2026 ECNP Congress

PS01-1080

Peripheral immune cell phenotypes associated with depression risk, diagnosis and remission in adolescents

Naghmeh Nikkheslat — S. Solanky, Z. Zajkowska, J. Hardman-Smart, I. Tosi, N. Dand, P. Manfro, L. Souza, R. Pereira, F. Rohrsetzer, J. Piccin, A. Viduani, B.A. Kohrt, H. Fisher, J. Swartz, C. Kieling, P. Di Meglio, V. Mondelli · Institute of Psychiatry- Psychology & Neuroscience- King’s College London, Department of Psychological Medicine, London, United Kingdom

2026 ECNP Congress

Background

Immune dysregulation has been implicated in major depressive disorder (MDD), but most evidence derives from adult populations and focuses on circulating inflammatory markers. Less is known about cellular immune alterations during adolescence, a developmental period characterised by substantial neuroimmune maturation and increased vulnerability to depression. Understanding peripheral immune cell phenotypes associated with depression risk, diagnosis, and clinical trajectory may provide insight into early pathophysiological mechanisms.

Aims

We aimed to investigate peripheral blood cellular immunophenotypes associated with (1) current MDD, (2) risk for future depression, and (3) clinical trajectory (remission versus persistence of MDD) in adolescents, with a particular focus on sex-dependent patterns.

Methods

Baseline peripheral blood mononuclear cells were obtained from a longitudinal cohort of 139 adolescents (mean age 15.6 ± 0.8 years; 49% female) recruited from schools in Porto Alegre in Brazil [1,2]. Participants included 43 with current MDD and 96 without depression, stratified into low-risk (n=49) and high-risk (n=47) groups based on a validated sociodemographic risk score [3]. Follow-up after three years assessed remission or persistence of MDD. High-dimensional spectral flow cytometry was used to characterise immune cell populations using phenotypic and functional panels. After quality control, 127 samples (phenotypic panel) and 102 samples (functional panel) were analysed. Data were examined using unsupervised clustering and supervised manual gating. Group differences were assessed using non-parametric tests (Mann–Whitney U and Kruskal–Wallis), with false discovery rate correction applied within immune cell compartments. Sex-stratified analyses were conducted to explore potential sex-dependent effects.

Results

No statistically significant differences were observed in the full cohort after correction for multiple comparisons. However, sex-stratified analyses revealed distinct patterns. Intermediate monocytes were higher in females with MDD compared with those without (median 7.9%, range 2.10-19.70 vs 3.8%, range 1.15%-19.90, p=0.016). In addition, female adolescents with MDD showed a higher frequency of activated central memory cluster of CD4 positive T cells expressing CD69 compared with those without MDD (median 2.24%, range 0.31–4.43 vs 1.22%, 0.31–4.43; p=0.0007) and compared with low-risk adolescents (median 2.24%, 0.78–5.09 vs 1.17%, 0.38–2.67; p=0.0051). In males, the same cell population was higher in high-risk compared with low-risk adolescents (median 1.58%, 0.71–4.65 vs 0.95%, 0.09–3.45; p=0.016) and compared with those with MDD (median 1.09%, 0.31–2.37; p=0.026). At three-year follow-up, adolescents who remitted from MDD had a greater baseline frequency of naïve FOXP3-expressing CD8 positive T cells compared with those with persistent depression (mean 20.45% ± 8.47 vs 13.24% ± 6.31; p=0.012), particularly among males.

Conclusions

These findings suggest that adolescent depression is associated with alterations in both innate and adaptive immune cell populations, with evidence for sex-dependent patterns. Activated central memory cluster of CD4 positive T cells expressing CD69 may be linked to current depression and elevated risk for future depression, while naïve FOXP3-expressing CD8 positive T cells may be associated with remission. These findings support the utility of immunophenotyping for stratifying adolescent depression and highlight immune pathways that contribute to the development of depression in adolescence.

References

  1. Kieling C, Buchweitz C, Caye A, Manfro P, Pereira R, Viduani A, et al. The Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo): Rationale, Methods, and Baseline Characteristics. Front Psychiatry. 2021;12:697144.
  2. Piccin J, Viduani A, Buchweitz C, Pereira RB, Zimerman A, Amando GR, et al. Prospective Follow-Up of Adolescents With and at Risk for Depression: Protocol and Methods of the Identifying Depression Early in Adolescence Risk Stratified Cohort Longitudinal Assessments. JAACAP Open. 2024;2:145–159.
  3. Rocha TB-M, Fisher HL, Caye A, Anselmi L, Arseneault L, Barros FC, et al. Identifying Adolescents at Risk for Depression: A Prediction Score Performance in Cohorts Based in 3 Different Continents. J Am Acad Child Adolesc Psychiatry. 2021;60:262–273.