We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1,048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Objective: COVID-19-related inequities experienced by racial and ethnic minority groups including healthcare professionals mirror wider health inequities, which risk being perpetuated by lower uptake of vaccination. We aim to better understand lower uptake among racial and ethnic minority staff groups to inform initiatives to enhance uptake. Design: Twenty-five semi-structured interviews were conducted (October 2020-January 2021) with UK-based healthcare staff. Data were inductively and thematically analysed. Results: Vaccine decision-making processes were underpinned by an overarching theme, 'weighing up risks of harm against potential benefits to self and others'. Sub-themes included 'fear of harm', 'moral/ethical objections', 'potential benefits to self and others', 'information and misinformation', and 'institutional or workplace pressure'. We identified ways in which these were weighted more heavily towards vaccine hesitancy for racial and ethnic minority staff groups influenced by perceptions about institutional and structural discrimination. This included suspicions and fear around institutional pressure to be vaccinated, racial injustices in vaccine development and testing, religious or ethical concerns, and legitimacy and accessibility of vaccine messaging and communication. Conclusions: Drawing on a critical race perspective, we conclude that acknowledging historical and contemporary abuses of power is essential to avoid perpetuating and aggravating mistrust by decontextualising hesitancy from the social processes affecting hesitancy, undermining efforts to increase vaccine uptake.
BackgroundThe increasingly large sample size requirements of modern adult mental health research suggests the need for a data collection and diagnostic application that can be used across a broad range of clinical and research populations.AimsTo develop a data collection and diagnostic application that can be used across a broad range of clinical and research settings.MethodWe expanded and redeveloped the OPCRIT system into a broadly applicable diagnostic and data-collection package and carried out an interrater reliability study of this new tool.ResultsOPCRIT+ performed well in an interrater reliability study with relatively inexperienced clinicians, giving a combined, weighted kappa of 0.70 for diagnostic reliability.ConclusionsOPCRIT+ showed good overall interrater reliability scores for diagnoses. It is now incorporated in the electronic patient record of the Maudsley and associated hospitals. OPCRIT+ can be downloaded free of charge at .
In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
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