Physical exercise as a catalyst for neuroimmune balance in schizophrenia: Targeting the kynurenine pathway in the PsyLetics project

Altered tryptophan–kynurenine metabolism has been associated with schizophrenia. Beyond healthy-control differences, elevated brain kynurenic acid and reduced peripheral metabolites have been linked to symptoms and cognitive deficits. Nonetheless, exercise has been shown to rebalance this pathway by enhancing peripheral kynurenine turnover, with no clear evidence yet in schizophrenia. This pilot trial from the PsyLetics project investigated whether high-intensity exercise can alter kynurenine metabolism in patients with schizophrenia, and whether improvements in symptoms, psychosocial functioning, and physical health accompany such changes. Ten patients with schizophrenia or schizoaffective disorder and ten matched healthy controls participated. Patients were randomly assigned to either high-intensity training or whole-body vibration training, which served as a control condition. Both interventions lasted eight weeks, three times per week. Pre- and post-intervention assessments included blood analysis of tryptophan metabolites, inflammation, psychiatric interviews, psychosocial functioning scales, physical fitness testing, and body composition. At baseline, patients had lower plasma kynurenine and picolinic acid levels than healthy controls. After the intervention, picolinic acid increased in both training groups, while other metabolites remained unchanged. High-intensity training led to greater improvements in psychosocial functioning and muscular strength than the control condition. Positive symptoms improved in both groups; negative symptoms showed no change. This pilot study suggests that exercise can modulate kynurenine metabolism in schizophrenia, with picolinic acid emerging as a potential marker of clinical improvement. Psychosocial and fitness gains support exercise as a feasible adjunctive intervention, warranting larger studies to clarify underlying mechanisms within the kynurenine pathway. • Exercise modulates kynurenine metabolism in schizophrenia patients • High-intensity interval training enhances psychosocial functioning and strength • Picolinic acid rises after training, marking a potential link to clinical improvement and fitness benefits