Paschos Konstantinos A, Veletza Stavroula, Chatzaki Ekaterini
Laboratory of Pharmacology, School of Medicine, Democritus University of Thrace (DUTH), Alexandroupolis 68100, Thrace, Greece.
CNS Drugs. 2009 Sep;23(9):755-72. doi: 10.2165/11310830-000000000-00000.
Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.
作为最常见的精神疾病之一，抑郁症在西方世界的发病率正在上升。它表现出各种各样涉及中枢神经系统和外周的症状。多项药理学观察结果促成了单胺理论的发展，该理论作为抑郁症的生物学基础，认为中枢神经系统内神经传递减弱，包括多巴胺、去甲肾上腺素和血清素系统的神经传递减弱，是该疾病的主要原因。目前使用选择性单胺再摄取抑制剂、三环类抗抑郁药和单胺氧化酶抑制剂的传统药理学抗抑郁疗法，旨在增强单胺能神经传递。然而，使用这些药物存在严重缺点，包括缓解抑郁症状延迟、明显的不良反应以及无反应患者的高发生率。近几十年来的神经内分泌学数据表明，由于下丘脑 - 垂体 - 肾上腺（HPA）轴功能亢进，抑郁症和焦虑症可能同时发生。因此，应激素质模型得以发展，该模型试图将遗传和环境影响与抑郁症的病因联系起来。杏仁核和海马体以相互平衡的方式控制HPA轴的活动，并且涉及大量调节性神经肽信号通路。对这些分子靶点进行干预可能会带来替代抗抑郁治疗方案，有望克服现有抗抑郁药的局限性。这一前景基于对促肾上腺皮质激素释放因子、P物质、甘丙肽、加压素和神经肽Y等神经肽作用进行药理学和基因修饰的临床前证据。最近合成的口服有效非肽小分子能够选择性地与各种神经肽受体结合，这使得评估其抗抑郁疗效的临床试验得以开展。
