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Cited by 457Schizophrenia research and treatmentAdvanced MRI Techniques and ApplicationsAmino Acid Enzymes and Metabolism

Glutamate in Schizophrenia: A Focused Review and Meta-Analysis of 1H-MRS Studies

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Marsman, Anouk, van den Heuvel, Martijn P., Klomp, Dennis W. J., Kahn, René S., Luijten, Peter R., Hulshoff Pol, Hilleke E.·2013·Schizophrenia Bulletin
DOI 10.1093/schbul/sbr069PMC PMC3523901
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Abstract

Schizophrenia is a severe chronic psychiatric illness, characterized by hallucinations and delusions. Decreased brain volumes have been observed in the disease, although the origin of these changes is unknown. Changes in the n-methyl-d-aspartate (NMDA)-receptor mediated glutamatergic neurotransmission are implicated, since it is hypothesized that NMDA-receptor dysfunction in schizophrenia leads to increased glutamate release, which can have excitotoxic effects. However, the magnitude and extent of changes in glutamatergic metabolites in schizophrenia are not clear. With (1)H magnetic resonance spectroscopy ((1)H-MRS), in vivo information about glutamate and glutamine concentrations can be obtained in the brain. A systematic search through the MEDLINE database was conducted to identify relevant (1)H-MRS studies that examined differences in glutamate and glutamine concentrations between patients with schizophrenia and healthy control subjects. Twenty-eight studies were identified and included a total of 647 patients with schizophrenia and 608 healthy-control subjects. For each study, Cohen's d was calculated and main effects for group analyses were performed using the random-effects model. Medial frontal region glutamate was decreased and glutamine was increased in patients with schizophrenia as compared with healthy individuals. Group-by-age associations revealed that in patients with schizophrenia, glutamate and glutamine concentrations decreased at a faster rate with age as compared with healthy controls. This could reflect aberrant processes in schizophrenia, such as altered synaptic activity, changed glutamate receptor functioning, abnormal glutamine-glutamate cycling, or dysfunctional glutamate transport.

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Written from the paper’s full text.

TL;DR

This focused review and random-effects meta-analysis of 1H-MRS studies found lower medial frontal glutamate and higher medial frontal glutamine in schizophrenia, with both metabolites declining faster with age in patients than controls. Hippocampal and thalamic glutamate did not differ significantly, and the authors caution that cross-sectional design, small study numbers, medication, and brain-volume effects limit conclusions.

Key findings

  • Medial frontal glutamate was lower in patients than controls (9 studies; 166 patients, 171 controls; combined Cohen’s d = −0.391, P = .006), while medial frontal glutamine was higher (8 studies; 140 patients, 135 controls; d = 0.403, P = .045).
  • Glx was not significantly different in the medial frontal region (8 studies; 186 patients, 144 controls; d = 0.122, P = .393), and the gln/glu ratio was not significant (6 studies; 112 patients, 116 controls; d = 0.308, P = .062). NAA was lower (19 studies; 401 patients, 378 controls; d = −0.320, P = .019), and the glu/NAA ratio was lower (7 studies; d = −0.357, P = .038).
  • Age meta-regressions showed faster age-related decreases in patients for frontal glutamate (P = .008), glutamine (P = .0005), gln/glu ratio (P = .02), NAA (P = .04), and glu/NAA ratio (P = .049).
  • Hippocampal glutamate (3 studies; 47 patients, 60 controls; d = 0.031, P = .92) and thalamic glutamate (3 studies; 64 patients, 64 controls; d = −0.286, P = .20) did not differ significantly.

Methods

  • Systematic MEDLINE search using keywords “glutamate,” “spectroscopy,” and “schizophrenia”; inclusion required 1H-MRS measurement of glutamate in schizophrenia, healthy control comparison, no interventions, and English-language publication. Twenty-eight articles published between 1994 and 2011 met criteria, including 647 patients and 608 healthy controls; field strength ranged from 1.5 to 4.0 Tesla, patient numbers from 9 to 40, and control numbers from 11 to 46.
  • Studies were divided into high risk, first-episode, and chronic patient populations. For each study, Cohen’s d was calculated; random-effects meta-analyses and meta-regressions were performed using Comprehensive Meta-Analysis V2, with heterogeneity tested by Cochran’s Q and I². Meta-analysis was performed when 3 or more studies were available for glutamate, glutamine, or glx in a given brain region.
  • Two studies reported insufficient information to calculate Cohen’s d and were excluded from the meta-analysis; one of two studies reporting the same subjects was excluded to prevent overlap. Additional meta-analyses and meta-regressions were performed for NAA and the gln/glu ratio when data were available.

Limitations

  • Paper-stated: there were only a small number of studies, most focused on frontal brain areas; the hippocampus, thalamus, basal ganglia, and temporal, parietal, and occipital lobes were examined in few studies. Differences in magnetic field strength, acquisition mode, quantification method, and frontal brain region may affect between-study variability.
  • Paper-stated: the meta-analysis includes only cross-sectional data, so the conclusion that glutamatergic concentrations progressively decrease with age is preliminary. The age-related decline was not corrected for brain volume changes, and not all included studies accounted for partial voluming. Medication effects could not be taken into account, and antipsychotic effects cannot be discounted. 1H-MRS alone cannot establish neurochemical alterations, and glutamate and glutamine are difficult to distinguish at lower magnetic field strengths.
  • Evident from the text: the Discussion states that 24 studies were analyzed for changes in glutamate and glutamine, fewer than the 28 identified. The authors also note that studies did not adequately control for medication intake, duration of illness, or severity of symptoms, and that Cohen’s d does not account for possible age-related changes in healthy controls.

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Integrity signals

Registry

Crossref · 10.1093/schbul/sbr069

Cites

93 of 93 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 49 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Glutamatergic levels appear to decrease progressively with age in patients with schizophrenia as compared with healthy controls.

    “In conclusion, glutamatergic levels appear to decrease progressively with age in patients with schizophrenia as compared with healthy controls.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional age differences in glutamatergic levels reflect progressive within-patient changes over time.
    • Rests on an assumption: Pooling data across different brain regions and magnetic field strengths yields valid estimates of glutamate and glutamine effects.
  • Findingown data

    In patients with schizophrenia compared with healthy controls, glutamine levels in the medial frontal region decrease progressively with age.

    “The meta-regression of age on effect size across 8 studies with a total of 140 patients and 135 healthy controls showed a progressive decrease with age of glutamine in the frontal region in patients as compared with healthy controls 25,26,28,33,41,42,[44][45][46] (P = .0005)(figure 3B).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.
  • Findingown data

    In patients with schizophrenia compared with healthy controls, the glu/NAA ratio in the medial frontal region decreases progressively with age.

    “The meta-regression of age on effect size across 7 studies with a total of 121 patients and 126 healthy controls showed a progressive decrease with age of the glu/NAA ratio in the frontal region in patients as compared with controls 26,28,33,[40][41][42]44 (P = .049).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.
  • Findingown data

    In patients with schizophrenia compared with healthy controls, glutamate levels in the medial frontal region decrease progressively with age.

    “The meta-regression of age on effect size across 9 studies with a total of 166 patients and 171 healthy controls showed a progressive decrease with age of glutamate in the frontal region in patients as compared with healthy controls 25,26,28,33,41,42,[44][45][46] (P = .008)(figure 2B).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.
  • Findingown data

    In patients with schizophrenia compared with healthy controls, glutamate levels in the medial frontal region are lower.

    “Medial frontal region glutamate was decreased and glutamine was increased in patients with schizophrenia as compared with healthy individuals.”
    • Also stated in: § Discussion · plain
      “We found that frontal region glutamate is lower, and glutamine is higher in patients as compared with healthy controls.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.
  • May combine two claims. 28
  • The quote only partly states this claim. 4
  • Classified as probably not a substantial claim. 16

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In patients with schizophrenia compared with healthy controls, the gln/glu ratio in the medial frontal region is higher but the difference is not statistically significant.

    “The gln/glu ratio in the frontal region was higher in patients than in controls but this was not significant (combined-effect Cohen's d = 0.308, P = .062)(see online supplementary figure 2A)”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.

  • The quote only partly states this claim.

    Findingown data

    In patients with schizophrenia compared with healthy controls, the glu/NAA ratio in the medial frontal region is lower.

    “The glu/NAA ratio in the frontal region was lower in patients than in controls (combined-effect Cohen's d = À0.357,P = .038).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.

  • The quote only partly states this claim.

    Findingown data

    In patients with schizophrenia compared with healthy controls, NAA levels in the medial frontal region are lower.

    “NAA in the frontal region was lower in patients than in controls (combined-effect Cohen's d = À0.320,P = .019)(see online supplementary figure 3A).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In patients with schizophrenia compared with healthy controls, glx levels in the medial frontal region are lower but the difference is not statistically significant.

    “The glx level in the frontal region was lower in patients than in controls but this finding was not significant (combined-effect Cohen's d = 0.122, P = .393)(see online supplementary figure 1).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.

  • May combine two claims.

    Findingreasoning

    The gln/glu ratio is most prominently increased in patients with schizophrenia as compared with controls at a young age and seems to normalize in older patients.

    “In fact, the gln/glu ratio is most prominently increased in patients with schizophrenia as compared with the controls at a young age and seems to normalize in older patients”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    With 1H-MRS, both physiologically active and inactive glutamate are measured.

    “With 1 H-MRS, both physiologically active and inactive glutamate are measured.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NMDA-receptors are glutamate-gated ion channels that play an important role in excitatory neurotransmission, plasticity, and excitotoxicity.

    “NMDA-receptors are glutamate-gated ion channels, which play an important role in excitatory neurotransmission, plasticity, and excitotoxicity.11,12”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Cull-Candy, 2001, NMDA receptor subunits: diversity, development and disease, Curr Opin Neurobiol source

      Not checked in the free run.

    • cites [12] Paoletti, 2007, NMDA receptor subunits: function and pharmacology, Curr Opin Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The most important limitation of the meta-analysis is that only a small number of studies reported on glutamatergic changes in schizophrenia as measured with in vivo 1H-MRS, and most focused on frontal brain areas.

    “The most important limitation is that there is only a small number of studies that reported on glutamatergic changes in schizophrenia, as measured with in vivo 1 H-MRS of which most focused on frontal brain areas.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In patients with schizophrenia, particularly older patients compared with older controls, glutamate is decreased and glutamine is increased in the brain.

    “Thus, the findings from this meta-analysis suggests a decrease glutamate and an increased glutamine contentration in the brain of patients with schizophrenia, particularly in older patients compared with older controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The progressive brain changes in schizophrenia are familial, and possibly genetic, and cannot be solely explained by antipsychotic medication intake.

    “Interestingly, progressive brain changes are also present in discordant cotwins of patients with schizophrenia, suggesting that these changes are familial, and possibly genetic, and can therefore not solely be explained by antipsychotic medication intake.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Brans, 2008, Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia, Arch Gen Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glutamatergic transmission and metabolism are strongly coupled, and findings on glutamate and glutamine levels in schizophrenia could give insight into possible changes in neuronal activity during the course of the disease.

    “Theglutamatergictransmission and metabolism are strongly coupled, and findings on glutamate and glutamine levels in schizophrenia could give an insight in possible changes in neuronal activity during the course of the disease.21”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Rothman, 2003, In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function, Annu Rev Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It has been suggested that glutamate levels decrease with age in healthy individuals.

    “It has beensuggested that glutamatelevelsdecrease with age in healthyindividuals, 20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Kaiser, 2005, Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T, Neurobiol Aging source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of antipsychotic medication cannot be discounted because it has been suggested that haloperidol, clozapine, and olanzapine cause reductions in glutamatergic levels in the rat brain.

    “The effects of antipsychotic medication cannot be discounted because it has been suggested that haloperidol, clozapine, and olanzapine cause reductions in glutamatergic levels in the rat brain.58”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] McLoughlin, 2009, Analyzing the effects of psychotropic drugs on metabolite profiles in rat brain using 1H NMR spectroscopy, J Proteome Res source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The effect size statistic Cohen's d displays the deviation of patients as compared with healthy controls, which means that possible age-related changes in healthy controls are not taken into account in the meta-analysis.

    “Also, the effect size statistic Cohen's d displays the deviation of patients as compared with healthy controls, which means that possible age-related changes in healthy controls are not taken into account in the meta-analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    According to Cohen, absolute d-values of 0.2 represent small effects, d-values between 0.4 and 0.6 moderate effects, and d values of 0.8 or higher large effects.

    “According to Cohen, absolute d-values of 0.2 represent small effects, d-values between 0.4 and 0.6 moderate effects, and d values of 0.8 or higher large effects.51”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Cohen, 1988

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Measurement of glutamatergic levels alone is not sufficient to draw conclusions about possible neurochemical alterations in patients with schizophrenia.

    “Thirdly, in this meta-analysis, we focused on glutamatergic neurotransmission, however, of course, the measurement of glutamatergic levels alone is not sufficient to draw conclusions about possible neurochemical alterations in patients with schizophrenia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A longitudinal study found reductions in precuneal gray matter after 10 months and in frontal, temporal, parietal, and limbic lobes after 30 months of treatment, which was correlated with thalamic glutamine reductions.

    “A longitudinal study which assessed patients when medicationnaive and after treatment found reductions in precuneal gray matter after 10 months and in frontal, temporal, parietal, and limbic lobes after 30 months of treatment, which was correlated with thalamic glutamine reductions.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Théberge, 2007, Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia, Br J Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisereasoning

    The majority of physiologically active glutamate is derived from glutamine; therefore, high levels of glutamine may suggest high glutamatergic activity.

    “The majority of physiologically active glutamate is derived from glutamine; therefore, high levels of glutamine may suggest highglutamatergicactivity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Glutamate and glutamine are difficult to distinguish at lower magnetic field strengths, which makes the quantification of glutamate and glutamine problematic.

    “Glutamate and glutamine are difficult to distinguish at lower magnetic field strengths, which makes the quantification of glutamate and glutamine problematic.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Tkac, 2001, In vivo 1H NMR spectroscopy of the human brain at 7T, Magn Reson Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Structural MRI studies have established that schizophrenia is a brain disease with approximately a 3% tissue loss.

    “Structural magnetic resonance imaging (sMRI) studies have established that schizophrenia is a brain disease with approximately a 3% tissue loss. 1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Wright, 2000, Meta-analysis of regional brain volumes in schizophrenia, Am J Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Two studies reported on the same group of subjects, and to prevent potential bias of overlap, only one study was included in the meta-analysis.

    “Two studies reported on the same group of subjects 33,34 and to prevent potential bias of overlap, we decided to include only 1 study 33 in the meta-analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    This results in disinhibition and hyperactivity of excitatory pathways, which will eventually cause neuronal damage.

    “This results in disinhibition and hyperactivity of excitatory pathways, which will eventually cause neuronal damage.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Olney, 1999, NMDA receptor hypofunction model of schizophrenia, J Psychiatr Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An earlier meta-analysis made clear that N-acetyl aspartate levels are reduced in patients with schizophrenia in frontal lobe gray and white matter.

    “An earlier meta-analysis made clear that N-acetyl aspartate levels are reduced in patients with schizophrenia in frontal lobe gray and white matter.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Steen, 2005, Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis, Neuropsychopharmacology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glutamine is the major precursor for neuronal glutamate (and GABA).

    “while glutamine represents the major precursor for neuronal glutamate (and GABA)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Bak, 2006, The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer, J Neurochem source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Up until now, studies were mostly cross-sectional and investigated different brain areas.

    “Up until now, studies were mostly cross-sectional and investigated different brain areas.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Diminished activation of NMDA-receptors results in insufficient excitatory activity, disrupting the monitoring function of GABAergic inhibitory neurons.

    “Diminished activation of NMDA-receptors results in insufficient excitatory activity, disrupting the monitoring function of GABAergic inhibitory neurons.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Lisman, 2008, Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia, Trends Neurosci source

      Not checked in the free run.

    • cites [80] Lewis, 2006, Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations, Arch Neurol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Diminished glutamate receptor activation, in particular of the NMDA-type, may be a possible underlying mechanism of reduced synaptic activity because NMDA-receptor antagonists produce the same symptoms as those seen in schizophrenia.

    “In fact, diminished glutamate receptor activation, in particular of the NMDA-type of glutamate receptor, may be a possible underlying mechanism of reduced synaptic activity because NMDA-receptor antagonists produce the same symptoms as those seen in schizophrenia.17,18,25”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Olney, 1999, NMDA receptor hypofunction model of schizophrenia, J Psychiatr Res source

      Not checked in the free run.

    • cites [18] Kondziella, 2007, How do glial-neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia?, Neurochem Int source

      Not checked in the free run.

    • cites [25] Stone, 2009, Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume, Biol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glutamate can also be synthesized from the tricarboxylic acid cycle.

    “glutamate can also be synthesized from the tricarboxylic acid cycle 62”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Bak, 2006, The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer, J Neurochem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increase in membrane breakdown products has been measured in FE schizophrenia, while a reduction of membrane breakdown products has been measured in chronic schizophrenia.

    “An increase in membrane breakdown products has been measured in FE schizophrenia, while a reduction of membrane breakdown products has been measured in chronic schizophrenia.[92][93][94]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92][93][94]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The gln/glu ratio increase may reflect a deficiency in glutaminase, the enzyme that converts glutamine into glutamate, which results in reduced glutamate levels and increased glutamine levels in the frontal region.

    “This may reflect a deficiency in glutaminase, the enzyme that converts glutamine into glutamate, which results in reduced glutamate levels and increased glutamine levels in the frontal region.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Gaisler-Salomon, 2009, Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of subunits of metabotropic glutamate receptors induces glutamatergic function deficits and schizophrenia-like symptoms.

    “Deletion of subunits of metabotropic glutamate receptors induce glutamatergic function deficits 82,83 and schizophrenia-like symptoms.84,85”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [82] Gray, 2009, Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation, Int J Neuropsychopharmacol source

      Not checked in the free run.

    • cites [83] Cartmell, 2000, Regulation of neurotransmitter release by metabotropic glutamate receptors, J Neurochem source

      Not checked in the free run.

    • cites [84] Patil, 2007, Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The amount of glutamate released into the synaptic cleft and taken up by astrocytes would decrease.

    “In line with this, the amount of glutamate that is released into the synaptic cleft and taken up by astrocytes would decrease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Dysfunction of glutamate transport in the synaptic cleft, and also glutamate transport inside presynaptic neurons, can play a role in the altered glutamatergic levels.

    “Dysfunction of glutamate transport in the synaptic cleft, and also glutamate transport inside presynaptic neurons, can play a role in the altered glutamatergic levels.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Changes in the membrane metabolism in schizophrenia may also be implicated in the changed concentrations of glutamate in schizophrenia.

    “Changes in the membrane metabolism in schizophrenia may also be implicated in the changed concentrations of glutamate in schizophrenia.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Ohrmann, 2007, Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study, J Psychiatr Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Changes in glutamate may also present changes in this second pathway (tricarboxylic acid cycle synthesis).

    “and changes in glutamate may also present changes in this second pathway.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is evidence that knockout of AMPA receptor subunits is implicated in psychosislike behavior.

    “There is evidence that knockout of a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor subunits is implicated in psychosislike behavior. 81”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Fuchs, 2007, Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior, Neuron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    In astrocytes, diminishing levels of glutamate are converted back into glutamine, which in the long term could result in reduced glutamine levels.

    “In astrocytes, diminishing levels of glutamate are converted back into glutamine, which in the long term could result in reduced glutamine levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Studies did not control adequately for medication intake, duration of illness, and severity of symptoms.

    “Also, studies did not control adequately for medication intake, duration of illness, and severity of symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mouse models have shown that a number of proteins associated with glutamate receptors, some of which are directly linked with schizophrenia susceptibility genes, have been suggested to show modifications in patients, which in turn cause schizophrenia-like phenotypes.

    “Interestingly, mouse models have shown that a number of proteins associated with glutamate receptors, some of which are directly linked with schizophrenia susceptibility genes, have been suggested to show modifications in patients, which in turn cause schizophrenia-like phenotypes.86,87”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] Szumlinski, 2005, Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia, Genes Brain Behav source

      Not checked in the free run.

    • cites [87] Miyakawa, 2003, Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Injection of NMDA-receptor antagonists leads to increased glutamine levels and decreased glutamate levels.

    “Injection of these NMDAreceptor antagonists leads to increased glutamine levels and decreased glutamate levels 15,63,64”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Moghaddam, 1997, Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex, J Neurosci source

      Not checked in the free run.

    • cites [63] Iltis, Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized 1H MRS study, NMR Biomed

      Not checked in the free run.

    • cites [64] Rowland, 2005, Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study, Am J Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Together with increased glutamatergic metabolites in early schizophrenia followed by decreased glutamatergic metabolites in chronic schizophrenia, this is consistent with an excitotoxic process.

    “Together with increased glutamatergic metabolites in early schizophrenia followed by decreased glutamatergic metabolites in chronic schizophrenia, this is consistent with an excitotoxic process.94”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Miller, Longitudinal 4.0 Tesla 31P magnetic resonance spectroscopy changes in the anterior cingulate and left thalamus in first episode schizophrenia, Psychiat Res Neuroim

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The NMDA-receptor hypofunction hypothesis was evolved from studies with NMDA-receptor antagonists, such as PCP and ketamine.

    “The NMDA-receptor hypofunction hypothesis was evolved from studies with NMDA-receptor antagonists, such as PCP and ketamine.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Olney, 1999, NMDA receptor hypofunction model of schizophrenia, J Psychiatr Res source

      Not checked in the free run.

42 of 42

  • The authors state this as an assumption.

    A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.

    “A random-effects model assumes that the effect size estimated by different studies varies among studies not only because of coincidence but also because of differences in samples or paradigms and that these effect sizes have a normal distribution.54”

  • The paper relies on this without support.

    Evidence of aberrant glutamate levels in schizophrenia is inconsistent.

    “Although its agonist glutamate can be measured in vivo, evidence of aberrant glutamate levels in schizophrenia is inconsistent.”

  • The paper relies on this without support.

    The magnitude and extent of changes in glutamatergic metabolites in schizophrenia are not clear.

    “However, the magnitude and extent of changes in glutamatergic metabolites in schizophrenia are not clear.”

  • The paper relies on this without support.

    It is not known whether glutamate levels change with longer illness duration.

    “but it is not known whether glutamate levels change with longer illness duration.”

  • The paper relies on this without support.

    Cross-sectional age differences in glutamatergic levels reflect progressive within-patient changes over time.

    “In conclusion, glutamatergic levels appear to decrease progressively with age in patients with schizophrenia as compared with healthy controls.”
    “Up until now, studies were mostly cross-sectional and investigated different brain areas.”

  • The paper relies on this without support.

    Pooling data across different brain regions and magnetic field strengths yields valid estimates of glutamate and glutamine effects.

    “Up until now, studies were mostly cross-sectional and investigated different brain areas.”
    “Data were recorded from the following anatomical regions: anterior cingulate cortex (Stone et al 25 , The ´berge et al 33 , Bustillo et al 28 , O ¨ngu ¨r et al 41 ), medial prefrontal cortex (Bartha et al 26 , Lutkenhoff et al 40 , Shirayama et al 46 ).”

  • The paper relies on this without support.

    The age of 35 years is a meaningful threshold for the transition to chronic phase and for glutamine levels dropping below control.

    “Indeed, from the meta-regression, it appears that glutamine levels drop below the healthy control level after patients have reached the age of 35 years, when the majority has reached the chronic phase of the illness.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported effect-size signs conflict with the stated calculation

    Minor

    The stated calculation subtracts the patient mean from the control mean. Under that convention, lower glutamate in patients would give a positive effect size, not the reported negative one.

  • Control-group range excludes sample sizes shown in Table 1

    Minor

    The methods give 11 as the smallest healthy-control group, but Table 1 lists 10 controls for Bartha et al 26 and Bustillo et al 28.

  • Older-patient glutamine conclusion reverses the reported age trend

    Minor

    The discussion says increased glutamine is particularly apparent in older patients versus older controls, but later says patient glutamine falls below the control level after age 35.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Hedges, 1985, Statistical Methods for Meta-Analysis
  2. Olson, 2003, Relaxation effects in spectroscopic studies of schizophrenia, 79

Cited by

Sorted by citations

Related

Authors
Marsman, A., van den Heuvel, M. P., Klomp, D. W. J., Kahn, R. S., Luijten, P. R., & Hulshoff Pol, H. E.
Affiliations
University Medical Center Utrecht (NL)
ORCID
Venue
Schizophrenia Bulletin
Publisher
Oxford University Press (OUP)
Published
2011-07-11
Volume
39
Issue
1
Pages
120-129
ISSN
  • 0586-7614 (ISSN-L)
  • 1745-1701
DOI
10.1093/schbul/sbr069
PMC
PMC3523901
OpenAlex
W2170946434
Cited by
457
References
93
Citations by year
2026: 15 · 2025: 22 · 2024: 31 · 2023: 23 · 2022: 17 · 2021: 29 · 2020: 31 · 2019: 33 · 2018: 34 · 2017: 35 · 2016: 40 · 2015: 58 · 2014: 45 · 2013: 27 · 2012: 15
FWCI
3.69
Type
journal article
Language
en
Open access
Locations
  • Schizophrenia Bulletin (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (917.46.370)
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 › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
schizophrenia, glutamate
MeSH terms
Glutamine, Humans, Magnetic Resonance Spectroscopy, Schizophrenia, Glutamic Acid

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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