Peripheral BDNF Levels in Individuals at Ultra-High Risk for Psychosis: A Systematic Review

Background/Objectives: Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for neurogenesis and synaptic plasticity, and alterations in its peripheral levels have been associated with schizophrenia and other psychotic disorders. However, findings on peripheral BDNF levels in individuals at ultra-high risk (UHR) for psychosis have been inconsistent. This review synthesizes current evidence comparing peripheral BDNF levels in UHR populations with those in healthy controls (HCs), first-episode psychosis (FEP), and chronic schizophrenia (CS), focusing on BDNF's potential relevance as a biomarker of psychosis risk and subsequent clinical course. Methods: A systematic search of PubMed, Scopus, and Web of Science identified studies reporting baseline peripheral BDNF levels in UHR individuals compared with HC, FEP, or CS. Of 755 records retrieved, 608 unique titles/abstracts were screened, 49 full texts reviewed, and 8 studies included. Two reviewers independently screened, extracted data, and assessed risk of bias. Given marked clinical and methodological variability, results were synthesized narratively. Results: Eight studies met eligibility criteria and were synthesized across three analytical categories: (1) UHR vs. HC; (2) UHR vs. FEP or CS; and (3) longitudinal outcomes. Findings were inconsistent; some studies reported lower BDNF in UHR relative to comparison groups, whereas others found no differences or higher levels, often influenced by clinical or methodological factors. Longitudinal analyses did not reveal consistent prognostic value, and heterogeneity precluded meta-analysis. Conclusions: Findings across studies were inconsistent and limited by small samples, as well as by methodological heterogeneity. While current evidence does not support its prognostic use, peripheral BDNF may still hold potential as part of a biomarker framework if evaluated in larger, standardized, and rigorously controlled studies.