| Autor: |
Lesche D; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne & Melbourne Health, Melbourne, VIC, Australia., Mostafa S; myDNA Life Australia Limited, South Yarra, VIC, Australia.; Centre for Medicine Use and Safety, Monash University, Parkville, VIC, Australia., Everall I; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne & Melbourne Health, Melbourne, VIC, Australia.; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.; The Cooperative Research Centre (CRC) for Mental Health, VIC, Australia., Pantelis C; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne & Melbourne Health, Melbourne, VIC, Australia.; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.; The Cooperative Research Centre (CRC) for Mental Health, VIC, Australia., Bousman CA; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne & Melbourne Health, Melbourne, VIC, Australia. chad.bousman@ucalgary.ca.; The Cooperative Research Centre (CRC) for Mental Health, VIC, Australia. chad.bousman@ucalgary.ca.; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. chad.bousman@ucalgary.ca.; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. chad.bousman@ucalgary.ca.; Departments of Medical Genetics, Psychiatry, and Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada. chad.bousman@ucalgary.ca. |
| Abstrakt: |
Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes. Among 66 adult schizophrenia patients treated with clozapine-based combination therapies, we explored the impact of genotype-predicted CYP1A2, CYP2D6, and CYP2C19 activity on dose-adjusted clozapine concentrations and symptom severity, with and without correction for inhibitors and inducers of these enzymes. Uncorrected activity scores were not associated with dose-adjusted clozapine concentrations or symptom severity. CYP1A2 and CYP2D6 activity scores corrected for known inducers (i.e., smoking) and inhibitors (e.g., concomitant medications) were associated with dose-adjusted clozapine levels and in the case of CYP1A2, symptom severity. However, smoking status and certain inhibitors of clozapine metabolism (i.e., esomeprazole) explained significantly more variance in dose-adjusted clozapine levels relative to corrected activity scores. These findings highlight the clinical importance of nongenetic factors (smoking, concomitant medications) and suggest that the added utility of CYP1A2, CYP2D6, and CYP2C19 activity scores to guide clozapine dosing is currently limited. |
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