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Antipsychotic Treatment Resistance in Schizophrenia Associated with Elevated Glutamate Levels but Normal Dopamine Function
To the Editor: pproximately a third of patients with schizophrenia show a limited response to antipsychotic medication (1). This might be due to distinct neurochemical abnormalities in a subgroup of patients, but to date there is little evidence to support this hypothesis (2). Increased presynaptic dopamine synthesis has consistently been reported in patients with schizophrenia (316). In a recent 3,4-dihydroxy-6-[18F]uoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) study, we found that, although an increase in striatal dopamine synthesis capacity was evident in patients who had responded to antipsychotic treatment, there was no increase in patients who were treatment-resistant (8). In a separate proton magnetic resonance spectroscopy (1H-MRS) study in rst-episode psychosis, we found elevated glutamate levels in the anterior cingulate cortex in patients who had persistent psychotic symptoms despite antipsychotic treatment, relative to patients in whom there had been a good symptomatic response (17). Taken together, these studies suggest that neuroimaging measures of dopamine and glutamate function might provide a means of stratifying patients with psychosis according to their response to treatment. More specically, treatment responders seem to have more marked dopaminergic abnormalities, whereas treatment nonresponders seem to have more marked glutamatergic abnormalities. However, these studies were conducted in separate samples differing in age, duration of illness, and treatment history. We therefore used 18F-DOPA PET and 1H-MRS to assess dopamine and glutamate function in the same group of patients (8). We hypothesized that treatment resistance would be associated with elevated anterior cingulate glutamate levels in the context of relatively normal striatal dopamine synthesis capacity, whereas treatment response would be associated with relatively normal anterior cingulate glutamate levels and elevated striatal dopamine synthesis capacity. The study was approved by the local research ethics committee and the Administration of Radioactive Substances Advisory Committee, UK. All subjects gave written informed consent to participate. All of the patients who had participated in the previous 18F-DOPA PET investigation (8) were contacted and invited to attend for a 1H-MRS scan. The 1H-MRS measures were acquired in 14 of the original group of 24 patients. All patients met DSM-IV criteria for schizophrenia, as determined by the Operational Criteria Checklist (18), and were currently receiving antipsychotic medication, with adherence determined by measuring antipsychotic drug serum levels and by reviewing pharmacy and medical records. Patients in the treatment-resistant group (n 6) met modied Kane criteria for treatment resistance (19). Patients in the responder group (n 8) met the Remission in Schizophrenia Working Group Criteria for treatment remission (20). For comparison, data were also acquired in healthy volunteers (n 10), who had no history of psychiatric illness. The 18 F-DOPA PET data acquisition and analysis in this sample has been previously described (8). The 1H-MRS spectra (point reSolved spectroscopy; echo time 30 msec; repetition time 3000 msec; 96 averages) were acquired on a General Electric (Milwaukee, Wisconsin) 3 Tesla HDx magnetic resonance system, in a 20 20 20 mm voxel in the anterior cingulate cortex, with the standard GE PROBE (proton brain examination) sequence, which involves a standardized chemically-selective suppression water suppression routine. Spectra were analyzed with LCModel version 6.1-4 F(21), with a standard basis set, as detailed in the LCModel manual ( shtml). Poorly tted metabolite peaks (Cramr Rao Lower Bounds of more than 20%) were excluded from further analysis. Waterscaled 1H-MRS metabolite values were corrected for partial volume cerebral spinal uid contamination as previously described (22). Due to partially overlapping resonances, contamination by glutamine might account for 10%30% of the estimated glutamate concentration at 3 Tesla (23). The LCModel also provides an estimate for the sum of glutamate plus glutamine. Data were analyzed with analysis of variance (ANOVA), Fishers exact or independent samples t tests as appropriate, and statistical signicance was taken at p .05. There were no group differences in age, gender, weight, cigarette smoking, 18F-DOPA dose or specic activity, 1H-MRS spectral quality, or metabolite percentage Cramr Rao Lower Bounds. Data are presented in Table 1 and Figure 1. Striatal dopamine synthesis capacity in treatment-resistant patients did not differ from that in healthy volunteers (t14 6.90, p .50) or responders (t12 1.52, p .15). In contrast, dopamine synthesis capacity was signicantly higher in responders than in healthy volunteers (t16 2.43, p .03; effect size 1.20). Anterior cingulate glutamate estimates showed the opposite pattern across groups; relative to that in healthy volunteers, glutamate was elevated in the treatment-resistant group (t14 2.80, p .01; effect size 1.68) but not in the responder group (t16 .29,

Table 1. Neurochemical Measures in Each Group Healthy Volunteers (n 10)

-1 Dopamine synthesis capacity (18F-DOPA Kcer i , min ) Striatum Anterior cingulate cortex metabolite concentrations (institutional units) Glutamate Glx NAA Choline Creatine Myo-inositol 18 a

Responders (n 8) .0141 .0015a 8.87 13.33 7.48 2.15 7.25 6.48 2.44 2.85 1.21a .55 1.37 1.64

Treatment-Resistant (n 6) .0132 .0014 10.32 13.76 9.77 2.41 8.44 7.42 1.41a 2.86 .87 .48 .83 1.69

.0127 .0015 8.62 12.18 9.27 2.28 8.11 6.39 1.02 1.61 1.44 .22 1.08 1.07

F-DOPA, 3,4-dihydroxy-6-[18F]uoro-L-phenylalanine; Glx, glutamate plus glutamine; NAA, N-acetylaspartate. Signicant group difference relative to healthy volunteers (t test, two-tailed, p .05). Glutamate concentration estimates are likely to include some contamination by glutamine.


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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 dopaminergic 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 schizophrenia. 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, Kings College London; b Psychiatric Imaging, MRC Clinical Sciences Centre; and the cCentre for Mental Health, Division of Brain Sciences, Imperial College London. *Corresponding author E-mail:

Figure 1. Striatal dopamine function (3,4-dihydroxy-6-[18F]uoro-L-phe-1 nylalanine inux rate constant, kcer i , min ) and anterior cingulate glutamate concentration (institutional units) in each group. *Signicant group difference relative to healthy volunteers (t test, two-tailed, p .05).

p .77). Glutamate in the treatment-resistant and responder groups did not differ signicantly (t12 1.30, p .22). Although the glutamate estimates likely include contamination from glutamine, there were no signicant group differences in the sum of glutamine plus glutamate. The ANOVA for the four remaining metabolites (N-acetylaspartate [NAA], choline, myo-inositol, and creatine), about which there were no a priori hypotheses, identied a signicant overall effect of group on NAA (F2 5.62, p .011), which survived correction for multiple comparisons (Bonferroni adjusted .05/4 .013). Subsequent Bonferroni post hoc comparisons within the ANOVA model indicated that NAA levels were lower in the responder compared with both treatment-resistant (p .02) and the healthy volunteer groups (p .05), which did not differ (p 1.00). These data suggest that treatment resistance in schizophrenia is associated with a combination of relatively normal striatal dopamine synthesis and elevated anterior cingulate cortex glutamate levels. In contrast, symptomatic remission after antipsychotic treatment might be associated with an elevation in striatal dopamine synthesis, reduced NAA, and relatively normal glutamate levels. We cannot determine whether the differences in glutamate and dopamine function were a cause or a consequence of poor antipsychotic response, because the data are cross-sectional, and the small sample sizes limit the generalizability of the ndings. The results thus require

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, Kings 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, Kings College London and at GE Imanet, Hammersmith Hospital. ODH has received unrestricted investigator-led charitable funding from or spoken at meetings organized by AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Roche, and Eli Lilly. SK has served as consultant/speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Otsuka, Pzer, and Roche and serves on the scientic advisory boards for Lundbeck and Roche. RM has received honoraria for lectures from Janssen, Lilly, AstraZeneca, Bristol-Myers Squibb, and Roche. JMS has received a nonrestricted academic fellowship from GlaxoSmithKline and honoraria from Roche, AstraZeneca, Behrenberg Bank, and Pzer. AE and PM have received funding from Roche. AD reports no biomedical nancial interests or potential conicts of interest.

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