Duloxetine increases serotonin and norepinephrine availability in healthy subjects: A double-blind, controlled study
Duloxetine increases serotonin and norepinephrine availability in healthy subjects: A double-blind, controlled study
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DOI：
10.1038/sj.npp.1300209
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发表时间：
2003-09-01
影响因子：
7.6
通讯作者：
Potter, WZ
中科院分区：
文献类型：
--
作者：
Chalon, SA;Granier, LA;Potter, WZ
有证据表明，增加一种以上神经递质的突触可用性的化合物在治疗抑郁症方面比单作用药物具有更大的功效。临床前研究表明，度洛西汀可抑制5-羟色胺（5-HT）和去甲肾上腺素（NE）转运蛋白。在12名健康男性受试者中测试了度洛沙汀改变5-HT和NE再摄取的能力。安慰剂，地昔帕明50 mg，每日两次，和度洛西汀（80 mg q.d.或60 mg b.i.d.）在12名健康男性受试者中进行了一项随机、双盲、三阶段交叉研究。在稳态下测量全血5-HT、NE和主要代谢物的尿排泄以及TYR PD 30（使收缩压升高30 mmHg所需的IV酪胺升压剂量）。定期测量生命体征。度洛沙汀影响5-HT再摄取，与安慰剂相比，全血5-HT耗竭（80 mg q.d.：p = 0.07; 60 mg b.i.d.：p = 0.02;联合方案：p = 0.01）。度洛沙汀和地昔帕明均观察到反映交感神经张力增加的心血管变化，两种治疗均显著降低全身NE转换（p < 0.01）。度洛沙丁胺和地昔帕明与神经元NE浓度分数的平均增加相似，尽管这些变化未达到统计学显著性。TYR PD 30随着地昔帕明剂量的增加而显著增加（p < 0.01）。总之，全血测量证实度洛沙汀抑制体内血小板5-HT摄取。尿液和心血管测量结果表明，度洛沙汀对NE合成和转换有影响，表明NE再摄取抑制。度洛沙汀对TYR PD 30的影响不可检测，表明在评估双重再摄取抑制剂时，这可能不是NE再摄取的最灵敏间接测量方法。
Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine ( NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three-period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p = 0.07; 60 mg b.i.d.: p = 0.02; combined regimens: p = 0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (p < 0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD30 increased significantly with desipramine dosing (p < 0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.