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Article

Integrating Genetic Variants and Expression Profiles of Pharmacogenes to Investigate Resistance to Antidepressant Treatment

by
Claudia Pisanu
1,†,
Alessio Squassina
1,*,†,
Júlia Perera-Bel
2,
Rosana Carvalho Silva
3,
Lisa Buson
4,
Anna Martinez Sires
2,
Marco Bortolomasi
5,
Valentina Menesello
3,4,
Giulia Perusi
3,
Bernardo Carpiniello
6,
Ewa Ferensztajn-Rochowiak
7,
Filip Rybakowski
7,
Ferran Sanz
2,8,
Mirko Manchia
6,9,
Marie Claude Potier
10,
Mara Dierssen
11,12,
PROMPT Study Group
,
Bernhard T. Baune
13,14,15,
Massimo Gennarelli
3,4 and
Alessandra Minelli
3,4,*
1
Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
2
Hospital del Mar Medical Research Institute (HMRIB), 08003 Barcelona, Spain
3
Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
4
Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy
5
Psychiatric Hospital “Villa Santa Chiara”, 37142 Verona, Italy
6
Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy
7
Department of Adult Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland
8
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08005 Barcelona, Spain
9
Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
10
Paris Brain Institute (ICM), National Centre for Scientific Research (CNRS), 75794 Paris, France
11
Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), 08036 Barcelona, Spain
12
Biomedical Research Networking Center for Rare Diseases (CIBERER), 08003 Barcelona, Spain
13
Department of Psychiatry, University of Münster, 48149 Münster, Germany
14
Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
15
Department of Psychiatry, University of Melbourne, Parkville, VIC 3010, Australia
 
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*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Medicina 2026, 62(5), 965; https://doi.org/10.3390/medicina62050965
Submission received: 9 March 2026 / Revised: 16 April 2026 / Accepted: 21 April 2026 / Published: 15 May 2026
(This article belongs to the Special Issue Implementing Technological Advances in Psychiatry: Challenges and Opportunities)
Versions Notes

Abstract

Background and Objectives: Treatment-resistant depression (TRD) is a major clinical challenge in the management of major depressive disorder (MDD). While pharmacogenetics has been suggested to be clinically useful in guiding antidepressant treatment, few studies have explored if and how pharmacogenes can be involved in TRD pathophysiology and its clinical outcomes. Material amd Methods: We explored the role of differences in metabolizer phenotypes, gene expression levels, and microRNAs of three key pharmacogenes (CYP2D6, CYP2C19, CYP2B6) in TRD pathophysiology and antidepressant response in a cohort of 300 patients with MDD from the PROMPT consortium. Results: CYP2D6 phenotype distribution did not differ significantly between TRD and non-TRD groups, but mRNA expression was significantly upregulated in TRD. Hsa-miR-26b-5p, a microRNA predicted to regulate CYP2D6, was significantly downregulated in TRD. For CYP2C19, intermediate metabolizers (IMs) were underrepresented in TRD versus non-TRD (IMs vs. normal metabolizers (NMs): χ2 = 6.07, p = 0.019). microRNA hsa-let-7d-5p and hsa-miR-27a-3p, predicted to regulate CYP2C19, were significantly downregulated in TRD. No significant differences were found for CYP2B6. Conclusions: This study contributes valuable insights to the PROMPT project on how pharmacokinetic gene variants and their expression and regulatory mechanisms may influence antidepressant response and resistance in MDD.
Keywords: pharmacogenetics; precision psychiatry; CYP2D6; CYP2C19; antidepressants; treatment-resistant depression; mRNA; miRNA pharmacogenetics; precision psychiatry; CYP2D6; CYP2C19; antidepressants; treatment-resistant depression; mRNA; miRNA

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MDPI and ACS Style

Pisanu, C.; Squassina, A.; Perera-Bel, J.; Silva, R.C.; Buson, L.; Sires, A.M.; Bortolomasi, M.; Menesello, V.; Perusi, G.; Carpiniello, B.; et al. Integrating Genetic Variants and Expression Profiles of Pharmacogenes to Investigate Resistance to Antidepressant Treatment. Medicina 2026, 62, 965. https://doi.org/10.3390/medicina62050965

AMA Style

Pisanu C, Squassina A, Perera-Bel J, Silva RC, Buson L, Sires AM, Bortolomasi M, Menesello V, Perusi G, Carpiniello B, et al. Integrating Genetic Variants and Expression Profiles of Pharmacogenes to Investigate Resistance to Antidepressant Treatment. Medicina. 2026; 62(5):965. https://doi.org/10.3390/medicina62050965

Chicago/Turabian Style

Pisanu, Claudia, Alessio Squassina, Júlia Perera-Bel, Rosana Carvalho Silva, Lisa Buson, Anna Martinez Sires, Marco Bortolomasi, Valentina Menesello, Giulia Perusi, Bernardo Carpiniello, and et al. 2026. "Integrating Genetic Variants and Expression Profiles of Pharmacogenes to Investigate Resistance to Antidepressant Treatment" Medicina 62, no. 5: 965. https://doi.org/10.3390/medicina62050965

APA Style

Pisanu, C., Squassina, A., Perera-Bel, J., Silva, R. C., Buson, L., Sires, A. M., Bortolomasi, M., Menesello, V., Perusi, G., Carpiniello, B., Ferensztajn-Rochowiak, E., Rybakowski, F., Sanz, F., Manchia, M., Potier, M. C., Dierssen, M., PROMPT Study Group, Baune, B. T., Gennarelli, M., & Minelli, A. (2026). Integrating Genetic Variants and Expression Profiles of Pharmacogenes to Investigate Resistance to Antidepressant Treatment. Medicina, 62(5), 965. https://doi.org/10.3390/medicina62050965

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