Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P< 0.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (P < 0.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

European Commission Seventh Framework Program.

It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits.

Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.

Our results provide further evidence for P3a/b amplitude deficits and cognitive deficits in AN-FES patients, which are neither due to antipsychotics nor to disease progress. Furthermore, our data showed significant, yet weak associations between P3b and cognition. Therefore, our data do not supply evidence for deficient P3a/b amplitudes as direct underlying factors for cognitive deficits in schizophrenia.

Background:Reduced mismatch negativity and P3a amplitude have been suggested to be among the core deficits in schizophrenia since the late 1970s. Blockade of dopamine D2 receptors play an important role in the treatment of schizophrenia. In addition, there is some evidence indicating that deficits in mismatch negativity and P3a amplitude are related to increased dopaminergic activity. This is the first study investigating the effect of amisulpride, a potent D2-antagonist, on mismatch negativity and P3a amplitude in a large group of antipsychotic-naïve, first-episode schizophrenia patients.Methods:Fifty-one antipsychotic-naïve, first-episode schizophrenia patients were tested in a mismatch negativity paradigm at baseline and after 6 weeks of treatment with amisulpride. We further examined 48 age- and gender-matched controls in this paradigm.Results:At baseline, the patients showed significantly reduced P3a amplitude compared with healthy controls, but no differences in mismatch negativity. Although the treatment with amisulpride significantly improved the patients’ psychopathological (PANSS) and functional (GAF) scores, it did not influence their mismatch negativity amplitude, while also their reduced P3a amplitude persisted.Conclusion:Our findings show that antipsychotic naïve, first-episode patients with schizophrenia have normal mismatch negativity yet reduced P3a amplitude compared with healthy controls. In spite of the fact that the 6-week amisulpride treatment improved the patients both clinically and functionally, it had no effect on either mismatch negativity or P3a amplitude. This suggests that even though there is a dopaminergic involvement in global functioning and symptomatology in schizophrenia, there is no such involvement in these particular measures of early information processing.

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Electroencephalography in patients with a first episode of psychosis (FEP) may contribute to the diagnosis and treatment response prediction. Findings in the literature vary due to small sample sizes, medication effects, and variable illness duration. We studied macroscale resting-state EEG characteristics of antipsychotic naïve patients with FEP. We tested (1) for differences between FEP patients and controls, (2) if EEG could be used to classify patients as FEP, and (3) if EEG could be used to predict treatment response to antipsychotic medication. In total, we studied EEG recordings of 62 antipsychotic-naïve patients with FEP and 106 healthy controls. Spectral power, phase-based and amplitude-based functional connectivity, and macroscale network characteristics were analyzed, resulting in 60 EEG variables across four frequency bands. Positive and Negative Symptom Scale (PANSS) were assessed at baseline and 4–6 weeks follow-up after treatment with amisulpride or aripiprazole. Mann-Whitney U tests, a random forest (RF) classifier and RF regression were used for statistical analysis. Our study found that at baseline, FEP patients did not differ from controls in any of the EEG characteristics. A random forest classifier showed chance-level discrimination between patients and controls. The random forest regression explained 23% variance in positive symptom reduction after treatment in the patient group. In conclusion, in this largest antipsychotic- naïve EEG sample to date in FEP patients, we found no differences in macroscale EEG characteristics between patients with FEP and healthy controls. However, these EEG characteristics did show predictive value for positive symptom reduction following treatment with antipsychotic medication.