Clement C Zai1,2,3,4, Arun K Tiwari1,2, Gwyneth C Zai1,2, Miriam S Maes1, James L Kennedy1,2,4. 1. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health. 2. Department of Psychiatry. 3. Laboratory Medicine and Pathobiology. 4. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Abstract
PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects. RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications. SUMMARY: The findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings.
PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects. RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications. SUMMARY: The findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings.
Authors: Clement C Zai; Arun K Tiwari; Gwyneth C Zai; Natalie Freeman; Jennie G Pouget; James Greco; Maria Tampakeras; Sajid A Shaikh; Deanna Herbert; Heather Emmerson; Sheraz Y Cheema; Nicole Braganza; Daniel J Müller; Aristotle N Voineskos; Gary Remington; James L Kennedy Journal: Front Pharmacol Date: 2019-11-26 Impact factor: 5.810
Authors: Victor Mazereel; Johan Detraux; Davy Vancampfort; Ruud van Winkel; Marc De Hert Journal: Front Endocrinol (Lausanne) Date: 2020-10-09 Impact factor: 5.555
Authors: Rodrigo R Nieto; Andrea Carrasco; Sebastian Corral; Rolando Castillo; Pablo A Gaspar; M Leonor Bustamante; Hernan Silva Journal: Front Psychiatry Date: 2021-06-16 Impact factor: 4.157
Authors: Clement C Zai; Frankie H Lee; Arun K Tiwari; Justin Y Lu; Vincenzo de Luca; Miriam S Maes; Deanna Herbert; Anashe Shahmirian; Sheraz Y Cheema; Gwyneth C Zai; Anupama Atukuri; Michael Sherman; Sajid A Shaikh; Maria Tampakeras; Natalie Freeman; Nicole King; Daniel J Müller; Lior Greenbaum; Bernard Lerer; Aristotle N Voineskos; Steven G Potkin; Jeffrey A Lieberman; Herbert Y Meltzer; Gary Remington; James L Kennedy Journal: Front Pharmacol Date: 2018-09-18 Impact factor: 5.810
Authors: Paula Soria-Chacartegui; Gonzalo Villapalos-García; Pablo Zubiaur; Francisco Abad-Santos; Dora Koller Journal: Front Pharmacol Date: 2021-07-14 Impact factor: 5.810