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 - Stone, James
AU - McGuire, Philip
AU - Egerton, Alice
N1 - Funding Information:
This work was supported by MRC Grant Reference MR/S003436/1 (TD) and Medical Research Council grant MR/L003988/1 (AE). RM is funded by an NIHR clinical lectureship. OH is funded by Medical Research Council-UK (no. MC_A656_5QD30_2135), Maudsley Charity (no. 666), and Wellcome Trust (no. 094849/Z/10/Z). This study presents independent research funded in part by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London.
Publisher Copyright:
© 2023, The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85148369255&partnerID=8YFLogxK
U2 - 10.1038/s41380-023-01991-7
DO - 10.1038/s41380-023-01991-7
M3 - Article
C2 - 36806762
SN - 1359-4184
VL - 28
SP - 2039
EP - 2048
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 5
ER -