Genetic Determinants of Antidepressant Response

抗抑郁反应的遗传决定因素

• 批准号: 8939980
• 负责人: Francis J McMahon
• 金额: $ 64.36万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939980
• 关键词: Accounting; Adverse effects; Adverse event; Affect; African; Alleles; Antidepressive Agents; Anxiety; Candidate Disease Gene; Clinical Trials; Code; Collaborations; Disease; Disease remission; Drops; Drug Targeting; Enrollment; Ethnic Origin; Etiology; Family Study; Feeling suicidal; Funding; Future; Genes; Genetic; Genetic Determinism; Genetic Markers; Genome; Genotype; Goals; High-Throughput Nucleotide Sequencing; Human Genome; Individual; Institutes; Ketamine; Learning; Light; London; Major Depressive Disorder; Mental Depression; Meta-Analysis; Methods; Minority; Monitor; Morbidity - disease rate; Outcome; Outcome Study; Participant; Patients; Pharmaceutical Preparations; Placebos; Play; Race; Recovery; Research; Research Personnel; Resistance; Risk; Risk Factors; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Sexual Dysfunction; Substance Use Disorder; Symptoms; Testing; Time; Treatment Factor; Treatment outcome; Twin Studies; Universities; Variant; Withdrawal; Work; alternative treatment; base; college; cost; effective therapy; exome; experience; genetic analysis; genome wide association study; genome-wide; improved; insight; mortality; non-genetic; novel; rare variant; response; treatment response; treatment-resistant depression

Strong evidence from family and twin studies demonstrates that major depressive disorder (MDD) is heritable, yet there has been limited progress in identifying the actual genes involved. A separate, perhaps overlapping set of genes is expected to play a role in individual variation in treatment response in MDD. We seek to characterize genetically, using a large set of markers in many genes, patients who differ in their response to standard antidepressant treatments. Our initial focus was on two sets of genes most likely to play a role in the etiology of major depression. More recently we have expanded our studies to include genetic markers representing every common functional variation in the human genome. We utilize state-of-the-art, high-throughput genotyping methods as well as sophisticated methods of genetic analysis that take into account genetic and non-genetic influences on treatment outcome. In the first years of this project, we completed genotyping 738 markers in a set of 68 candidate genes selected by an expert panel. Results implicated several of these genes in treatment outcome and other genes that contribute to adverse effects. We also discovered genetic markers that help identify those at risk for sexual dysfunction during antidepressant therapy. We also identified potential genetic markers that increase risk of suicidal ideation that may occasionally emerge during antidepressant treatment. Future studies are needed to determine whether individuals who carry such genetic markers may benefit from closer monitoring or alternative treatments. In 2011, we joined a collaboration with investigators from Harvard, the Max Planck Institute Munich, UCSF, and University College London to carry out a meta-analysis of STAR*D along with the two other genome-wide association studies of antidepressant outcome that have been completed, known as MARS and GENDEP. Despite greater power of this combined sample to confer to uncover association with common genetic markers, no genome-wide significant associations were uncovered. We concluded that no common alleles of large effect on antidepressant outcome exist in these samples. In the past year, work led by an extramurally-funded fellow investigated why minority participants in clinical trials like STAR*D drop out of treatment and experience poorer treatment response than non-minorities. The goal here is to boost minority retention in clinical trials and identify genetic markers of treatment response and associated adverse effects, which often vary by ancestry. The research showed that race, ethnicity, genetic ancestry, and other factors affect SSRI treatment response, but genetic African ancestry remains a significant risk factor for poor response, even after other factors are taken into account. We are now using new, high-throughput sequencing methods to test for rarer alleles that may exert larger effects, at least on treatment resistance. Rarer alleles may show larger effects, especially among patients with unusual treatment outcomes. Sequencing studies may uncover alleles that play a major role in a minority of patients. Few patients will carry such alleles, but the genes involved will point to attractive new drug targets. Patients who respond to antidepressant treatment constitute a mixture of true responders, placebo responders, and spontaneous remitters. Patients who fail to respond to multiple treatments may be less heterogeneous, since placebo responders and spontaneous remitters are removed. From over 4,000 patients enrolled in STAR*D, we find that only 10% show treatment resistance that is not explained by non-adherence, comorbid substance use disorder, or other factors, and only 3% are highly treatment-resistant. Sequencing of the coding regions of the genome (exome)has now been completed on 75 treatment-resistant and 25 "typically responsive" patients. Initial analyses have uncovered some promising leads, but additional studies in larger samples are needed. In the coming year, we will further investigate the genetic basis of treatment-resistant depression in additional samples. These will include patients who respond to novel antidepressants such as ketamine and those referred for electroconvulsive or other neurostimulation therapies.

来自家庭和双胞胎研究的有力证据表明，重度抑郁症 (MDD) 是可遗传的，但在确定相关的实际基因方面进展有限。一组独立的、可能重叠的基因预计将在 MDD 治疗反应的个体差异中发挥作用。我们试图使用许多基因中的大量标记来从遗传学上描述对标准抗抑郁治疗反应不同的患者。我们最初的重点是两组最有可能在重度抑郁症病因中发挥作用的基因。最近，我们扩大了研究范围，将代表人类基因组中每个常见功能变异的遗传标记纳入其中。我们利用最先进的高通量基因分型方法以及复杂的遗传分析方法，考虑到遗传和非遗传对治疗结果的影响。 在该项目的最初几年，我们完成了专家小组选出的 68 个候选基因中 738 个标记的基因分型。结果表明其中一些基因与治疗结果有关，而其他基因则导致不良反应。我们还发现了遗传标记，可以帮助识别那些在抗抑郁治疗期间有性功能障碍风险的人。我们还发现了潜在的遗传标记，这些标记会增加抗抑郁治疗期间偶尔出现的自杀意念风险。未来的研究需要确定携带此类遗传标记的个体是否可以从更密切的监测或替代治疗中受益。 2011 年，我们与哈佛大学、慕尼黑马克斯普朗克研究所、加州大学旧金山分校和伦敦大学学院的研究人员合作，对 STAR*D 以及另外两项抗抑郁结果的全基因组关联研究进行了荟萃分析。已完成，称为 MARS 和 GENDEP。尽管这种组合样本具有更大的能力来揭示与常见遗传标记的关联，但没有发现全基因组的显着关联。我们得出的结论是，这些样本中不存在对抗抑郁结果产生重大影响的常见等位基因。 去年，一位外部资助研究员领导的研究调查了为什么 STAR*D 等临床试验中的少数族裔参与者会比非少数族裔参与者放弃治疗且治疗反应较差。这里的目标是提高临床试验中少数人的保留率，并确定治疗反应和相关不良反应的遗传标记，这些标记通常因血统而异。研究表明，种族、族裔、遗传血统和其他因素会影响 SSRI 治疗反应，但即使考虑到其他因素，非洲遗传血统仍然是反应不佳的重要风险因素。 我们现在正在使用新的高通量测序方法来测试可能产生更大影响（至少对治疗耐药性）的更罕见等位基因。越罕见的等位基因可能表现出更大的影响，尤其是在治疗结果不寻常的患者中。测序研究可能会发现在少数患者中起主要作用的等位基因。很少有患者会携带这样的等位基因，但所涉及的基因将指向有吸引力的新药物靶点。对抗抑郁药物治疗有反应的患者包括真实反应者、安慰剂反应者和自发缓解者。对多种治疗均无效的患者可能具有较少的异质性，因为安慰剂反应者和自发缓解者被排除。在参加 STAR*D 的 4,000 多名患者中，我们发现只有 10% 的患者表现出治疗抵抗力，且不能用不依从性、共病物质使用障碍或其他因素来解释，并且只有 3% 的患者具有高度治疗抵抗力。现已完成对 75 名治疗耐药患者和 25 名“通常有反应”患者的基因组（外显子组）编码区的测序。初步分析发现了一些有希望的线索，但还需要在更大的样本中进行更多研究。 来年，我们将在更多样本中进一步研究难治性抑郁症的遗传基础。这些患者包括对氯胺酮等新型抗抑郁药有反应的患者，以及转诊接受电休克或其他神经刺激疗法的患者。