Pharmacotherapy of Major Depressive Disorder: Focus on Duloxetine

K. Muneoka
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Abstract

The serotonin-noradrenaline reuptake inhibitor duloxetine is a second-generation antidepressant for the treatment of major depressive disorder (MDD). Its inhibitory potency for serotonin (5-HT) and noradrenaline (NA) reuptake has been demonstrated in animal and in vitro studies. Human studies of peripheral markers of neurotransmission show inhibition of 5-HT reuptake by duloxetine and also support its potency in NA reuptake inhibition. Moreover, a positron emission tomography study in human brains shows that therapeutic doses of duloxetine result in .80% occupancy of 5-HT transporters. Duloxetine is metabolized by hepatic enzymes and cytochromes P450 CYP2D6 and CYP1A2, and plasma duloxetine concentrations increase linearly according to oral dose. In double-blind, randomized, placebo-control studies of MDD, duloxetine-treated patients show significantly increased response and remission rates and significantly longer time to relapse compared to placebo-treated patients. Moreover, duloxetine is efficacious for the treatment of generalized anxiety disorder (GAD) and pain-related diseases such as diabetic peripheral neuropathic pain (DPNP). A daily dose of 60 mg daily seems most effective for treating MDD, GAD and DPNP. Duloxetine is similar in efficacy to fluoxetine, paroxetine and escitalopram for MDD, although escitalopram is better for improving sleep. The most common treatment-emergent side effects of duloxetine are nausea, dry mouth, fatigue and decreased appetite. Studies suggest an association with the incidence of increased sweating or somnolence at higher doses and an association with irritability or anxiety at high plasma levels of duloxetine. Discontinuation rates due to adverse events are higher in patients who receive duloxetine versus placebo in short-term but not long-term studies. Interestingly, there is not a strong correlation between clinical efficacy and plasma levels of duloxetine. Therefore, although duloxetine is safe and tolerated at therapeutic doses of 60–120 mg/day, the dose should be adjusted while the patient is carefully monitored for efficacy and adverse events.
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重度抑郁症的药物治疗:以度洛西汀为重点
5 -羟色胺-去甲肾上腺素再摄取抑制剂度洛西汀是治疗重度抑郁症(MDD)的第二代抗抑郁药。其对血清素(5-HT)和去甲肾上腺素(NA)再摄取的抑制效力已在动物和体外研究中得到证实。神经传递的外周标志物的人体研究显示,度洛西汀抑制5-羟色胺再摄取,也支持其抑制NA再摄取的效力。此外,一项人脑正电子发射断层扫描研究表明,治疗剂量的度洛西汀可使5-羟色胺转运体占据0.80%。度洛西汀被肝酶和细胞色素P450 CYP2D6和CYP1A2代谢,血浆度洛西汀浓度随口服剂量线性增加。在MDD的双盲、随机、安慰剂对照研究中,与安慰剂治疗的患者相比,度洛西汀治疗的患者反应和缓解率显著提高,复发时间显著延长。此外,度洛西汀对广泛性焦虑障碍(GAD)和疼痛相关疾病(如糖尿病周围神经性疼痛(DPNP))的治疗有效。每天服用60毫克似乎对治疗重度抑郁症、广泛性焦虑症和DPNP最有效。度洛西汀对重度抑郁症的疗效与氟西汀、帕罗西汀和艾司西酞普兰相似,但艾司西酞普兰对改善睡眠效果更好。度洛西汀最常见的副作用是恶心、口干、疲劳和食欲下降。研究表明,高剂量的度洛西汀与增加出汗或嗜睡的发生率有关,与高血浆水平的度洛西汀与易怒或焦虑有关。在短期但非长期研究中,服用度洛西汀的患者因不良事件而停药的比例高于安慰剂。有趣的是,临床疗效与血浆度洛西汀水平之间没有很强的相关性。因此,尽管在60 - 120mg /天的治疗剂量下度洛西汀是安全且耐受的,但在仔细监测患者的疗效和不良事件时,剂量应进行调整。
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