Age-dependent associations between plasma neurofilament light chain protein and symptom severity in treatment-resistant Schizophrenia: a moderation analysis

• Wei-Hsuan Chiu ^[1] ; Anita M.Y. Goh ^[1] ; Dhamidhu Eratne ^[1] ; Charles B. Malpas ^[4] ; Alexander F. Santillo ^[4] ; Shorena Janelidze ^[2] ; Oskar Hansson ^[5] ; Cassandra M.J. Wannan ^[1] ; Antonia H. Merritt ^[1] ; Mahesh Jayaram ^[1] ; Naveen Thomas ^[6] ; Chad A. Bousman ^[1] ; Ian Everall ^[3] ; Dennis Velakoulis ^[1] ; Christos Pantelis ^[1] ; Samantha M. Loi ^[1]
  1. [1] University of Melbourne

     University of Melbourne

     Australia

     
  2. [2] Lund University

     Lund University

     Suecia

     
  3. [3] King's College London

     King's College London

     Reino Unido

     
  4. [4] Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia g Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia h Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Victoria, Australia
  5. [5] Clinical Memory Research Unit, Department of Clinical Sciences Malm¨o, Faculty of Medicine, Lund University, Lund, Sweden j Memory Clinic, Skåne University Hospital, Lund, Sweden
  6. [6] Mental Health and Wellbeing Services, Western Health, St Albans, Victoria, Australia

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• Localización: European journal of psychiatry, ISSN 0213-6163, Vol. 40, Nº 3, 2026
• Idioma: inglés
• DOI: 10.1016/j.ejpsy.2026.100362
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  • Background and objectives: Treatment-resistant schizophrenia (TRS) is a severe subtype of schizophrenia. While negative and disorganised symptoms have been associated with cognitive dysfunction, the underlying neuro- biological mechanisms remain unclear. Plasma neurofilament light chain protein (NfL), a biomarker of neuro- axonal damage, has shown promising associations in TRS. This study investigates the interrelationships between symptomatology, cognition, and NfL in TRS.

    Methods: Eighty-two clozapine-treated TRS participants were assessed using the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms.

    Cognitive functions were evaluated using the Cambridge Neuropsychological Test Automated Battery and Wis- consin Card Sorting Test. Plasma NfL concentrations were measured using a Single Molecule Array assay. General linear models and moderation analyses were employed.

    Results: In younger participants, NfL levels negatively correlated with excited factor (r = -0.26, 95% confidence interval [CI] = [-0.47, -0.04]), whereas in older participants, NfL levels positively correlated with blunted affect (r [95% CI] = 0.27 [0.05, 0.47]). Disorganised (unstandardised beta [B] = -0.07, 95% CI = [-0.11, -0.02]) and positive (B [95% CI] = -0.04 [-0.07, -0.005]) factors were significant predictors of executive dysfunction, in- dependent of NfL levels. Importantly, NfL moderated the relationship between positive formal thought disorder and executive dysfunction (B [95% CI = 0.02 [0.001, 0.05]).