Nathan J Wellington, Ana P Boųcas, Jim Lagopoulos, Bonnie L Quigley, Anna V Kuballa
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引用次数: 0
摘要
理由：现有研究主要集中在氯胺酮对创伤后应激障碍（PTSD）急性治疗作用的分子和神经生物学机制上。这种强调在很大程度上忽视了其持续的治疗效果，这对开发有针对性的干预措施具有重大潜力。目的：本系统综述探讨氯胺酮对创伤后应激障碍的药代动力学和药效学影响，区分即时和持续的分子效应。方法：综合检索数据库（Web of Science, Scopus, Global Health, PubMed）和灰色文献共317篇，其中29篇研究符合纳入标准。这些研究包括临床前模型和临床试验，通过神经递质调控、基因表达、突触可塑性和神经通路（PROSPERO ID: CRD42024582874）。结果：我们发现越来越多的证据表明氯胺酮的直接作用，包括GABA、谷氨酸和谷氨酰胺水平的变化，触发BDNF的重新调节，通过TrkB和PSD-95等途径增强突触可塑性。其他分子影响还包括c-Fos、GSK-3、HDAC、HCN1，以及激素如CHR和ACTH的调节，以及免疫反应（IL-6、IL-1β、TNF-α）。持续的影响源于神经递质的调节，并涉及基因表达的长期变化。这些包括mtor介导的BDNF表达、GSK-3β、FkBP5、GFAP、ERK磷酸化的改变和表观遗传修饰（DNMT3、MeCP2、H3K27me3、mir-132、mir-206、HDAC）。结论：这些分子变化促进了长期突触稳定性和脑关键区域的再调节，有助于延长治疗效果。了解氯胺酮作用背后的持续分子和表观遗传机制对于开发安全有效的个性化治疗至关重要，这可能会导致更有效的康复。
Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD.
Rationale: Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine's acute treatment effects on post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for the development of targeted interventions.
Objectives: This systematic review examines the pharmacokinetic and pharmacodynamic effects of ketamine on PTSD, differentiating between immediate and sustained molecular effects.
Method: A comprehensive search across databases (Web of Science, Scopus, Global Health, PubMed) and grey literature yielded 317 articles, where 29 studies met the inclusion criteria. These studies included preclinical models and clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, and neural pathways (PROSPERO ID: CRD42024582874).
Results: We found accumulating evidence that the immediate effects of ketamine, which involve changes in GABA, glutamate, and glutamine levels, trigger the re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95. Other molecular influences also include c-Fos, GSK-3, HDAC, HCN1, and the modulation of hormones like CHR and ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained effects arise from neurotransmitter remodulations and involve prolonged changes in gene expression. These include mTOR-mediated BDNF expression, alterations in GSK-3β, FkBP5, GFAP, ERK phosphorylation, and epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC).
Conclusion: These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine's effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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