Laboratory of Neuroscience-LIM 27, Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos 785, São Paulo, SP, Brazil.
J Psychiatr Res. 2012 Aug;46(8):1053-8. doi: 10.1016/j.jpsychires.2012.04.020. Epub 2012 May 22.
Abnormal regulation of glycogen synthase kinase 3-beta (GSK3B) activity has been implicated in the pathophysiology of mood disorders. Many pharmacological agents, including antidepressants, can modulate GSK3B. The aim of the present study was to investigate the effect of short-and long-term sertraline treatment on the expression and phosphorylation of GSK3B in platelets of patients with late-life major depression.
Thirty-nine unmedicated elderly adults with major depressive disorder (MDD) were initially included in this study. The comparison group comprised 18 age-matched, healthy individuals. The expression of total and Ser-9 phosphorylated GSK3B (pGSK3B) was determined by Enzyme Immunometric Assay (EIA) in platelets of patients and controls at baseline, and after 3 and 12 months of sertraline treatments for patients only. During this period, patients were continuously treated with therapeutic doses of sertraline. GSK3B activity was indirectly estimated by calculating the proportion of inactive (phosphorylated) forms (pGSK3B) in relation to the total expression of the enzyme (i.e., GSK3B ratio).
Depressed patients had significantly higher levels of pGSK3B as compared to controls (p < 0.001). Within the MDD group, after 3 months of sertraline treatment no significant changes were observed in GSK3B expression and phosphorylation state, as compared to baseline levels. However, after 12 months of treatment we found a significant increase in the expression of total GSK3B (p = 0.05), in the absence of any significant changes in pGSK3B (p = 0.12), leading to a significant reduction in GSK3B ratio (p = 0.001).
Our findings indicate that GSK3B expression was upregulated by the continuous treatment with sertraline, along with an increment in the proportion of active forms of the enzyme. This is compatible with an increase in overall GSK3B activity, which may have been induced by the long-term treatment of late-life depression with sertraline.
糖原合酶激酶 3-β（GSK3β）活性的异常调节与心境障碍的病理生理学有关。许多药理学药物，包括抗抑郁药，都可以调节 GSK3β。本研究旨在探讨短期和长期舍曲林治疗对老年重度抑郁症患者血小板中 GSK3β表达和磷酸化的影响。
最初纳入本研究的 39 名未经治疗的老年重度抑郁症患者。对照组包括 18 名年龄匹配的健康个体。在基线时和仅患者接受舍曲林治疗 3 个月和 12 个月后，通过酶免疫测定法（EIA）测定患者和对照组血小板中总 GSK3β 和丝氨酸 9 磷酸化 GSK3β（pGSK3β）的表达。在此期间，患者持续接受治疗剂量的舍曲林治疗。通过计算无活性（磷酸化）形式（pGSK3β）与酶总表达（即 GSK3β 比）的比例，间接估计 GSK3β 活性。
与对照组相比，抑郁患者的 pGSK3β 水平明显升高（p<0.001）。在 MDD 组中，与基线水平相比，在舍曲林治疗 3 个月后，GSK3β 的表达和磷酸化状态没有明显变化。然而，在治疗 12 个月后，我们发现总 GSK3β 的表达显著增加（p=0.05），而 pGSK3β 没有明显变化（p=0.12），导致 GSK3β 比显著降低（p=0.001）。
我们的研究结果表明，舍曲林的持续治疗上调了 GSK3β 的表达，并增加了酶的活性形式比例。这与 GSK3β 活性的总体增加相一致，这可能是由于舍曲林对老年重度抑郁症的长期治疗所致。
