TY - JOUR
T1 - Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders
T2 - a meta-analysis of 1H-magnetic resonance spectroscopy studies
AU - Nakahara, Tomomi
AU - Tsugawa, Sakiko
AU - Noda, Yoshihiro
AU - Ueno, Fumihiko
AU - Honda, Shiori
AU - Kinjo, Megumi
AU - Segawa, Hikari
AU - Hondo, Nobuaki
AU - Mori, Yukino
AU - Watanabe, Honoka
AU - Nakahara, Kazuho
AU - Yoshida, Kazunari
AU - Wada, Masataka
AU - Tarumi, Ryosuke
AU - Iwata, Yusuke
AU - Plitman, Eric
AU - Moriguchi, Sho
AU - de la Fuente-Sandoval, Camilo
AU - Uchida, Hiroyuki
AU - Mimura, Masaru
AU - Graff-Guerrero, Ariel
AU - Nakajima, Shinichiro
N1 - Funding Information:
TN, ST, SH, MK, HS, NH, YM, HW, KN, MW, CdlF-S, RT, AG-G, and HU report no biomedical interests. YN has received a Grant-in-Aid for Young Scientists (18K15375) and a Grant-in-Aid for Scientific Research (B) (21H02813) from the Japan Society for the Promotion of Science (JSPS), research grants from Japan Agency for Medical Research and development (AMED), an investigator-initiated clinical study grant from TEIJIN PHARMA LIMITED. He also receives research grants from Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi Sankyo Scholarship Donation Program. He receives equipment-in-kind support for an investigator-initiated study from Magventure Inc and research supports from Otsuka Pharmaceutical, Shionogi, and Meiji Seika Pharma. FU has received fellowship grants from Discovery Fund, Nakatani Foundation, and the Canadian Institutes of Health Research (CIHR); and consultant fee from VeraSci, and Uchiyama Underwriting within the past three years. KY has received manuscript fees from Sumitomo Dainippon Pharma, fellowship grants from the Japan Research Foundation for Clinical Pharmacology and Azrieli Adult Neurodevelopmental Centre Postdoctoral Fellowship at CAMH, and consultant fees from Signant Health, VeraSci, and MedAvante-ProPhase within the past three years.YI has received fellowship grants from Canadian Institute of Health Research (CIHR), Keio University Medical Science Foundation, Mitsukoshi Foundation. YI has also received manuscript fees from Dainippon Sumitomo Pharma. EP reports receiving funding from the Healthy Brains for Healthy Lives Postdoctoral Fellowship, Vanier Canada Graduate Scholarship, the Ontario Graduate Scholarship, and the Canada Graduate Scholarship – Master’s. YI has also received manuscript fees from Dainippon Sumitomo Pharma. A.G-G. has received support from the United States National Institute of Health, CIHR, Ontario Mental Health Foundation, the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award during the last 5 years. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Daiichi Sankyo Company, Mochida Pharmaceutical, and Meiji-Seika Pharma; speaker’s honoraria from Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Eisai, and Meiji-Seika Pharma; and advisory panel payments from Dainippon-Sumitomo Pharma within the past three years. MM has received research support from Japan Society for the Promotion of Science and grants or speaker’s honoraria from Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. SN has received grants from Japan Society for the Promotion of Science, Japan Agency for Medical Research and development (AMED), Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past three years. SN has also received research support, manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past three years.
Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers 18H02755, PE19015, 19H03587, 20K20603, and National Institutes of Health Grant Numbers R01 MH110270.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/1
Y1 - 2022/1
N2 - Background: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. Results: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01). Conclusions: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.
AB - Background: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. Results: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01). Conclusions: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.
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U2 - 10.1038/s41380-021-01297-6
DO - 10.1038/s41380-021-01297-6
M3 - Review article
C2 - 34584230
AN - SCOPUS:85115884429
VL - 27
SP - 744
EP - 757
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 1
ER -