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The Pharmacogenetics of Lithium Response Depends upon Clinical Co-Morbidity

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Abstract

Background: Based on results from randomized, controlled clinical trials, lithium monotherapy or lithium with the addition of an antipsychotic remains a first-line treatment option for both acute and long-term mood stabilization in bipolar mania. However, response to lithium is poor in bipolar patients who exhibit clinical characteristics such as rapid cycling and mixed manic states, suggesting that they may have a biologically and genetically distinct form of bipolar disorder. A test that could predict response to lithium based upon genetic factors would have significant clinical value.

Methods: Eight clinical characteristics were assessed in 92 lithium responders and 92 nonresponders; all probands were from families recruited for linkage studies. Lithium response was rated retrospectively from a standardized interviews and medical records. Eight candidate genes were selected from those reported to be associated with susceptibility to illness, lithium response, or lithium mechanism of action. Sixty-seven single nucleotide polymorphisms (SNPs) were genotyped in these subjects and analyzed for association with the defined clinical characteristics.

Results: Using q-value analysis for multiplicity correction, we found significant interactions between lithium response and SNPs (rs1387923 and rs1565445) in the gene encoding neurotrophic tyrosine kinase receptor type 2 (NTRK2) and suicidal ideation, and between SNP rs2064721 in the gene encoding inositol polyphosphate-1-phosphatase (INPP1) and post-traumatic stress disorder.

Conclusion: These data support the idea that response to lithium has a multi-genetic etiology dependent upon manifestations of other clinical co-diagnoses.

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Acknowledgments

This study was supported by a matching grant from the University of California Discovery Grants Program (grant no. LSIT01–10097) and Prediction Sciences, Inc., San Diego, with the Advanced Technology Program (grant no. ATP 20024937). This study was also supported in part by grants to J.R. Kelsoe from the National Institutes of Health (NIH) [grant nos. MH47612, MH59567, MH68503, DA13769], the Department of Veterans Affairs and by the University of California, San Diego, General Clinical Research Center (grant no. M01 RR00827). J.R. Kelsoe and T.B. Barrett are cofounders and hold equity in Psynomics, Inc. Some of the research described in this manuscript is related to the interests of the company. C. Diamond is employed by and owns shares in Prediction Sciences. C. Herold owns shares in Prediction Sciences. T. Bremer is employed by Prediction Sciences. Prediction Sciences has a patent pending on a corresponding diagnostic.

The authors would like to thank A. Dessa Sadovnick, Ronald Remick, Susan McElroy, and Paul Keck for contributing a portion of the samples analyzed. We would also like to thank the patients who participated in this study, without whom it would not have been possible.

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Authors and Affiliations

  1. Prediction Sciences, Inc., San Diego, California, USA

    Troy Bremer, Cornelius Diamond & Chris Herold

  2. Department of Psychiatry, University of California, San Diego, California, USA

    Rebecca McKinney, Tatyana Shehktman, Thomas B. Barrett & John R. Kelsoe

  3. Department of Psychiatry, San Diego VA Healthcare System, San Diego, California, USA

    Rebecca McKinney, Tatyana Shehktman, Thomas B. Barrett & John R. Kelsoe

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  1. Troy Bremer
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Correspondence to Troy Bremer.

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Bremer, T., Diamond, C., McKinney, R. et al. The Pharmacogenetics of Lithium Response Depends upon Clinical Co-Morbidity. Mol Diag Ther 11, 161–170 (2007). https://doi.org/10.1007/BF03256238

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