Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives
Authors: Eratne Dhamidhu , Janelidze Shorena , Malpas Charles B , Loi Samantha , Walterfang Mark , Merritt Antonia , Diouf Ibrahima , Blennow Kaj , Zetterberg Henrik , Cilia Brandon , Wannan Cassandra , Bousman Chad , Everall Ian , Zalesky Andrew , Jayaram Mahesh , Thomas Naveen , Berkovic Samuel F , Hansson Oskar , Velakoulis Dennis , Pantelis Christos , Santillo Alexander , Li Qiao-Xin , Stehmann Christiane , Cadwallader Claire , Fowler Christopher , Ravanfar Parsa , Farrand Sarah , Keem Michael , Kang Matthew , Watson Rosie , Yassi Nawaf , Kaylor-Hughes Cath , Kanaan Richard , Perucca Piero , Vivash Lucy , Ali Rashida , O’Brien Terence J. , Masters Colin L , Collins Steven , Kelso Wendy , Evans Andrew , King Anna , Kwan Patrick , Gunn Jane , Goranitis Ilias , Pan Tianxin , Lewis Courtney , Kalincik Tomas 
Published: November 2021

Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging 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 potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative 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 = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/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 schizophrenia 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.