Depression is a leading cause of disability among adolescents, yet the biological mechanisms underlying its onset and clinical course remain poorly understood. Dysregulation of immune and metabolic pathways has been increasingly implicated in adolescent depression, but longitudinal data linking these mechanisms to clinical trajectories are still limited. We investigated transcriptomic profiles in a three-year longitudinal study of n=50 adolescents with major depressive disorder (MDD) and n=50 adolescents at high sociodemographic risk (HR) for developing MDD, recruited as part of the IDEA-RiSCo cohort in Brazil. Remission (for the MDD group) or transition to depression (for the HR group) were evaluated at 3-year follow-up. Peripheral blood transcriptomics were analyzed using RNA-sequencing, and differentially expressed transcripts were subjected to pathway analysis. Baseline and 3-year follow-up transcriptomics profiles were compared between (i) adolescents with remitted versus persistent MDD, and between (ii) HR adolescents who transitioned to MDD versus those who did not. Adolescents with MDD at baseline who later remitted showed a change in activation of inflammatory pathways between baseline and 3-year follow-up when compared with those with persistent MDD, presenting an initial stronger pro-inflammatory signature which reversed at follow-up with a recovery of adaptive immune pathways, including upregulation of IL-4 signaling and downregulation of CTLA4 and neutrophil degranulation pathways. In contrast, HR adolescents who transitioned to MDD displayed early dysregulation of immune and GABAergic and glutamatergic pathways, with subsequent downregulation of cell cycle regulation, intracellular signaling, and serotonin receptor pathways at follow-up. This study identifies distinct transcriptomic signatures underlying divergent trajectories of adolescent depression. A dynamic regulation of inflammatory responses appears to support remission, while progressive impairment of immune, metabolic, GABAergic, glutamatergic and serotoninergic pathways characterizes both persistence of MDD and the transition from high-risk status to disorder onset. These findings highlight potential biological targets for prevention and stratified interventions in adolescent depression.

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