¹Taipei City Psychiatric Center, Taipei City Hospital, Department of Psychiatry, Taipei, Taiwan, ²College of Medicine, Taipei Medical University, Taiwan, Department of Psychiatry, School of Medicine, Taipei, Taiwan

Background: Schizophrenia involves neuroaxonal disruption linked to psychotic symptoms and clinical remission. Blood neurofilament light chain (NfL), a neuronal scaffolding protein essential for axonal integrity and synaptic activity, is released into the cerebrospinal fluid and blood upon neurodegeneration. Often described as a "troponin for the brain," NfL was recently FDA-approved as a surrogate endpoint for neuroaxonal injury. Prior studies in schizophrenia have yielded inconsistent results, likely due to limited phenotypic stratification. While most reports suggest NfL levels in schizophrenia are comparable to healthy controls (HC), elevations have been observed in specific subgroups, such as first-episode psychosis, antipsychotic (APD)-free active psychosis, and patients receiving clozapine. Furthermore, the impact of APD exposure on neuroaxonal structural changes remains unclear.

Aims & Objectives: This study examined the association between serum NfL levels and psychotic remission in patients with schizophrenia, while controlling for covariates including APD treatment status.

Method: This cross-sectional study measured serum NfL levels in 127 patients with schizophrenia—comprising 29 APD-free patients (at least 24 weeks drug-free) and 98 APD-treated patients (receiving aripiprazole or clozapine for at least 24 weeks)—and 56 HCs. Symptom severity was assessed using the 18-item Brief Psychiatric Rating Scale (BPRS), and psychotic remission was defined by the Andreasen criteria. Serum NfL was measured using Single Molecule Array (Simoa™) technology.

Results: Serum NfL levels did not differ significantly between patients with schizophrenia and HCs, nor between APD-treated and APD-free patients. However, a significant difference was observed across clinical states: unremitted patients (7.7 ± 3.9 pg/ml, n=32), remitted patients (6.4 ± 3.8 pg/ml, n=66), and HCs (6.0 ± 2.5 pg/ml, n=57) (F_(2,183)=3.37, p=0.04). Subgroup analyses confirmed that the association between higher NfL and unremitted status was consistently replicated in both aripiprazole- and clozapine-treated patients. Multivariate regression indicated that in patients with schizophrenia, NfL levels were significantly associated with remission status (B = –1.594, 95% CI [–2.895, –0.329], p = 0.01), but not with medication type (aripiprazole vs. clozapine) after adjustment. NfL correlated positively with BPRS total scores (r = 0.33, p < 0.001) and all subscales (r = 0.26, 0.27, 0.23 for positive, negative, and general psychopathology, respectively; all p < 0.05).

Discussion & Conclusions: NfL levels are associated with the remission state in schizophrenia rather than APD treatment status. These results suggest that NfL may serve as a medication-independent biomarker for non-remission and underlying neuroaxonal pathology in patients with schizophrenia. While this cross-sectional study cannot establish causality, the findings warrant further prospective longitudinal studies to clarify the relationship between neurodegeneration and persistent psychosis.