Do biological alterations precede the onset of psychosis? A systematic review and meta-analysis of immune, cardiometabolic, prolactin and HPA axis alterations in clinical high-risk for psychosis.

First episode psychosis (FEP) individuals show biological abnormalities preceding antipsychotic treatment. However, it remains unclear whether such alterations are also present before the onset of psychosis. We aim to provide estimates of standardized mean differences for immune, cardiometabolic, prolactin, and HPA axis parameters in individuals at clinical high-risk for psychosis (CHR-P) compared to healthy controls (HC) and FEP individuals, and between CHR-P transitioning to psychosis (CHR-T) compared non-transitioning (CHR-NT). A multistep literature search was performed from database inception until September 25, 2023. PRISMA/MOOSE-compliant and pre-registered (PROSPERO: CRD42024507670) systematic review identified studies reporting on immune, cardiovascular or endocrine parameters in CHR-P samples compared with HC or FEP samples or comparing CHR-T vs CHR-NT. Inter-group differences in magnitude of effect were estimated using Hedges g and estimates were pooled using random-effects meta-analysis. Heterogeneity was high for most outcomes. 37 studies were included, total sample 2509 CHR-P, 710 FEP, and 1444 HC individuals. A statistically significant elevation of pro-inflammatory proteins was found among CHR-P compared with HC (k = 12; N = 1710; g = 0.16; p < 0.01) and FEP (k = 7; g = 0.15; p = 0.04) subjects. Interleukin-6 (IL-6) was increased in CHR-P compared to HC (k = 9; N = 1243; g = 0.54; p < 0.01), and interleukin-4 (IL-4) was increased in CHR-T compared with CHR-NT (k = 2; N = 318; g = 0.36; p < 0.01). CHR-P exhibited stronger cortisol awakening response than FEP subjects (k = 3; N = 173; g = 0.51; p = 0.01). CHR-P and FEP individuals did not show statistically significant differences in terms of prolactin levels. An inflammatory state (particularly marked by elevated IL-6 and IL-4 levels) and HPA axis alterations are present in CHR-P individuals.