¹University of Udine, Department of Medicine, Unit of Psychiatry and Eating Disorders, Udine, Italy, ²Hôpital Universitaire de Bruxelles, Department of Child and Adolescent Psychiatry, Site Anderlecht, Bruxelles, Belgium, ³Friuli Centrale Health University Authority (ASUFC), Unit of Psychiatry and Eating Disorders, Udine, Italy, ⁴University of Udine, Department of Medicine, Institute of Clinical Pathology, Udine, Italy, ⁵King's College London, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom

Background: Clinical high-risk (CHR) for psychosis state still lacks effective and safe treatments. Recent evidence supports the anti-neuroinflammatory properties of fatty acid palmitoylethanolamide (PEA) dietary supplementation across the psychosis spectrum. However, despite its safe profile, the effect of PEA supplementation in CHR remains unexplored.

Aims & Objectives: This mechanistic study aims to fill this gap through the following objectives (i) to assess trajectories of CHR symptoms and peripheral neuroimmune biomarkers during PEA supplementation; (ii) to assess associations between baseline levels of peripheral neuroimmune biomarkers and subsequent symptom trajectories during PEA supplementation; (iii) to assess associations between changes in peripheral neuroimmune biomarkers and longitudinal trajectories of CHR symptoms during PEA supplementation.

Method: Sixteen subjects at CHR for psychosis with attenuated psychotic symptoms (APS) enrolled in a 12-week, open-label, nonrandomized, single-arm clinical trial of ultramicronized-PEA (um-PEA, 600 mg/day). Biobehavioral assessments were conducted at baseline, 4 weeks, and 12 weeks, particularly using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and quantifying changes in peripheral neuroimmune biomarkers. Trial registration: ClinicalTrials.gov Identifier NCT06037993.

Results: Linear mixed-effects models showed significant reductions in CAARMS total APS (Δ_12-weeks = −3.8 units, −30.0 %) and Unusual Thought Content (UTC; Δ_12-weeks = −2.0, −52.5 %). No treatment-emergent side effects were reported. In exploratory analyses including neuroimmune biomarkers as covariates and potential moderators, lower baseline Interleukin (IL)-1β was associated with greater improvement in UTC, while time-varying IL-10/IL-6 ratio, Interferon (IFN)-γ, and IL-6 were linked to changes in CAARMS total APS and UTC.

Discussion & Conclusions: A reduction in APS was observed in subjects at CHR for psychosis receiving PEA supplementation, possibly through immune-inflammatory modulation, warranting further research into its therapeutic potential for this condition.