Pacher Pal, Kecskemeti Valeria
National Institutes of Health, National Institute on Alcohol Abuse & Alcoholism, Laboratory of Physiologic Studies, Rockville, MD 20852, USA.
Curr Med Chem. 2004 Apr;11(7):925-43. doi: 10.2174/0929867043455594.
Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors. The introduction of selective serotonin reuptake inhibitors (SSRIs) over twenty years ago had been the next major step in the evolution of antidepressants to develop drugs as effective as the TCAs but of higher safety and tolerability profile. During the past two decades SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) gained incredible popularity and have become the most widely prescribed medication in the psychiatric practice. The evolution of antidepressants continued resulting in introduction of selective and reversible monoamine oxidase inhibitors (eg. moclobemid), selective noradrenaline (eg. reboxetine), dual noradrenaline and serotonin reuptake inhibitors (milnacipram, venlafaxin, duloxetin) and drugs with distinct neurochemical profiles such as mirtazapine, nefazadone and tianeptine. Different novel serotonin receptor ligands have also been intensively investigated. In spite of the remarkable structural diversity, most currently introduced antidepressants are 'monoamine based'. Furthermore, these newer agents are neither more efficacious nor rapid acting than their predecessors and approximately 30% of the population do not respond to current therapies. By the turn of the new millennium, we are all witnessing a result of innovative developmental strategies based on the better understanding of pathophysiology of depressive disorder. Several truly novel concepts have emerged suggesting that the modulation of neuropeptide (substance P, corticotrophin-releasing factor, neuropeptide Y, vasopressin V1b, melanin-concentrating hormone-1), N-methyl-D-aspartate, nicotinic acetylcholine, dopaminergic, glucocorticoid, delta-opioid, cannabinoid and cytokine receptors, gamma-amino butyric acid (GABA) and intracellular messenger systems, transcription, neuroprotective and neurogenic factors, may provide an entirely new set of potential therapeutic targets, giving hope that further major advances might be anticipated in the treatment of depressive disorder soon. The goal of this review is to give a brief overview of the major advances from monoamine-based treatment strategies, and particularly focus on the new emerging approaches in the treatment of depression.
自20世纪50年代中期三环类抗抑郁药（TCAs）和单胺氧化酶抑制剂（MAOIs）问世以来，抑郁症的治疗一直受单胺假说主导。TCAs和MAOIs已确立的临床疗效至少部分归因于去甲肾上腺素能或5-羟色胺能机制的增强，或两者兼而有之。不幸的是，它们非常广泛的作用机制还包括许多与其对胆碱能、肾上腺素能和组胺能受体的强效活性相关的不良反应。二十多年前选择性5-羟色胺再摄取抑制剂（SSRIs）的引入是抗抑郁药发展历程中的下一个重要步骤，旨在研发出与TCAs一样有效但安全性和耐受性更高的药物。在过去二十年中，SSRIs（氟西汀、氟伏沙明、帕罗西汀、舍曲林、西酞普兰）广受欢迎，已成为精神科实践中处方最广泛的药物。抗抑郁药不断发展，导致选择性和可逆性单胺氧化酶抑制剂（如吗氯贝胺）、选择性去甲肾上腺素（如瑞波西汀）、去甲肾上腺素和5-羟色胺双重再摄取抑制剂（米那普明、文拉法辛、度洛西汀）以及具有独特神经化学特征的药物（如米氮平、奈法唑酮和噻奈普汀）的出现。不同的新型5-羟色胺受体配体也得到了深入研究。尽管结构差异显著，但目前引入的大多数抗抑郁药都是“基于单胺的”。此外，这些新型药物并不比其前身更有效或起效更快，约30%的患者对当前治疗无反应。到新千年之交，我们都见证了基于对抑郁症病理生理学更好理解的创新发展策略的成果。一些全新的概念已经出现，表明调节神经肽（P物质、促肾上腺皮质激素释放因子、神经肽Y、血管加压素V1b、黑色素浓缩激素-1）、N-甲基-D-天冬氨酸、烟碱型乙酰胆碱、多巴胺能、糖皮质激素、δ-阿片样物质、大麻素和细胞因子受体、γ-氨基丁酸（GABA）以及细胞内信使系统、转录、神经保护和神经源性因子，可能会提供一整套全新的潜在治疗靶点，让人期待在抑郁症治疗方面很快能取得进一步的重大进展。本综述的目的是简要概述基于单胺的治疗策略的主要进展，并特别关注抑郁症治疗中新兴的方法。
