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Pharmacopsychiatry 2024; 57(05): 232-244
DOI: 10.1055/a-2313-9979
Original Paper

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study

Farhana Islam
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
2   Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
,
Amanda Lisoway
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
3   Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
,
Edward S. Oh
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
,
Laura M. Fiori
4   McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
,
Leen Magarbeh
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
2   Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
,
Samar S. M. Elsheikh
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
,
Helena K. Kim
5   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
,
Stefan Kloiber
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
2   Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
3   Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
5   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
,
James L. Kennedy
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
3   Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
5   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
,
Benicio N. Frey
6   Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
7   St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
,
Roumen Milev
8   Department of Psychiatry, Queen's University, Providence Care, Kingston, Ontario, Canada
,
Claudio N. Soares
8   Department of Psychiatry, Queen's University, Providence Care, Kingston, Ontario, Canada
,
Sagar V. Parikh
9   Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
,
Franca Placenza
10   Centre for Mental Health, University Health Network, Toronto, Ontario, Canada
,
Stefanie Hassel
11   Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada; Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
,
Valerie H. Taylor
11   Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada; Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
,
Francesco Leri
12   Department of Psychology and Neuroscience, University of Guelph, Guelph, Ontario, Canada
,
Pierre Blier
13   The Royal Institute of Mental Health Research, Ottawa, Ontario, Canada
,
Rudolf Uher
14   Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
,
Faranak Farzan
15   Mechatronic Systems Engineering, Simon Fraser University, Surrey, British Columbia, Canada
,
Raymond W. Lam
16   Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
,
Gustavo Turecki
4   McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
,
Jane A. Foster
6   Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
10   Centre for Mental Health, University Health Network, Toronto, Ontario, Canada
17   St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
,
Susan Rotzinger
3   Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
18   Department of Psychiatry, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
,
Sidney H. Kennedy
3   Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
5   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
10   Centre for Mental Health, University Health Network, Toronto, Ontario, Canada
18   Department of Psychiatry, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
19   Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada
,
Daniel J. Müller
1   Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
2   Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
3   Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
5   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
20   Department of Psychiatry, Psychosomatics and Psychotherapy, University Clinic of Würzburg, Würzburg, Germany
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Abstract

Introduction Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes.

Methods The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects.

Results Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated.

Discussion These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

Keywords

antidepressant - depression - escitalopram - aripiprazole - methylation - quantitative trait loci

Supplementary Material



Publication History

Received: 23 December 2023
Received: 13 March 2024

Accepted: 15 April 2024

Article published online:
25 June 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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