Medical and Health Sciences, Basic Medicine, Neurosciences, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Neurovetenskaper

Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroim- aging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as poten- tially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegen- erative disorders such as Alzheimer and frontotemporal dementias. Methods: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n=13), and age- and sex-matched controls (n=59). Results: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M=6.3pg/ mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M=6.7pg/mL, 95% confidence interval: [5.2,8.2]; parents, M after adjusting for age=6.7pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M=5.8pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M=4.9pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman’s r=0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r=0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = −0.305, 95% confidence interval: [−0.504, −0.076]). Conclusion: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizo- phrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.