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Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Molecular Psychiatry volume 9, pages 442–473 (2004)Cite this article

Abstract

Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970–2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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Acknowledgements

The support for this work has been provided by grants from the German Ministry of Education and Research, BMBF Grant No. 01 GG 9845/5 and from the National Institutes of Health: GM61394, K30HL04526, RR16996, HG002500, RR017611, DK063240, DK58851 (JL), RR017365, MH062777, RR000865 (M-LW), and by awards from the Dana Foundation, Amgen, Inc. (JL), and NARSAD (M-LW).

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Campus Charité Mitte, University Medicine Berlin, Berlin, Germany

    J Kirchheiner, K Nickchen & I Roots

  2. Department of Psychiatry and Psychotherapy, Campus Charité Mitte, University Medicine Berlin, Berlin, Germany

    M Bauer

  3. Center for Pharmacogenomics and Interdepartmental Clinical Pharmacology Center, Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    M-L Wong & J Licinio

  4. Department of Clinical Pharmacology, Georg August University Göttingen, Berlin, Germany

    J Brockmöller

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  1. J Kirchheiner
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  2. K Nickchen
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  3. M Bauer
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  4. M-L Wong
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  5. J Licinio
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  6. I Roots
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  7. J Brockmöller
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Correspondence to J Kirchheiner.

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Kirchheiner, J., Nickchen, K., Bauer, M. et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9, 442–473 (2004). https://doi.org/10.1038/sj.mp.4001494

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  • DOI: https://doi.org/10.1038/sj.mp.4001494

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