Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder. We included patients aged 18-64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of cannabis use carried the highest odds for psychotic disorder. Using Europe-wide and national data on the expected concentration of Δ9-tetrahydrocannabinol (THC) in the different types of cannabis available across the sites, we divided the types of cannabis used by participants into two categories: low potency (THC <10%) and high potency (THC ≥10%). Assuming causality, we calculated the population attributable fractions (PAFs) for the patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across the study sites. Between May 1, 2010, and April 1, 2015, we obtained data from 901 patients with first-episode psychosis across 11 sites and 1237 population controls from those same sites. Daily cannabis use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3·2, 95% CI 2·2-4·1), increasing to nearly five-times increased odds for daily use of high-potency types of cannabis (4·8, 2·5-6·3). The PAFs calculated indicated that if high-potency cannabis were no longer available, 12·2% (95% CI 3·0-16·1) of cases of first-episode psychosis could be prevented across the 11 sites, rising to 30·3% (15·2-40·0) in London and 50·3% (27·4-66·0) in Amsterdam. The adjusted incident rates for psychotic disorder were positively correlated with the prevalence in controls across the 11 sites of use of high-potency cannabis (r = 0·7; p=0·0286) and daily use (r = 0·8; p=0·0109). Differences in frequency of daily cannabis use and in use of high-potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availability of high-potency cannabis, this has important implications for public health. Medical Research Council, the European Community's Seventh Framework Program grant, São Paulo Research Foundation, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR BRC at University College London, Wellcome Trust.

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy‐genetic liability measures suggest gene‐environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS‐SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene‐environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS‐SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early‐life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS‐SCZ at 75% with alternative cut‐points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures.

High adherence to the Mediterranean diet (MD) has been associated with a reduced risk of depression in prospective cohort studies, but whether MD interventions are effective among adults with depression is uncertain. This study aimed to synthesize findings on the effects of MD interventions on the severity of depressive symptoms in adults with depression. PubMed, Cochrane CENTRAL, PsycINFO, Scopus, and Web of Science were systematically searched from database inception to March 2023. The Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines and the Cochrane recommendations were followed. We included randomized controlled trials (RCTs) comparing outcomes after MD interventions with outcomes for control conditions in adults with depressive disorders or depressive symptoms. Two authors extracted the data independently. The Sidik-Jonkman estimator, the I² metric, and the prediction interval were used to estimate between-study heterogeneity. To determine the risk of bias and the certainty of evidence from RCTs, we used the Cochrane Collaboration’s Risk of Bias 2 and Grades of Recommendation, Assessment, Development, and Evaluation tools, respectively. In total, 1507 participants (mean age range: 22.0 years–53.3 years) with depression were initially included in the 5 RCTs of this review. Compared with control conditions, MD interventions significantly reduced depressive symptoms among young and middle-aged adults with major depression or mild to moderate depressive symptoms (standardized mean difference: –0.53; 95% confidence interval: –0.90 to –0.16; I² = 87.1%). The prediction interval ranged from –1.86 to 0.81. The overall risk of bias was within the range of “some concerns” to “high,” while the certainty of evidence was low. MD interventions appear to have substantial potential for alleviating depressive symptoms in people experiencing major or mild depression. However, to establish robust recommendations, there remains a need for high-quality, large-scale, and long-term RCTs. PROSPERO registration no. CRD42022341895.

Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic “risk” and show how predictive modeling approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke’s R² were compared. The ES_{Meta-analyses} performed the worst, whereas the sum score and the ES_GNB were worse than the ES_LR that performed similar to the ES_LASSO and ES_RIDGE. The ES_LR distinguished patients from controls (odds ratio [OR] = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ES_LR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ES_LR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome.

Background: The neurocognitive trajectory in bipolar disorder (BD) is variable, with controversial findings, and most evidence come from cross-sectional studies. We aimed to examine the course of neurocognitive functioning in a sample of euthymic BD patients in comparison with a control group during a 5-year follow-up.Methods: Ninety-nine euthymic bipolar patients and 40 healthy controls were assessed using a comprehensive neurocognitive battery (six neurocognitive domains) at baseline (T1) and then at 5-year follow-up (T2) in a longitudinal study.Results: No evidence of a progression in neurocognitive dysfunction was found either in cognitive composite index or in any of the neurocognitive domains for the whole cohort. However, there was a negative correlation between number of manic episodes and hospitalisations due to manic episodes and change in neurocognitive composite index (NCI) during the follow-up. Moreover, patients with higher number of manic and hypomanic episodes have a greater decrease in NCI, working memory and visual memory. History of psychotic symptoms was not related to the trajectory of neurocognitive impairment.Conclusions: Our results suggest that, although the progression of cognitive decline is not a general rule in BD, BD patients who have a greater number of manic or hypomanic episodes may constitute a subgroup characterised by the progression of neurocognitive impairment. Prevention of manic and hypomanic episodes could have a positive impact on the trajectory of cognitive function.

Importance: Recent evidence syntheses have supported the protective role of daily steps in decreasing the risk of cardiovascular disease and all-cause mortality. However, step count–based recommendations should cover additional health outcomes.Objective: To synthesize the associations between objectively measured daily step counts and depression in the general adult population.Data Sources: In this systematic review and meta-analysis, a systematic search of the PubMed, PsycINFO, Scopus, SPORTDiscus, and Web of Science databases was conducted from inception until May 18, 2024, to identify observational studies using search terms related to physical activity, measures of daily steps, and depression, among others. Supplementary search methods were also applied.Study Selection: All identified studies were uploaded to an online review system and were considered without restrictions on publication date or language. Included studies had objectively measured daily step counts and depression data.Data Extraction and Synthesis: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted the published data.Main Outcomes and Measures: Pooled effect sizes (correlation coefficient, standardized mean difference [SMD], and risk ratio [RR]) with 95% CIs were estimated using the Sidik-Jonkman random-effects method.Results: Thirty-three studies (27 cross-sectional and 6 longitudinal [3 panel and 3 prospective cohort]) involving 96 173 adults aged 18 years or older (range of mean [SD] ages: 18.6 [0.6] to 91.2 [1.6] years) were included. Daily steps were inversely correlated with depressive symptoms in both cross-sectional and panel studies. Compared with fewer than 5000 steps/d, pooled SMDs from cross-sectional studies revealed that 10 000 or more steps/d (SMD, −0.26; 95% CI, −0.38 to −0.14), 7500 to 9999 steps/d (SMD, −0.27; 95% CI, −0.43 to −0.11), and 5000 to 7499 steps/d (SMD, −0.17; 95% CI, −0.30 to −0.04) were significantly associated with fewer depressive symptoms. Pooled estimates from prospective cohort studies indicated that participants with 7000 or more steps/d had reduced risk of depression compared with their counterparts with fewer than 7000 steps/d (RR, 0.69; 95% CI, 0.62-0.77). An increase of 1000 steps/d was associated with a lower risk of depression (RR, 0.91; 95% CI, 0.87-0.94).Conclusions and Relevance: In this systematic review and meta-analysis of 33 observational studies involving 96 173 adults, higher daily step counts were associated with fewer depressive symptoms in cross-sectional and longitudinal studies in the general adult population. Further prospective cohort studies are needed to clarify the potential protective role of daily steps in mitigating the risk of depression during adulthood.