Lu Yi, Xiong Ying, Karlsson Robert, Song Jie, Kowalec Kaarina, Rück Christian, Sigstrom Robert, Jonsson Lina, Clements Caitlin, Andersson Evelyn, Boberg Julia, Lewis Cathryn, Sullivan Patrick, Landén Mikael
Karolinska Institutet.
University of Pennsylvania.
Res Sq. 2023 Feb 20:rs.3.rs-2556941. doi: 10.21203/rs.3.rs-2556941/v1.
Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) within ~ 4 500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores of antidepressant and lithium response for individuals with MDD, and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1 778 ECT-treated MDD cases, nearly all (94%) used antidepressants before first ECT, and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We found that TRD cases tend to have lower genetic load of antidepressant response than non-TRD, although the difference was not significant; furthermore, TRD cases had significantly higher genetic load of lithium response (OR = 1.10-1.12 under different definitions). The results support evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.
重度抑郁症（MDD）的治疗反应和耐药性被认为具有遗传性。由于在定义与治疗相关的表型方面存在重大挑战，我们对其遗传基础的理解有限。本研究旨在得出治疗耐药性的严格定义，并调查MDD中治疗反应和耐药性之间的遗传重叠。利用瑞典登记处关于抗抑郁药使用和电休克疗法（ECT）的电子病历，我们在三个瑞典队列中约4500名MDD患者中得出了治疗抵抗性抑郁症（TRD）的表型。考虑到抗抑郁药和锂分别是MDD的一线治疗药物和增效药物，我们为MDD患者生成了抗抑郁药和锂反应的多基因风险评分，并通过比较TRD和非TRD来评估它们与治疗耐药性的关联。在1778例接受ECT治疗的MDD病例中，几乎所有患者（94%）在首次ECT之前都使用过抗抑郁药，绝大多数患者至少使用过一种（84%）或两种（61%）足够疗程的抗抑郁药，这表明这些接受ECT治疗的MDD病例对抗抑郁药耐药。我们发现，TRD病例的抗抑郁药反应遗传负荷往往低于非TRD病例，尽管差异不显著；此外，TRD病例的锂反应遗传负荷显著更高（在不同定义下OR = 1.10 - 1.12）。这些结果支持了与治疗相关表型中遗传成分的证据，并突出了TRD中锂敏感性的整体遗传特征。这一发现进一步为锂治疗TRD的疗效提供了遗传学解释。
