Psychiatry

Adolescent SSRI exposure does not alter later nonaffective psychosis risk

This Welsh quasi-experimental study followed 6615 adolescents with depression treated in Child and Adolescent Mental Health Services. Regional SSRI prescribing variation served as an instrumental variable to estimate the causal effect of cumulative adolescent SSRI treatment on later nonaffective psychosis. Across 1-, 2-, and 3-year exposure windows, cumulative SSRI prescriptions showed no significant association with subsequent psychosis risk, with confidence intervals spanning the null. Findings argue against both psychosis-protective and psychosis-inducing causal effects of SSRI treatment in depressed adolescents. 1

EEG-based dlPFC sensitivity index predicts rTMS benefit in MDD

Investigators developed a dorsolateral prefrontal cortex sensitivity index from EEG functional connectivity using L1-regularized logistic regression. Patients with major depressive disorder were prospectively stratified as EEG-sensitive, non-sensitive, or sham and all received a two-week personalized neuronavigated bilateral dlPFC rTMS protocol. Baseline sensitivity index significantly predicted clinical and cognitive outcomes, including larger reductions in hostility and paranoia and better emotional attention task performance in sensitive patients. Post-treatment EEG demonstrated network-specific modulation only in sensitivity-defined responders, supporting mechanistic specificity. 2

Distinct cytokine signatures in clinical vs genetic psychosis high-risk states

This network meta-analysis synthesized 30 studies including 1601 clinical high-risk, 675 genetic high-risk, and 1980 healthy control participants. Clinical high-risk individuals showed higher IL-6 levels than genetic high-risk participants, indicating greater immune activation in symptomatic states. Genetic high-risk groups had lower IL-6 and IL-1β levels than healthy controls, suggesting a distinct, possibly hypo-inflammatory profile. Within clinical high-risk samples, converters to psychosis had higher IL-13 levels than non-converters, implicating Th2-related pathways in transition risk. 3

Genetically proxied TNF-α inhibition associated with lower MDD risk

This study combined drug-target Mendelian randomization with a large UK Biobank cohort to examine TNF-α–related inflammation in major depressive disorder. Genetic proxies for TNF-α inhibition, defined by TNF-locus variants lowering C-reactive protein and leukocyte counts, were associated with reduced MDD risk in Mendelian randomization analyses. Specific depressive features, including mood, weight loss, hypersomnia, and suicidal thoughts, showed potential improvement, whereas insomnia risk increased. In 421,062 UK Biobank participants, a higher TNF-α inhibitor genetic score predicted lower incident MDD, with consistent effects across demographic and clinical subgroups. 4