Longitudinal effects of clozapine concentration and clozapine to N-desmethylclozapine ratio on cognition: A mediation model.
García-Portilla, María Paz
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
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Dal Santo, F., Jarratt-Barnham, I., González-Blanco, L., García-Portilla, M. P., Bobes, J., & Fernández-Egea, E. (2020). Longitudinal effects of clozapine concentration and clozapine to N-desmethylclozapine ratio on cognition: A mediation model.. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 33 158-163. https://doi.org/10.1016/j.euroneuro.2020.01.016
Previous cross-sectional studies have found clozapine to N-desmethylclozapine (CLZ:NDMC) ratio to be negatively correlated with cognition in clozapine-treated patients with schizophrenia. However, no work has examined the association between CLZ:NDMC ratio and cognition using a within-subjects design. Here, we investigate the longitudinal effects of changes in the clozapine load and the CLZ:NDMC ratio on cognition whilst controlling for a range of independent factors. We analyzed data from a cohort of seventeen clozapine-treated patients who have been repeatedly assessed with the Brief Assessment of Cognition for Schizophrenia (BACS). The Positive symptoms sub-score of the Clinical Global Impression for Schizophrenia (CGI-P) was used to assess severity of psychosis. Blood samples were collected to measure the plasmatic levels of clozapine (CLZ) and of N-desmethylclozapine, allowing calculation of the CLZ:NDMC ratio. Our analyses included bivariate and partial correlations, along with a mediation model analysis. We found that both plasmatic levels of CLZ and the CLZ:NDMC ratio were negatively correlated with cognitive performance, and that these associations were independent of changes in both daily clozapine dose and severity of psychotic symptoms. Mediation analyses further revealed the association between CLZ concentration and cognition to be partially mediated by changes in the CLZ:NDMC ratio. This is the first longitudinal analysis of the influence of CLZ concentration and CLZ:NDMC ratio on cognition. Our findings suggest that reduction of CLZ concentration and the CLZ:NDMC ratio might favorably affect cognition. Thus, the CLZ:NDMC ratio may represent a promising target for novel therapeutic strategies aiming to ameliorate cognitive impairment in clozapine-treated patients.
Role of Funding Source: The “Treatment-resistant schizophrenia clinical and research database” was supported by intramural funding from CPFT and the UK National Institute of Health Research (NIHR) - Cambridge Biomedical Research Centre (BRC). Our funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
External DOI: https://doi.org/10.1016/j.euroneuro.2020.01.016
This record's URL: https://www.repository.cam.ac.uk/handle/1810/301398
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Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/