The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

Abstract Schizophrenia and especially defcit schizophrenia (DSCZ)) are characterized by highly significantly increased activities of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There are no data whether the interleukin(IL)-6/IL-23/Thelper-17 (IL6/IL23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL6/IL23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and phenome of schizophrenia. Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL6/IL23/Th17-axis score, as assessed by a LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL6/IL23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL6/IL23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). In conclusion, the pathogenic IL6/IL23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia and especially that of DSCZ due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.