Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, sp 6, 09042, Cagliari, Italy.
Department of Neuroscience, Unit of Functional Pharmacology, Uppsala University, Uppsala, Sweden.
Mol Diagn Ther. 2018 Aug;22(4):409-420. doi: 10.1007/s40291-018-0335-y.
Bipolar disorder (BD) is a common and disabling psychiatric condition with a severe socioeconomic impact. BD is treated with mood stabilizers, among which lithium represents the first-line treatment. Lithium alone or in combination is effective in 60% of chronically treated patients, but response remains heterogenous and a large number of patients require a change in therapy after several weeks or months. Many studies have so far tried to identify molecular and genetic markers that could help us to predict response to mood stabilizers or the risk for adverse drug reactions. Pharmacogenetic studies in BD have been for the most part focused on lithium, but the complexity and variability of the response phenotype, together with the unclear mechanism of action of lithium, limited the power of these studies to identify robust biomarkers. Recent pharmacogenomic studies on lithium response have provided promising findings, suggesting that the integration of genome-wide investigations with deep phenotyping, in silico analyses and machine learning could lead us closer to personalized treatments for BD. Nevertheless, to date none of the genes suggested by pharmacogenetic studies on mood stabilizers have been included in any of the genetic tests approved by the Food and Drug Administration (FDA) for drug efficacy. On the other hand, genetic information has been included in drug labels to test for the safety of carbamazepine and valproate. In this review, we will outline available studies investigating the pharmacogenetics and pharmacogenomics of lithium and other mood stabilizers, with a specific focus on the limitations of these studies and potential strategies to overcome them. We will also discuss FDA-approved pharmacogenetic tests for treatments commonly used in the management of BD.
双相情感障碍（BD）是一种常见且具有严重社会经济影响的精神疾病。BD 的治疗方法是使用情绪稳定剂，其中锂是一线治疗药物。单独使用锂或与其他药物联合使用，对 60%的慢性治疗患者有效，但反应仍然存在异质性，许多患者在数周或数月后需要改变治疗方法。迄今为止，许多研究试图确定分子和遗传标记，以帮助我们预测对情绪稳定剂的反应或药物不良反应的风险。BD 的药物遗传学研究大多集中在锂上，但由于反应表型的复杂性和可变性，以及锂作用机制的不明确，这些研究识别稳健生物标志物的能力受到限制。最近关于锂反应的药物基因组学研究提供了有希望的发现，表明将全基因组研究与深入表型、计算分析和机器学习相结合，可能使我们更接近针对 BD 的个性化治疗。然而，迄今为止，药物遗传学研究中提示的与情绪稳定剂相关的基因都没有被美国食品和药物管理局（FDA）批准的任何药物疗效基因检测所包含。另一方面，遗传信息已被纳入药物标签，以测试卡马西平和丙戊酸的安全性。在这篇综述中，我们将概述现有的研究，调查锂和其他情绪稳定剂的药物遗传学和药物基因组学，特别关注这些研究的局限性以及克服这些局限性的潜在策略。我们还将讨论 FDA 批准的用于治疗 BD 的常用药物的药物遗传学检测。
