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Antipsychotic Treatment Resistance in Schizophrenia Associated with

Elevated Glutamate Levels but Normal Dopamine Function

Article  in  Biological psychiatry · July 2013

DOI: 10.1016/j.biopsych.2013.06.011 · Source: PubMed


108 967

7 authors, including:

Arsime Demjaha Alice Egerton

King's College London King's College London


Robin Murray Shitij Kapur

King's College London King's College London


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Antipsychotic Treatment Resistance in Schizophrenia met DSM-IV criteria for schizophrenia, as determined by the
Associated with Elevated Glutamate Levels but Normal Operational Criteria Checklist (18), and were currently receiving
Dopamine Function antipsychotic medication, with adherence determined by mea-
suring antipsychotic drug serum levels and by reviewing phar-
To the Editor: macy and medical records. Patients in the treatment-resistant
group (n ¼ 6) met modified Kane criteria for treatment resistance

pproximately a third of patients with schizophrenia show a
limited response to antipsychotic medication (1). This (19). Patients in the responder group (n ¼ 8) met the Remission
might be due to distinct neurochemical abnormalities in in Schizophrenia Working Group Criteria for treatment remission
a subgroup of patients, but to date there is little evidence to (20). For comparison, data were also acquired in healthy volun-
support this hypothesis (2). Increased presynaptic dopamine teers (n ¼ 10), who had no history of psychiatric illness. The
synthesis has consistently been reported in patients with schizo- F-DOPA PET data acquisition and analysis in this sample has
phrenia (3–16). In a recent 3,4-dihydroxy-6-[18F]fluoro-L-phenyla- been previously described (8). The 1H-MRS spectra (point
lanine (18F-DOPA) positron emission tomography (PET) study, we reSolved spectroscopy; echo time ¼ 30 msec; repetition time ¼
found that, although an increase in striatal dopamine synthesis 3000 msec; 96 averages) were acquired on a General Electric
capacity was evident in patients who had responded to anti- (Milwaukee, Wisconsin) 3 Tesla HDx magnetic resonance system,
psychotic treatment, there was no increase in patients who were in a 20  20  20 mm voxel in the anterior cingulate cortex, with
treatment-resistant (8). In a separate proton magnetic resonance the standard GE PROBE (proton brain examination) sequence,
spectroscopy (1H-MRS) study in first-episode psychosis, we found which involves a standardized chemically-selective suppression
elevated glutamate levels in the anterior cingulate cortex in water suppression routine. Spectra were analyzed with LCModel
patients who had persistent psychotic symptoms despite anti- version 6.1-4 F(21), with a standard basis set, as detailed in the
psychotic treatment, relative to patients in whom there had been LCModel manual (
a good symptomatic response (17). shtml). Poorly fitted metabolite peaks (Cramér Rao Lower Bounds
Taken together, these studies suggest that neuroimaging of more than 20%) were excluded from further analysis. Water-
measures of dopamine and glutamate function might provide a scaled 1H-MRS metabolite values were corrected for partial
means of stratifying patients with psychosis according to their volume cerebral spinal fluid contamination as previously
response to treatment. More specifically, treatment responders described (22). Due to partially overlapping resonances, contam-
seem to have more marked dopaminergic abnormalities, whereas ination by glutamine might account for 10%–30% of the
treatment nonresponders seem to have more marked glutama- estimated glutamate concentration at 3 Tesla (23). The LCModel
tergic abnormalities. However, these studies were conducted in also provides an estimate for the sum of glutamate plus
separate samples differing in age, duration of illness, and glutamine. Data were analyzed with analysis of variance (ANOVA),
treatment history. We therefore used 18F-DOPA PET and 1H-MRS Fisher’s exact or independent samples t tests as appropriate, and
to assess dopamine and glutamate function in the same group of statistical significance was taken at p ⬍ .05.
patients (8). We hypothesized that treatment resistance would be There were no group differences in age, gender, weight,
associated with elevated anterior cingulate glutamate levels in cigarette smoking, 18F-DOPA dose or specific activity, 1H-MRS
the context of relatively normal striatal dopamine synthesis spectral quality, or metabolite percentage Cramér Rao Lower
capacity, whereas treatment response would be associated with Bounds. Data are presented in Table 1 and Figure 1. Striatal
relatively normal anterior cingulate glutamate levels and elevated dopamine synthesis capacity in treatment-resistant patients did
striatal dopamine synthesis capacity. not differ from that in healthy volunteers (t14 ¼ 6.90, p ¼ .50) or
The study was approved by the local research ethics commit- responders (t12 ¼ 1.52, p ¼ .15). In contrast, dopamine synthesis
tee and the Administration of Radioactive Substances Advisory capacity was significantly higher in responders than in healthy
Committee, UK. All subjects gave written informed consent to volunteers (t16 ¼ 2.43, p ¼ .03; effect size ¼ 1.20). Anterior
participate. All of the patients who had participated in the cingulate glutamate estimates showed the opposite pattern
previous 18F-DOPA PET investigation (8) were contacted and across groups; relative to that in healthy volunteers, glutamate
invited to attend for a 1H-MRS scan. The 1H-MRS measures were was elevated in the treatment-resistant group (t14 ¼ 2.80, p ¼ .01;
acquired in 14 of the original group of 24 patients. All patients effect size ¼ 1.68) but not in the responder group (t16 ¼ .29,

Table 1. Neurochemical Measures in Each Group

Healthy Volunteers Responders Treatment-Resistant
(n ¼ 10) (n ¼ 8) (n ¼ 6)

Dopamine synthesis capacity (18F-DOPA Kcer -1

i , min )
Striatum .0127 ⫾ .0015 .0141 ⫾ .0015a .0132 ⫾ .0014
Anterior cingulate cortex metabolite concentrations (institutional units)
Glutamate 8.62 ⫾ 1.02 8.87 ⫾ 2.44 10.32 ⫾ 1.41a
Glx 12.18 ⫾ 1.61 13.33 ⫾ 2.85 13.76 ⫾ 2.86
NAA 9.27 ⫾ 1.44 7.48 ⫾ 1.21a 9.77 ⫾ .87
Choline 2.28 ⫾ .22 2.15 ⫾ .55 2.41 ⫾ .48
Creatine 8.11 ⫾ 1.08 7.25 ⫾ 1.37 8.44 ⫾ .83
Myo-inositol 6.39 ⫾ 1.07 6.48 ⫾ 1.64 7.42 ⫾ 1.69
F-DOPA, 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine; Glx, glutamate plus glutamine; NAA, N-acetylaspartate.
Significant group difference relative to healthy volunteers (t test, two-tailed, p ⬍ .05). Glutamate concentration estimates are likely to include some
contamination by glutamine.

0006-3223/$36.00 BIOL PSYCHIATRY 2013;]:]]]–]]]

& 2013 Society of Biological Psychiatry
2 BIOL PSYCHIATRY 2013;]:]]]–]]] A. Demjaha et al.

replication, ideally in large prospective studies of therapeutic

response in patients who are initially medication-naive. A
further limitation is the contamination of the glutamate signal
by glutamine (23). Nevertheless, these preliminary data suggest
that neurochemical imaging measures could be used to stratify
patients with schizophrenia according to antipsychotic
response. The results are consistent with evidence that dopa-
minergic blockade is ineffective in patients with treatment
resistance and that glutamatergic treatments can be effective
in reducing symptoms (24). The glutamate system is thus a
logical target for the treatment of residual symptoms in

Arsime Demjahaa,b
Alice Egertona,b,n
Robin M. Murraya
Shitij Kapura
Oliver D. Howesa,b
James M. Stonec
Philip K. McGuirea
Department of Psychosis Studies, Institute of Psychiatry, King’s College London;
Psychiatric Imaging, MRC Clinical Sciences Centre; and the cCentre for Mental
Health, Division of Brain Sciences, Imperial College London.
*Corresponding author E-mail:

Authors AD and AE contributed equally to this work.

Authors ODH, JMS, and PKM contributed equally to this work.
This work was supported by the National Institute for Health Research Biomedical
Research Centre for Mental Health at the South London and Maudsley National Health
Service Foundation Trust and Institute of Psychiatry, King’s College London, and Grant
U.1200.04.007.00001.01 from the Medical Research Council, UK.
We would like to thank the study participants and the radiography teams at the
Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London and at
Figure 1. Striatal dopamine function (3,4-dihydroxy-6-[18F]fluoro-L-phe- GE Imanet, Hammersmith Hospital.
nylalanine influx rate constant, kcer -1
i , min ) and anterior cingulate gluta- ODH has received unrestricted investigator-led charitable funding from or spoken at
mate concentration (institutional units) in each group. *Significant group meetings organized by AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Roche, and Eli
difference relative to healthy volunteers (t test, two-tailed, p ⬍ .05). Lilly. SK has served as consultant/speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly,
Janssen, Otsuka, Pfizer, and Roche and serves on the scientific advisory boards for
p ¼ .77). Glutamate in the treatment-resistant and responder Lundbeck and Roche. RM has received honoraria for lectures from Janssen, Lilly, Astra-
groups did not differ significantly (t12 ¼ 1.30, p ¼ .22). Although Zeneca, Bristol-Myers Squibb, and Roche. JMS has received a nonrestricted academic
fellowship from GlaxoSmithKline and honoraria from Roche, AstraZeneca, Behrenberg
the glutamate estimates likely include contamination from gluta-
Bank, and Pfizer. AE and PM have received funding from Roche. AD reports no
mine, there were no significant group differences in the sum of biomedical financial interests or potential conflicts of interest.
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