This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Massively parallel cDNA sequencing (RNA-seq) experiments are gradually superseding microarrays in quantitative gene expression profiling. However, many biologists are uncertain about the choice of differentially expressed gene (DEG) analysis methods and the validity of cost-saving sample pooling strategies for their RNA-seq experiments. Hence, we performed experimental validation of DEGs identified by Cuffdiff2, edgeR, DESeq2 and Two-stage Poisson Model (TSPM) in a RNA-seq experiment involving mice amygdalae micro-punches, using high-throughput qPCR on independent biological replicate samples. Moreover, we sequenced RNA-pools and compared their results with sequencing corresponding individual RNA samples. False-positivity rate of Cuffdiff2 and false-negativity rates of DESeq2 and TSPM were high. Among the four investigated DEG analysis methods, sensitivity and specificity of edgeR was relatively high. We documented the pooling bias and that the DEGs identified in pooled samples suffered low positive predictive values. Our results highlighted the need for combined use of more sensitive DEG analysis methods and high-throughput validation of identified DEGs in future RNA-seq experiments. They indicated limited utility of sample pooling strategies for RNA-seq in similar setups and supported increasing the number of biological replicate samples.

Background: Depression in old age is an important public health problem causing considerable morbidity and disability worldwide. There is a dearth of community studies from India investigating geriatric depression and its associated risk factors. This study aimed to establish the nature, prevalence and factors associated with geriatric depression in a rural south Indian community.Methods: We recruited 1000 participants aged over 65 years from Kaniyambadi block, Vellore, India. We assessed their socio-demographic profile, psychiatric morbidity, cognitive functioning, anthropometrics and disability status using the following structured assessment tools: Geriatric Mental State, Community Screening Instrument for Dementia, Modified CERAD 10 word list learning task, History and Aetiology Schedule Dementia Diagnosis and Subtype, WHO Disability Assessment Scale II, and Neuropsychiatric Inventory. We adopted a case control framework to study the factors associated with geriatric depression.Results: Prevalence of geriatric depression (ICD-10) within the previous one month was 12.7% (95% CI 10.64–14.76%). Low income (OR 1.78; 95% CI 1.08–2.91), experiencing hunger (OR 2.58; 95% CI 1.56–4.26), history of cardiac illnesses (OR 4.75; 95% CI 1.96–11.52), transient ischemic attack (OR 2.43; 95% CI 1.17–5.05), past head injury (OR 2.70; 95% CI 1.36–5.36) and diabetes (OR 2.33; 95% CI 1.15–4.72) increased the risk for geriatric depression after adjusting for other determinants using conditional logistic regression. Having more confidants (OR 0.13; 95% CI 0.06–0.26) was the significant protective factor. Age, female gender, cognitive impairment and disability status were not significantly associated with geriatric depression. DSM-IV diagnosis of major depression was significantly correlated with experiencing hunger, diabetes, transient ischemic attack, past head injury, more disability and less nourishment; having more friends was protective.Conclusions: Geriatric depression is prevalent in rural south India. Poverty and physical ill health are risk factors for depression among elderly while good social support is protective.