Validation of an algorithm-based definition of treatment resistance in patients with schizophrenia

Large-scale pharmacoepidemiological research on treatment resistance relies on accurate identification of people with treatment-resistant schizophrenia (TRS) based on data that are retrievable from administrative registers. This is usually approached by operationalising clinical treatment guidelines by using prescription and hospital admission information. We examined the accuracy of an algorithm-based definition of TRS based on clozapine prescription and/or meeting algorithm-based eligibility criteria for clozapine against a gold standard definition using case notes. We additionally validated a definition entirely based on clozapine prescription. 139 schizophrenia patients aged 18–65 years were followed for a mean of 5 years after first presentation to psychiatric services in South-London, UK. The diagnostic accuracy of the algorithm-based measure against the gold standard was measured with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A total of 45 (32.4%) schizophrenia patients met the criteria for the gold standard definition of TRS; applying the algorithm-based definition to the same cohort led to 44 (31.7%) patients fulfilling criteria for TRS with sensitivity, specificity, PPV and NPV of 62.2%, 83.0%, 63.6% and 82.1%, respectively. The definition based on lifetime clozapine prescription had sensitivity, specificity, PPV and NPV of 40.0%, 94.7%, 78.3% and 76.7%, respectively. Although a perfect definition of TRS cannot be derived from available prescription and hospital registers, these results indicate that researchers can confidently use registries to identify individuals with TRS for research and clinical practices

Gliclazide may have an antiapoptotic effect related to its antioxidant properties in human normal and cancer cells

Experimental and clinical studies suggest that gliclazide may protect pancreatic β-cells from apoptosis induced by an oxidative stress. However, the precise mechanism(s) of this action are not fully understood and requires further clarification. Therefore, using human normal and cancer cells we examined whether the anti-apoptotic effects of this sulfonylurea is due to its free radical scavenger properties. Hydrogen peroxide (H2O2) as a model trigger of oxidative stress was used to induce cell death. Our experiments were performed on human normal cell line (human umbilical vein endothelial cell line, HUVEC-c) and human cancer cell lines (human mammary gland cell line, Hs578T; human pancreatic duct epithelioid carcinoma cell line, PANC-1). To assess the effect of gliclazide the cells were pre-treated with the drug. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was employed to measure the impact of gliclazide on cell viability. Generation of reactive oxygen species, mitochondrial membrane potential (∆Ψm), and intracellular Ca2+ concentration [Ca2+] were monitored. Furthermore, the morphological changes associated with apoptosis were determined using double staining with Hoechst 33258-propidium iodide (PI). Gliclazide protects the tested cells from H2O2-induced cell death most likely throughout the inhibition of ROS production. Moreover, the drug restored loss of ΔΨm and diminished intracellular [Ca2+] evoked by H2O2. Double staining with Hoechst 33258-PI revealed that pre-treatment with gliclazide diminished the number of apoptotic cells. Our findings indicate that gliclazide may protect both normal and cancer human cells against apoptosis induced by H2O2. It appears that the anti-apoptotic effect of the drug is most likely associated with reduction of oxidative stress

Metabolic profile at first-time schizophrenia diagnosis: a population-based cross-sectional study

Henriette Thisted Horsdal,1,2 Michael Eriksen Benros,2,3 Ole Köhler-Forsberg,2–4 Jesper Krogh,3 Christiane Gasse1,2,5 1National Centre for Register-based Research, Department of Economics and Business Economics, Aarhus BSS, Aarhus University, Aarhus, 2The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, 3Faculty of Health Sciences, Mental Health Centre Copenhagen, University of Copenhagen, Copenhagen, 4Psychosis Research Unit, Aarhus University Hospital, Risskov, 5Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark Objective: Schizophrenia and/or antipsychotic drug use are associated with metabolic abnormalities; however, knowledge regarding metabolic status and physician’s monitoring of metabolic status at first schizophrenia diagnosis is sparse. We assessed the prevalence of monitoring for metabolic blood abnormalities and characterized the metabolic profiles in people with a first-time schizophrenia diagnosis. Methods: This is a population-based cross-sectional study including all adults born in Denmark after January 1, 1955, with their first schizophrenia diagnosis between 2000 and 2012 in the Central Denmark Region. Information on metabolic parameters was obtained from a clinical laboratory information system. Associations were calculated using Wilcoxon rank-sum tests, chi-square tests, logistic regression, and Spearman’s correlation coefficients. Results: A total of 2,452 people with a first-time schizophrenia diagnosis were identified, of whom 1,040 (42.4%) were monitored for metabolic abnormalities. Among those monitored, 58.4% had an abnormal lipid profile and 13.8% had an abnormal glucose profile. People who had previously filled prescription(s) for antipsychotic drugs were more likely to present an abnormal lipid measure (65.7% vs 46.8%, P<0.001) and abnormal glucose profile (16.4% vs 10.1%, P=0.01). Conclusion: Metabolic abnormalities are common at first schizophrenia diagnosis, particularly among those with previous antipsychotic prescription(s). Increased metabolic abnormalities already present in the early phase of schizophrenia emphasize the need for increased monitoring and management. Keywords: schizophrenia, metabolism, epidemiology, lipids, glucos