Karpa Kelly D, Cavanaugh Jane E, Lakoski Joan M
Departments of Pharmacology and Anesthesiology, Pennsylvania State College of Medicine, MC H078, 500 University Drive, Hershey, PA 17033-2390, USA.
CNS Drug Rev. 2002 Winter;8(4):361-76. doi: 10.1111/j.1527-3458.2002.tb00234.x.
Dysregulation within central monoaminergic systems is believed to underlie the pathology of depression. Drugs that selectively inhibit the reuptake of central monoamines have been used clinically to alleviate symptoms of depressive illnesses. Duloxetine, a novel compound currently under investigation for the treatment of depression, binds selectively with high affinity to both norepinephrine (NE) and serotonin (5-HT) transporters and lacks affinity for monoamine receptors within the central nervous system. It has been suggested that dual inhibition of monoamine reuptake processes may offer advantages over other antidepressants currently in use. In preclinical studies, duloxetine mimics many physiologic effects of antidepressants. Consistent with other antidepressants, duloxetine, by acute administration, elevates extracellular monoamine levels, while by chronic administration it does not alter basal monoamine levels. Like the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic application, duloxetine inhibits neuronal cell firing. However, in comparison with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor. Furthermore, in behavioral experiments, duloxetine attenuates immobility in forced swim tests in animal models of depression to a greater extent than several other commonly used antidepressants. In a six-week open label uncontrolled study, duloxetine was evaluated in patients with a history of depression. Duloxetine was effective in treating depression as determined by marked reduction in Hamilton Depression Rating scores. Adverse effects reported during duloxetine treatment were minor and similar to those of other antidepressants. In an eight-week multicenter, double-blind, placebo-controlled study in patients with a major depressive disorder, duloxetine was effective as an antidepressant, particularly in patients with greater symptom severity. Only limited data are available regarding the pharmacokinetic profile of duloxetine in humans, although a half-life of 10 to 15 h has been reported. Studies conducted in healthy human subjects confirm the preclinical profile of duloxetine as an inhibitor of 5-HT and NE reuptake. Taken together, existing data suggest that duloxetine is a novel and effective antidepressant.
中枢单胺能系统的调节异常被认为是抑郁症病理的基础。临床上已使用选择性抑制中枢单胺再摄取的药物来缓解抑郁症的症状。度洛西汀是一种目前正在研究用于治疗抑郁症的新型化合物，它以高亲和力选择性地与去甲肾上腺素（NE）和5-羟色胺（5-HT）转运体结合，对中枢神经系统内的单胺受体缺乏亲和力。有人提出，对单胺再摄取过程的双重抑制可能比目前使用的其他抗抑郁药具有优势。在临床前研究中，度洛西汀模拟了许多抗抑郁药的生理效应。与其他抗抑郁药一致，度洛西汀通过急性给药可提高细胞外单胺水平，而通过慢性给药则不会改变基础单胺水平。与选择性5-羟色胺再摄取抑制剂氟西汀一样，通过微离子电渗法应用，度洛西汀可抑制神经元细胞放电。然而，与氟西汀相比，度洛西汀是一种更强效的5-羟色胺再摄取抑制剂。此外，在行为实验中，度洛西汀在抑郁症动物模型的强迫游泳试验中比其他几种常用抗抑郁药更能显著减轻不动状态。在一项为期六周的开放标签非对照研究中，对有抑郁症病史的患者进行了度洛西汀评估。根据汉密尔顿抑郁量表评分显著降低确定，度洛西汀治疗抑郁症有效。度洛西汀治疗期间报告的不良反应轻微，与其他抗抑郁药相似。在一项针对重度抑郁症患者的为期八周的多中心、双盲、安慰剂对照研究中，度洛西汀作为抗抑郁药有效，尤其是对症状较严重的患者。关于度洛西汀在人体内的药代动力学特征，仅有有限的数据，尽管报告的半衰期为10至15小时。在健康人体受试者中进行的研究证实了度洛西汀作为5-HT和NE再摄取抑制剂的临床前特征。综上所述，现有数据表明度洛西汀是一种新型有效的抗抑郁药。
