Antipsychotic-disease duration interaction on glymphatic function in first-episode schizophrenia: Evidence from DTI-ALPS.

BACKGROUND

The glymphatic system's role in early schizophrenia remains unclear. This study investigated glymphatic function using the DTI-ALPS index in first-episode schizophrenia (FES), exploring its relationships with clinical features, antipsychotic treatment, and cognitive function.

METHODS

The study included 37 first-episode drug-naïve (FESDN) patients, 22 first-episode treated (FEST) patients, and 42 demographically matched healthy controls (HCs). ALPS indices were calculated, and clinical assessments included cognitive function (RBANS), psychiatric symptoms (PANSS), and peripheral biomarkers.

RESULTS

FES patients exhibited left-hemisphere predominant reductions in ALPS indices (p < 0.01). An interaction was observed between disease duration and treatment: the FEST group had lower DTI-ALPS than the FESDN group in patients with shorter illness durations, but this group difference diminished with longer disease duration (βinter = -0.8 × 10-2, p < 0.05). The ALPS-cognition association pattern differed between patients and HCs: left ALPS was positively correlated with RBANS in HCs (βHC > 0, p < 0.01) but negatively correlated in FES patients (βFESDN = -16.6, βFEST = -21.6, p < 0.1). Peripheral white blood cell count and total bilirubin were negatively associated with left ALPS in the FEST group (WBC: β = -0.63 × 10-2, p = 0.025; TBIL: β = -0.80 × 10-2, p = 0.039), with significant group interaction effects (p < 0.05).

CONCLUSION

FES patients demonstrate left-lateralized glymphatic dysfunction, the severity of which is dynamically modulated by treatment and disease duration. The observed negative ALPS‑cognition correlation raises the possibility of a compensatory mechanism in early schizophrenia. Associations noted between peripheral inflammatory/metabolic markers and ALPS offer tentative support for an interactive "periphery-brain" clearance system. DTI-ALPS may serve as a dynamic biomarker reflecting neuropathological mechanisms in early schizophrenia.