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Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

The treatment of bipolar disorder (BD) usually requires combination therapies, with the critical issue of the emergence of adverse drug reactions (ADRs) and the possibility of low treatment adherence. Genetic polymorphisms are hypothesized to modulate the pharmacodynamics of psychotropic drugs, representing potential biological markers of ADRs. This study investigated genes involved in the regulation of neuroplasticity (BDNF, ST8SIA2), second messenger cascades (GSK3B, MAPK1, and CREB1), circadian rhythms (RORA), transcription (SP4, ZNF804A), and monoaminergic system (HTR2A and COMT) in the risk of neurological, psychic, autonomic, and other ADRs. Two independent samples of BD patients naturalistically treated were included (COPE-BD n = 147; STEP-BD n = 659). In the COPE-BD 34 SNPs were genotyped, while in the STEP-BD polymorphisms in the selected genes were extracted from the genome-wide dataset. Each ADRs group was categorized as absent-mild or moderate-severe and logistic regression with appropriate covariates was applied to identify possible risk genotypes/alleles. 58.5 and 93.5 % of patients were treated with mood stabilizers, 44.2 and 50.7 % were treated with antipsychotics, and 69.4 and 46.1 % were treated with antidepressants in the COPE-BD and STEP-BD, respectively. Our findings suggested that ST8SIA2 may be associated with psychic ADRs, as shown in the COPE-BD (rs4777989 p = 0.0017) and STEP-BD (rs56027313, rs13379489 and rs10852173). A cluster of RORA SNPs around rs2083074 showed an effect on psychic ADRs in the STEP-BD. Trends supporting the association between HTR2A and autonomic ADRs were found in both samples. Confirmations are needed particularly for ST8SIA2 and RORA since the few available data regarding their role in relation to psychotropic ADRs.

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Acknowledgments

The STEP-BD project was funded in whole or in part with Federal Funds from the National Institute of Mental Health (NIMH), under contract N01MH8001. Collection of DNA from consenting participants in STEP-BD was supported by N01MH80001 (Gary S. Sachs, M.D., principal investigator). Sample collection funding was supported by NIH grants (MH067288, Pamela Sklar; MH063445, Jordan W. Smoller; MH63420, Vish Nimgaonkar). Genotyping was funded by grants from NIH (MH067288 Pamela Sklar, PI), Johnson & Johnson Pharmaceutical Research and Development, Sylvan C. Herman Foundation, Stanley Medical Research Foundation, and Merck Genome Research Institute (Edward Scolnick, PI). We thank Manuel Mayhaus (University of Saarlandes, Germany) for technical assistance with Sequenom MassArray platform.

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Authors and Affiliations

  1. Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy

    Chiara Fabbri, Alberto Chiesa, Rosalba Martines & Alessandro Serretti

  2. Laboratoire de Psychologie Medicale, Université Libre de Bruxelles and Psy Pluriel, Brussels, Belgium

    Daniel Souery

  3. IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy

    Raffaella Calati

  4. Department of Biomedical Science and Morphological and Functional Images, University of Messina, Messina, Italy

    Concetta Crisafulli

  5. Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy

    Armando Chierchia, Diego Albani & Gianluigi Forloni

  6. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Alberto Chiesa

  7. Département de Psychiatrie Hôpitaux Universitaires de Genève, Faculté de Médecine de Genève, Geneva, Switzerland

    Othman Sentissi

  8. Université Libre de Bruxelles, Brussels, Belgium

    Julien Mendlewicz

  9. IRCCS Fatebenefratelli, Brescia, Italy

    Giovanni De Girolamo & Alessandro Serretti

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  1. Chiara Fabbri
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Fabbri, C., Souery, D., Calati, R. et al. Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients. J Neural Transm 122, 43–58 (2015). https://doi.org/10.1007/s00702-014-1290-3

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