Serum kynurenine metabolites might not be associated with risk factors of treatment-resistant schizophrenia

Abstract

BackgroundAbout a third of patients with schizophrenia do not respond adequately to currently available antipsychotics and thus experiences symptoms of greater severity, known as treatment-resistant schizophrenia (TRS). Some evidence suggests that the tryptophan (TRP) pathway (comprising 5-HT and kynurenine sub-pathways) has an important influence on response to antipsychotics. We therefore hypothesized that TRS is linked to metabolites of TRP pathway. MethodsWe measured TRP metabolites in 54 patients with TRS and compared them to 49 age- and sex-matched patients who responded to antipsychotics (NTRS), and 62 healthy controls using liquid chromatography-tandem mass spectrometry. Psychopathology and clinical symptoms were assessed by means of schizophrenia positive and negative scales. Working memory abilities, cortical thickness and white matter diffusion tensor imaging fractional anisotropy were appraised in enrolled subjects by neurophysiological tests, as spatial span and digital sequencing tests, and 3T magnetic resonance imaging. ResultsPatients with TRS had a significantly higher 5-HT/TRP ratio (p = 0.009) than patients with NTRS. However, the two groups did not differ in kynurenine-pathway metabolites or ratios. Additionally, 5-HT/TRP was positively correlated with disorganized symptoms in TRS (r = 0.59, p < 0.001), and negatively correlated with digit-sequencing test scores (r = −0.34, p = 0.02). These correlations were insignificant among patients with NTRS and healthy controls. In patients with TRS, 5-HT/TRP was strongly linked to the right supramarginal cortex (t = −3.2, p = 0.003), and in healthy controls, to the right transverse temporal (t = 3.40, p = 0.001), but significance disappeared after FDR correction. ConclusionsPresent results indicate that an upregulated 5-HT biosynthetic pathway can be associated to TRS, suggesting that targeting mechanisms of 5-HT conversion from tryptophan could shed light on the development of new pharmacological approaches of TRS.