Peripheral neurotransmitter metabolic signatures in schizophrenia: a targeted metabolomics study

To investigate peripheral metabolic alterations in patients with schizophrenia using a two-stage metabolomic workflow of untargeted analysis and targeted re-analysis,explore the associated metabolic pathways, identify potential peripheral metabolic biomarkers, and elucidate the underlying metabolic dysregulation mechanisms.

Plasma samples were collected from 24 schizophrenia patients and 10 healthy controls for non-derivatized targeted metabolomics analysis. Differential metabolites were identified and visualized using box plots. Hierarchical clustering analysis was performed to evaluate expression pattern differences across samples, and KEGG pathway enrichment analysis was conducted to map the involved biological pathways. False discovery rate (FDR) correction was applied for multiple comparisons.

Among the 21 quantified metabolites, four exhibited significant differences after FDR correction (FDR < 0.05). α-Ketoglutarate was significantly elevated in the patient group, whereas succinic acid, tryptamine, and amino butyric acid were significantly reduced. The opposite variations of α-ketoglutarate and succinic acid suggest a peripheral TCA cycle metabolic bottleneck. Hierarchical clustering based on these four metabolites effectively distinguished patients from healthy controls. KEGG enrichment demonstrated that these metabolites converged predominantly on amino acid metabolism, energy metabolism, and most notably the GABAergic synapse pathway, offering peripheral evidence supporting the core position of GABAergic dysfunction in schizophrenia.

Schizophrenia patients display significant peripheral metabolic disturbances characterized by dysregulated amino acid metabolism, synaptic transmission abnormalities, and energy metabolism imbalance. The four-metabolite panel (α-ketoglutarate, succinic acid, tryptamine, and amino butyric acid) may provide experimental basis for further mechanistic research and therapeutic development.