2026 ECNP Congress

PS02-2193

Longitudinal cytokine remodeling in antipsychotic-naïve paediatric patients treated with second-generation antipsychotics: evidence for a biphasic immunomodulatory response

Simone Pisano — G. perruolo, P. formisano, S. cabaro, M.G. petruzzelli, G. frigieri, G. colacicco, C. Isone, N. Marani, C. avitabile, A. casertano, E. Mozzillo, C. bravaccio · University Federico II Naples, Department of Translational Medical Sciences, Naples, Italy

2026 ECNP Congress

Background

Second-generation antipsychotics (SGAs) are widely used in pediatric populations, yet they are associated with metabolic dysfunction and weight gain. However, the longitudinal dynamics of cytokine profiles in antipsychotic-naïve patients are not well understood, which limits our knowledge of early immunometabolic adaptation. We hypothesize an early reduction in inflammatory citokines during SGA treatment. We also tentatively hypothesize a medium-long term inversed trend.

Methods

We conducted a multicenter observational study including pediatric patient that, irrespective of the diagnosis, were considered eligible for initiating naturalistically an SGA treatment with Risperidone or Aripiprazole (SGA-naïve). Serum cytokines were quantified using a multiplex immunoassay at baseline (T0) and at three follow-up time points at 1, 3 and 6 months (T1, T2, and T3). Preliminary, longitudinal paired analyses were performed using nonparametric tests (Wilcoxon signed-rank test and Friedman test). Statistical significance was set at p < 0.05.

Results

A total of 48 patients were enrolled, with 12 completing all four timepoints (T0–T3). Longitudinal analysis revealed non-linear, time-dependent remodeling of the cytokine network characterized by three distinct phases.

Phase 1: Early anti-inflammatory reduction (T0–T1):

IL-8 showed a rapid and substantial decrease (median Δ −33.9%, p = 0.029).

PDGF-bb decreased significantly as well (Δ −17.2%, p = 0.049).

IL-1β decreased as well (Δ −29.3%, p = 0.026).

Phase 2: compensatory immune rebound (T1 → T2):

IL-1ra, the natural antagonist of IL-1β, exhibited a dramatic surge (Δ +1007%, p = 0.014), suggesting a powerful counter-regulatory mechanism.

Phase 3: Late immunomodulatory stabilization (T0 → T3):

PDGF-bb remained the most consistently reduced cytokine (Δ −36.3%, p = 0.023).

IP-10 (CXCL10) showed a significant late increase (Δ +38.7%, p = 0.023), indicating a potential adaptive immune remodeling.

MIP-1β decreased significantly by −10.9% (p = 0.028), and IL-9 decreased significantly by −15.8% (p = 0.019).

Global trend analysis (Friedman test, n = 12 complete cases):

PDGF-bb showed a progressive, significant reduction over time (p = 0.030).

G-CSF showed a strongly significant global decrease (p = 0.008).

Notably, IL-8 did not reach statistical significance in the T0→T3 comparison (p ≈ 0.075), confirming that its reduction is an early, transient phenomenon rather than a sustained effect.

In conclusion, SGA exposure in antipsychotic-naïve pediatric patients induces selective, biphasic, and time-dependent remodeling of the cytokine network. Key findings include:

  1. Early attenuation of innate inflammatory signals (IL-8, IL-1β, PDGF-bb).

  2. A powerful compensatory surge of the anti-inflammatory IL-1ra

  3. Late emergence of adaptive immune-related chemokines (IP-10).

These findings, although very preliminary and based on a small sample size that completed the whole follow up, suggest a complex immunometabolic adaptation to SGA treatment with potential implications for long-term metabolic and inflammatory outcomes. PDGF-bb is the most robust candidate biomarker of a sustained SGA effect. An early anti-inflammatory effect of SGA was initially confirmed, but a mid/long term remodelling towards a more pro-inflammatory pattern is also evident. Further analyses will refine the model with clinical and anthropometric variables.

References

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