Pretreatment plasma amino acid profiles in first-episode schizophrenia: a case-control study with exploratory clinical correlates

Amino acid dysregulation has been implicated in schizophrenia, but baseline plasma amino acid profiles in first-episode schizophrenia and their clinical relevance remain unclear. We hypothesized that antipsychotic-naïve patients would show distinct amino acid alterations associated with subsequent clinical improvement. Plasma levels of 31 amino acids were measured by ultra-performance liquid chromatography–tandem mass spectrometry in 80 antipsychotic-naïve patients with first-episode schizophrenia and 40 healthy controls.

Between-group differences were assessed using Mann–Whitney U tests with Benjamini–Hochberg false discovery rate correction. Amino acid-derived indices, receiver operating characteristic analysis, and Spearman correlation analyses were used to characterize metabolic patterns, discriminatory performance, and associations with PANSS improvement. Discriminatory performance was further evaluated using repeated stratified 10-fold cross-validation with feature selection performed independently within each training set, and multiple testing in the exploratory clinical correlation analyses was controlled using the Benjamini–Hochberg procedure.

Eleven amino acids differed significantly between patients and controls after false discovery rate correction. Patients showed lower kynurenine, arginine, homoarginine, aminoadipic acid, and methionine, and higher ornithine, alanine, glutamate, serine, glycine, and GABA. Arginine/ornithine, kynurenine/tryptophan, citrulline/arginine, and tyrosine/phenylalanine ratios also differed between groups.

A multivariable amino acid model showed an apparent AUC of 0.949, while repeated stratified 10-fold cross-validation yielded a mean out-of-fold AUC of 0.869 (SD = 0.011). In exploratory analyses among patients with paired PANSS data (n = 26), the baseline glutamate/GABA ratio was negatively associated with improvement in PANSS positive symptoms and remained significant after false discovery rate correction (ρ = −0.618, q = 0.015). However, this association was attenuated and no longer significant after additional adjustment for baseline PANSS positive score.

Antipsychotic-naïve first-episode schizophrenia was associated with plasma amino acid abnormalities involving arginine-related metabolism, kynurenine pathway activity, aromatic amino acid conversion, and glutamate/GABA-related balance. These findings support the relevance of peripheral amino acid metabolism in first-episode schizophrenia but require validation in independent cohorts. These authors contributed equally: Yong Xue, Li Wang, Xin Wang.

Huai’an No.3 People’s Hospital Huaian, Second Clinical College of Xuzhou Medical University, Huaian, China Jinan Municipal Institute of Dermatology and Venereology, Jinan, Shandong, China Jining Medical University, Jining, Shandong, China Department of Psychology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.