Ising Marcus, Holsboer Florian, Myhsok Marius, Müller-Myhsok Bertram
Max Planck Institute of Psychiatry, Munich, Germany.
HMNC Holding GmbH, Munich, Germany.
Pharmacopsychiatry. 2025 May;58(3):132-138. doi: 10.1055/a-2508-5834. Epub 2025 Jan 29.
A subgroup of patients with acute depression show an impaired regulation of the hypothalamic-pituitary-adrenocortical axis, which can be sensitively diagnosed with the combined dexamethasone (dex)/corticotropin releasing hormone (CRH)-test. This neuropathological alteration is assumed to be a result of hyperactive AVP/V1b signalling. Given the complicated procedure of the dex/CRH-test, this study aimed to develop a genetic variants-based alternative approach to predict the outcome of the dex/CRH-test in acute depression.Using data of a representative cohort of 352 patients with severe depression participating in the dex/CRH-test, a genome-wide interaction analysis was performed starting with an anchor single nucleotide polymorphism located in the upstream transcriptional region of the human V1b-receptor gene to predict the adrenocorticotropic hormone (ACTH) response to this test. A probabilistic neural-network-algorithm was used to develop the optimal prediction model.Overall prediction accuracy for correctly identifying high ACTH responders in the dex/CRH-test was 93.5% (sensitivity 90%; specificity 95%). Analysis of pituitary RNAseq expression data confirmed that the identified genetic interactions of the gene test translate into an interactive network of corresponding transcripts in the pituitary gland, which is the biologically relevant target tissue, with the aggregated strength of the transcript interactions significantly stronger than expected from chance.The findings suggest the suitability of the presented gene test as a proxy for hyperactive AVP/V1b signalling during an acute depressive episode, highlighting its potential as companion test for identifying patients with acute depression whose pathology can be optimally treated by specific drugs targeting the AVP/V1b-signaling cascade.
一部分急性抑郁症患者表现出下丘脑 - 垂体 - 肾上腺皮质轴调节受损，联合地塞米松（dex）/促肾上腺皮质激素释放激素（CRH）试验可对此进行灵敏诊断。这种神经病理学改变被认为是精氨酸加压素（AVP）/V1b信号过度活跃的结果。鉴于dex/CRH试验程序复杂，本研究旨在开发一种基于基因变异的替代方法，以预测急性抑郁症患者dex/CRH试验的结果。利用352名参与dex/CRH试验的重度抑郁症患者的代表性队列数据，从位于人类V1b受体基因上游转录区域的一个锚定单核苷酸多态性开始进行全基因组相互作用分析，以预测该试验中促肾上腺皮质激素（ACTH）的反应。使用概率神经网络算法来开发最优预测模型。在dex/CRH试验中正确识别高ACTH反应者的总体预测准确率为93.5%（敏感性90%；特异性95%）。垂体RNA测序表达数据分析证实，基因检测中确定的基因相互作用转化为垂体中相应转录本的相互作用网络，垂体是生物学上相关的靶组织，转录本相互作用的聚集强度显著强于随机预期。研究结果表明，所提出的基因检测适用于作为急性抑郁发作期间AVP/V1b信号过度活跃的替代指标，突出了其作为辅助检测的潜力，用于识别急性抑郁症患者，这些患者的病理状况可通过靶向AVP/V1b信号级联的特定药物得到最佳治疗。
