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Pharmacogenetics of Response to Antipsychotics in Patients with Schizophrenia

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Abstract

This review presents the findings of pharmacogenetic studies exploring the influence of gene variants on antipsychotic treatment response, in terms of both symptom improvement and adverse effects, in patients with schizophrenia.

Despite numerous studies in the field, replicating findings across different cohorts that include subjects of different ethnic groups has been challenging. It is clear that non-genetic factors have an important contribution to antipsychotic treatment response. Differing clinical, demographic and environmental characteristics of the cohorts studied have added substantial complexity to the interpretation of the positive and negative findings of many studies.

Pharmacogenomic genome-wide investigations are beginning to yield interesting data although they have failed to replicate the most robust findings of candidate gene studies, and are limited by the sample size, especially given the need for studying homogeneous cohorts.

Most of the studies conducted on cohorts treated with single anti-psychotics have investigated clozapine, olanzapine or risperidone response. These studies have provided some of the most replicated associations with treatment efficacy. Serotonergic system gene variants are significantly associated with the efficacy of clozapine and risperidone, but may have less influence on the efficacy of olanzapine. Dopamine D3 receptor polymorphisms have been more strongly associated with the efficacy of clozapine and olanzapine, and D2 genetic variants with the efficacy of risperidone.

Serotonin influences the control of feeding behaviour and has been hypothesized to have a role in the development of antipsychotic-induced weight gain. Numerous studies have linked the serotonin receptor 2C (5-HT2C) −759-C/T polymorphism with weight gain. The leptin gene variant, −2548-G/A, has also been associated with weight gain in several studies. Pharmacogenetic studies support the role of cytochrome P450 enzymes and dopamine receptor variants in the development of antipsychotic-induced movement disorders, with a contribution of serotonergic receptors and other gene variants implicated in the mechanism of action of antipsychotics. Clozapine-induced agranulocytosis has been associated with polymorphisms in the major histocompatibility complex gene (HLA).

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Acknowledgements

No specific funding was received for the completion of this review. Maria J. Arranz and Margarita Rivera have no conflicts of interest that may have interfered with this work. Margartia Rivera is funded by a Postdoctoral Marie Curie Intra-European Fellowship with the 7th European Framework Programme. Janet C. Munro is a co-founder of Optimal Medicine LTD., a company developing pharmacogenomic tests and companion diagnostics for antipsychotic medications, and she has received honoraria from Lundbeck A/S.

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Authors and Affiliations

  1. Department of Psychological Medicine, Institute of Psychiatry, King’s College London, PO 51-room N2.07, Denmark Hill, London, SE5 8AF, UK

    Maria J. Arranz

  2. MRC Social, Genetic and Developmental Psychiatry, Institute of Psychiaty, King’s College London, London, UK

    Margarita Rivera

  3. Section of Psychiatry, Institute of Neurosciences, Biomedical Research Centre (CIBM), CIBERSAM, University of Granada, Granada, Spain

    Margarita Rivera

  4. Optimal Medicine Ltd., Warwick Enterprise Park, Wellesbourne, Warwick, UK

    Janet C. Munro

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  1. Maria J. Arranz
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Arranz, M.J., Rivera, M. & Munro, J.C. Pharmacogenetics of Response to Antipsychotics in Patients with Schizophrenia. CNS Drugs 25, 933–969 (2011). https://doi.org/10.2165/11595380-000000000-00000

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