Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Kate Merritt; Robert A. McCutcheon; André Aleman; Sarah Ashley; Katherine Beck; Wolfgang Block; Oswald J.N. Bloemen; Faith Borgan; Christiana Boules; Juan R. Bustillo; Aristides A. Capizzano; Jennifer M. Coughlin; Anthony David; Camilo de la Fuente-Sandoval; Arsime Demjaha; Kara Dempster; Kim Q. Do; Fei Du; Peter Falkai; Beata Galińska-Skok; Jürgen Gallinat; Charles Gasparovic; Cedric E. Ginestet; Naoki Goto; Ariel Graff-Guerrero; Beng Choon Ho; Oliver Howes; Sameer Jauhar; Peter Jeon; Tadafumi Kato; Charles A. Kaufmann; Lawrence S. Kegeles; Matcheri S. Keshavan; Sang Young Kim; Bridget King; Hiroshi Kunugi; J. Lauriello; Pablo León-Ortiz; Edith Liemburg; Meghan E. Mcilwain; Gemma Modinos; Elias Mouchlianitis; Jun Nakamura; Igor Nenadic; Dost Öngür; Miho Ota; Lena Palaniyappan; Christos Pantelis; Tulsi Patel; Eric Plitman; Sotirios Posporelis; Scot E. Purdon; Jürgen R. Reichenbach; Perry F. Renshaw; Francisco Reyes-Madrigal; Bruce R. Russell; Akira Sawa; Martin Schaefer; Dikoma C. Shungu; Stefan Smesny; Jeffrey A. Stanley; James Stone; Agata Szulc; Reggie Taylor; Katharine N. Thakkar; Jean Théberge; Philip G. Tibbo; Thérèse van Amelsvoort; Jerzy Walecki; Peter C. Williamson; Stephen J. Wood; Lijing Xin; Hidenori Yamasue; Philip McGuire; Alice Egerton; Camilo de la Fuente-Sandoval; Thérèse van Amelsvoort; Philip K. McGuire

doi:10.1038/s41380-023-01991-7

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Kate Merritt, Robert A. McCutcheon, André Aleman, Sarah Ashley, Katherine Beck, Wolfgang Block, Oswald J.N. Bloemen, Faith Borgan, Christiana Boules, Juan R. Bustillo, Aristides A. Capizzano, Jennifer M. Coughlin, Anthony David, Camilo de la Fuente-Sandoval, Arsime Demjaha, Kara Dempster, Kim Q. Do, Fei Du, Peter Falkai, Beata Galińska-SkokJürgen Gallinat, Charles Gasparovic, Cedric E. Ginestet, Naoki Goto, Ariel Graff-Guerrero, Beng Choon Ho, Oliver Howes, Sameer Jauhar, Peter Jeon, Tadafumi Kato, Charles A. Kaufmann, Lawrence S. Kegeles, Matcheri S. Keshavan, Sang Young Kim, Bridget King, Hiroshi Kunugi, J. Lauriello, Pablo León-Ortiz, Edith Liemburg, Meghan E. Mcilwain, Gemma Modinos, Elias Mouchlianitis, Jun Nakamura, Igor Nenadic, Dost Öngür, Miho Ota, Lena Palaniyappan, Christos Pantelis, Tulsi Patel, Eric Plitman, Sotirios Posporelis, Scot E. Purdon, Jürgen R. Reichenbach, Perry F. Renshaw, Francisco Reyes-Madrigal, Bruce R. Russell, Akira Sawa, Martin Schaefer, Dikoma C. Shungu, Stefan Smesny, Jeffrey A. Stanley, James Stone, Agata Szulc, Reggie Taylor, Katharine N. Thakkar, Jean Théberge, Philip G. Tibbo, Thérèse van Amelsvoort, Jerzy Walecki, Peter C. Williamson, Stephen J. Wood, Lijing Xin, Hidenori Yamasue, Philip McGuire, Alice Egerton, Camilo de la Fuente-Sandoval, Thérèse van Amelsvoort, Philip K. McGuire

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Original language	English (US)
Pages (from-to)	2039-2048
Number of pages	10
Journal	Molecular psychiatry
Volume	28
Issue number	5
DOIs	https://doi.org/10.1038/s41380-023-01991-7
State	Published - May 2023

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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10.1038/s41380-023-01991-7

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Merritt, K., McCutcheon, R. A., Aleman, A., Ashley, S., Beck, K., Block, W., Bloemen, O. J. N., Borgan, F., Boules, C., Bustillo, J. R., Capizzano, A. A., Coughlin, J. M., David, A., de la Fuente-Sandoval, C., Demjaha, A., Dempster, K., Do, K. Q., Du, F., Falkai, P., ... McGuire, P. K. (2023). Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis. Molecular psychiatry, 28(5), 2039-2048. https://doi.org/10.1038/s41380-023-01991-7

Merritt, K, McCutcheon, RA, Aleman, A, Ashley, S, Beck, K, Block, W, Bloemen, OJN, Borgan, F, Boules, C, Bustillo, JR, Capizzano, AA, Coughlin, JM, David, A, de la Fuente-Sandoval, C, Demjaha, A, Dempster, K, Do, KQ, Du, F, Falkai, P, Galińska-Skok, B, Gallinat, J, Gasparovic, C, Ginestet, CE, Goto, N, Graff-Guerrero, A, Ho, BC, Howes, O, Jauhar, S, Jeon, P, Kato, T, Kaufmann, CA, Kegeles, LS, Keshavan, MS, Kim, SY, King, B, Kunugi, H, Lauriello, J, León-Ortiz, P, Liemburg, E, Mcilwain, ME, Modinos, G, Mouchlianitis, E, Nakamura, J, Nenadic, I, Öngür, D, Ota, M, Palaniyappan, L, Pantelis, C, Patel, T, Plitman, E, Posporelis, S, Purdon, SE, Reichenbach, JR, Renshaw, PF, Reyes-Madrigal, F, Russell, BR, Sawa, A, Schaefer, M, Shungu, DC, Smesny, S, Stanley, JA, Stone, J, Szulc, A, Taylor, R, Thakkar, KN, Théberge, J, Tibbo, PG, van Amelsvoort, T, Walecki, J, Williamson, PC, Wood, SJ, Xin, L, Yamasue, H, McGuire, P, Egerton, A, de la Fuente-Sandoval, C, van Amelsvoort, T & McGuire, PK 2023, 'Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis', Molecular psychiatry, vol. 28, no. 5, pp. 2039-2048. https://doi.org/10.1038/s41380-023-01991-7

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title = "Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis",

abstract = "Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan{\textquoteright}s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.",

author = "Kate Merritt and McCutcheon, {Robert A.} and Andr{\'e} Aleman and Sarah Ashley and Katherine Beck and Wolfgang Block and Bloemen, {Oswald J.N.} and Faith Borgan and Christiana Boules and Bustillo, {Juan R.} and Capizzano, {Aristides A.} and Coughlin, {Jennifer M.} and Anthony David and {de la Fuente-Sandoval}, Camilo and Arsime Demjaha and Kara Dempster and Do, {Kim Q.} and Fei Du and Peter Falkai and Beata Gali{\'n}ska-Skok and J{\"u}rgen Gallinat and Charles Gasparovic and Ginestet, {Cedric E.} and Naoki Goto and Ariel Graff-Guerrero and Ho, {Beng Choon} and Oliver Howes and Sameer Jauhar and Peter Jeon and Tadafumi Kato and Kaufmann, {Charles A.} and Kegeles, {Lawrence S.} and Keshavan, {Matcheri S.} and Kim, {Sang Young} and Bridget King and Hiroshi Kunugi and J. Lauriello and Pablo Le{\'o}n-Ortiz and Edith Liemburg and Mcilwain, {Meghan E.} and Gemma Modinos and Elias Mouchlianitis and Jun Nakamura and Igor Nenadic and Dost {\"O}ng{\"u}r and Miho Ota and Lena Palaniyappan and Christos Pantelis and Tulsi Patel and Eric Plitman and Sotirios Posporelis and Purdon, {Scot E.} and Reichenbach, {J{\"u}rgen R.} and Renshaw, {Perry F.} and Francisco Reyes-Madrigal and Russell, {Bruce R.} and Akira Sawa and Martin Schaefer and Shungu, {Dikoma C.} and Stefan Smesny and Stanley, {Jeffrey A.} and James Stone and Agata Szulc and Reggie Taylor and Thakkar, {Katharine N.} and Jean Th{\'e}berge and Tibbo, {Philip G.} and {van Amelsvoort}, Th{\'e}r{\`e}se and Jerzy Walecki and Williamson, {Peter C.} and Wood, {Stephen J.} and Lijing Xin and Hidenori Yamasue and Philip McGuire and Alice Egerton and {de la Fuente-Sandoval}, Camilo and {van Amelsvoort}, Th{\'e}r{\`e}se and McGuire, {Philip K.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = may,

doi = "10.1038/s41380-023-01991-7",

language = "English (US)",

volume = "28",

pages = "2039--2048",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - Variability and magnitude of brain glutamate levels in schizophrenia

T2 - a meta and mega-analysis

AU - Merritt, Kate

AU - McCutcheon, Robert A.

AU - Aleman, André

AU - Ashley, Sarah

AU - Beck, Katherine

AU - Block, Wolfgang

AU - Bloemen, Oswald J.N.

AU - Borgan, Faith

AU - Boules, Christiana

AU - Bustillo, Juan R.

AU - Capizzano, Aristides A.

AU - Coughlin, Jennifer M.

AU - David, Anthony

AU - de la Fuente-Sandoval, Camilo

AU - Demjaha, Arsime

AU - Dempster, Kara

AU - Do, Kim Q.

AU - Du, Fei

AU - Falkai, Peter

AU - Galińska-Skok, Beata

AU - Gallinat, Jürgen

AU - Gasparovic, Charles

AU - Ginestet, Cedric E.

AU - Goto, Naoki

AU - Graff-Guerrero, Ariel

AU - Ho, Beng Choon

AU - Howes, Oliver

AU - Jauhar, Sameer

AU - Jeon, Peter

AU - Kato, Tadafumi

AU - Kaufmann, Charles A.

AU - Kegeles, Lawrence S.

AU - Keshavan, Matcheri S.

AU - Kim, Sang Young

AU - King, Bridget

AU - Kunugi, Hiroshi

AU - Lauriello, J.

AU - León-Ortiz, Pablo

AU - Liemburg, Edith

AU - Mcilwain, Meghan E.

AU - Modinos, Gemma

AU - Mouchlianitis, Elias

AU - Nakamura, Jun

AU - Nenadic, Igor

AU - Öngür, Dost

AU - Ota, Miho

AU - Palaniyappan, Lena

AU - Pantelis, Christos

AU - Patel, Tulsi

AU - Plitman, Eric

AU - Posporelis, Sotirios

AU - Purdon, Scot E.

AU - Reichenbach, Jürgen R.

AU - Renshaw, Perry F.

AU - Reyes-Madrigal, Francisco

AU - Russell, Bruce R.

AU - Sawa, Akira

AU - Schaefer, Martin

AU - Shungu, Dikoma C.

AU - Smesny, Stefan

AU - Stanley, Jeffrey A.

AU - Stone, James

AU - Szulc, Agata

AU - Taylor, Reggie

AU - Thakkar, Katharine N.

AU - Théberge, Jean

AU - Tibbo, Philip G.

AU - van Amelsvoort, Thérèse

AU - Walecki, Jerzy

AU - Williamson, Peter C.

AU - Wood, Stephen J.

AU - Xin, Lijing

AU - Yamasue, Hidenori

AU - McGuire, Philip

AU - Egerton, Alice

AU - de la Fuente-Sandoval, Camilo

AU - van Amelsvoort, Thérèse

AU - McGuire, Philip K.

PY - 2023/5

Y1 - 2023/5

N2 - Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

AB - Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

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JO - Molecular psychiatry

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Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

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