Vladimir Đorđević

Serotonin 5-HT2 receptor agonists are returning to psychiatric drug development, but separating the three receptor subtypes pharmacologically remains difficult, and agonism at 5-HT2B carries a risk of valvular heart disease. A recent study reported affinities of 46 N-benzyltryptamines and N-benzyl-5-methoxytryptamines at all three human subtypes and analyzed them with an additive substituent model, which gave fragment coefficients of the same sign at every subtype and suggested that selectivity within this scaffold would be hard to achieve. We revisited that conclusion with non-additive models built under a protocol designed for small datasets: fifty stratified partitions with all filtering and hyperparameter tuning inside each training set, external statistics reported as distributions, response permutation on three partitions per endpoint, and partitions that withhold an entire scaffold or an entire substitution position. We repeated the analysis with two descriptor sets that share no variables and are built on different principles. Penalized linear models were predictive and transferable, whereas gradient boosting reproduced the training set exactly, and neither tree ensemble transferred to a held-out scaffold. Fragment contributions at 5-HT2A and 5-HT2C correlated at 0.25 compared with 0.77 for whole-molecule affinities, and both descriptor sets gave the same figure within 0.01. All models failed on para-substituted analogs, which distance-based applicability-domain criteria did not flag, whereas models trained without the ortho or the meta block stayed above a mean-predictor baseline. Aggregation over the whole molecule, rather than descriptor choice, conceals subtype divergence. One group drives the divergence: the N-benzyl substituent raises the predicted 5-HT2A affinity and lowers the predicted 5-HT2C affinity; excluding it raised the correlation to 0.93.

Background/Objectives: Emerging evidence suggests a role of immune–inflammatory mechanisms in the pathophysiology of schizophrenia, particularly in the early stages of the illness. Cytokines, as key mediators of inflammation, may affect brain function and clinical presentation. Drug-naive patients with first-episode psychosis (FEDN) offer a unique opportunity to investigate these associations free from confounding pharmacological effects. Methods: This study included 38 patients with drug-naive first episode psychosis and 22 age- and sex-matched healthy controls. Serum concentrations of IL-1β, IL-2, IL-6, and IL-10 were measured using ELISA. Clinical symptoms were assessed using the PANSS scale. Statistical analyses included Mann–Whitney U tests, Spearman’s correlations, and ROC curve analysis. Results: Significantly elevated serum levels of IL-1β, IL-2, and IL-10 were observed in the FEDN group compared to the controls (p < 0.01), while IL-6 levels did not differ significantly. IL-2 exhibited the highest discriminatory power in differentiating the patients from the controls (AUC = 0.917; 95% CI: 0.759–1000.0; p < 0.001). IL-1β levels positively correlated with negative and general psychopathology symptoms, including hostility and grandiosity. IL-10 was associated with volitional disturbance and overall PANSS severity. Conclusions: Our findings underscore the relevance of immune dysregulation in the early stages of psychosis and highlight the potential of specific cytokines, particularly IL-2 and IL-1β, as peripheral biomarkers. Their diagnostic utility and correlation with symptom dimensions suggest a promising role in the development of precision psychiatry approaches, including early detection strategies and individualised therapeutic targeting. Longitudinal studies are needed to validate these findings and to assess their prognostic significance.

Background: The COVID-19 pandemic has brought into focus the mental health of the student population. The study aimed to analyze the psychological response to the COVID-19 outbreak in terms of perceived stress and its related factors among university students in south-east Serbia. The study was conducted during the increased incidence of COVID-19 in Serbia. Method: A total of 434 students from the public university in south-east Serbia enrolled in the study and completed the measures of socio-demographic data, the perceived stress scale (PSS-10), the Coping Strategy Indicator (CSI) and the General Health Questionnaire (GHQ-28). The data were analyzed through quantitative and qualitative methods. Results: Study findings suggest that the mean perceived stress score was placed to 20.43 (± 7.67). Our model showed that female gender, higher scores on anxiety/insomnia and depression subscale as well as the coping strategy avoidance predicted higher perceived stress, while higher scores on social dysfunction were related to the reduced perceived stress scores. Conclusion: Notwithstanding the study limitation, findings provided authentic data of stress reactions of the students in south-east Serbia during the COVID-19 outbreak. The findings confirm the need to examine students' experiences in emergencies and crises, as well as to make a plan for online stress management programs that would help alleviate stress during a global pandemic.