSM-IV
Xu et al,^Citation21 2012	China	MDD: 26 (M7F19) CTRL: 25 (M9F16)	MDD: 32.4 (8.9) CTRL: 32.1 (8.2)	MDD: 51.72 (33.67) CTRL: 51.72 (33.67)	μmol/L	Plasma	MS-based method	First-onset treatment-naïve MDD	Fasting blood	DSM-IV
Mayoral-Mariles et al,^Citation22 2012	Mexico	MDD: 18 (M0F18) CTRL: 45 (M0F45)	MDD: not available for 18 MDD CTRL: not available for 45 CTRL	MDD: 44.1 (14.0) CTRL: 39.3 (12.75)	μM/L	Plasma	HPLC	Medication-free MDD	Fasting blood	Beck Depression Inventory
Woo et al,^Citation18 2015	Korea	MDD: 68 (M16F52) CTRL: 22 (M4F18)	MDD: 65.3 (7.0) CTRL: 68.9 (6.3)	MDD: 58.53 (28.63) CTRL: 49.5 (21.0)	μmol/L	Plasma	LC-MS/MS	Medication-free MDD	Fasting blood	DSM-IV
Hashimoto et al,^Citation24 2016	Japan	MDD: 70 (M33F37) CTRL: 78 (M31F47)	MDD: 40.2 (9.9) CTRL: 37.2 (9.8)	MDD: 4.78 (2.24) CTRL: 4.57 (2.03)	μM	Serum	HPLC	Among 70 MDD, 66 were medicated with antidepressants	No information	DSM-IV
Umehara et al,^Citation14 2017	Japan	MDD: 33 (M10F23) CTRL: 33 (M10F23)	MDD: 47.1 (13.2) CTRL: 46.5 (10.1)	MDD: 0.061 (0.030) CTRL: 0.021 (0.0061)	Relative concentration	Plasma	CE-TOFMS	Medication-free MDD	Not fasting blood (drawn in the morning)	DSM-IV
Ogawa et al,^Citation19 2018. sample set A	Japan	MDD: 147 (M74F73) CTRL: 217 (M100F117)	MDD: 42.1 (12.1) CTRL: 41.2 (13.9)	MDD: 44.53 (24.53) CTRL: 37.27 (19.04)	μM	Plasma	HPLC	Most MDD patients were medicated	Not fasting blood	DSM-IV
Ogawa et al,^Citation19 2018. sample set B	Japan	MDD: 51 (M27F24) CTRL: 65 (M20F45)	MDD: 44.2 (13.4) CTRL: 43.4 (13.4)	MDD: 44.55 (18.74) CTRL: 34.52 (13.23)	μM	Plasma	LC/MS	Most MDD patients were medicated	Not fasting blood	DSM-IV

Abbreviations: MDD, major depressive disorder; CTRL, control; HPLC, high-performance liquid chromatography; DSM, Diagnostic and Statistical Manual of Mental Disorders; LC-MS/MS, liquid chromatography–tandem mass spectrometry; CE-TOFMS, capillary electrophoresis-time-of-flight mass spectrometry.

Figure 1 RE meta-analysis of association studies between peripheral blood glutamate levels and MDD.

Abbreviations: RE, random effect; MDD, major depressive disorder; SMD, standardized mean difference.

Figure 2 Publication bias assessed with funnel plot.

Abbreviation: SMD, standardized mean difference.

Table 2 Results of subgroup analyses analysis of association studies between peripheral blood glutamate levels and MDD

Variables	Number of association studies	Subgroup analysis				Heterogeneity
		SMD	95% CI lower	95% CI upper	p-value	l^2 (%)	Q (p-value)
Blood sampling
Plasma	10	0.62	0.31	0.93	0.0001	75.9	2.9×10^−4
Serum	2	0.16	−0.12	0.45	0.26	0	0.42
Glutamate assay
HPLC	8	0.41	0.22	0.60	<0.0001	28.5	0.22
MS	4	0.69	−0.069	1.45	0.075	89.7	<1.0×10^−4
Medication
Medication free	8	0.59	0.19	1.00	0.004	72.9	6.8×10^−4
Food consumption
Fasting	4	0.33	0.063	0.59	0.015	0	0.51
Not fasting	3	0.90	0.031	1.77	0.042	94.1	<1.0×10^−4
Ethnicity
Asian	7	0.58	0.14	1.02	0.01	88.6	<1.0×10^−4
Non-Asian	5	0.48	0.21	0.76	0.0006	0	0.84

Abbreviations: MDD, major depressive disorder; SMD, standardized mean difference; HPLC, high-performance liquid chromatography; MS, mass spectroscopy.

Table 3 Result of a meta-regression analysis in patients with MDD and controls

Moderator	Number of association studies	Meta-regression analysis				Heterogeneity
		Slope	95% CI lower	95% CI upper	p-value	l^2 (%)	Q (p-value)
Age (mean year)	10	0.0078	−0.027	0.042	0.66	82.3	<1.0×10^−4
Gender (% male)	11	0.0006	−0.018	0.019	0.95	79.7	<1.0×10^−4
Medication exposure (% medication-received patients)	10	−0.0018	−0.012	0.0083	0.73	74.8	1.2×10^−4
Sample size	12	−0.0012	−0.0041	0.0017	0.42	72.2	2.4×10^−4
Published year	12	−0.0018	−0.035	0.032	0.92	77.3	<1.0×10^−4

Abbreviation: MDD, major depressive disorder.

Figure S1 Flow chart of the study selection process.

Table S1 Result of leave-one-out sensitivity analysis

Omitting study	SMD	95% CI lower	95% CI upper	p-value	I^2 (%)	Q (p-value)
Altamura et al,^Citation1 1993	0.52	0.25	0.80	2.2×10^−4	76.9	1.2×10^−4
Altamura et al,^Citation2 1995	0.56	0.26	0.85	2.4×10^−4	78.1	<1.0×10^−4
Mauri et al,^Citation3 1998	0.54	0.24	0.84	3.7×10^−4	78.0	<1.0×10^−4
Maes et al,^Citation4 1998	0.56	0.26	0.86	2.1×10^−4	78.0	<1.0×10^−4
Mitani et al,^Citation5 2006	0.51	0.22	0.79	4.5×10^−4	75.4	3.3×10^−4
Xu et al,^Citation6 2012	0.59	0.31	0.87	<1.0×10^−4	75.0	2.1×10^−4
Mayoral-Mariles et al,^Citation7 2012	0.56	0.27	0.86	2.0×10^−4	77.8	<1.0×10^−4
Woo et al,^Citation8 2015	0.57	0.27	0.87	1.9×10^−4	77.5	<1.0×10^−4
Hashimoto et al,^Citation9 2016	0.60	0.31	0.88	<1.0×10^−4	72.7	5.5×10^−4
Umehara et al,^Citation10 2017	0.40	0.24	0.55	<1.0×10^−4	22.3	0.22
Ogawa et al,^Citation11 2018. sample set A	0.57	0.27	0.88	2.2×10^−4	72.8	1.4×10^−4
Ogawa et al,^Citation11 2018. sample set B	0.54	0.24	0.84	4.9×10^−4	77.0	1.1×10^−4

Abbreviation: SMD, standardized mean difference.

AltamuraCAMauriMCFerraraAPlasma and platelet excitatory amino acids in psychiatric disordersAm J Psychiatry199315011173117338214185

 PubMed Web of Science ®Google Scholar

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 PubMed Web of Science ®Google Scholar

MauriMCFerraraABoscatiLPlasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatmentNeuropsychobiology19983731241299597668

 PubMed Web of Science ®Google Scholar

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 PubMed Web of Science ®Google Scholar

MitaniHShirayamaYYamadaTCorrelation between plasma levels of glutamate, alanine and serine with severity of depressionProg Neuropsychopharmacol Biol Psychiatry20063061155115816707201

 PubMed Web of Science ®Google Scholar

XuHBFangLHuZCPotential clinical utility of plasma amino acid profiling in the detection of major depressive disorderPsychiatry Res20122002–31054105722749229

 PubMed Web of Science ®Google Scholar

Mayoral-MarilesACruz-RevillaCVega-ManriquezXPlasma amino acid levels discriminate between control subjects and mildly depressed elderly womenArch Med Res201243537538222871334

 PubMed Web of Science ®Google Scholar

WooHIChunMRYangJSPlasma amino acid profiling in major depressive disorder treated with selective serotonin reuptake inhibitorsCNS Neurosci Ther201521541742425611566

 PubMed Web of Science ®Google Scholar

HashimotoKYoshidaTIshikawaMIncreased serum levels of serine enantiomers in patients with depressionActa Neuropsychiatr201628317317826512905

 PubMed Web of Science ®Google Scholar

UmeharaHNumataSWatanabeSYAltered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorderSci Rep201771485528687801

 PubMed Web of Science ®Google Scholar

OgawaSKogaNHattoriKPlasma amino acid profile in major depressive disorder: analyses in two independent case-control sample setsJ Psychiatr Res201896233228950111

 PubMed Web of Science ®Google Scholar

AltamuraCAMauriMCFerraraAPlasma and platelet excitatory amino acids in psychiatric disordersAm J Psychiatry199315011173117338214185

 PubMed Web of Science ®Google Scholar

AltamuraCMaesMDaiJPlasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depressionEur Neuropsychopharmacol19955 Suppl71758775762

 PubMed Web of Science ®Google Scholar

MauriMCFerraraABoscatiLPlasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatmentNeuropsychobiology19983731241299597668

 PubMed Web of Science ®Google Scholar

MaesMVerkerkRVandoolaegheESerum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivityActa Psychiatr Scand19989743023089570492

 PubMed Web of Science ®Google Scholar

MitaniHShirayamaYYamadaTCorrelation between plasma levels of glutamate, alanine and serine with severity of depressionProg Neuropsychopharmacol Biol Psychiatry20063061155115816707201

 PubMed Web of Science ®Google Scholar

XuHBFangLHuZCPotential clinical utility of plasma amino acid profiling in the detection of major depressive disorderPsychiatry Res20122002–31054105722749229

 PubMed Web of Science ®Google Scholar

Mayoral-MarilesACruz-RevillaCVega-ManriquezXPlasma amino acid levels discriminate between control subjects and mildly depressed elderly womenArch Med Res201243537538222871334

 PubMed Web of Science ®Google Scholar

WooHIChunMRYangJSPlasma amino acid profiling in major depressive disorder treated with selective serotonin reuptake inhibitorsCNS Neurosci Ther201521541742425611566

 PubMed Web of Science ®Google Scholar

HashimotoKYoshidaTIshikawaMIncreased serum levels of serine enantiomers in patients with depressionActa Neuropsychiatr201628317317826512905

 PubMed Web of Science ®Google Scholar

UmeharaHNumataSWatanabeSYAltered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorderSci Rep201771485528687801

 PubMed Web of Science ®Google Scholar

OgawaSKogaNHattoriKPlasma amino acid profile in major depressive disorder: analyses in two independent case-control sample setsJ Psychiatr Res201896233228950111

 PubMed Web of Science ®Google Scholar