Therapeutic response to paroxetine in major depressive disorder predicted by DNA Methylation
Abstract
BACKGROUND: Antidepressants have variable therapeutic effects, depending on genetic and environmental factors. Approximately 30% of major depressive disorder (MDD) patients do not respond significantly to antidepressants such as paroxetine, a selective serotonin reuptake inhibitor (SSRI). However, the biological mechanisms behind this phenomenon are mostly unknown. Here, we examined the role of patients' epigenetic background in SSRI efficacy. METHODS: Genome-wide DNA methylation analysis of the peripheral blood of Japanese MDD patients was performed by using the Infinium HumanMethylation450 BeadChip. RESULTS: We compared the results of the 10 patients who best responded to paroxetine (BR) with the 10 worst responders (WR), and found 623 CpG sites with a >10% difference in DNA methylation level. Among them, 218 sites were nominally significant between BR and WR (p < 0.05), and 2 sites (cg00594917 and cg07260927) were significantly different after false discovery rate (FDR) correction (q < 0.05). The methylation difference was greatest at cg00594917, located in the first exon of the PPFIA4 gene, which codes for liprin-α (p = 0.00012). Hierarchical cluster analysis of 23 CpG sites in the PPFIA4 gene distinguished BR and WR, except for 1 WR patient. The cg07260927 site was located in the 5'UTR of the heparin sulfate-glucosamine 3-sulfotransferase 1 (HS3ST1) gene (p = 0.00013). Hierarchical cluster analysis of 28 CpG sites in HS3ST1 distinguished BR and WR, except for 1 WR and 2 BR patients. CONCLUSION: Our results suggest that patients' DNA methylation profile at specific genes such as PPFIA4 and HS3ST1 is associated with individual variations in therapeutic responses to paroxetine.
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Only 4 pilot studies have investigated genome-wide DNA methylation patterns for their potential as predictors of response to pharmacological antidepressant treatment.
“Thus far, only 4 pilot studies have investigated genome-wide DNA methylation patterns for their potential as predictors of response to pharmacological antidepressant treatment”
From Epigenome-wide DNA methylation in unipolar depression: predictive biomarker of antidepressant treatment response? (2024) · cites this paper as Takeuchi et al. (2017)
The presently identified hits did not overlap with CpGs associated with antidepressant treatment response in previous EWAS.
“The presently identified hits did not overlap with CpGs associated with antidepressant treatment response in previous EWAS (cf. Takeuchi et al., 2017; Ju et al., 2019; Martinez-Pinteno et al., 2021; Engelmann et al., 2022).”
From Epigenome-wide DNA methylation in unipolar depression: predictive biomarker of antidepressant treatment response? (2024) · cites this paper as Takeuchi et al., 2017
Previous EWAS sample sizes were very small and differed in sample composition and statistical approaches, limiting comparability.
“However, previous sample sizes were very small and differed both in sample composition (e.g., age, ethnicity) and statistical approaches, thus limiting comparability.”
From Epigenome-wide DNA methylation in unipolar depression: predictive biomarker of antidepressant treatment response? (2024) · cites this paper as Takeuchi et al., 2017
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“One of the earliest studies, by Takeuchi et al. [17], analyzed Japanese patients treated with paroxetine and identified two CpGs in the PPFIA4 and HS3ST1 significantly associated with therapeutic response.”
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“DNAm modification is induced by developmental and exogenous factors, such as diet [28], cigarette smoking [29], age [30], medication [31], and physical activity [32].”
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Silva, R. C., Zareifi, D., Giannakou, D., Afantitis, A., & Minelli, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27136089
“The identification of epigenetic biomarkers with predictive value could therefore contribute to more personalized and effective treatment selection [16,22,23].”
- Authors
- Takeuchi, N., Nonen, S., Kato, M., Wakeno, M., Takekita, Y., Kinoshita, T., & Kugawa, F.
- Affiliations
- Hyogo University of Health Sciences (JP)
- Kansai Medical University (JP)
- Venue
- Neuropsychobiology
- Publisher
- S. Karger AG
- Published
- 2017
- Volume
- 75
- Issue
- 2
- Pages
- 81-88
- ISSN
- 0302-282X (ISSN-L)
- 1423-0224
- OpenAlex
- W2765970627
- Cited by
- 26
- References
- 35
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 1
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropsychobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (15K09813)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, paroxetine, antidepressant response, DNA methylation, epigenetics, Liprin-α, selective serotonin reuptake inhibitors, treatment resistance, CpG sites, peripheral blood
- MeSH terms
- Adult, Aged, Major Depressive Disorder, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Sulfotransferases, Cluster Analysis, Selective Serotonin Reuptake Inhibitors, Paroxetine, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Adaptor Proteins, Signal Transducing
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