Background
The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission
is fundamental to the development of the disorder. In addition, its potential to mediate
neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic
changes in schizophrenia. Here we determine whether changes in brain glutamate are
present in subjects at ultra high risk of developing psychosis and whether these changes
are related to reductions in cortical gray matter volume.
Methods
Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers
underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance
imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior
cingulate, left hippocampus, and left thalamus. These measures were then related to
cortical gray matter volume.
Results
At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than
control subjects in the thalamus (p < .05) but higher glutamine in the anterior cingulate (p < .05). Within the ARMS group, the level of thalamic glutamate was directly correlated
with gray matter volume in the medial temporal cortex and insula (p < .01).
Conclusions
This study provides the first evidence that brain glutamate function is perturbed
in people with prodromal signs of schizophrenia and that glutamatergic dysfunction
is associated with a reduction in gray matter volume in brain regions thought to be
critical to the pathogenesis of the disorder. These findings support the hypothesis
that drugs affecting the glutamate system may be of benefit in the early stages of
psychotic illness.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.Am J Psychiatry. 2001; 158: 1367-1377
- Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia.Ann NY Acad Sci. 2003; 1003: 318-327
- Glutamate and dopamine dysregulation in schizophrenia—A synthesis and selective review.J Psychopharmacol. 2007; 21: 440-452
- Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: Modulation by a Group II selective metabotropic glutamate receptor agonist LY379268.Neuroscience. 2003; 117: 697-706
- 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. 1997; 17: 2921-2927
- Glutamate receptor dysfunction and schizophrenia.Arch Gen Psychiatry. 1995; 52: 998-1007
- Psychosis: Pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia?.Trends Neurosci. 2001; 24: 330-334
- First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients.Mol Psychiatry. 2006; 11: 118-119
- Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers.Am J Psychiatry. 2002; 159: 1944-1946
- Glutamate and glutamine in the anterior cingulate and thalamus of medicated patients with chronic schizophrenia and healthy comparison subjects measured with 4.0-T proton MRS.Am J Psychiatry. 2003; 160: 2231-2233
- In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function.Annu Rev Physiol. 2003; 65: 401-427
- Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: A 4-T proton MRS study.Am J Psychiatry. 2005; 162: 394-396
- Brain volume in first-episode schizophrenia: Systematic review and meta-analysis of magnetic resonance imaging studies.Br J Psychiatry. 2006; 188: 510-518
- Progressive brain volume loss in schizophrenia over the course of the illness: Evidence of maturational abnormalities in early adulthood.Biol Psychiatry. 2008; 63: 106-113
- Brain volume changes in the first year of illness and 5-year outcome of schizophrenia.Br J Psychiatry. 2006; 189: 381-382
- What have we learned from proton magnetic resonance spectroscopy about schizophrenia?.Curr Opin Psychiatry. 2006; 19: 135-139
- A revised excitotoxic hypothesis of schizophrenia: Therapeutic implications.Clin Neuropharmacol. 2001; 24: 43-49
- The empirical status of the ultra high-risk (prodromal) research paradigm.Schizophr Bull. 2007; 33: 661-664
- Psychosis prediction: 12-Month follow up of a high-risk (“prodromal”) group.Schizophr Res. 2003; 60: 21-32
- Neuroanatomical abnormalities before and after onset of psychosis: A cross-sectional and longitudinal MRI comparison.Lancet. 2003; 361: 281-288
- Regional gray matter volume abnormalities in the at risk mental state.Biol Psychiatry. 2007; 61: 1148-1156
- Structural brain alterations in subjects at high-risk of psychosis: A voxel-based morphometric study.Schizophr Res. 2008; 102: 150-162
- G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences.Behav Res Methods. 2007; 39: 175-191
- Identification of young people at risk of psychosis: Validation of Personal Assessment and Crisis Evaluation Clinic intake criteria.Aust N Z J Psychiatry. 2000; 34: S164-S169
- The positive and negative syndrome scale (PANSS) for schizophrenia.Schizophr Bull. 1987; 13: 261-276
- The assessment of anxiety states by rating.Br J Med Psychol. 1959; 32: 50-55
- A rating scale for depression.J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
- Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia.Br J Psychiatry. 2007; 191: 325-334
- Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.Trends Neurosci. 2008; 31: 234-242
- Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses.Neuroreport. 2001; 12: 2971-2974
- The hippocampus in schizophrenia: A review of the neuropathological evidence and its pathophysiological implications.Psychopharmacology. 2004; 174: 151-162
- Estimation of metabolite concentrations from localized in vivo proton NMR spectra.Magn Reson Med. 1993; 30: 672-679
- Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain.IEEE Trans Med Imaging. 1999; 18: 32-42
- Regarding “Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study.”.Biol Psychiatry. 2007; 61 (author reply: 1219–1220): 1218-1219
- Assessment of glutamate and glutamine contribution to in vivo N-acetylaspartate quantification in human brain by (1)H-magnetic resonance spectroscopy.Magn Reson Med. 2005; 54: 1333-1339
- T1 and T2 relaxation times in schizophrenia as measured with magnetic resonance imaging.Schizophr Res. 1991; 5: 223-232
- Nicotine dependence in schizophrenia: Clinical phenomena and laboratory findings.Am J Psychiatry. 1998; 155: 1490-1501
- Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: A historical-prospective cohort study.Am J Psychiatry. 2004; 161: 1219-1223
- Meta-analysis of gray matter anomalies in schizophrenia: Application of anatomic likelihood estimation and network analysis.Biol Psychiatry. 2008; 64: 774-781
- Duration of untreated psychosis vs. N-acetylaspartate and choline in first episode schizophrenia: A 1H magnetic resonance spectroscopy study at 4.0 Tesla.Psychiatry Res. 2004; 131: 107-114
- 3-T proton MRS investigation of glutamate and glutamine in adolescents at high genetic risk for schizophrenia.Am J Psychiatry. 2004; 161: 1116-1118
- Changes in gray matter volume in patients with bipolar disorder.Biol Psychiatry. 2005; 58: 151-157
Article info
Publication history
Published online: June 26, 2009
Accepted:
May 7,
2009
Received in revised form:
May 1,
2009
Received:
January 9,
2009
Identification
Copyright
© 2009 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
