Signant Health, Boston, MA, USA.
Pax Neuroscience, Glenview, IL, USA.
Mol Psychiatry. 2022 Mar;27(3):1640-1646. doi: 10.1038/s41380-021-01399-1. Epub 2022 Jan 5.
In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsα) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.
与健康对照组相比，在患有重度抑郁症（MDD）的患者中，三聚体 G 蛋白 Gsalpha（Gsα）主要位于脂筏中，导致腺苷酸环化酶的刺激受损。在这项小型概念验证研究中，我们检验了以下假设：Gsα从脂筏向更易激活腺苷酸环化酶的转位是抗抑郁药临床反应的生物标志物。在筛选时，有 49 名 MDD 患者（HamD 评分≥15）和 59 名健康对照者。AlphaScreen（PerkinElmer）检测同时测量了 Gsα-腺苷酸环化酶的基础活性和前列腺素 E1（PGE1）刺激，以评估 Gsα与腺苷酸环化酶的偶联程度。在筛选时，从 MDD 患者获得的血小板样本显示 PGE1 对腺苷酸环化酶活性的刺激明显低于对照组（p=0.02）。随后，19 名同意参加的 MDD 患者完成了为期 6 周的开放标签抗抑郁治疗试验。11 名抗抑郁药应答者（与筛选相比，HamD 改善≥50%）与非应答者相比，PGE1 刺激的腺苷酸环化酶显著增加（p=0.05），PGE1/Gsα 脂筏生物标志物的效应大小为 0.83。在 8 名应答者（72.7%）和 2 名非应答者（25.0%）中，从筛选评估到 PGE1 刺激的增加≥30%[Fisher 确切检验=0.07]，应答的阳性预测值为 80.0%。在这项小型的初步研究中，PGE1 刺激的腺苷酸环化酶增加与 MDD 患者的抗抑郁反应相关。这些数据表明，可以开发一种简单、高通量的抗抑郁药和抗抑郁反应检测方法。需要进一步的研究来评估该生物标志物在 MDD 治疗中的效用。
