Longitudinal transcriptomic profiles associated with onset and remission of adolescent depression

Authors

• Valentina Zonca, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. Electronic address: [email protected].
• Samantha Saleri, Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni, 4, 25125 Brescia, Italy.
• Moira Marizzoni, Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni, 4, 25125 Brescia, Italy.
• Pedro H. Manfro, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Child & Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350-400N, Porto Alegre, RS 90035-903, Brazil.
• Naghmeh Nikkheslat, King's College London, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, King's College London, London, UK.
• Jader Piccin, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Child & Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350-400N, Porto Alegre, RS 90035-903, Brazil.
• Laila Souza, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Child & Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350-400N, Porto Alegre, RS 90035-903, Brazil.
• Anna Viduani, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Child & Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350-400N, Porto Alegre, RS 90035-903, Brazil.
• Zuzanna Zajkowska, King's College London, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, London, UK.
• Johnna R. Swartz, Department of Human Ecology, University of California, Davis, CA 95616, USA.
• Helen L. Fisher, King's College London, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; ESRC Centre for Society and Mental Health, King's College London, London, UK.
• Brandon A. Kohrt, Center for Global Mental Health Equity, Department of Psychiatry and Behavioral Health, School of Medicine and Health Sciences, The George Washington University, 2120 L St NW, Ste 600, Washington, DC 20037D, USA.
• Christian Kieling, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Child & Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350-400N, Porto Alegre, RS 90035-903, Brazil; Instituto de Pesquisa, Hospital Moinhos de Vento, Porto Alegre, RS, Brazil.
• Annamaria Cattaneo, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni, 4, 25125 Brescia, Italy.
• Valeria Mondelli, King's College London, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, King's College London, London, UK.

Document Type

Journal Article

Publication Date

3-27-2026

Journal

Brain, behavior, and immunity

DOI

10.1016/j.bbi.2026.106566

Keywords

Adolescent depression; High-risk adolescents; Immune pathways; Inflammation; Longitudinal Study; Major depressive disorder (MDD); RNA-sequencing; Remission

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

APA Citation

Zonca, Valentina; Saleri, Samantha; Marizzoni, Moira; Manfro, Pedro H.; Nikkheslat, Naghmeh; Piccin, Jader; Souza, Laila; Viduani, Anna; Zajkowska, Zuzanna; Swartz, Johnna R.; Fisher, Helen L.; Kohrt, Brandon A.; Kieling, Christian; Cattaneo, Annamaria; and Mondelli, Valeria, "Longitudinal transcriptomic profiles associated with onset and remission of adolescent depression" (2026). GW Authored Works. Paper 8817.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8817

Department

Psychiatry and Behavioral Sciences