Anterior Cingulate Glutamate Levels Related to Clinical Status
Following Treatment in First-Episode Schizophrenia
Alice Egerton*,1, Stefan Brugger1,2, Marie Raffin1, Gareth J Barker3, David J Lythgoe3, Philip K McGuire1,5
and James M Stone1,4,5
1Department of Psychosis Studies, Institute of Psychiatry, King’s College London, De Crespigny Park, London, UK;2St George’s Hospital, University
of London, London, UK;3Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London,
De Crespigny Park, London, UK;4Experimental Medicine, Imperial College London, Hammersmith Hospital, London, UK
Many patients with schizophrenia show a limited symptomatic response to treatment with dopaminergic antipsychotics. This may reflect
the additional involvement of non-dopaminergic neurochemical dysfunction in the pathophysiology of the disorder. We tested the
hypothesis that brain glutamate levels would differ between patients with first-episode psychosis who were symptomatic compared with
those with minimal symptoms following antipsychotic treatment. Proton magnetic resonance spectroscopy (1H-MRS) spectra were
acquired at 3Tesla in the anterior cingulate cortex and left thalamus in 15 patients with first-episode psychosis in symptomatic remission,
and 17 patients with first-episode psychosis who were still symptomatic following at least one course of antipsychotic treatment.
Metabolite levels were estimated in ratio to creatine (Cr) using LCModel. Levels of glutamate/Cr in the anterior cingulate cortex were
significantly higher in patients who were still symptomatic than in those in remission (T(30)¼3.02; P¼0.005). Across the entire sample,
higher levels of glutamate/Cr in the anterior cingulate cortex were associated with a greater severity of negative symptoms (r¼0.42;
P¼0.017) and a lower level of global functioning (r¼?0.47; P¼0.007). These findings suggest that clinical status following antipsychotic
treatment in schizophrenia is linked to glutamate dysfunction. Treatment with compounds acting on the glutamatergic system might
therefore be beneficial in patients who respond poorly to dopaminergic antipsychotics.
Neuropsychopharmacology (2012) 37, 2515–2521; doi:10.1038/npp.2012.113; published online 4 July 2012
Keywords: psychosis; magnetic resonance spectroscopy; glutamate; treatment response; anterior cingulate cortex; thalamus
In the treatment of schizophrenia with antipsychotic drugs,
on average around 60% occupancy of brain D2 dopamine
receptors is required to produce a therapeutic response
(Kapur et al, 2000). However, a substantial proportion of
patients still show a poor response even when D2 occupancy
is at this level (Pilowsky et al, 1993). This may reflect the
importance of non-dopaminergic neurochemical dysfunc-
tion in the pathophysiology of schizophrenia. Increasing
evidence from pharmacological, neuropharmacological, and
genetic studies suggests that the primary deficit in schizo-
phrenia may be a developmentally driven abnormality in
the glutamate system (see (Egerton et al, 2012; Stone et al,
2007)). Several clinical trials have demonstrated the efficacy
of adjunctive glutamatergic therapies in treating symptoms
that have not responded to antipsychotic medication (Javitt,
2004). The greater efficacy of clozapine compared with other
antipsychotics, and its effectiveness in otherwise treatment-
resistant patients, has been linked to its glutamatergic
actions (Javitt et al, 2005). It has thus been suggested that
patients who are still sympto matic following antipsychotic
medication may exhibit persistent glutamatergic abnorm-
alities, and may therefore benefit from treatments that act
on the glutamate system (Stone et al, 2010).
Proton magnetic resonance imaging (1H-MRS) studies at
field strengths of 3Tesla or above in antipsychotic naive or
minimally medicated first-episode psychosis patients have
identified increases in the glutamate metabolite glutamine
(Gln) or the Gln/glutamate ratio in the anterior cingulate
cortex (Bustillo et al, 2010; Theberge et al, 2002), increases
in Gln in the thalamus (Theberge et al, 2002), and increases
in glutamate in the associative striatum (de la Fuente-
Sandoval et al, 2011). This suggests that brain glutamatergic
activity is increased in the early stages of the disorder, when
patients are usually experiencing acute psychotic symp-
toms. 1H-MRS studies of the glutamate system in medicated
Received 16 April 2012; revised 11 May 2012; accepted 30 May 2012
*Correspondence: Dr A Egerton, Department of Psychosis Studies,
Institute of Psychiatry, King’s College London, De Crespigny Park,
London SE5 8AF, UK. Tel: +1 44 207 848 0879, Fax: +1 44 207 848
0976, E-mail: Alice.Egerton@kcl.ac.uk
5These authors contributed equally to this work
Neuropsychopharmacology (2012) 37, 2515–2521
& 2012 American College of Neuropsychopharmacology.All rights reserved 0893-133X/12
patients with chronic schizophrenia have produced less
consistent findings (Jessen et al, 2011; Reid et al, 2011;
Shirayama et al, 2010; Tayoshi et al, 2009; Theberge et al,
2003; Wood et al, 2007). A recent meta-analysis indicated
that although frontal glutamatergic activity may be elevated
in untreated patients in the early phase of schizophrenia,
reductions in frontal glutamate and Gln are evident in older
patients at later stages of the disorder (Marsman et al,
2011). This apparent difference between the early and later
stages of the disorder is not simply an effect of cumulative
antipsychotic exposure, as prolonged treatment (for up to
80 months) is not associated with a change in glutamate
metabolites in the anterior cingulate cortex (Aoyama et al,
2011; Bustillo et al, 2010; Theberge et al, 2007).
Some of the differences in the findings in studies of
glutamate in schizophrenia may be related to differences in
the symptom profiles of the patients studied, as glutamate
metabolite levels may vary with the level of negative
symptoms (Reid et al, 2011), cognitive deficits (Bustillo
et al, 2011; Shirayama et al, 2010), and global functioning
(Aoyama et al, 2011; Tibbo et al, 2004; Van Elst et al, 2005).
In the present study, we tested the hypothesis that
glutamate metabolite levels in the anterior cingulate cortex
and thalamus would be higher in first-episode psychosis
patients who were symptomatic compared with those with
minimal symptoms following treatment.
PATIENTS AND METHODS
The study was approved by the Joint South London and
Maudsley and the Institute of Psychiatry Research Ethics
Committee. All subjects gave written informed consent to
participate. Thirty-two patients who had presented with a
first episode of schizophrenia (as defined by DSM-IV
criteria), and who had completed at least one course of
treatment with antipsychotic medication were recruited
from the South London and Maudsley NHS Foundation
Trust. Only patients who had presented within the past 2
years, and who had experienced a single episode of psy-
chosis were included. The mean±SD time since first
presentation was 10.6±7.1 months. Exclusion criteria
included a history of head injury, concomitant medical or
neurological illness, drug or alcohol dependence (except
nicotine), presence of metallic implants contraindicated at
3Tesla, and pregnancy. Current and previous use of
nicotine, cannabis, alcohol and antipsychotic medication,
and family history of psychiatric illness were determined
through self-report data. Symptoms at the time of imaging
were assessed using the Positive and Negative Syndrome
Scale (PANSS; Kay et al, 1987) and global functioning was
assessed using the global assessment of functioning scale
(Hall, 1995). Symptom severity scores were used to allocate
patients to group (symptomatic remission vs no remission)
according to established criteria (Andreasen et al, 2005).
Symptomatic remission was defined as having scores of
mild or less on the all eight of the following PANSS positive
(P), negative (N), or general (G) syndrome scale items:
Delusions (P1); Conceptual Disorganization (P2); Halluci-
natory behavior (P3); Blunted affect (N1); Social withdrawal
(N4); Lack of spontaneity (N6); Mannerisms/posturing
(G5), and Unusual thought content (G9) (Andreasen et al,
2005). No remission was defined as having scores of mode-
rate or more on the same items.
All scans were acquired on a General Electric (Milwaukee,
Wisconsin) 3Tesla HDx magnetic resonance system as
detailed previously (Stone et al, 2009). An initial localizer
scan was followed by acquisition of structural images,
including an axial 2D T2-weighted fast spin echo scan and
an axial fast fluid-attenuated inversion recovery scan.
1H-MRS voxels were prescribed in the anterior cingulate
cortex and left thalamus. The anterior cingulate cortex voxel
was prescribed from the midline sagittal localizer, with the
centre of the 20?20?20mm voxel placed 13mm above
the genu of corpus callosum perpendicular to the AC–PC
line (Figure 1a). A second (15 (right–left)?20?20mm)
voxel was placed in centre of the left thalamus to include the
maximum amount of grey matter (Figure 1b).
spectra (PRESSFPoint RESolved Spectroscopy; TE¼
30msec; Tr¼3000msec; 96 averages) were acquired using
the standard GE PROBE (proton brain examination) sequence,
which uses a standardized chemically selective suppression
water suppression routine. Shimming was optimized, with
auto-prescan performed twice before each scan.
Spectra were analyzed using LCModel version 6.1-4 F
(Provencher, 1993), using a standard basis set of 16 meta-
bolites (L-alanine, aspartate, creatine, phosphocreatine,
GABA, glucose, Gln, glutamate, glycerophosphocholine,
glycine, myo-inositol, L-lactate, N-acetylaspartate, N-acet-
ylaspartylglutamate, phosphocholine, and taurine), acquired
with the same field strength (3Tesla), localization sequence
(PRESS), and echo time (30msec). Model metabolites and
concentrations used in the basis set are fully detailed in
the LCModel manual (http://s-provencher-.com/pages/lcm-
manual.shtml). Poorly fitted metabolite peaks (Cramer–Rao
minimum variance bounds of 420% as reported by LCModel)
were excluded from further analysis. As information on voxel
cerebrospinal fluid content was not available for correction of
water-scaled metabolite concentration estimates, the ratio of
the reported metabolite concentration to that of the creatine
(Cr) plus phosphocreatine resonance was used for analysis.
cortex. Glutamate levels were significantly higher in non-remitted (n¼17)
than remitted (n¼15) schizophrenia patients (T(30)¼3.02; P¼0.005).
This difference remained significant T(28)¼ 2.79; P¼0.009) after removal
of the two outlying values as identified by Cook’s D and indicated by the
Level of glutamate (scaled to creatine) in the anterior cingulate
Glutamate and clinical status in schizophrenia
A Egerton et al
Statistical analysis was performed in SPSS version 15.0
(Chicago, Illinois). Group differences in demographic and
clinical variables, spectral quality and glutamate/Cr ratios
were explored using Fisher’s exact test or independent-
samples t-tests as appropriate. Levene’s test was used to
check for equality of variance across groups. Statistical
significance was defined as Po0.05. Relationships between
glutamate/Cr ratio and symptom scores were explored using
Pearson’s product moment correlation, correcting for the
number of correlations performed (threshold P¼0.05/4
comparisons¼0.013). Potential influences of age, medica-
tion status, or outlying values (as indicated by Cook’s D) on
significant findings were subsequently determined using
partial correlation or exclusion of specific cases.
Clinical and Demographic Characteristics
Clinical and demographic variables are presented in Table 1.
Fifteen patients met the criteria for symptomatic remission
(mean±SD age¼30±6 years, 11 male, 14 right handed),
while seventeen were still symptomatic (‘no remission’;
mean±SD age¼26±7 years, 13 male, 17 right handed).
There were no significant group differences in age, gender,
handedness, or current tobacco, alcohol or cannabis use, or
history of amphetamine, cocaine, ecstasy or ketamine
use. In the symptomatic remission group, one patient was
receiving amisulpride, one aripiprazole, five olanzapine,
three risperidone, one quetiapine, and four were no longer
receiving any antipsychotic medication. In the symptomatic
non-remission group, one patient was receiving amisulpride,
seven aripiprazole, three olanzapine, three risperidone, two
quetiapine, and one was no longer taking any antipsychotic
medication. There was no significant difference in the type
of antipsychotic medication between groups. As expected,
symptom severity on all PANSS subscales and the level of
global functioning were significantly worse in the no remis-
sion compared with the remission group (Table 1).
Quality of 1H-MRS Spectra
Representative spectra for the anterior cingulate cortex and
left thalamus voxels are provided in Supplemental Figure S1
available online. Serial water-scaled phantom data did not
provide any evidence of step changes or scanner drift over
the course of the study. Spectral quality was assessed as the
NAA signal to noise ratios (S/N, defined as the ratio of the
peak height at 2.01 ppm minus baseline to twice the root
mean square of the residuals of the fit, as reported by
LCModel) and linewidths as reported by LCModel. Spectra
were of good quality in the anterior cingulate cortex and
thalamus and there were no significant group differences in
spectral quality in either region (anterior cingulate cortex:
S/N mean±SD remission¼22.3±4.2; no remission 20.0±
5.0; t30¼1.42; P¼0.17; linewidth ±SD remission¼
P¼0.49; or in the left thalamus (S/N mean±SD re-
mission¼19.1±2.7; no remission 18.5±3.5; t29¼0.58;
P¼0.56; linewidth ±SD remission¼0.056±0.018 ppm;
no remission 0.047±0.007 ppm; t29¼1.78; P¼0.09). The
mean±SD% CRLB for each metabolite in each voxel for
remitted and non-remitted patients are presented in Sup-
plemental Table 1 available online. There were no significant
group differences in metabolite %CRLBs (P values range
from 0.07 to 0.95).
Table 1 Demographic and Clinical Characteristics
Remission, N¼15 No Remission, N¼17Statistic
Age, mean±SD, years30±625±7 T(30)¼1.80; P¼0.08
Gender (male/female) 11/413/4
Handedness (right/left) 14/117/0
Family history (yes/no/uk)
Education, mean±SD, years
Current tobacco use (yes/no)12/3 9/8
Current alcohol use (yes/no) 9/612/5
Current cannabis use (yes/no)4/115/12
Amphetamine use, ever (yes/no)4/114/13
Cocaine use, ever (yes/no)3/125/12
Ecstasy use ever (yes/no)5/106/11
Ketamine use ever (yes/no)1/14 4/13
Current antipsychotic medication Am/Ar/Ol/Ri/Qu/N
Time since presentation, mean±SD, months
GAF score, mean±SD
Abbreviations: Am, amisulpride; Ar, aripiprazole; N, none; Ol, olanzapine; Qu, quetiapine; Ri, risperidone; uk, unknown.
Glutamate and clinical status in schizophrenia
A Egerton et al
Metabolite Levels in Remitted vs Non Remitted Patients
The non-remitted patients had significantly higher levels of
glutamate/Cr in the anterior cingulate cortex than those in
remission (Figure 1; T(30)¼3.02; P¼0.005). There was a
tendency towards higher variance in glutamate/Cr estimates
in the no remission compared with the remission group
(Levene’s test: F¼3.54; P¼0.07), and the group difference
in glutamate/Cr remained significant accounting for in-
homogeneity of variance (T(24.3)¼3.14; P¼0.004) and
after removal of two outlying values (as identified by Cook’s
D and shown in Figure 1; T(28)¼ 2.79; P¼0.009). The
higher levels of anterior cingulate glutamate/Cr in non-
remitted patients compared with remitted patients also
remained significant after exclusion of the five patients no
longer taking antipsychotics (T(25)¼2.36; P¼0.026), and
when analyzed as water-scaled glutamate levels (T(30)¼
2.23; P¼0.03). Across all patients, there was a significant
decline in anterior cingulate cortex glutamate/Cr with
increasing age (r¼?0.425; P¼0.015). However, the group
difference in glutamate/Cr remained significant after con-
trolling for age effects (F(1,31)¼5.774; P¼0.023). There
were no significant effects of current tobacco (mean±SD, n:
non-smokers 1.29±0.27, 11; smokers 1.25±0.23, 21;
T(30)¼0.45; P¼0.67), current alcohol use (mean±SD, n:
non-alcohol drinkers 1.24±0.24, 11; alcohol drinkers
1.28±0.24, 21; T(30)¼0.44; P¼0.66), current cannabis
use (mean ± s.d., n: non-cannabis users 1.27±0.26, 9;
cannabis users 1.26±0.24, 23; T(30)¼0.11; P¼0.91), or
history of ever using other recreational drugs (ampheta-
mine: T(30)¼0.87; P¼0.39; cocaine: T(30)¼0.51; P¼0.61;
ecstasy: T(30)¼0.39;P¼0.70; ketamine: T(30)¼0.33; P¼0.74)
on anterior cingulate glutamate/Cr levels, and no significant
relationship between time since presentation and anterior
cingulate glutamate/Cr levels (n¼32; r¼?0.05; P¼0.77).
Although there was no significant group difference in
glutamate plus Gln (Glx)/Cr (T(30)¼1.24; P¼0.223), levels
of Glx/Cr were higher in non-remitted than remitted
patients following the removal of three outlying values as
identified with Cook’s D (Figure 2, T(27)¼2.20; P¼0.036).
There were no significant group differences in the other
metabolites quantifiable in the anterior cingulate cortex
spectra, including Cr (Table 2), and no significant group
differences in any of the metabolites quantifiable in the left
thalamus (Table 2).
Relationships with Symptoms
Across the entire sample, higher levels of glutamate/Cr
in the anterior cingulate cortex were associated with a
greater severity of negative symptoms (Figure 3a; r¼0.42;
P¼0.017) and a lower level of global functioning (Figure 3b;
r¼?0.47; P¼0.007), but not severity of positive (r¼0.232;
P¼0.202) or general (r¼0.071; P¼0.698) symptoms. The
relationship between anterior cingulate cortex glutamate/
Cr and global functioning survived correction for multi-
ple comparisons (threshold P¼0.05/4 comparisons¼
0.013). The relationships between anterior cingulate
cortex glutamate/Cr and negative symptoms or global
functioning remained significant after exclusion of the
five patients no longer taking antipsychotic medication
(PANSS negative: r¼0.401; P¼0.038; global functioning:
r¼?0.436; P¼0.023), and after controlling for age
(PANSS negative: r¼0.465; P¼0.008; global functioning:
r¼?0.447; P ¼0.012). Significant relationships between
anterior cingulate Glx/Cr and PANSS negative symptom
severity (r¼0.384; P¼0.040) and global functioning
(r¼?0.404; P¼0.030) were also evident after exclusion
of three outlying values as identified with Cook’s D.
No significant relationships between symptoms and
either glutamate or Glx levels in the left thalamus were
the anterior cingulate cortex. There was no significant group difference in
Glx including all cases (T(30)¼1.24; P¼0.223), but levels of Glx/Cr were
significantly higher in non-remitted than remitted patients (T(27)¼2.20;
P¼0.036) after removal of three outlying values as identified with Cook’s
D and indicated by the filled symbols.
Level of Glx (glutamate plus glutamine, scaled to creatine) in
Table 2 1H-MRS Metabolite Levels (mean±SD) in the Anterior
Cingulate Cortex and Left Thalamus in First Episode Psychosis
Patients Who were or were not in Symptomatic Remission
Following Antipsychotic Treatment
Creatine 6.63±0.60, 14
Abbreviations: Choline, total choline plus phosphocholine. Cr, creatine plus
phosphocreatine; Glx, glutamate plus glutamine; NAA, total N-acetyl aspartate
plus N-acetyl aspartyl glutamic acid.
Glutamate and clinical status in schizophrenia
A Egerton et al
To our knowledge, this is the first evidence that anterior
cingulate glutamate levels differ between patients with
schizophrenia in remission following antipsychotic treat-
ment and patients who are still symptomatic. Higher levels
of glutamate and Glx in the anterior cingulate cortex in
symptomatic compared with remitted patients are con-
sistent with reports of elevated anterior cingulate gluta-
mate turnover in non-medicated or minimally treated
patients, who generally have high levels of psychotic
symptoms (Bustillo et al, 2010; Theberge et al, 2002). It is
also in line with evidence that frontal glutamate is reduced
in chronic patients with a long history of antipsychotic
treatment and who are generally less symptomatic (Mars-
man et al, 2011; Tayoshi et al, 2009; Theberge et al, 2003).
Our finding is broadly consistent with the numerous
reports of abnormalities in the anterior cingulate cortex in
early psychosis. For example, structural abnormalities in
this area are present at onset of psychosis and may be
predictive of conversion to psychosis in those at high risk
of developing the disorder (Borgwardt et al, 2007; Dazzan
et al, 2011; Fornito et al, 2008; Pantelis et al, 2003;
Rothlisberger et al, 2012; Fusar-Poli et al, 2011). Moreover,
functional magnetic resonance imaging studies show that
antipsychotic treatment may be particularly effective in
normalizing activity in the anterior cingulate cortex ((Snitz
et al, 2005) and see (Karch et al, 2012) for review).
Our finding may suggest that this is linked to glutamater-
We also found that higher levels of anterior cingulate
glutamate or Glx were associated with both an increased
severity of negative symptoms and a lower level of global
functioning. A relationship between glutamate levels and
global functioning is in accordance with similar findings in
patients with chronic schizophrenia (Van Elst et al, 2005),
while the association with negative symptoms is consistent
with an inverse relationship between anterior cingulate
glutamate levels and sensation seeking (Gallinat et al, 2007).
However, negative symptom severity has also been linked
to reduced anterior cingulate glutamate levels in stable,
medicated schizophrenia patients (Reid et al, 2011). The
reason for the difference in the direction of the correlation
in this and the present study is unclear, but may reflect
differences in the part of the anterior cingulate cortex from
which spectra were acquired, or in the characteristics of the
respective patient samples.
No differences in left thalamic metabolite concentrations
were detected between remitted and non-remitted patients.
Previous studies suggest that increased thalamic Gln levels
in never-treated first-episode patients return to normal after
30, but not 10 months of antipsychotic treatment (Theberge
et al, 2007), and that thalamic Glx levels decrease over 80
months of treatment (Aoyama et al, 2011). Given that in the
present study the average length of time since presentation
was 10 months, and both groups had similar treatment
histories, the absence of group differences is unlikely to be
related to an effect of antipsychotic treatment.
One limitation of the present study is that in the majority
of spectra, we were unable to reliably quantify Gln concen-
trations. At field strengths of 3Tesla or below, glutamate
and Gln are difficult to separate due to overlapping reson-
ances (Hancu, 2009). It is therefore possible that in some
cases, glutamate values may have been contaminated by
Gln. In this study, metabolite concentrations were reported
in ratio to Cr. Compared with absolute quantitation, this
approach is associated with high levels of accuracy, resilient
to variation in signal-to-noise ratio (Kanowski et al, 2004).
The limitation of this method is that it assumes there is no
group difference in Cr concentration. However, our findings
were significant both when assessed as the estimate of
water-scaled glutamate concentration, and as the ratio of
estimated glutamate concentration to Cr, and furthermore,
there was no group difference in estimates of absolute Cr
concentration. A further limitation is that glutamate levels
are higher in grey than white matter (Pan et al, 1996;
Pouwels and Frahm, 1998) and, as we did not assess voxel
tissue content, the influence of individual differences in
voxel percentage grey and white matter on glutamate levels
cannot be determined.
Although there was no significant difference in medica-
tion type between patients who were or were not in remis-
sion, the sample comprised patients on a variety of different
antipsychotics, and medication adherence was assessed
through self-report. The absence of precise information on
duration of antipsychotic treatment is a weakness, although
at the recruitment site, all first-episode patients are prescri-
bed antipsychotics, ideally for the first 2 years, and the
duration of treatment is correlated with the time since first
presentation. Antipsychotics may differentially impact on
regional glutamatergic function (McLoughlin et al, 2009),
and their potentially confounding effects could be better
cingulate cortex were associated with (a) greater severity of negative
symptoms (left; r¼0.42; P¼0.017), and with (b) lower levels of global
functioning (right; r¼?0.47; P¼0.007).
Higher levels of glutamate (scaled to creatine) in the anterior
Glutamate and clinical status in schizophrenia
A Egerton et al
assessed in a prospective design involving a standardized
treatment protocol or monitoring of prescribing and adhe-
rence from presentation. As we did not exclude subjects on
the basis of recreational drug use, or perform urine drugs
screens at the time of imaging, we cannot exclude the possi-
bility that drug use may have impacted on our findings.
However, there were no significant group differences in self-
reported recreational drug use or differences in anterior
cingulate glutamate/Cr levels between subjects who did or
did not report use of each drug. Finally, as our study was
designed to compare patients who were symptomatic vs
remitted following treatment, we did not include a healthy
control group, therefore we could not assess whether the
metabolite levels in the patients differed from those in
One interpretation of our findings is that within our
sample of patients with schizophrenia, pre-existing differ-
ences in anterior cingulate glutamate levels predicted the
subsequent response to antipsychotic treatment. However,
we cannot exclude the possibility that the entire sample had
elevated glutamate levels before treatment and that there
was a longitudinal reduction in the patients who reached
criteria for symptomatic remission, or that less severe sym-
ptoms were also associated with lower anterior cingulate
glutamate levels before treatment. Prospective studies are
required to address these issues. Nonetheless, our findings
suggest that presence of residual symptoms in schizophre-
nia may be linked to glutamate dysfunction. Patients not
in remission following initial antipsychotic treatment may
therefore benefit from treatment with antipsychotics that
have glutamatergic as well as dopaminergic actions (eg,
clozapine), or other drugs that act on the glutamate system.
This work was supported by the NIHR Biomedical Research
Centre for Mental Health at the South London and
Maudsley NHS Foundation Trust and Institute of Psychia-
try, King’s College London. We thank the study participants
and the radiography team at the Centre for Neuroimaging
Sciences, Institute of Psychiatry, King’s College London.
GJB received honoraria for teaching from General Electric
during the course of this work. In the past 3 years, JS has
received a non-restricted academic fellowship from Glaxo
SmithKline, and honoraria from Roche, AstraZeneca,
Behrenberg Bank, and Pfizer. The authors declare no con-
flict of interest.
Andreasen NC, Carpenter Jr WT, Kane JM, Lasser RA, Marder SR,
Weinberger DR (2005). Remission in schizophrenia: proposed
criteria and rationale for consensus. Am J Psychiatry 162:
Aoyama N, Theberge J, Drost DJ, Manchanda R, Northcott S,
Neufeld RW et al. (2011). Grey matter and social functioning
correlates of glutamatergic metabolite loss in schizophrenia. Br J
Psychiatry 198: 448–456.
Borgwardt SJ, McGuire PK, Aston J, Berger G, Dazzan P,
Gschwandtner U et al. (2007). Structural brain abnormalities
in individuals with an at-risk mental state who later develop
psychosis. Br J Psychiatry Suppl 51: s69–s75.
Bustillo JR, Chen H, Gasparovic C, Mullins P, Caprihan A, Qualls C
et al. (2011). Glutamate as a marker of cognitive function in
schizophrenia: a proton spectroscopic imaging study at 4 Tesla.
Biol Psychiatry 69: 19–27.
Bustillo JR, Rowland LM, Mullins P, Jung R, Chen H, Qualls C et al.
(2010). (1)H-MRS at 4 Tesla in minimally treated early
schizophrenia. Mol Psychiatry 15: 629–636.
Dazzan P, Soulsby B, Mechelli A, Wood SJ, Velakoulis D, Phillips
LJ et al. (2011). Volumetric abnormalities predating the onset of
schizophrenia and affective psychoses: an MRI study in subjects
at ultrahigh risk of psychosis. Schizophr Bull; e-pub ahead of
print 25 April 2011.
de la Fuente-Sandoval C, Leon-Ortiz P, Favila R, Stephano S,
Mamo D, Ramirez-Bermudez J et al. (2011). Higher levels of
glutamate in the associative-striatum of subjects with prodromal
symptoms of schizophrenia and patients with first-episode
psychosis. Neuropsychopharmacology 36: 1781–1791.
Egerton A, Fusar-Poli P, Stone JM (2012). Glutamate and psychosis
risk. Curr Pharm Des 18: 466–478.
Fornito A, Yung AR, Wood SJ, Phillips LJ, Nelson B, Cotton S et al.
(2008). Anatomic abnormalities of the anterior cingulate cortex
before psychosis onset: an MRI study of ultra-high-risk
individuals. Biol Psychiatry 64: 758–765.
Fusar-Poli P, Radua J, McGuire P, Borgwardt S (2011). Neuroa-
natomical maps of psychosis onset: voxel-wise meta-analysis of
antipsychotic-naive VBM studies. Schizophr Bull; e-pub ahead of
print 10 November 2011.
Gallinat J, Kunz D, Lang UE, Neu P, Kassim N, Kienast T et al. (2007).
Association between cerebral glutamate and human behaviour: the
sensation seeking personality trait. Neuroimage 34: 671–678.
Hall RC (1995). Global assessment of functioning. A modified
scale. Psychosomatics 36: 267–275.
Hancu I (2009). Optimized glutamate detection at 3T. J Magn
Reson Imaging 30: 1155–1162.
Javitt DC (2004). Glutamate as a therapeutic target in psychiatric
disorders. Mol Psychiatry 9: 984–997.
Javitt DC, Duncan L, Balla A, Sershen H (2005). Inhibition of
system A-mediated glycine transport in cortical synaptosomes
by therapeutic concentrations of clozapine: implications for
mechanisms of action. Mol Psychiatry 10: 275–287.
Jessen F, Fingerhut N, Sprinkart AM, Kuhn KU, Petrovsky N,
Maier W et al. (2011). N-acetylaspartylglutamate (NAAG) and
N-acetylaspartate (NAA) in patients with schizophrenia. Schi-
zophr Bull; e-pub ahead of print 12 September 2011.
Kanowski M, Kaufmann J, Braun J, Bernarding J, Tempelmann C
(2004). Quantitation of simulated short echo time 1H human brain
spectra by LCModel and AMARES. Magn Reson Med 51: 904–912.
Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000).
Relationship between dopamine D(2) occupancy, clinical response,
and side effects: a double-blind PET study of first-episode
schizophrenia. Am J Psychiatry 157: 514–520.
Karch S, Pogarell O, Mulert C (2012). Functional magnetic
resonance imaging and treatment strategies in schizophrenia.
Curr Pharm Biotechnol 13: 1622–1629.
Kay SR, Fiszbein A, Opler LA (1987). The positive and negative syn-
drome scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276.
Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR,
Hulshoff Pol HE (2011). Glutamate in schizophrenia: a focused
review and meta-analysis of 1H-MRS studies. Schizophr Bull;
e-pub ahead of print 11 July 2011.
McLoughlin GA, Ma D, Tsang TM, Jones DN, Cilia J, Hill MD et al.
(2009). Analyzing the effects of psychotropic drugs on metabo-
lite profiles in rat brain using 1H NMR spectroscopy. J Proteome
Res 8: 1943–1952.
Glutamate and clinical status in schizophrenia
A Egerton et al
Pan JW, Mason GF, Pohost GM, Hetherington HP (1996). Download full-text
Spectroscopic imaging of human brain glutamate by water-
suppressed J-refocused coherence transfer at 4.1 T. Magn Reson
Med 36: 7–12.
Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J,
Phillips LJ et al. (2003). Neuroanatomical abnormalities before
and after onset of psychosis: a cross-sectional and longitudinal
MRI comparison. Lancet 361: 281–288.
Pilowsky LS, Costa DC, Ell PJ, Murray RM, Verhoeff NP, Kerwin
RW (1993). Antipsychotic medication, D2 dopamine receptor
blockade and clinical response: a 123I IBZM SPET (single
photon emission tomography) study. Psychol Med 23: 791–797.
Pouwels PJ, Frahm J (1998). Regional metabolite concentrations in
human brain as determined by quantitative localized proton
MRS. Magn Reson Med 39: 53–60.
Provencher SW (1993). Estimation of metabolite concentrations
from localized in vivo proton NMR spectra. Magn Reson Med 30:
Reid MA, Stoeckel LE, White DM, Avsar KB, Bolding MS, Akella
NS et al. (2011). Assessments of function and biochemistry of
the anterior cingulate cortex in schizophrenia. Biol Psychiatry
Rothlisberger M, Riecher-Rossler A, Aston J, Fusar-Poli P, Radu
EW, Borgwardt S (2012). Cingulate volume abnormalities in
emerging psychosis. Curr Pharm Des 18: 495–504.
Shirayama Y, Obata T, Matsuzawa D, Nonaka H, Kanazawa Y,
Yoshitome E et al. (2010). Specific metabolites in the medial
prefrontal cortex are associated with the neurocognitive
deficits in schizophrenia: a preliminary study. Neuroimage 49:
Snitz BE, MacDonald III A, Cohen JD, Cho RY, Becker T, Carter CS
(2005). Lateral and medial hypofrontality in first-episode
schizophrenia: functional activity in a medication-naive state
and effects of short-term atypical antipsychotic treatment. Am J
Psychiatry 162: 2322–2329.
Stone JM, Day F, Tsagaraki H, Valli I, McLean MA, Lythgoe DJ
et al. (2009). Glutamate dysfunction in people with prodromal
symptoms of psychosis: relationship to gray matter volume. Biol
Psychiatry 66: 533–539.
Stone JM, Morrison PD, Pilowsky LS (2007). Glutamate and
dopamine dysregulation in schizophrenia–a synthesis and
selective review. J Psychopharmacol 21: 440–452.
Stone JM, Raffin M, Morrison P, McGuire PK (2010). Review: the
biological basis of antipsychotic response in schizophrenia.
J Psychopharmacol 24: 953–964.
Tayoshi S, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S,
Iga J et al. (2009). Metabolite changes and gender differences in
schizophrenia using 3-Tesla proton magnetic resonance spectro-
scopy (1H-MRS). Schizophr Res 108: 69–77.
Theberge J, Al-Semaan Y, Williamson PC, Menon RS, Neufeld RW,
Rajakumar N et al. (2003). Glutamate and glutamine in the
anterior cingulate and thalamus of medicated patients with
chronic schizophrenia and healthy comparison subjects mea-
sured with 4.0-T proton MRS. Am J Psychiatry 160: 2231–2233.
Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J et al.
(2002). Glutamate and glutamine measured with 4.0 T proton
MRS in never-treated patients with schizophrenia and healthy
volunteers. Am J Psychiatry 159: 1944–1946.
Theberge J, Williamson KE, Aoyama N, Drost DJ, Manchanda R,
Malla AK et al. (2007). Longitudinal grey-matter and glutama-
tergic losses in first-episode schizophrenia. Br J Psychiatry 191:
Tibbo P, Hanstock C, Valiakalayil A, Allen P (2004). 3-T proton
MRS investigation of glutamate and glutamine in adolescents
at high genetic risk for schizophrenia. Am J Psychiatry 161:
Van Elst LT, Valerius G, Buchert M, Thiel T, Rusch N, Bubl E et al.
(2005). Increased prefrontal and hippocampal glutamate con-
centration in schizophrenia: evidence from a magnetic reso-
nance spectroscopy study. Biol Psychiatry 58: 724–730.
Wood SJ, Yucel M, Wellard RM, Harrison BJ, Clarke K, Fornito A
et al. (2007). Evidence for neuronal dysfunction in the anterior
cingulate of patients with schizophrenia: a proton magnetic
resonance spectroscopy study at 3 T. Schizophr Res 94: 328–331.
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Glutamate and clinical status in schizophrenia
A Egerton et al