Psychiatry

Convergent brain–blood molecular signatures in MDD highlight shared pathways and GWAS‑linked hub genes

This systematic review integrated 54 omics studies of brain and blood in major depressive disorder, including bulk and single‑nucleus data. Across studies, 744 differentially expressed genes and 544 differentially methylated genes were altered concordantly in brain and blood. A subset of these genes overlapped with MDD GWAS loci, anchoring peripheral signals to genetically implicated risk pathways. Hub genes converged on developmental, inflammatory, transcriptional, apoptotic, and mitochondrial pathways rather than single, disorder‑specific markers. Findings support pursuing pathway‑level and cell‑type–specific biomarkers, rather than isolated genes, for stratification and target discovery. 1

Inflammatory–metabolic multi‑omics subtypes of MDD predict antidepressant response

In 134 adults with DSM‑5 MDD, multi‑omics profiling (CyTOF, cytokines, metabolomics) identified three biological subtypes using integrative clustering. Subtype MoS2 showed significantly poorer 8‑week antidepressant response than MoS1, with very low odds of response on weighted analyses. MoS2 was characterized by elevated triglycerides and increased regulatory T cells, suggesting an immune–metabolic depression phenotype. MoS1 showed enhanced T‑cell activity and higher growth factors, while MoS3 had elevated monocytes and modest cytokine changes. Subtype membership independently predicted treatment outcome, indicating potential for future stratified antidepressant trials and tailored interventions. 2

Cortical excitability maps define two biologically distinct first‑episode schizophrenia subtypes

This study mapped cortical excitability in 77 drug‑naïve first‑episode schizophrenia patients versus 76 controls using voxel‑wise analyses. Patients showed excitability abnormalities mainly in bilateral frontal, sensorimotor, and right cuneus regions compared with healthy controls. Clustering revealed two subtypes: FES1 with widespread cortical excitability reductions and greater affective and cognitive burden, and FES2 with milder changes. Longitudinal follow‑up over 12 months linked these excitability patterns to distinct clinical trajectories under antipsychotic treatment. Transcriptomic and receptor mapping suggested that FES1 reflects synaptic and neurodevelopmental disruption, whereas FES2 involves broader, possibly compensatory, systems. 3

Combined oral contraceptives are linked to poorer escitalopram response in premenopausal women with MDD

In 60 unmedicated premenopausal women with MDD, EEG biomarkers were measured before 8 weeks of escitalopram treatment. Groups included non‑users, combined oral contraceptive users, and progestin‑only contraceptive users. Baseline EEG biomarkers did not differ meaningfully by contraceptive status, but adding contraceptive group improved EEG‑based prediction models of response. Clinically, combined oral contraceptive users had substantially lower antidepressant response rates than non‑users, while progestin‑only users were intermediate. LASSO models suggested contraceptive status may interact with alpha peak frequency and anterior cingulate theta in predicting treatment outcome. 4