Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.

School of Psychology, Deakin University, Burwood, VIC, Australia.

IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia.

Hormones in Psychiatry Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.

School of Medicine, Deakin University, Waurn Ponds, VIC, Australia.

Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.

Lithium has been shown to have some therapeutic efficacy as an adjunctive treatment for intractable forms of major depression. Activation of mammalian target of rapamycin (mTOR) and inhibition of glycogen synthase kinase-3β (GSK3β) have been implicated in its putative mechanisms of action. These proteins are integral components of the insulin signaling pathway, which may serve as a critical co-regulator of drug action. Utilizing an animal model of tricyclic antidepressant resistance, we investigated the relationship between insulin signaling and antidepressant response to lithium augmentation. Pre-treatment with adrenocorticotropic hormone (ACTH 100 µg/day i.p.) for 14 days effectively blocked the immobility-reducing effects of an acute dose of imipramine (10 mg/kg i.p.) in the forced swim test (FST). Lithium augmentation (100 mg/kg i.p.) rescued the antidepressant-like effects of imipramine in this model. Total and phosphorylated (p) levels of protein kinase B (Akt), mTOR, and GSK3β protein were quantified in the infralimbic cortex (ILPFC) following FST stress via Western blot. Levels of mTOR and pmTOR were further quantified in isolated peripheral blood mononuclear cells (PBMCs) following insulin stimulation (10 mg/mL for 5 min) via ELISA. Elevated levels of phosphorylated insulin signaling proteins were present in the ILPFC of ACTH-pretreated animals that received both imipramine and lithium, together with a concurrent increase in mTOR activation in PBMCs. Large correlations were observed between immobility time and insulin-stimulated mTOR levels in PBMCs. We propose that PBMC insulin challenge may be a useful probe for predicting antidepressant response to lithium administration, and potentially other therapies acting via similar mechanisms of action. 中文翻译： 锂已显示出作为顽固性重度抑郁症的辅助治疗方法具有一定的治疗功效。雷帕霉素（mTOR）的哺乳动物靶标的激活和糖原合酶激酶3β（GSK3β）的抑制与它的推测作用机制有关。这些蛋白质是胰岛素信号传导途径不可或缺的组成部分，可作为药物作用的关键协同调节剂。利用三环抗抑郁药抗性的动物模型，我们调查了胰岛素信号传导和抗抑郁药对锂增加的反应之间的关系。促肾上腺皮质激素（ACTH 100 µg /天ip）预处理14天有效地阻止了急性游泳剂量（FST）中急性剂量的丙咪嗪（10 mg / kg ip）的固定减少作用。锂增高（100 mg / kg ip ）挽救了该模型中丙咪嗪的抗抑郁样作用。通过蛋白质印迹法在FST应激后，在下肢皮质（ILPFC）中定量蛋白激酶B（Akt），mTOR和GSK3β蛋白的总和磷酸化（p）水平。胰岛素刺激（10 mg / mL，持续5分钟）后，通过ELISA在分离的外周血单核细胞（PBMC）中进一步定量了mTOR和pmTOR的水平。接受丙咪嗪和锂的ACTH预处理动物的ILPFC中磷酸化胰岛素信号蛋白的水平升高，同时PBMC中mTOR激活的同时增加。在PBMC中，固定时间与胰岛素刺激的mTOR水平之间存在很大的相关性。