Abstract
Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and “multi-omics” approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.
Highlights
Bipolar disorder (BD) is a common affective disorder with a high burden worldwide that leads to impaired quality of life and disability (Merikangas et al, 2011)
30–55% of individuals treated with lithium do not Pharmacogenetics of Lithium Treatment benefit from it and experience side effects (Burgess et al, 2001)
Several reviews of pharmacogenetic studies on lithium response have been published in recent years (Severino et al, 2013; Geoffroy et al, 2014; Alda, 2015; Pisanu et al, 2016; Budde et al, 2017, 201)
Summary
Bipolar disorder (BD) is a common affective disorder with a high burden worldwide that leads to impaired quality of life and disability (Merikangas et al, 2011). A recent meta-analysis revealed that about 50–60% of patients with bipolar mania do not respond sufficiently to lithium and require a change to another mood-stabilizing drug (Yildiz et al, 2011; Sienaert et al, 2013). As a result of insufficient response to lithium, polypharmacy, e.g., the combination of mood stabilizers and antipsychotics, has become more frequent and may even become standard care in BD (Baldessarini et al, 2008; Weinstock et al, 2014; Fung et al, 2019). BD is a chronic disease, so most patients require long-term or even life-long mood-stabilizing treatment. Against this background, knowledge of the mode of action and prediction of response to and side effects of lithium and other drugs prescribed in BD is highly relevant. A recent genome-wide association study (GWAS) provided insight into a single locus of four linked single-nucleotide polymorphisms (SNPs) on chromosome 21 that met genome-wide significance criteria for association with lithium response (Hou et al, 2016)
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