Untargeted 1 H NMR-based metabolomics unveils distinct circulating biochemical signatures between treatment-resistant and non-treatment-resistant Schizophrenia patients: a pilot study

Schizophrenia is a severe psychiatric disorder impacting roughly 1% of individuals. The effectiveness of antipsychotic therapy greatly varies, with around 30% of patients categorised as treatment-resistant (TRS). TRS is characterised by a lack of response to at least two clinical trials involving antipsychotic medications at suitable dosages and for at least six weeks of treatment. Patients are usually prescribed with clozapine, the only medication with specific indication for this condition. While various causes of resistance have been suggested, there are limited studies examining circulating metabolite variations in TRS patients. In the present cross-sectional study, we conducted an untargeted nuclear magnetic resonance (NMR)-based metabolomics investigation to assess serum metabolomic variations in 13 TRS patients compared to 13 therapy-responsive patients (non-TRS). Notably, NMR-based metabolomics identifies a peculiar metabolic signature associated with drug resistance to antipsychotics. This includes an increase in inflammation-related biomarkers associated with dysregulated arginine and proline metabolism, alterations in membrane components such as sphingolipids and phosphoethylethanolamines, and variations in NMDA-related amino acids and their direct precursors like glycine and serine. In conclusion, this study highlights differentially expressed serum metabolites in TRS patients compared to non-TRS, providing novel insights into the metabolomic biomarkers of this mental illness.