Higher peripheral blood homocysteine levels are associated with schizophrenia: evidence from a case-control study and...

Several studies suggest that homocysteine is associated with schizophrenia (SCZ), but existing evidence has been limited by small sample sizes. We aimed to investigate the association between blood homocysteine levels and schizophrenia. We conducted a case-control study followed by a meta-analysis. In the case-control study, 1159 patients with SCZ diagnosed according to DSM-5 (mean age 22.6 ± 8.4 years; 51.9% male) and 1440 healthy controls (HC) (mean age 38.4 ± 9.7 years; 51.3% male) were recruited. Plasma homocysteine levels were measured using an AU5800 automated biochemical analyzer and compared between groups. For the meta-analysis, PubMed, Embase, Cochrane Library, and Web of Science were systematically searched through February 2024 for case-control studies comparing blood homocysteine levels between patients with SCZ and HC. Ratios of means (RoM) with 95% confidence intervals were pooled using random effects models. In the case-control study, patients with SCZ had significantly higher homocysteine levels than HC (14.4 [11.3-21.6] vs. 12.3 [10.1-15.7] µmol/L; P < 0.001), and the association remained significant after adjustment for age and sex. Consistently, the meta-analysis of 54 case-control studies including 9781 participants (4526 patients with SCZ and 5255 HC) showed significantly higher homocysteine levels in patients with SCZ than in HC (RoM 1.34, 95% CI 1.28-1.41; P < 0.001). Subgroup analyses stratified by disease course, sample type, sex, study region, and homocysteine measurement method yielded consistent results. Blood homocysteine levels are elevated in patients with SCZ in both the case-control analysis and meta-analysis. These preliminary findings suggest a possible association between homocysteine and SCZ, although further well-controlled prospective and longitudinal studies are needed to clarify its clinical significance.