Pharmacogenomics of Lithium Response in Bipolar Disorder

doi:10.3390/ph14040287

Review

. 2021 Mar 24;14(4):287.

doi: 10.3390/ph14040287.

Pharmacogenomics of Lithium Response in Bipolar Disorder

Courtney M Vecera^{1

2}, Gabriel R Fries^{2

3

4}, Lokesh R Shahani², Jair C Soares^{1

2}, Rodrigo Machado-Vieira^{1

2}

Affiliations

¹ Experimental Therapeutics and Molecular Pathophysiology Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
² Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
³ Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
⁴ Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA.

PMID: 33804842
PMCID: PMC8063790
DOI: 10.3390/ph14040287

Review

Pharmacogenomics of Lithium Response in Bipolar Disorder

Courtney M Vecera et al. Pharmaceuticals (Basel). 2021.

. 2021 Mar 24;14(4):287.

doi: 10.3390/ph14040287.

Authors

Courtney M Vecera^{1

2}, Gabriel R Fries^{2

3

4}, Lokesh R Shahani², Jair C Soares^{1

2}, Rodrigo Machado-Vieira^{1

2}

Affiliations

¹ Experimental Therapeutics and Molecular Pathophysiology Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
² Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
³ Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
⁴ Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA.

PMID: 33804842
PMCID: PMC8063790
DOI: 10.3390/ph14040287

Abstract

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium's therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium's exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

Keywords: Genome-Wide Association Study (GWAS); bipolar disorder; lithium; personalized medicine; pharmacogenomics; predictive models.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram [12].

**Figure 2**
Genetic, Biological, and Clinical Predictors of Lithium Response in Bipolar Disorder [5,8,9,10,11,15,16,17,18,19,20,21,40,44,49,50,51,52,53,54,55,56,57,58,59,60,61,62].

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References

1. Machado-Vieira R., Manji H.K., Carlos A.Z., Jr. The Role of Lithium in the Treatment of Bipolar Disorder: Convergent Evidence for Neurotrophic Effects as a Unifying Hypothesis. Bipolar Disord. 2009;11:92–109. doi: 10.1111/j.1399-5618.2009.00714.x. - DOI - PMC - PubMed
1. Oedegaard K.J., Alda M., Anand A., Andreassen O.A., Balaraman Y., Berrettini W.H., Bhattacharjee A., Brennand K.J., Burdick K.E., Calabrese J.R., et al. The Pharmacogenomics of Bipolar Disorder Study (PGBD): Identification of Genes for Lithium Response in a Prospective Sample. BMC Psychiatry. 2016;16:129. doi: 10.1186/s12888-016-0732-x. - DOI - PMC - PubMed
1. Rybakowski J.K., Chlopocka-Wozniak M., Suwalska A. The Prophylactic Effect of Long-Term Lithium Administration in Bipolar Patients Entering Treatment in the 1970s and 1980s. Bipolar Disord. 2001;3:63–67. doi: 10.1034/j.1399-5618.2001.030203.x. - DOI - PubMed
1. Pagani R., Gasparini A., Ielmini M., Caselli I., Poloni N., Ferrari M., Marino F., Callegari C. Twenty Years of Lithium Pharmacogenetics: A Systematic Review. Psychiatry Res. 2019;278:42–50. doi: 10.1016/j.psychres.2019.05.036. - DOI - PubMed
1. Alda M. Lithium in the Treatment of Bipolar Disorder: Pharmacology and Pharmacogenetics. Mol. Psychiatry. 2015;20:661–670. doi: 10.1038/mp.2015.4. - DOI - PMC - PubMed

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[1] Machado-Vieira R., Manji H.K., Carlos A.Z., Jr. The Role of Lithium in the Treatment of Bipolar Disorder: Convergent Evidence for Neurotrophic Effects as a Unifying Hypothesis. Bipolar Disord. 2009;11:92–109. doi: 10.1111/j.1399-5618.2009.00714.x. - DOI - PMC - PubMed

[2] Machado-Vieira R., Manji H.K., Carlos A.Z., Jr. The Role of Lithium in the Treatment of Bipolar Disorder: Convergent Evidence for Neurotrophic Effects as a Unifying Hypothesis. Bipolar Disord. 2009;11:92–109. doi: 10.1111/j.1399-5618.2009.00714.x. - DOI - PMC - PubMed

[3] Oedegaard K.J., Alda M., Anand A., Andreassen O.A., Balaraman Y., Berrettini W.H., Bhattacharjee A., Brennand K.J., Burdick K.E., Calabrese J.R., et al. The Pharmacogenomics of Bipolar Disorder Study (PGBD): Identification of Genes for Lithium Response in a Prospective Sample. BMC Psychiatry. 2016;16:129. doi: 10.1186/s12888-016-0732-x. - DOI - PMC - PubMed

[4] Oedegaard K.J., Alda M., Anand A., Andreassen O.A., Balaraman Y., Berrettini W.H., Bhattacharjee A., Brennand K.J., Burdick K.E., Calabrese J.R., et al. The Pharmacogenomics of Bipolar Disorder Study (PGBD): Identification of Genes for Lithium Response in a Prospective Sample. BMC Psychiatry. 2016;16:129. doi: 10.1186/s12888-016-0732-x. - DOI - PMC - PubMed

[5] Rybakowski J.K., Chlopocka-Wozniak M., Suwalska A. The Prophylactic Effect of Long-Term Lithium Administration in Bipolar Patients Entering Treatment in the 1970s and 1980s. Bipolar Disord. 2001;3:63–67. doi: 10.1034/j.1399-5618.2001.030203.x. - DOI - PubMed

[6] Rybakowski J.K., Chlopocka-Wozniak M., Suwalska A. The Prophylactic Effect of Long-Term Lithium Administration in Bipolar Patients Entering Treatment in the 1970s and 1980s. Bipolar Disord. 2001;3:63–67. doi: 10.1034/j.1399-5618.2001.030203.x. - DOI - PubMed

[7] Pagani R., Gasparini A., Ielmini M., Caselli I., Poloni N., Ferrari M., Marino F., Callegari C. Twenty Years of Lithium Pharmacogenetics: A Systematic Review. Psychiatry Res. 2019;278:42–50. doi: 10.1016/j.psychres.2019.05.036. - DOI - PubMed

[8] Pagani R., Gasparini A., Ielmini M., Caselli I., Poloni N., Ferrari M., Marino F., Callegari C. Twenty Years of Lithium Pharmacogenetics: A Systematic Review. Psychiatry Res. 2019;278:42–50. doi: 10.1016/j.psychres.2019.05.036. - DOI - PubMed

[9] Alda M. Lithium in the Treatment of Bipolar Disorder: Pharmacology and Pharmacogenetics. Mol. Psychiatry. 2015;20:661–670. doi: 10.1038/mp.2015.4. - DOI - PMC - PubMed

[10] Alda M. Lithium in the Treatment of Bipolar Disorder: Pharmacology and Pharmacogenetics. Mol. Psychiatry. 2015;20:661–670. doi: 10.1038/mp.2015.4. - DOI - PMC - PubMed

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Pharmacogenomics of Lithium Response in Bipolar Disorder

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Pharmacogenomics of Lithium Response in Bipolar Disorder

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