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Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies
Open accessAbstract
IMPORTANCE: Alterations in glutamatergic neurotransmission may be fundamental to the pathophysiology of schizophrenia, and the glutamatergic system is a target for novel therapeutic interventions in the disorder. OBJECTIVE: To investigate the nature of brain glutamate alterations in schizophrenia by conducting a meta-analysis of glutamate proton magnetic resonance (MRS) spectroscopy studies. DATA SOURCES: The MEDLINE database was searched for studies published from January 1, 1980, to April 1, 2015. Search terms included magnetic resonance spectroscopy, schizophrenia, psychosis, clinical or genetic high risk, and schizoaffective. Inclusion criteria were single voxel 1H-MRS studies reporting glutamate, glutamine or Glx values for a patient or risk group in comparison to a healthy volunteer group. STUDY SELECTION: Fifty-nine studies were identified, which included 1686 patients and 1451 healthy individuals serving as controls. DATA EXTRACTION AND SYNTHESIS: A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were determined for glutamate, glutamine, and Glx in brain regions that had been examined in at least 3 different studies. A secondary analysis grouped studies into those examining patients at different stages of illness (high risk, first-episode psychosis, or chronic schizophrenia). Effects of age, antipsychotic dose, and symptom severity were determined using meta-regression. RESULTS: In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus (g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia (g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe (g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in individuals at high risk for schizophrenia (g = 0.26; 95% CI, 0.05-0.46) but not in those with first-episode psychosis or chronic schizophrenia, whereas elevated Glx in the medial temporal lobe was seen with chronic schizophrenia (g = 0.40; 95% CI, 0.08-0.71) but not in the high-risk or first-episode groups. Meta-regression found no association with age, symptom severity, or antipsychotic dose. CONCLUSIONS AND RELEVANCE: Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.
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“Evidence from magnetic resonance spectroscopy suggests that alterations in glutamatergic neurotransmission may change over the course of schizophrenia (96, 97).”
From The Predictive Coding Account of Psychosis (2018) · cites this paper as [96]
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InfluentialSpatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
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“Disrupted glutamatergic signaling has been observed in multiple similar studies, and has been consistently implicated in SCZ pathogenesis (Merritt et al., 2016).”
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“By contrast, current data do not show very consistent alterations of glutamate and glutamine levels in first-episode and chronic patients (Merritt et al., 2016; Wang et al., 2019).”
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“Accordingly, a meta-analysis of proton magnetic resonance spectroscopy ((1)H-MRS) studies showed increased glutamate levels in schizophrenia [84], and there is also emerging PET evidence for lower NMDAR availability in schizophrenia [85].”
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“…at odds with several prior MRS studies (see Reviews8, 27), including the main finding of a recent comprehensive meta-analysis.19 As documented in Merritt et al., 2016, glutamatergic metabolites are, on average, higher in “cases” — a designation that includes individuals with chronic…”
Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia
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“Indeed, the overactivation of glutamatergic system in the medial prefrontal cortex (mPFC) is considered a pathophysiological hallmark of schizophrenia and an increased glutamate efflux in prefrontal cortex (PFC) plays a significant role in the development/progression of both positive and negative symptoms [30,36,37].”
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“Yet notably, the current 7 T (1)HMRS meta-analytic findings appear to contradict those reported in a large 3 T (1)HMRS meta-analysis of PSY, in which glutamate-related metabolites (Gln and Glx) were found to be, on average, higher in patients compared to controls (Merritt et al., 2016).”
BackgroundResultInfluentialToward recovery in schizophrenia: Current concepts, findings, and future research directions
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“13 with this psychiatric disorder (76, 77) and the close relationship between metabolites and 454 neurofunction, abnormalities in brain function should arise.”
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“In line with these findings, a recent meta-analysis noted no significant correlations between glutamatergic markers and symptom severity in patients with schizophrenia [17].”
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“A recent metaanalysis observed elevated Glu within the thalamus (Thal), and elevated Glx within the medial temporal lobe (mTem) and basal ganglia (BG), in patients compared to healthy controls (HCs) (Merritt et al., 2016).”
Haarsma, J., Knolle, F., Griffin, J. D., Taverne, H., Mada, M., Goodyer, I. M., The NSPN Consortium, Fletcher, P. C., & Murray, G. K. (2020) · Journal of Abnormal Psychology · doi:10.1037/abn0000494 · Cited by 60
“It has been proposed that glutamatergic abnormalities may be prominent in the early stages of psychotic illness (Merritt et al 2016, Kumar et al 2018), and that these may be key in driving pathophysiology of illness, predictive processing dysfunction, and psychopathology (Corlett et al., 2009 &…”
BackgroundInfluentialBianciardi, B., & Uhlhaas, P. J. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.02.005 · Cited by 59
Duan, C., Cosgrove, J., & Deligiannidis, K. M. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0824-4 · Cited by 59
Goh, K. K., Wu, T., Chen, C.-H., & Lu, M. (2021) · Journal of Psychopharmacology · doi:10.1177/0269881120965937 · Cited by 56
“For example, excess glutamatergic neurotransmission in the brain is associated with schizophrenia patients (Merritt et al., 2016), particularly in those with treatment-refractory schizophrenia (Shah et al.”
BackgroundPrestwood, T. R., Asgariroozbehani, R., Wu, S., Agarwal, S. M., Logan, R. W., Ballon, J. S., Hahn, M., & Freyberg, Z. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113101 · Cited by 67
“Indeed, increased glutamate levels in the thalamus, basal ganglia, and medial temporal cortex have been reported in schizophrenia [163].”
BackgroundApproaches to neuromodulation for schizophrenia
Gault, J., Davis, R. A., Cascella, N. G., Saks, E. R., Corripio, I., Anderson, W. S., D, A. O. M., Thompson, J. A., Pomarol‐Clotet, E., Sawa, A., et al. (2017) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-316946 · Cited by 57
Anterior Cingulate Glutamate and GABA Associations on Functional Connectivity in Schizophrenia
Shukla, D. K., Wijtenburg, S. A., Chen, H., Chiappelli, J., Kochunov, P., Hong, L. E., & Rowland, L. M. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sby075 · Cited by 52
Pillinger, T., Rogdaki, M., McCutcheon, R. A., Hathway, P., Egerton, A., & Howes, O. D. (2019) · Psychopharmacology · doi:10.1007/s00213-019-5188-5 · Cited by 53
Adaptive baseline fitting for MR spectroscopy analysis
Wilson, M. (2020) · Magnetic Resonance in Medicine · doi:10.1002/mrm.28385 · Cited by 53
Yuan, A., Veeranna, Sershen, H. W., Basavarajappa, B. S., Smiley, J. F., Hashim, A., Bleiwas, C., Berg, M. J., Guifoyle, D. N., Subbanna, S., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0194-7 · Cited by 54
GABAergic System Dysfunction and Challenges in Schizophrenia Research
Jahangir, M., Zhou, J., Lang, B., & Wang, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.663854 · Cited by 55
Das, T. K., Dey, A., Sabesan, P., Javadzadeh, A., Théberge, J., Raduà, J., & Palaniyappan, L. K. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00438 · Cited by 49
Smucny, J., Carter, C. S., & Maddock, R. J. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.06.008 · Cited by 50
“(15) meta-analysis covered studies published before April 1, 2015.”
InfluentialTrends in big data analyses by multicenter collaborative translational research in psychiatry
Onitsuka, T., Hirano, Y., Nemoto, K., Hashimoto, N., Kushima, I., Koshiyama, D., Koeda, M., Takahashi, T., Noda, Y., Matsumoto, J., et al. (2021) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13311 · Cited by 53
“It was also concluded that there were no regions showing a consistent reduction in glutamate metabolites in the patient group.(128) These findings supported the hypothesis that SZ”
ResultGomes, J. S., Trevizol, A. P., Ducos, D. V., Gadelha, A., Ortiz, B. B., Fonseca, A. O., Akiba, H. T., de Azevedo, C. C., Guimarães, L. S. P., Shiozawa, P., et al. (2018) · Schizophrenia Research Cognition · doi:10.1016/j.scog.2018.02.003 · Cited by 48
“Moreover, the role of GABA in negative and cognitive symptoms of schizophrenia has been discussed (Wassef et al., 2003) and reducing glutamatergic neurotransmission is suggested as a promising intervention (Merritt et al., 2016) for persistent symptoms.”
Wenneberg, C., Glenthøj, B., Hjorthøj, C., Zingenberg, F. J. B., Glenthøj, L., Rostrup, E., Broberg, B., & Nordentoft, M. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.10.050 · Cited by 51
Molecular imaging of schizophrenia: Neurochemical findings in a heterogeneous and evolving disorder
Cumming, P. D., Abi‐Dargham, A., & Gründer, G. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113004 · Cited by 53
The influence of the glutamatergic system on cognition in schizophrenia: A systematic review
Thomas, E. H. X., Bozaoglu, K., Rossell, S. L., & Gurvich, C. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.04.005 · Cited by 47
“…these early findings, evidence from Magnetic Resonance Spectroscopy (MRS) studies have demonstrated increased glutamatergic metabolites in cortical and subcortical areas of the brain, indicating that excess glutamatergic neurotransmission is associated with schizophrenia (Merritt et al., 2016).”
BackgroundResultKim, S.-Y., Kaufman, M. J., Cohen, B. M., Jensen, J. E., Coyle, J. T., Du, F., & Öngür, D. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.022 · Cited by 47
Mehta, M. A., Schmechtig, A., Kotoula, V., McColm, J., Jackson, K. A., Brittain, C. F., Tauscher‐Wisniewski, S., Kinon, B. J., Morrison, P. D., Pollak, T. A., et al. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4877-9 · Cited by 47
“This has been demonstrated in the frontal cortex of rats following phencyclidine (Moghaddam 1998) and ketamine (Lorrain et al. 2003) and in humans using magnetic resonance spectroscopy (Stone Fig.”
Xu, M. K., Guo, Y., Cheng, J., Xue, K., Yang, M., Song, X., Feng, Y., & Cheng, J. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102736 · Cited by 47
“, 2000), and a broad elevation of glutamate metabolites in the thalamus and basal ganglia of schizophrenia patients (Merritt et al., 2016; Yang et al., 2019).”
BackgroundFrontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum
Sabaroedin, K., Razi, A., Chopra, S., Tran, N., Pozaruk, A., Chen, Z.-L., Finlay, A., Nelson, B., Allott, K., Alvarez-Jimenez, M., et al. (2022) · Brain : a journal of neurology · doi:10.1093/brain/awac018 · Cited by 43
Kani, A. S., Shinn, A. K., Lewandowski, K. E., & Öngür, D. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.10.012 · Cited by 46
Sami, M. B., & Bhattacharyya, S. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881118760662 · Cited by 45
“These include: (1) drug-induced models with NMDA receptor antagonists ketamine and PCP producing schizophrenia-like psychosis; and (2) Magnetic resonance spectroscopy (MRS) studies indicating altered glutamatergic metabolites in psychosis patients compared with controls (Merritt et al., 2016).”
BackgroundDecreased Brain pH and Pathophysiology in Schizophrenia
Park, H. J., Choi, I., & Leem, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168358 · Cited by 48
Shakory, S., Watts, J. J., Hafizi, S., Silva, T. M. S., Khan, S. M., Michael Kiang, A., Bagby, R. M., Chavez, S., & Mizrahi, R. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0163-0 · Cited by 44
Kraguljac, N. V., Morgan, C. J., Reid, M. A., White, D. M., Jindal, R. D., Sivaraman, S., Martinak, B. K., & Lahti, A. C. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2018.12.028 · Cited by 44
“, 2014), that aberrations may be variable across brain regions (Gallinat et al., 2016; Merritt et al., 2016), and that these are potentially affected by antipsychotic medications (Bustillo et al.”
BackgroundAllen, P., Sommer, I. E., Jardri, R., Eysenck, M. W., & Hugdahl, K. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.02.004 · Cited by 43
“suggested that illness phases are associated with different glutamate profiles, both increased and deceased, and suggests a more complex picture (Marsman et al., 2013; Merritt et al., 2016).”
Schoonover, K. E., Dienel, S. J., & Lewis, D. A. (2020) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2020.100015 · Cited by 45
“However, in contrast to consistent and replicated findings of alterations to these neurotransmitter systems reported in postmortem studies, the MRS literature on glutamate and GABA levels in schizophrenia is mixed [151,152].”
ResultWang, M., Barker, P. B., Cascella, N. G., Coughlin, J. M., Nestadt, G., Nucifora, F. C., Sedlak, T. W., Kelly, A., Laurent Younes, B., Geman, D., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-01969-5 · Cited by 44
Neurofunctional correlates of glutamate and GABA imbalance in psychosis: A systematic review
Zahid, U., Onwordi, E. C., Hedges, E. P., Wall, M. B., Modinos, G., Murray, R. M., & Egerton, A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.105010 · Cited by 45
Ultra-High-Field Magnetic Resonance Spectroscopy in Psychiatry
Godlewska, B. R., Clare, S., Cowen, P. J., & Emir, U. E. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00123 · Cited by 42
“(58) in SCZ suggested elevations in glutamatergic metabolites across several brain regions, including limbic areas and frontal regions.”
BackgroundDisrupted Intersubject Variability Architecture in Functional Connectomes in Schizophrenia
Sun, X., Liu, J., Ma, Q., Duan, J., Wang, X., Xu, Y., Xu, Z., Ke Cheng, X. U., Wang, F., Tang, Y., et al. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaa155 · Cited by 42
Mehta, M. A., & Hawkins, P. C. T. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-820480-1.00068-1 · Cited by 42
Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function
Thomson, P. A., Duff, B. J., Blackwood, D., Romaniuk, L., Watson, A., Whalley, H. C., Li, X., Dauvermann, M. R., Moorhead, T. W. J., Bois, C., et al. (2016) · Schizophrenia · doi:10.1038/npjschz.2016.24 · Cited by 41
Efficacy of Memantine in Schizophrenic Patients: A Systematic Review
Iorio, G. D., Baroni, G., Lorusso, M., Montemitro, C., Spano, M. C., & Giannantonio, M. D. (2017) · Journal of Amino Acids · doi:10.1155/2017/7021071 · Cited by 41
“Furthermore, a recent meta-analysis indicates that schizophrenia is associated with glutamate level increase in several brain regions [6].”
BackgroundOverbeek, G., Gawne, T. J., Reid, M. A., Salibi, N., Kraguljac, N. V., White, D. M., & Lahti, A. C. (2018) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2018.10.002 · Cited by 41
Wijtenburg, S. A., Wang, M., Korenic, S. A., Chen, S., Barker, P. B., & Rowland, L. M. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.656459 · Cited by 40
Ćurĉić‐Blake, B., Bais, L., Sibeijn‐Kuiper, A., Pijnenborg, H. M., Knegtering, H., Liemburg, E. J., & Aleman, A. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.05.020 · Cited by 40
“It should be noted though that both increases and decreases of glutamate levels in the DLPFC have been reported in schizophrenia patients (Merritt et al., 2016; Poels et al., 2014a).”
InfluentialStone, J. M., Morrison, P. D., Koychev, I. G., Gao, F., Reilly, T. J., Kolanko, M., Mohammadinasab, A., Kapur, S., & McGuire, P. K. (2016) · Psychological Medicine · doi:10.1017/s0033291716002245 · Cited by 38
“If SNP does act via glutamatergic mechanisms, as hypothesized (Hallak et al. 2013), it may be predicted that it would work most effectively in patients earlier on in the illness (Stone, 2011) where basal ganglia glutamatergic abnormalities are more prominent (Merritt et al. 2016).”
Background
Metadata
- Authors
- Merritt, K., Egerton, A., Kempton, M. J., Taylor, M. J., & McGuire, P. K.
- Affiliations
- King's College London (GB)
- Corresponding author
- Merritt, Kate
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2016-07-01
- Volume
- 73
- Issue
- 7
- Pages
- 665
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2424710696
- Cited by
- 367
- References
- 82
- Citations by year
- 2026: 26 · 2025: 23 · 2024: 25 · 2023: 37 · 2022: 33 · 2021: 50 · 2020: 55 · 2019: 44 · 2018: 41 · 2017: 28 · 2016: 5
- FWCI
- 34.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research
- King's College London
- Medical Research Council (MR/L003988/1, MR/J008915/1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, glutamate, glutamine, glutamatergic neurotransmission, basal ganglia, thalamus, medial temporal lobe, medial frontal cortex, first-episode psychosis, clinical high risk for psychosis, chronic schizophrenia, schizoaffective disorder, antipsychotic dosing, symptom severity, neuroimaging biomarkers
- MeSH terms
- Brain, Brain Mapping, Glutamine, Humans, Synaptic Transmission, Reference Values, Risk Factors, Schizophrenia, Glutamic Acid, Genetic Predisposition to Disease, Proton Magnetic Resonance Spectroscopy
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