Biomarkers for Psychosis: Are We There Yet? Umbrella Review of 1478 Biomarkers.

Background and Hypothesis: This umbrella review aims to comprehensively synthesize the evidence of association between peripheral, electrophysiological, neuroimaging, neuropathological, and other biomarkers and diagnosis of psychotic disorders. Study Design: We selected systematic reviews and meta-analyses of observational studies on diagnostic biomarkers for psychotic disorders, published until February 1, 2018. Data extraction was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Evidence of association between biomarkers and psychotic disorders was classified as convincing, highly suggestive, suggestive, weak, or non-significant, using a standardized classification. Quality analyses used the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Study Results: The umbrella review included 110 meta-analyses or systematic reviews corresponding to 3892 individual studies, 1478 biomarkers, and 392 210 participants. No factor showed a convincing level of evidence. Highly suggestive evidence was observed for transglutaminase autoantibodies levels (odds ratio [OR] = 7.32; 95% CI: 3.36, 15.94), mismatch negativity in auditory event-related potentials (standardized mean difference [SMD] = 0.73; 95% CI: 0.5, 0.96), P300 component latency (SMD = -0.6; 95% CI: -0.83, -0.38), ventricle-brain ratio (SMD = 0.61; 95% CI: 0.5, 0.71), and minor physical anomalies (SMD = 0.99; 95% CI: 0.64, 1.34). Suggestive evidence was observed for folate, malondialdehyde, brain-derived neurotrophic factor, homocysteine, P50 sensory gating (P50 S2/S1 ratio), frontal N-acetyl-aspartate, and high-frequency heart rate variability. Among the remaining biomarkers, weak evidence was found for 626 and a non-significant association for 833 factors. Conclusions: While several biomarkers present highly suggestive or suggestive evidence of association with psychotic disorders, methodological biases, and underpowered studies call for future higher-quality research.

Plasma ratio of clozapine to N-desmethylclozapine can predict cognitive performance in treatment-resistant psychotic patients.

Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition. The opposite effects of clozapine and n-desmethylclozapine (NDMC) on cholinergic system have been suggested to underlie these inconclusive findings. The aim of this study is to determine whether clozapine/NDMC ratio can predict cognitive performance in patients with treatment-resistant psychosis. Nineteen clinically stable patients with schizophrenia or schizoaffective disorder treated with clozapine monotherapy completed demographic and clinical interviews. For the purpose of the study, patients were assessed with a neuropsychological battery and on the same day a blood sampling was obtained from each patient to measure plasma levels of clozapine and NDMC. Our results showed that clozapine/NDMC ratio, but not clozapine or NDMC plasma levels separately, was a predictive factor of cognitive performance, specifically of executive functioning. Our results showed that lower clozapine/NDMC ratios are associated with better executive functioning in clinically stable patients. These findings could be interpreted by the different pharmacodynamic properties on cholinergic, dopaminergic and serotonergic systems of NDMC compared to clozapine.

Altered amplitude of low frequency fluctuations in schizophrenia patients with persistent auditory verbal hallucinations.

The aim of this study is to analyze the differences in low frequency fluctuation (LFF) values between schizophrenia patients with and without auditory verbal hallucinations (AVH). Nineteen schizophrenia patients with persistent AVH (HP), fourteen non-hallucinating schizophrenia patients (nHP) and twenty healthy controls (HC) underwent R-fMRI. LFF values were calculated in the slow frequency band (0.01-0.08Hz). By means of group level contrasts, we performed direct voxel-wise group comparisons. Both groups of patients showed decreased amplitude LFF (ALFF) values in the occipital pole and lingual gyrus compared to HC, whereas increased ALFF values were found in the temporal pole and fusifom gyrus. Schizophrenia patients exhibited decreased fractional ALFF (fALFF) values in the precuneus, occipital pole and bilateral occipital cortex, and increased fALFF in the insula compared to HC. There were also differences between patients with and without AVH. (Ok to start with lower case?) fALFF values were higher in the putamen and insular cortex and lower in the frontal pole in HP compared to nHP and HC. ALFF increased in HP patients in the bilateral thalamus and bilateral parahippocampal gyrus, compared to nHP patients and HC. Our results suggest that altered dynamics in low-frequency fluctuations may play a key role in the neurophysiology of auditory hallucinations.