Pharmacopsychiatry 2022; 55(04): 211-219
DOI: 10.1055/a-1778-5125
Original Paper

Epigenetics for Drug Discovery: Dissecting the Effect of High Antipsychotic Dosage and D2 Blockage on Peripheral DNA Methylation

Christopher Adanty
1   Centre for Addiction and Mental Health, Toronto, Canada
,
Julia Kim
1   Centre for Addiction and Mental Health, Toronto, Canada
,
John Strauss
3   Department of Psychiatry, University of Toronto, Canada
,
Jessica Qian
1   Centre for Addiction and Mental Health, Toronto, Canada
,
Gary Remington
1   Centre for Addiction and Mental Health, Toronto, Canada
3   Department of Psychiatry, University of Toronto, Canada
,
Carol Borlido
1   Centre for Addiction and Mental Health, Toronto, Canada
,
Ariel Graff
1   Centre for Addiction and Mental Health, Toronto, Canada
3   Department of Psychiatry, University of Toronto, Canada
,
Philip Gerretsen
1   Centre for Addiction and Mental Health, Toronto, Canada
3   Department of Psychiatry, University of Toronto, Canada
,
Vincenzo De Luca
1   Centre for Addiction and Mental Health, Toronto, Canada
2   St. Michael’s Hospital, Toronto, Canada
3   Department of Psychiatry, University of Toronto, Canada
› Author Affiliations
Funding Dr. Vincenzo De Luca is supported by an American Foundation for Suicide Prevention Grant, a Miner’s Lamp Award, and a Scholar Award from the Department of Psychiatry at the University of Toronto. Christopher Adanty is supported by the Canada Graduate Scholarship Master’s Award from the Canadian Institute for Health Research.

Abstract

Introduction The relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug receptors has been often investigated. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and antipsychotic dosage. The primary aim of this pilot study was to investigate the association between antipsychotic dosage and genome-wide DNA methylation in patients with schizophrenia (SCZ).

Methods Current dosage of antipsychotic medications was assessed in 136 patients with SCZ. Dosage was standardized using three different methods: chlorpromazine equivalent dose (CPZe), defined daily dose (DDD), and percentage of Lexicomp maximum dose (PM%). DNA methylation was measured in white blood cells. Antipsychotic dosage was the primary outcome variable in a model, including genome-wide methylation status as the main predictor.

Results This study did not show any association between DNA methylation and dosage variation for CPZe, PM%, and DDD. However, the probe cg271403389 was consistently associated with antipsychotic dosage across the three standardization methods. When looking at the genomic location of the most significant probes, we found that 15% were intergenic, 23% were in the distal promoter, 9% in the 3′untranslated region, 32% in the gene body, 3% in the 5′ untranslated region, 15% in the proximal promoter, and 3% in the first exon.

Discussion This study shows the importance of investigating the relationship between DNA methylation and optimal antipsychotic dosage to personalize treatment in SCZ. Future studies require larger prescription databases to build on the results of this analysis.

Supplementary Material



Publication History

Received: 04 August 2021
Received: 11 May 2021

Accepted: 30 January 2022

Article published online:
28 April 2022

© 2022. Thieme. All rights reserved.

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