Genetic propensity for obesity, socioeconomic position, and trajectories of body mass index in older adults

Identifying how socioeconomic positioning and genetic factors interact in the development of obesity is imperative for population-level obesity prevention strategies. The current study investigated whether social positioning, either independently or through interaction with a polygenic score for Body Mass Index (BMI-PGS), influences BMI trajectories across older adulthood. Data were analysed from 7,183 individuals from the English Longitudinal Study of Aging (ELSA). Interactions between the BMI-PGS and; lower educational attainment, self-perceived social status (SSS), and income, on BMI trajectories over 12 years across older adulthood were investigated through linear mixed effects models. Lower educational attainment, SSS and income were each associated with a higher baseline BMI for women, but not for men. There were interaction effects between BMI-PGS and social positioning such that men aged > 65 with a lower educational attainment (β = 0.62; 95%CI 0.00 - 1.24, p < 0.05), men aged ≤ 65 of a lower income (β = - 0.72, 95%CI - 1.21 - - 0.23, p < 0.01) and women aged ≤ 65 of lower SSS (β = - 1.41; 95%CI - 2.46 - 0.36, p < 0.01) showed stronger associations between the BMI-PGS and baseline BMI. There were few associations between markers of socioeconomic position and rate of change in BMI over the follow-up period. In sum, lower socioeconomic positioning showed adverse associations with women's BMI in older adulthood. Moreover, the expression of the BMI-PGS, or extent to which it translates to a higher BMI, was subtly influenced by socioeconomic standing in both women and in men

Higher risk of dementia in English older individuals who are overweight or obese

Background: Several risk factors contribute to dementia, but the role of obesity remains unclear. This study investigated whether increased body weight or central obesity were associated with a higher risk of developing dementia in a representative sample of older English adults. / Methods: We studied 6582 participants from the English Longitudinal Study of Ageing (ELSA) who were aged ≥50 years and were dementia-free at baseline, that being either wave 1 (2002–2003) for study members who started at wave 1, or at either wave 2 (2004–2005) or 4 (2008–2009) for those who began the study as refreshment samples. Body mass index (BMI) was measured at baseline and categorized into normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2) and obese (≥30 kg/m2). Central obesity was defined as a waist circumference (WC) >88 cm for women and >102 cm for men. Cumulative incidence of dementia was ascertained based on physician-diagnosed dementia, an overall score >3.38 on the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and Hospital Episodes Statistics (HES) data at every ELSA wave from baseline until wave 8 (2016–2017). Cox proportional hazards models were used to assess the association between baseline BMI levels or abdominal obesity in relation to dementia incidence during the mean follow-up period of 11 years. / Results: From the overall sample, 6.9% (n = 453) of participants developed dementia during the follow-up period of maximum 15 years (2002–2017). Compared with participants with normal weight, those who were obese at baseline had an elevated risk of dementia incidence [hazard ratio (HR) = 1.34, 95% confidence interval (CI) 1.07–1.61] independent of sex, baseline age, apolipoprotein E-ε4 (APOE-ε4), education, physical activity, smoking and marital status. The relationship was slightly accentuated after additionally controlling for hypertension and diabetes (HR = 1.31, 95% CI 1.03–1.59). Women with central obesity had a 39% greater risk of dementia compared with non-central obese women (HR = 1.39, 95% CI 1.12–1.66). When compared with a normal BMI and WC group, the obese and high WC group had 28% (HR = 1.28, 95% CI 1.03–1.53) higher risk of dementia. / Conclusions: Our results suggest that having an increased body weight or abdominal obesity are associated with increased dementia incidence. These findings have significant implications for dementia prevention and overall public health

Schizophrenia polygenic risk predicts general cognitive deficit but not cognitive decline in healthy older adults

There has been a long argument over whether schizophrenia is a neurodegenerative disorder associated with progressive cognitive impairment. Given high heritability of schizophrenia, ascertaning if genetic susceptibility to schizophrenia is also associated with cognitive decline in healthy people would support the view that schizophrenia leads to an accelerated cognitive decline. Using the population representative sample of 6817 adults aged >50 years from the English Longitudinal Study of Ageing, we investigated associations between the biennial rate of decline in cognitive ability and the schizophrenia polygenic score (SZ-PGS) during the 10-year follow-up period. SZ-PGS was calculated based on summary statistics from the Schizophrenia Working Group of the Psychiatric Genomics Consortium. Cognition was measured sequentially across four time points using verbal memory and semantic fluency tests. The average baseline verbal memory was 10.4 (SD = 3.4) and semantic fluency was 20.7 (SD = 6.3). One standard deviation (1-SD) increase in SZ-PGS was associated with lower baseline semantic fluency (β = −0.25, 95%CI = −0.40 to −0.10, p = 0.002); this association was significant in men (β = −0.36, 95%CI = −0.59 to −0.12, p = 0.003) and in those who were aged 60–69 years old (β = −0.32, 95%CI = −0.58 to −0.05, p = 0.019). Similarly, 1-SD increase in SZ-PGS was associated with lower verbal memory score at baseline in men only (β = −0.12, 95%CI = −0.23 to −0.01, p = 0.040). However, SZ-PGS was not associated with a greater rate of decline in these cognitive domains during the 10-year follow-up. Our findings highlight that while genetic susceptibility to schizophrenia conveys developmental cognitive deficit, it is not associated with an ongoing cognitive decline, at least in later life. These results do not support the neo-Kraepelinian notion of schizophrenia as a genetically determined progressively deteriorating brain disease

Remission and recovery from first-episode psychosis in adults: systematic review and meta-analysis of long-term outcome studies

Background: Remission and recovery rates for people with first-episode psychosis (FEP) remain uncertain. Aims: To assess pooled prevalence rates of remission and recovery in FEP and to investigate potential moderators. Method: We conducted a systematic review and meta-analysis to assess pooled prevalence rates of remission and recovery in FEP in longitudinal studies with more than 1 year of follow-up data, and conducted meta-regression analyses to investigate potential moderators. Results: Seventy-nine studies were included representing 19072 patients with FEP. The pooled rate of remission among 12301 individuals with FEP was 58% (60 studies, mean follow-up 5.5 years). Higher remission rates were moderated by studies from more recent years. The pooled prevalence of recovery among 9642 individuals with FEP was 38% (35 studies, mean follow-up 7.2 years). Recovery rates were higher in North America than in other regions. Conclusions: Remission and recovery rates in FEP may be more favourable than previously thought. We observed stability of recovery rates after the first 2 years, suggesting that a progressive deteriorating course of illness is not typical. Although remission rates have improved over time recovery rates have not, raising questions about the effectiveness of services in achieving improved recovery

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

The role of loneliness in the association between chronic physical illness and depressive symptoms among older adults: A prospective cohort study

BACKGROUND: Chronic physical illness increases the risk of subsequent depressive symptoms, but we know little about the mechanisms underlying this association that interventions can target. We investigated whether loneliness might explain associations between chronic illness and subsequent depressive symptoms. METHODS: We used English Longitudinal Study of Ageing data, a prospective cohort of adults over 50. Our exposure was chronic illnesses (wave two) including arthritis, cancer, diabetes, cardiovascular disease, stroke, and chronic obstructive pulmonary disease. Loneliness scores were a mediator on the short University of California, Los Angeles Loneliness Scale at wave three. Depressive symptom scores (outcome) were measured using the Centre for Epidemiologic Studies Depression Scale (wave four). We examined associations of chronic physical illness with loneliness and depressive symptoms in univariable and multivariable regression models. RESULTS: Fully-adjusted models included 2436 participants with the depression outcome and 2052 participants with the loneliness outcome. Chronic physical illness was associated with 21 % (incident rate ratio = 1.21, 95%CI = 1.03–1.42) higher depression scores at follow-up. We found no evidence of an association between chronic physical illness and loneliness and therefore did not proceed to analyses of mediation. LIMITATIONS: More prevalent chronic illnesses could have driven our results, such as cardiovascular disease. CONCLUSIONS: Chronic physical illnesses increase the risk of depressive symptoms in older adults. However, we did not find any that chronic physical illnesses were associated with an increased risk of subsequent loneliness. Therefore, interventions targeting loneliness to reduce depression in older adults with chronic physical illness may be insufficient

Sodium valproate and clozapine induced neutropenia: A case control study using register data

BACKGROUND: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine. METHOD: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment. RESULTS: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27–4.11, p = 0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p < 0.001), were younger (t = 5.86, df = 267, p < 0.001), and received lower doses of clozapine (t = − 2.587, p = 0.01) than those who did not develop neutropenia. CONCLUSION: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment

The association between loneliness and depressive symptoms among adults aged 50 years and older: a 12-year population-based cohort study

Background: Loneliness is experienced by a third of older adults in the UK and is a modifiable potential risk factor for depressive symptoms. It is unclear how the association between loneliness and depressive symptoms persists over time, and whether it is independent of related social constructs and genetic confounders. We aimed to investigate the association between loneliness and depressive symptoms, assessed on multiple occasions during 12 years of follow-up, in a large, nationally representative cohort of adults aged 50 years and older in England. / Methods: We did a longitudinal study using seven waves of data that were collected once every 2 years between 2004 and 2017, from adults aged 50 years and older in the English Longitudinal Study of Ageing (ELSA). The exposure was loneliness at baseline (wave two), measured with the short 1980 revision of the University of California, Los Angeles Loneliness Scale (R-UCLA). The primary outcome was a score indicating severity of depression measured at six subsequent timepoints (waves three to eight), using the eight-item version of the Centre for Epidemiologic Studies Depression Scale (CES-D). Analyses were linear multilevel regressions, before and after adjusting for social isolation, social support, polygenic risk scores, and other sociodemographic and health-related confounders. The secondary outcome was depression diagnosis, measured using a binary version of the CES-D. / Findings: 4211 (46%) of 9171 eligible participants had complete data on exposure, outcome, and confounders, and were included in our complete case sample. After all adjustments, a 1-point increase in loneliness score was associated with a 0·16 (95% CI 0·13–0·19) increase in depressive symptom severity score (averaged across all follow-ups). We estimated a population attributable fraction for depression associated with loneliness of 18% (95% CI 12–24) at 1 year of follow-up and 11% (3–19) at the final follow-up (wave eight), suggesting that 11–18% of cases of depression could potentially be prevented if loneliness were eliminated. Associations between loneliness and depressive symptoms remained after 12 years of follow-up, although effect sizes were smaller with longer follow-up. / Interpretation: Irrespective of other social experiences, higher loneliness scores at baseline were associated with higher depression symptom severity scores during 12 years of follow-up among adults aged 50 years and older. Interventions that reduce loneliness could prevent or reduce depression in older adults, which presents a growing public health problem worldwide. / Funding: National Institute on Aging and a consortium of UK Government departments coordinated by the National Institute for Health Research

Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample

Evidence suggests there are two treatment-resistant schizophrenia subtypes (i.e. early treatment resistant (E-TR) and late-treatment resistant (L-TR)). We aimed to develop prediction models for estimating individual risk for these outcomes by employing advanced statistical shrinkage methods. 239 first-episode schizophrenia (FES) patients were followed-up for approximately 5 years after first presentation to psychiatric services; of these, n=56 (25.2%) were defined as E-TR and n=24 (12.6%) were defined as L-TR. Using known risk factors for poor schizophrenia outcomes, we developed prediction models for E-TR and L-TR using LASSO and RIDGE logistic regression models. Models’ internal validation was performed employing Harrell's optimism-correction with repeated cross-validation; their predictive accuracy was assessed through discrimination and calibration. Both LASSO and RIDGE models had high discrimination, good calibration. While LASSO had moderate sensitivity for estimating an individual risk for E-TR and L-TR, sensitivity estimated for RIDGE model for these outcomes was extremely low, which was due to having a very large estimated optimism. Although it was possible to discriminate with sufficient accuracy who would meet criteria for E-TR and L-TR during the 5-year follow-up after first contact with mental health services for schizophrenia, further work is necessary to improve sensitivity for these models