The potential of SLC6A4 gene methylation analysis for the diagnosis and treatment of major depression
Open accessAbstract
We examined the utility of DNA methylation profiles at the CpG island of SLC6A4 (DMS) as a diagnostic biomarker for major depression (MD). In addition, the relationship between DMS and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) allele, the severity of symptoms, number of early adversities, and therapeutic responses to antidepressants were examined. Genomic DNA was extracted from peripheral blood of Japanese healthy controls and patients with MD before and after treatment. DMS was analyzed using a MassARRAY Compact System. The severity of depression was evaluated using the Hamilton Rating Scale for Depression, and early adversity was evaluated using the Early Trauma Inventory. We were unable to distinguish between and healthy controls, or between unmedicated patients and medicated patients using DMS. The 5-HTTLPR allele had no significant effect on DMS. The methylation rates for several CpGs differed significantly after treatment. Notably, the methylation rate of CpG 3 in patients with better therapeutic responses was significantly higher than that in patients with poorer responses. Although further studies examining the function of specific CpG units of SLC6A4 are required, these results suggest that the pre-treatment methylation rate of SLC6A4 is associated with therapeutic responses to antidepressants in unmedicated patients with MD.
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SSRIs may normalize some of these methylation changes.
“SSRIs may normalize some of these methylation changes”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [106]
The Discussion reports that CpG 3 methylation changed after antidepressant treatment, supporting a possible treatment-related effect. But Table 2 shows that CpG 3 moved away from the healthy-control level, not toward it, and the treatment group included milnacipran as well as SSRIs. The paper therefore does not establish that SSRIs normalize these changes; page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSLC6A4 methylation can be used as an indicator of treatment response to SSRIs or psychotherapy.
“SLC6A4 methylation can be used as an indicator of treatment response to SSRIs or psychotherapy”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [106]
The Results section reports that pretreatment methylation at SLC6A4 CpG 3 correlated with response after six weeks of antidepressant treatment, which included SSRIs. The Discussion describes this as a possible marker, not an established indicator, and the paper does not report psychotherapy response (page numbers unavailable). (LLM, conf=0.88)
Experimental — accuracy not yet measuredMethylation at a certain CpG site within SLC6A4 is significantly increased in patients with better therapeutic responses compared to those with worse responses.
“Methylation at a certain CpG site within SLC6A4 is significantly increased in patients with better therapeutic responses compared to those with worse responses.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [132]
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The molecular basis of depression: implications of sex-related differences in epigenetic regulation
Kawatake-Kuno, A., Murai, T., & Uchida, S. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.708004 · Cited by 23 · see citing works
The top-100 cited articles on biomarkers in the depression field: a bibliometric analysis
Shi, S.-Z., Gao, Y., Sun, Y., Liu, M., Shao, L., Zhang, J.-H., & Tian, J.-H. (2020) · Psychology, Health & Medicine · doi:10.1080/13548506.2020.1752924 · Cited by 24 · see citing works
Depressive disorder and antidepressants from an epigenetic point of view
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Ismaylova, E., Sante, J. D., Moshe Szyf, A., Nemoda, Z., Yu, W.-J., Pomares, F. B., Turecki, G., Gobbi, G., Vitaro, F., Tremblay, R. E., et al. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.07.005 · Cited by 23 · see citing works
Sun, L., Verkaik‐Schakel, R. N., Biber, K. P. H., Plösch, T., & Serchov, T. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.10.040 · Cited by 22 · see citing works
Decoding serotonin: the molecular symphony behind depression
Shu, Y. L., Tian, L., Wang, X., Meng, T., Yu, S., & Li, Y. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1572462 · Cited by 23 · see citing works
van Calker, D., & Serchov, T. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.019 · Cited by 19 · see citing works
Coelho, A. A., Bastos, S., Gobira, P. H., & Lisboa, S. F. D. S. (2023) · Neuronal Signaling · doi:10.1042/ns20220034 · Cited by 22 · see citing works
The Promise of Biomarkers in Diagnosing Major Depression in Primary Care: the Present and Future
Redei, E. E., & Mehta, N. S. (2015) · Current Psychiatry Reports · doi:10.1007/s11920-015-0601-1 · Cited by 19 · see citing works
Yamazaki, K., Yoshino, Y., Mori, T., Okita, M., Yoshida, T., Mori, Y., Ozaki, Y., Sao, T., Iga, J., & Ueno, S. (2016) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000447324 · Cited by 16 · see citing works
Influence of antidepressant treatment on SLC6A4 methylation in Korean patients with major depression
Moon, Y. K., Kim, H. S., Kim, S., Lim, S., & Kim, D. K. (2022) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32921 · Cited by 16 · see citing works
Musazzi, L., Paoli, C., Misztak, P., & Mazzini, G. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220201084536 · Cited by 15 · see citing works
Shi, M., Sun, H., Xu, Y., Wang, Z., Cui, H., Wang, C., Liu, W., An, G., & Hu, J. (2016) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0000000000000600 · Cited by 15 · see citing works
Hua, Y., Huang, C., Guo, Y., Du, X., Guo, L., Wang, W., Lu, C., & Guo, L. (2023) · BMC Psychiatry · doi:10.1186/s12888-023-04816-7 · Cited by 16 · see citing works
DNA Methylation of Fluoxetine Response in Child and Adolescence: Preliminary Results
Martínez-Pinteño, A., Rodríguez, N., Blázquez, A., Plana, M. T., Varela, E., Gassó, P., Lafuente, A., Lázaro, L., & Mas, S. (2021) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s289480 · Cited by 12 · see citing works
D’Addario, C., Macellaro, M., Bellia, F., Benatti, B., Annunzi, E., Palumbo, R., Conti, D., Fasciana, F., Vismara, M. E. M., Varinelli, A., et al. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666211208115536 · Cited by 10 · see citing works
DNA Methylation as a Therapeutic and Diagnostic Target in Major Depressive Disorder
Lax, E. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.759052 · Cited by 11 · see citing works
Wang, T., Li, L., Yue, Y., Liu, X., Chen, S., Shen, T., Xu, Z., & Yuan, Y. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.06.042 · Cited by 10 · see citing works
Bruzzone, S. E. P., Ozenne, B., Fisher, P. M., Ortega, G., Jensen, P. S., Dam, V. H., Svarer, C., Knudsen, G. M., Lesch, K., & Frøkjær, V. G. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01678-y · Cited by 10 · see citing works
Li, W., Wang, W., Lai, W., Li, X., Zhu, L., Shi, J., Teopiz, K. M., McIntyre, R. S., Guo, L., & Lu, C. (2022) · BMC Psychiatry · doi:10.1186/s12888-022-04392-2 · Cited by 9 · see citing works
Bečeheli, I., Horvatiček, M., Perić, M., Nikolić, B., Holuka, C., Klasić, M., Ivanišević, M., Starčević, M., Desoyé, G., Hranilović, D., et al. (2024) · Clinical Epigenetics · doi:10.1186/s13148-023-01610-w · Cited by 9 · see citing works
Dahrendorff, J., Currier, G. W., & Uddin, M. (2024) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32985 · Cited by 8 · see citing works
Javelle, F., Đào, G. J., Ringleb, M., Pulverer, W., & Bloch, W. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03356-w · Cited by 9 · see citing works
DNA Methylation Patterns in Relation to Acute Severity and Duration of Anxiety and Depression
Vidovič, E., Pelikán, S., Atanasova, M., Kouter, K., Pileckyte, I., Oblak, A., Šarotar, B. N., Paska, A. V., & Bon, J. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45090461 · Cited by 8 · see citing works
Guo, L., Wang, W., Guo, Y., Du, X., Shi, G., & Lu, C. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03576-6 · Cited by 8 · see citing works
DNA methylation of serotonin genes as predictive biomarkers of antidepressant treatment response
Bruzzone, S. E. P., Ozenne, B., Fisher, P. M., Ortega, G., Jørgensen, M. B., Knudsen, G. M., Lesch, K., & Frøkjær, V. G. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111160 · Cited by 7 · see citing works
Can Epigenetics Predict Drug Efficiency in Mental Disorders?
David, G. B., Amir, Y., Salalha, R., Sharvit, L. E., Richter‐Levin, G., & Atzmon, G. (2023) · Cells · doi:10.3390/cells12081173 · Cited by 6 · see citing works
Methylation of the serotonin reuptake transporter gene and non-motor symptoms in dystonia patients
Timmers, E. R., Plösch, T., Smit, M., Hof, I. H., Verkaik‐Schakel, R. N., Tijssen, M. A. J., de Koning, T. J., & Niezen‐Koning, K. E. (2022) · Clinical Epigenetics · doi:10.1186/s13148-022-01384-7 · Cited by 6 · see citing works
Hu, L., Wu, N., Wang, J., & Cai, D. (2025) · Scientific Reports · doi:10.1038/s41598-024-84771-9 · Cited by 5 · see citing works
Lai, W., Li, W., Du, X., Guo, Y., Wang, W., Guo, L., & Lu, C. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.761898 · Cited by 5 · see citing works
Models for depression recognition and efficacy assessment based on clinical and sequencing data
Hu, Y., Jiang, C., Li, J., & Xu, Z. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33973 · Cited by 5 · see citing works
Precision Psychiatry: Personalized Clinical Approach to Depression
Perna, G., Balletta, R., & Nemeroff, C. B. (2017) · Springer eBooks · doi:10.1007/978-981-10-6580-4_21 · Cited by 5 · see citing works
Epigenetic Mechanisms in Depression
Lévesque, M. L., Szyf, M., & Booij, L. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802456-0.00006-6 · Cited by 5 · see citing works
Montel Hayes, R., Mason, C. E., & Miller, J. J. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1671122 · Cited by 5 · see citing works
An Overview of Machine Learning Applications in Mood Disorders
Topolski, N., Jeong, S. H., & Mwangi, B. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108623018.017 · Cited by 4 · see citing works
Epigenetics of Major Depressive Disorder
Wang, K. Z., Dada, O. O., Bani‐Fatemi, A., Tasmim, S., Monda, M., Graff, A., & Luca, V. D. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-58131-8.00002-1 · Cited by 4 · see citing works
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Epigenetic biomarkers in neuropsychiatric disorders
Lin, C.-C., & Huang, T. L. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800226-1.00003-4 · Cited by 3 · see citing works
Handschuh, P. A., Murgaš, M., Winkler, D., Pjrek, E., Hartmann, A. M., Domschke, K., Baldinger, P., Rujescu, D., Lanzenberger, R. R., & Spies, M. (2025) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2025.2477463 · Cited by 2 · see citing works
Neuroimaging Studies of Effects of Psychotherapy in Depression
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Psychotropic drug use and suggestive depression symptoms associated with NR3C1 DNA methylation
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Serotonergic and Noradrenergic Neurotransmitter Systems in Suicide
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Electrophysiological Biomarkers for Mood Disorders
Ramakrishnan, N., Murphy, N., Selvaraj, S., & Cho, R. Y. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108623018.015 · Cited by 2 · see citing works
Chapter 8. Personalized Medicine in Psychiatry
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A review of the relationship between the SLC6A4 gene and mental disorders
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Early-life stress exposure and epigenetic programming
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Functional Connectome in Bipolar Disorder
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Imaging Genetic and Epigenetic Markers in Mood Disorders
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Brain Imaging of Reward Dysfunction in Unipolar and Bipolar Disorders
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Resting-State Functional Connectivity in Unipolar Depression
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- Authors
- Okada, S., Morinobu, S., Fuchikami, M., Segawa, M., Yokomaku, K., Kataoka, T., Okamoto, Y., Yamawaki, S., Inoue, T., Kusumi, I., Koyama, T., Tsuchiyama, K., Terao, T., Kokubo, Y., & Mimura, M.
- Affiliations
- Hiroshima University (JP)
- Hokkaido University (JP)
- Oita University (JP)
- SHOWA Medical University (JP)
- Corresponding author
- Morinobu, Shigeru
- ORCID
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 53
- Pages
- 47-53
- ISSN
- 0022-3956 (ISSN-L)
- OpenAlex
- W2035269052
- Cited by
- 125
- References
- 48
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 13 · 2021: 37 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 9 · 2015: 7
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 355 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Journal of Psychiatric Research (acceptedVersion)
- PubMed (publishedVersion)
- Hiroshima University Acedemic Information Repository (Hiroshima University) (submittedVersion)
- Funders
- Core Research for Evolutional Science and Technology
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Science and Technology Agency
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- serotonin transporter, DNA methylation, major depressive disorder, diagnostic biomarkers, antidepressant response, 5-HTTLPR, CpG islands, childhood adversity, depression severity, epigenetics
- MeSH terms
- Adult, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Female, Genotype, Humans, Male, Middle Aged, Pharmacogenetics, Psychiatric Status Rating Scales, Statistics as Topic, Case-Control Studies, CpG Islands, DNA Methylation, Serotonin Plasma Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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