Tryptophan Metabolic Dysregulation in Schizophrenia Pathogenesis and Therapeutic Implications

Schizophrenia (SCZ) is a severe psychiatric disorder with diverse clinical manifestations and limited treatment options, especially for negative and cognitive symptoms. Increasing evidence highlights abnormal tryptophan (Trp) metabolism as a key contributor to SCZ pathophysiology. This review summarizes advances across three major Trp metabolic pathways: the kynurenine pathway (KP), the serotonin (5-HT) pathway, and the indole pathway. KP dysregulation alters the balance between neurotoxic metabolites (e.g., quinolinic acid) and neuroprotective metabolites (e.g., kynurenic acid), leading to NMDA receptor dysfunction, oxidative stress, and cognitive impairment. Abnormal 5-HT synthesis and receptor signaling contribute to affective dysregulation and negative symptoms, whereas gut microbial metabolism through the indole pathway influences immune activation and neuroinflammation, further modulating KP and 5-HT systems. Emerging evidence, including recent studies on first-episode, drug-naive patients, supports peripheral Trp-KP alterations as potential biomarkers linked to symptom dimensions. Therapeutically, modulation of Trp metabolism shows promise; KP enzyme inhibitors, microbiota-directed interventions, and novel agents targeting Trp-related neurotransmission may offer new avenues beyond dopamine blockade. However, current evidence is limited by small sample sizes, study heterogeneity, and lack of replication. Overall, Trp metabolism provides a mechanistic framework linking genetics, immunity, and microbiota to the clinical diversity of SCZ. Further work should focus on stage-specific biomarkers and targeted interventions, with the goal of advancing personalized treatment strategies.