Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients.

Because increasing evidence point to the convergence of environmental
and genetic risk factors to drive redox dysregulation in schizophrenia,
we aim to clarify whether the metabolic anomalies associated with early
psychosis reflect an adaptation to oxidative stress. Metabolomic
profiling was performed to characterize the response to oxidative stress
in fibroblasts from control individuals (n = 20) and early psychosis
patients (n = 30), and in all, 282 metabolites were identified. In
addition to the expected redox/antioxidant response, oxidative stress
induced a decrease of lysolipid levels in fibroblasts from healthy
controls that were largely muted in fibroblasts from patients. Most
notably, fibroblasts from patients showed disrupted extracellular
matrix- and arginine-related metabolism after oxidative stress,
indicating impairments beyond the redox system. Plasma membrane and
extracellular matrix, 2 regulators of neuronal activity and plasticity,
appeared as particularly susceptible to oxidative stress and thus
provide novel mechanistic insights for pathophysiological understanding
of early stages of psychosis. Statistically, antipsychotic medication at
the time of biopsy was not accounting for these anomalies in the
metabolism of patients' fibroblasts, indicating that they might be
intrinsic to the disease. Although these results are preliminary and
should be confirmed in a larger group of patients, they nevertheless
indicate that the metabolic signature of reactivity to oxidative stress
may provide reliable early markers of psychosis. Developing protective
measures aimed at normalizing the disrupted pathways should prevent the
pathological consequences of environmental stressors.