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Article

Integrative Genomic–Epigenomic Analysis of Clozapine-Treated Patients with Refractory Psychosis

1
Department of Biological Systems, Metropolitan Autonomous University-Xochimilco, Mexico City 04960, Mexico
2
Department of Genetics, National Institute of Neurology and Neurosurgery, “Manuel Velasco Suárez”, Mexico City 14269, Mexico
3
Genomics of Psychiatric and Neurodegenerative Diseases Laboratory, Instituto Nacional de Medicina Genómica, SSA, Mexico City 14610, Mexico
4
Natural Sciences Department, Universidad Autónoma Metropolitana-Cuajimalpa, Mexico City 05348, Mexico
5
Grupo de Estudios Médicos y Familiares Carracci, Mexico City 03740, Mexico
*
Author to whom correspondence should be addressed.
Academic Editor: Alessio Squassina
Pharmaceuticals 2021, 14(2), 118; https://doi.org/10.3390/ph14020118
Received: 9 December 2020 / Revised: 19 January 2021 / Accepted: 26 January 2021 / Published: 4 February 2021
(This article belongs to the Special Issue The Pharmacogenomics of Mood Stabilizers)
Clozapine (CLZ) is the only antipsychotic drug that has been proven to be effective in patients with refractory psychosis, but it has also been proposed as an effective mood stabilizer; however, the complex mechanisms of action of CLZ are not yet fully known. To find predictors of CLZ-associated phenotypes (i.e., the metabolic ratio, dosage, and response), we explore the genomic and epigenomic characteristics of 44 patients with refractory psychosis who receive CLZ treatment based on the integration of polygenic risk score (PRS) analyses in simultaneous methylome profiles. Surprisingly, the PRS for bipolar disorder (BD-PRS) was associated with the CLZ metabolic ratio (pseudo-R2 = 0.2080, adjusted p-value = 0.0189). To better explain our findings in a biological context, we assess the protein–protein interactions between gene products with high impact variants in the top enriched pathways and those exhibiting differentially methylated sites. The GABAergic synapse pathway was found to be enriched in BD-PRS and was associated with the CLZ metabolic ratio. Such interplay supports the use of CLZ as a mood stabilizer and not just as an antipsychotic. Future studies with larger sample sizes should be pursued to confirm the findings of this study. View Full-Text
Keywords: clozapine; mood stabilizer; refractory psychosis; pharmacogenomics; predictive model; methylome; polygenic risk scores clozapine; mood stabilizer; refractory psychosis; pharmacogenomics; predictive model; methylome; polygenic risk scores
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MDPI and ACS Style

Mayén-Lobo, Y.G.; Martínez-Magaña, J.J.; Pérez-Aldana, B.E.; Ortega-Vázquez, A.; Genis-Mendoza, A.D.; Dávila-Ortiz de Montellano, D.J.; Soto-Reyes, E.; Nicolini, H.; López-López, M.; Monroy-Jaramillo, N. Integrative Genomic–Epigenomic Analysis of Clozapine-Treated Patients with Refractory Psychosis. Pharmaceuticals 2021, 14, 118. https://doi.org/10.3390/ph14020118

AMA Style

Mayén-Lobo YG, Martínez-Magaña JJ, Pérez-Aldana BE, Ortega-Vázquez A, Genis-Mendoza AD, Dávila-Ortiz de Montellano DJ, Soto-Reyes E, Nicolini H, López-López M, Monroy-Jaramillo N. Integrative Genomic–Epigenomic Analysis of Clozapine-Treated Patients with Refractory Psychosis. Pharmaceuticals. 2021; 14(2):118. https://doi.org/10.3390/ph14020118

Chicago/Turabian Style

Mayén-Lobo, Yerye G., José J. Martínez-Magaña, Blanca E. Pérez-Aldana, Alberto Ortega-Vázquez, Alma D. Genis-Mendoza, David J. Dávila-Ortiz de Montellano, Ernesto Soto-Reyes, Humberto Nicolini, Marisol López-López, and Nancy Monroy-Jaramillo. 2021. "Integrative Genomic–Epigenomic Analysis of Clozapine-Treated Patients with Refractory Psychosis" Pharmaceuticals 14, no. 2: 118. https://doi.org/10.3390/ph14020118

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