2026 ECNP Congress

PS01-1197

Interleukin-17 and T-helper 17 cells in treatment-resistant depression: from neuroinflammatory mechanisms to precision immunomodulatory strategies: a mini-review

Daniela Gheza — County Hospital Cluj Napoca, Psychiatric Clinic ward III, Cluj napoca, Romania

2026 ECNP Congress

Background:Major Depressive Disorder remains a premier global disease burden, predominantly driven by a complex interplay between genetic predisposition, environmental stressors, and neurochemical dysfunctions and traditional monoaminergic hypotheses, while foundational, fail to explain the pathophysiology of approximately one-third of patients who exhibit treatment-resistant depression[1]. Emerging paradigms suggest that systemic low-grade inflammation and gut microbiota dysbiosis contribute to treatment resistance by promoting barrier permeability and driving the differentiation of T-helper 17 cells toward a pro-inflammatory phenotype, which may subsequently migrate along the gut–brain axis to the central nervous system and further compromise barrier integrity[2]. Once across the blood-brain barrier, these cells trigger the tryptophan–kynurenine pathway, shifting tryptophan metabolism away from serotonin synthesis and toward the production of neurotoxic metabolites, thereby impairing glutamatergic signaling and reinforcing neuroinflammatory cascades implicated in depressive pathophysiology[3]. Crucially, Interleukin-17 has been shown to directly upregulate the expression and activity of serotonin transporters through the JAK1–STAT6 signaling pathway, mediating fluoxetine resistance[4]. These mechanisms justify T-helper 17-targeted immunomodulation as a promising precision approach for treatment-resistant depression.

Objective: This mini-review aims to synthesize recent clinical and translational evidence regarding the T-helper 17/Interleukin-17 axis, with particular emphasis on its role in treatment-resistant depression. We focus on bridging the gap between peripheral gut-derived immune activation and central neuroinflammatory resistance, evaluating the viability of this axis as a foundational pillar for precision medicine interventions in patients non-responsive to conventional antidepressant protocols.

Methods: A narrative review was conducted by synthesizing eight primary clinical and translational studies published between 2021 and 2025, identified via PubMed, Google Scholar, and other relevant medical databases. Studies were selected based on their relevance to immunophenotypic profiling, blood-brain barrier integrity, and documented responses to immunomodulatory interventions.

Results: Clinical data confirmed that peripheral Interleukin-17 levels were significantly elevated in depressed groups, positively correlating with symptom severity and Hamilton Depression Rating Scale scores, and although conventional antidepressants may reduce general systemic inflammation, Interleukin-17 concentrations often remain pathologically high, suggesting a persistent pro-inflammatory state, which exacerbates blood-brain barrier permeability and neuroinflammatory cascades, ultimately contributing to therapeutic non-response[5]. Clinical evidence from the SUPREME and ProLOGUE studies demonstrated that neutralizing this axis with monoclonal antibodies, such as Secukinumab and Brodalumab, leads to significant and sustained reductions in depressive symptoms[6] [7]. These antidepressant effects are most pronounced in patients with baseline systemic inflammation, determining Interleukin-17 as both a key factor of treatment resistance and a viable target for precision immunomodulatory strategies[8].

Conclusion: Targeting the Interleukin-17/T-helper 17 axis represents a paradigm shift in the management of treatment-resistant depression, adapting from empirical monoaminergic protocols to precision immunomodulatory interventions. Integrating immunophenotypic stratification into clinical practice is essential for identifying the inflammatory biotype and optimizing the efficacy of biological therapies in neuropsychiatry, ultimately paving the way for personalized, sustained remission in refractory mood disorders.

References

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  2. Jia X, Wang J, Ren D, Zhang K, Zhang H, Jin T, Wu S. Impact of the gut microbiota-Th17 cell axis on inflammatory depression. Front Psychiatry. 2024 Nov 25;15:1509191.
  3. Binder LB, Menegatti Bevilacqua L, Gro Lorentzen Thomassen F, Lebel M, Jensen BAH, Menard C. Across Barriers: Blood-Brain and Gut Barrier Signaling in Psychiatric Disorders. J Neurochem. 2025 Nov;169(11):e70282.
  4. Zhang M, Hong Y, Yu W, Zhang Y, Shen Y, Cai Z, Jia R, Pang Z, Huang X, Huang Y, Gao X, Liu Y, Qu Y, Yang Q, Zhang X, Zhu A, Ao H. IL-17 enhanced the susceptibility to fluoxetine resistance in depression via the JAK1-STAT6 signaling pathway. Int Immunopharmacol. 2025 May 16;155:114513.
  5. Mao L, Ren X, Wang X, Tian F. Associations between Autoimmunity and Depression: Serum IL-6 and IL-17 Have Directly Impact on the HAMD Scores in Patients with First-Episode Depressive Disorder. J Immunol Res. 2022 May 16;2022:6724881.
  6. Talamonti M, Malara G, Natalini Y, Bardazzi F, Conti A, Chiricozzi A, Mugheddu C, Gisondi P, Piaserico S, Pagnanelli G, Amerio P, Potenza C, Cantoresi F, Fargnoli MC, Balato A, Loconsole F, Offidani A, Bonifati C, Prignano F, Bartezaghi M, Rausa A, Aloisi E, Orsenigo R, Costanzo A; the SUPREME Study Group. Secukinumab Improves Patient Perception of Anxiety and Depression in Patients with Moderate to Severe Psoriasis: A Post hoc Analysis of the SUPREME Study. Acta Derm Venereol. 2021 Mar 31;101(3):adv00422.
  7. Ohata C, Kanai Y, Murotani K, Yamazaki F, Takahashi H, Tada Y, Mabuchi T, Mizutani Y, Nomura T, Imafuku S. Effectiveness of Long-Term Treatment with Brodalumab on Anxiety or Depressive Symptoms in Japanese Patients with Psoriasis: The ProLOGUE Study. Dermatol Ther (Heidelb). 2023 Apr;13(4):1039-1052.
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