2026 ECNP Congress

PS02-2215

PreDiction of trEatment response and clinicaL outcome in First episode psYchosis: from braiN imaging to molecular biology: DELFYN PROTOCOL

Chiara Moltrasio — A. Pigoni, P. Enrico, L. Squarcina, G. Delvecchio, L. Di Consoli, N. Citerà, G. Ratti, Y. Torrente, P. Brambilla · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Neurosciences and Mental Health, Milano, Italy

2026 ECNP Congress

Background

First-Episode Psychosis (FEP) is characterized by delayed diagnosis and treatment, resulting in a significant clinical and social burden [1]. Converging evidence supports the dysconnectivity hypothesis, with alterations in prefronto-limbic circuits and myelin integrity potentially predicting treatment response [2,3]. However, early patient stratification still remains an unmet need, as antipsychotic (AP) treatment still follows a trial-and-error approach.

Objectives

Using cutting-edge methodology and three complementary stratification approaches, DELFYN seeks to identify biomarkers of treatment resistance and elucidate their biological underpinnings through: (1) in vivo multimodal brain imaging; (2) in vitro single-cell transcriptomics; and (3) ex vivo postmortem lipidomic mapping of myelin via MALDI Imaging Mass Spectrometry (MALDI-MSI).

Study Design

The DELFYN protocol is a 3-year, multicenter, non-profit, non-randomized interventional study enrolling 80 participants (n = 20/group) over a 24-month recruitment period across four groups: (1) aripiprazole responders, (2) non-responders, (3) drug-naïve FEP patients, and (4) healthy controls (HC). An attrition rate of 20% due to dropout is expected. Treatment response is defined as a ≥30% reduction in the Positive and Negative Syndrome Scale (PANSS) total score after 4 (±1) weeks.

The Policlinico Hospital serves as Coordinating Center and Sponsor; participants are recruited from three clinical centers in Milan (Policlinico, ASST Santi Paolo e Carlo, ASST Fatebenefratelli-Sacco) and receive standard-of-care treatment. FEP patients undergo longitudinal assessments at baseline, 4 weeks, 12 weeks, and 12 months, while HC are assessed cross-sectionally at baseline. At each time point, all participants undergo: (1) clinical evaluations — including psychopathological, cognitive, and functional measures — and (2) peripheral blood sampling for immunoprofiling and single-cell RNA sequencing. At baseline, all participants additionally undergo multimodal 3T MRI with Dynamic Contrast-Enhanced (DCE) sequences, centralized at the Policlinico Hospital. For a subgroup, iPSC-derived brain organoids will be generated from peripheral blood samples, without the need for skin biopsies. Ex vivo lipidomic analyses, conducted through an international collaboration with the HBCC–NIMH, will be performed using MALDI-MSI.

Expected Results

Primary endpoint: to characterize differences in white matter connectivity — assessed via DiffusionTensor Imaging (DTI)-derived fractional anisotropy (FA) — along the DLPFC–hippocampus pathway between aripiprazole responders and non-responders.

Secondary endpoints are organized across the three stratification levels:

In vivo — differences in volumes, connectivity, resting-state activation, and DCE perfusion across all groups; development of a multimodal imaging-based predictive model of treatment response and a model of functioning and outcome trajectories over 12 months.

In vitro — alterations in inflammatory markers (cytokines, interleukins) between groups; differences in cytoarchitecture and receptor expression in patient-specific iPSC-derived cellular models.

Ex vivo — validation of connectivity biomarkers in postmortem brain specimens of chronic psychotic patients and healthy individuals.

Discussion

DELFYN represents a pioneering initiative in precision psychiatry, aiming to overcome the current empirical approach to FEP management by integrating cutting-edge methodologies across three complementary analytical levels: in vivo (multimodal neuroimaging), in vitro (transcriptomics and brain organoids), and ex vivo (postmortem lipidomics). The expected findings may substantially contribute to early patient stratification, reducing the burden of trial-and-error therapeutic approaches and mitigating the long-term clinical, social, and economic consequences of FEP.

References

  1. Lewandowski, K. E., Cohen, B. M., & Ongur, D. (2011). Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder. Psychological medicine, 41(2), 225–241. https://doi.org/10.1017/S0033291710001042
  2. Roussos, P., & Haroutunian, V. (2014). Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities. Frontiers in cellular neuroscience, 8, 5. https://doi.org/10.3389/fncel.2014.00005
  3. Dusi, N., Bellani, M., Perlini, C., Squarcina, L., Marinelli, V., Finos, L., Altamura, C. A., Ruggeri, M., & Brambilla, P. (2017). Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study. Schizophrenia research, 179, 104–111. https://doi.org/10.1016/j.schres.2016.09.013