Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia.
Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics.
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The participant will distinguish common genetic variants that exert effects on clozapine metabolism.
This program is designed for all psychiatrists in clinical practice, residents in Graduate Medical Education programs, medical students interested in psychiatry, and other physicians who wish to advance their current knowledge of clinical medicine.
Duration: 1 hour
Begin Date: June 1, 2019
End Date: May 31, 2021
In order to earn CME credit, subscribers should read through the material presented in the article. After reading the article, complete the quiz and submit your evaluation and study hours (up to 1 AMA PRA Category 1 Credit™). A score of 60% or higher is required to receive credit.
The American Psychiatric Association (APA) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
The APA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Title: Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism
Authors: Antonio F. Pardiñas, Ph.D., Mariana Nalmpanti, B.Sc., Andrew J. Pocklington, Ph.D., Sophie E. Legge, Ph.D., Christopher Medway, Ph.D., Adrian King, Ph.D., John Jansen, Ph.D., Marinka Helthuis, M.D., Stanley Zammit, M.R.C.Psych., Ph.D., James MacCabe, F.R.C.Psych., Ph.D., Michael J. Owen, F.R.C.Psych., Ph.D., Michael C. O’Donovan, F.R.C.Psych., Ph.D., James T.R. Walters, M.R.C.Psych., Ph.D.
Affiliations: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (A.F.P., M.N., A.J.P., S.E.L., C.M., S.Z., M.J.O., M.C.O.D., J.T.R.W.); Magna Laboratories, Ross-on-Wye, U.K. (A.K.); Leyden Delta, Nijmegen, the Netherlands (J.J., M.H.); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (S.Z.); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (S.Z.); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London (J.M.C.).
Disclosures: Drs. Helthuis and Jansen are full-time employees of Leyden Delta. Dr. King is a full-time employee of Magna Laboratories. Drs. Pocklington, Owen, O’Donovan, and Walters are supported by a collaborative research grant from Takeda (Takeda played no part in the conception, design, implementation, or interpretation of this study, which was completed prior to the funding award). The other authors report no financial relationships with commercial interests.
Discussion of unapproved or investigational use of products*: No.
*APA policy requires disclosure by CME authors of unapproved or investigational use of products discussed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by scientific literature and clinical experience.
Ned H. Kalin, M.D. (Editor-in-Chief, AJP); Carolyn Rodriguez, M.D., Ph.D. (Deputy Editor, AJP); Michael D. Roy (Editorial Director, AJP); Michael A. Pogachar (Online Content Manager, Journals). Dr. Kalin has served as a consultant to the Board of Scientific Advisors, the Pritzker Neuropsychiatric Disorders Research Consortium, and the Skyland Trail Advisory Board and as Councilor, Society of Biological Psychiatry. Dr. Rodriguez has served as a consultant to Allergan, Blackthorn, Epiodyne, and Rugen. Mr. Roy and Mr. Pogachar report no financial relationships with commercial interests.
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