New use of old drugs: rapid antidepressant effect and mechanism of ketamine [Abstract] Ketamine is a non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, often used as a general anesthetic for clinical use. In recent years, studies have found that ketamine has a rapid, effective and long-lasting antidepressant effect, which may be mediated by inhibitory interneurons, excitatory neurotransmitters, AMPA receptors and post-synaptic signaling pathways. Increased contact plasticity. This article briefly introduces the antidepressant effect of ketamine and its mechanism. ã€Key words】 Ketamine; Depression; Mechanism; Microalbuminic interneuron 0 Preface Depression is a common mental illness. It is characterized by depression and loss of interest. In severe cases, suicidal thoughts and behaviors can occur. The incidence rate is as high as 17% and is on the rise. Existing antidepressants have slow onset, often take 3 to 4 weeks, and have a high failure rate of up to 40%. Therefore, the development of fast and effective new antidepressants is one of the medical problems to be solved. Ketamine is a non-specific N-methyl-D-aspartic acid (NMDA) receptor blocker, which has been used clinically for nearly 50 years and is a commonly used general anesthetic. In recent years, clinical studies have found that ketamine can produce significant antidepressant effects within 2 to 4 hours. The single-use effect lasts for several days to 2 weeks, and it also has a good effect on patients with refractory depression. At the same time, a large number of animal experiments have also observed that ketamine can produce rapid and effective antidepressant effects in various depression models. The rapid and effective antidepressant effect of ketamine has made it a research hotspot in the field of depression treatment. 1 ketamine antidepressant clinical effect Professor Krystal, Department of Psychiatry, Yale University School of Medicine, conducted a randomized, double-blind, controlled study in 2000. He found that ketamine has a rapid and effective antidepressant effect. It was observed that a single intravenous infusion of ketamine 0.5 mg/kg resulted in 4 h. Effective antidepressant effect and its antidepressant effect lasts for at least 72 h. In 2006, Zarate et al conducted another randomized, double-blind, controlled trial of patients with refractory depression. The same administration and dose results indicated an intravenous infusion of 0.5 mg/kg subanesthetic dose of ketamine, 110 min after dosing. Depressive symptoms were significantly improved in these patients, and about 71% of patients had a significant improvement in depressive symptoms at 1 day after administration, and 29% had symptoms. In 2009, Price et al. confirmed the rapid and effective antidepressant effect of ketamine, and found that suicide in patients with depression can be effectively alleviated or eliminated within 24 hours after ketamine administration. From 2010 to 2015, Professor Zarate's research team reported a series of studies on the clinical efficacy of ketamine antidepressants. These findings indicate that ketamine produces rapid, effective and long-lasting antidepressant effects, and that ketamine not only rapidly relieves depression. Depressive symptoms in patients with symptoms can also improve the suicidal tendency of patients. In the past 5 years, more than 40 articles have reported the significant effects of about 500 patients with depression in the treatment of ketamine. The administration methods include intravenous, intramuscular, nasal, oral, etc., and the dosage range is from 0. . 25 to 0. 50 mg / kg, the dosing regimen includes single, repeated and combined use of other antidepressants, ranging from general depression to refractory depression, two-way depression and advanced depression of cancer pain. Although the study protocol is different, these studies have effectively confirmed the antidepressant effect of ketamine. As Professor Check said, "Ketamine, which begins with an anesthetic and is known as a hallucinogen, may now be the key to unlocking the door to depression." 2 Mechanism of antidepressant effect of ketamine The antidepressant effect of ketamine was first discovered in the clinic, followed by a large number of animal experiments to explore the target of ketamine and related mechanisms. Ketamine exhibited significant antidepressant effects in a variety of classic depression models. Studies have shown that intraperitoneal injections of small doses of ketamine (2.5 to 25 mg / kg) can produce significant antidepressant effects without schizophrenia-like manifestations; moderate doses of ketamine (30 mg / kg) can reduce forced swimming in rats The experiment did not move, but it also produced schizophrenic expression, which caused the rats to increase their ability to self-activity . The higher dose of ketamine (80 mg / kg) had no antidepressant effect, and the dose > 80 mg / kg ketamine could produce certain anesthetic effects. . Low-dose ketamine can produce antidepressant effects without obvious mental symptoms, and is currently widely used in the study of ketamine antidepressant related mechanisms. 2.1 α-amino-3 hydroxy-5 methyl-4-isoxazole (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor (AMPA) receptor ketamine is NMDA receptor blockade Agent, but its antidepressant mechanism may be related to AMPA receptor activation. The AMPA receptor is one of the excitatory ionotropic glutamate receptor subtypes. The study found that the AMPA receptor blocker quinoxaline (NBQX) pretreatment blocked the rapid antidepressant effects of ketamine. Baumbarger et al. found that the AMPA receptor activator LY392098 has a significant antidepressant effect. After NBQX pretreatment, ketamine-induced activation of the rapamycin target protein signaling pathway was blocked. After ketamine administration, the glutamate content in the cortex of rats increased significantly, and the duration of action was consistent with the change of mTOR signal pathway in ketamine antidepressant (increased 30 to 60 min after administration and returned to basal level at 2 h). These results suggest that activation of AMPA receptors is an important mechanism by which ketamine exerts an antidepressant effect. 2.2 brain-derived neurotrophic factor (BDNF) BDNF is an important neurotrophic factor, and its content plays an important role in the pathogenesis of depression. Autopsy found that BDNF levels in the cerebral cortex of patients with depression were significantly decreased, whereas patients with antidepressant treatment had no significant difference in cerebral cortex BDNF levels compared with normal subjects. Gatt et al found that BDNF gene abnormalities can increase the susceptibility to depression. Garcia et al. found that ketamine increased BDNF levels in a dose-dependent manner. Animal experiments have found that injection of BDNF into the lateral ventricle can produce significant antidepressant effects. The rapid antidepressant effect of ketamine was blocked in BDNF Met knock-in mice, and this study further confirmed the role of BDNF in ketamine antidepressant. 2. 3 The mammalian target of Rapamycin (m TOR) study suggests that ketamine can increase BDNF release by blocking NMDA receptors, and BDNF is activated by binding to its receptor tyrosine kinase receptor B (Trk B). Intracellular extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) signaling pathways increase pm TOR, which promotes synaptic protein PSD95 production and synapse development, and exerts antidepressant effects. Li et al found that pm TOR content increased significantly after ketamine administration. After sirolimus administration inhibited m TOR activity in the prefrontal cortex, ketamine induced dendritic spine formation, synaptic protein production and decreased swimming time were reversed. . 2. 4 Glycogen synthase kinase-3 (GSK-3) Beurel et al found that when ketamine was antidepressant, the content of p-GSK-3 in the prefrontal cortex and hippocampus of mice increased significantly, and the activity of GSK-3 decreased. After the application of the GSK-3 inhibitor, ketamine requires a larger dose to produce an antidepressant effect. It is believed that the decrease in GSK-3 activity is involved in the antidepressant effect of ketamine. Previous studies have confirmed that GSK-3 is the target of the mood stabilizer lithium, so it is believed that ketamine may also be associated with a decrease in GSK-3 activity in patients with bipolar disorder. 2. 5 eukaryotic elongation factor 2 (e EF2) study found that ketamine-mediated NMDA receptor blockade can inhibit the activity of e EF2, leading to decreased expression of pe EF2, pe EF2 inhibits BDNF synthesis, and its expression can be decreased Promotes BDNF transcription, thereby exerting an antidepressant effect. The study also found that e EF2 kinase inhibitors also have a rapid antidepressant effect, suggesting that inhibition of e EF2 is a key link in the antidepressant effect of ketamine. 2. 6 Other mechanisms The antidepressant effects of ketamine may also be associated with changes in sigma-1 receptors, metabotropic glutamate receptors, monoamine neurotransmitters, inflammatory factors, and histone acetylation. 3 Related work progress 3. 1 Clinical effect of ketamine antidepressant In 2012, our group took the lead in the clinical observation of ketamine antidepressant, and the results confirmed intravenous infusion of ketamine. 5 mg / kg can produce rapid and significant anti-depressant effects. In 2013, Biol Psychiatry reported that the anti-depressant effect of ketamine showed a significant increase in plasma p-GSK-3β levels in patients with depression. In the following two years, the research team completed a clinical study of 16 patients with depression. In 2015, Biol Psychiatry reported that the level of serum inflammatory factor interleukin-6 in patients with depression can be used as a predictor of ketamine antidepressant treatment. Good indicator. 3. 2 Mechanisms of antidepressant effects of ketamine Although several signaling pathways have been shown to be involved in the antidepressant effects of ketamine, unfortunately, these results still fail to elucidate the glutamate NMDA receptor agonism, the brain appears to be excited, and ketamine Antagonists of NMDA receptors also contribute to the "contradictory" phenomenon of brain excitement when treating depression. Our research team focused on the antidepressant mechanism of ketamine on the main types of inhibitory interneurons, parvalbumin (PV) interneurons. PV interneurons are calbindin-positive gamma-aminobutyric acid (GABA)-inhibiting interneurons whose primary function is to regulate pyramidal cell excitability by releasing the inhibitory neurotransmitter GABA. Our results showed that in the acute depression model of forced swimming in rats, the expression of PV and glutamate decarboxylase 67 (GAD67) in the prefrontal cortical PV interneurons decreased significantly after ketamine administration, GABA content decreased, and Glu content increased significantly. GAD67 is a key enzyme in the synthesis of GABA, and GABA is the major neurotransmitter that inhibits PV interneurons, so down-regulation of GAD67 can result in reduced release of GABA synthesis. Downregulation of PV interneurons results in decreased inhibition of Glu release, increased Glu content, and NMDA receptors are occupied by ketamine, so increased Glu acts on AMPA receptors, and AMPA receptors activate BDNF, m by activation. Related signaling pathways such as TOR, e EF2, and GSK enhance the transcription and translation of synaptic-related proteins, promote synaptic regeneration, and produce antidepressant effects. In addition, our study also found that inflammatory factors, neuregulin 1 (NRG1)-Erb B4, L-arginine/nitric oxide, AMP-dependent protein kinase (AMPK), p11 and microglia may also be in ketamine. Play a role in anti-depression. 4 Conclusion Ketamine has a fast, effective and long-lasting antidepressant effect, and it has good curative effect on patients with refractory depression. The adverse reactions are mild and easy to tolerate, which has brought new breakthroughs in the treatment of clinical depression. However, due to the side effects such as potential addiction and psychotic symptoms, and the lack of effective oral preparations, the current application beyond the specification only includes acute treatment for depression with suicidal concept and refractory patients, its effectiveness, Safety is still confirmed by a large sample of clinical studies. 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