Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
CNS Drugs. 2011 Jun 1;25(6):459-71. doi: 10.2165/11589420-000000000-00000.
Suicidal thoughts during antidepressant treatment have recently been the focus of several candidate gene and genome-wide association studies. Although the clinical risk factors for such events are well known, unfortunately they do not help to predict who will have a suicidal event during antidepressant treatment and who will not. Pharmacogenomic studies have therefore attempted to use genetic variants to predict individual susceptibility to treatment-related suicidal ideation. In this perspective, several genetic predictors have been highlighted, the majority of which relate to common mechanisms of antidepressant action: genes involved in the neurotrophic and synaptic plasticity systems (CREB1, and BDNF and its receptor NTRK2), noradrenergic system (ADRA2A), glutamatergic system (GRIA3, GRIK2 and GDA), inflammatory and hypothalamic-pituitary-adrenal (HPA) axis systems (IL28RA and FKBP5) and in other brain functions (PAPLN, APOO, KCNIP4 and ELP3). Although some of these genes may be of interest in predicting antidepressant-induced suicidal ideation, they still need to be validated in better phenotypically designed samples. Several methodological factors are indeed responsible for the problems involved in implicating these findings in the causation of a clinically relevant phenotype. These include discrepancies between studies in defining phenotypes, with several different thresholds used to establish significant suicidal ideation; the use of scales not truly designed to measure suicidal ideation; and the paucity of true suicidal events (suicide attempts and/or completion) in pharmacogenomic studies. In conclusion, pharmacogenomic studies are far from fulfilling their promise. There is a need for future pharmacogenetic studies targeting events that are clinically significant in order to find associated variants that will help clinicians to improve their treatment strategies. While awaiting these genetic predictors, clinicians need to bear in mind that all studies in this field support a beneficial effect of antidepressants on suicidal ideation. This should therefore encourage them to prescribe antidepressant medication even in patients with suicidal ideation.
抗抑郁治疗期间的自杀意念最近成为了几个候选基因和全基因组关联研究的焦点。尽管这些事件的临床风险因素众所周知，但不幸的是，它们无助于预测谁将在抗抑郁治疗期间发生自杀事件，谁又不会。因此，药物基因组学研究试图利用遗传变异来预测个体对治疗相关自杀意念的易感性。在这种观点下，已经强调了几个遗传预测因子，其中大多数与抗抑郁药作用的常见机制有关：涉及神经营养和突触可塑性系统的基因（CREB1、BDNF 及其受体 NTRK2）、去甲肾上腺素能系统（ADRA2A）、谷氨酸能系统（GRIA3、GRIK2 和 GDA）、炎症和下丘脑-垂体-肾上腺（HPA）轴系统（IL28RA 和 FKBP5）和其他脑功能（PAPLN、APOO、KCNIP4 和 ELP3）。尽管其中一些基因可能对抗抑郁药引起的自杀意念有预测价值，但它们仍需要在更好的表型设计样本中进行验证。事实上，有几个方法学因素导致了这些发现与临床相关表型的因果关系难以确定。这些因素包括在定义表型时研究之间存在差异，使用了几个不同的阈值来确定显著的自杀意念；使用的量表并非真正用于测量自杀意念；以及药物基因组学研究中真正的自杀事件（自杀企图和/或完成）很少。总之，药物基因组学研究远未达到预期。需要针对临床上有意义的事件进行未来的药物遗传学研究，以找到相关的变异，帮助临床医生改进他们的治疗策略。在等待这些遗传预测因子的同时，临床医生需要记住，该领域的所有研究都支持抗抑郁药对自杀意念的有益影响。这应该鼓励他们即使在有自杀意念的患者中也开抗抑郁药。
