Glymphatic dysfunction in early-onset schizophrenia: DTI-ALPS index reduction tracks illness burden and is independently associated with cognitive performance in treatment-resistant patients.

Early-onset schizophrenia (EOS) is associated with greater cognitive impairment than adult-onset disease, and many patients also develop treatment resistance. Glymphatic dysfunction has been described in adult schizophrenia but not in EOS or in relation to treatment resistance. We used diffusion tensor imaging along the perivascular space (DTI-ALPS) to assess glymphatic function in 30 adolescents with EOS (15 treatment-resistant, TRS; 15 non-treatment-resistant, nTRS) and 29 age- and sex-matched healthy controls (HC). Participants completed a neuropsychological battery covering verbal memory, processing speed, executive function, working memory, verbal fluency, and social cognition. ALPS differed across groups (F(2,56) = 34.66, p < 0.001, η² = 0.553), with values decreasing from HC (1.625 ± 0.072) to nTRS (1.501 ± 0.098) to TRS (1.439 ± 0.048); the TRS-nTRS difference was not significant (d = 0.81, p = 0.066). Patients showed broad cognitive deficits relative to HC, but nTRS and TRS did not differ on any measure after FDR correction. ALPS showed a nominal inverse association with the number of psychotic episodes (ρ = -0.391, p = 0.033) but was unrelated to PANSS scores or antipsychotic dose. Within TRS, ALPS was independently associated with phonemic verbal fluency (COWAT: β = +0.74, p = 0.003); a parallel association with categorical fluency (β = +0.88, p < 0.001) was partly driven by an influential observation and is exploratory. Glymphatic dysfunction appears to be a disease-intrinsic feature of EOS, lowest in TRS, possibly linked to cumulative episodes rather than current symptoms, and may contribute to cognitive impairment in treatment-resistant patients.