Amann F, Kochtyrew M, Zernig G, Gründer G, Hart X M
Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP), Working Group "Therapeutic Drug Monitoring", Germany.
Neurosci Appl. 2024 Jun 10;3:104077. doi: 10.1016/j.nsa.2024.104077. eCollection 2024.
The concentration-effect relationship for the serotonin and norepinephrine reuptake inhibitor duloxetine forms the basis of its therapeutic concentration reference range. However, it lacks systematic investigation and the range reported in the present therapeutic drug monitoring guidelines can only be considered preliminary. A systematic review and meta-analysis were conducted in four databases to determine the optimal target concentration for duloxetine's antidepressant effects and to identify factors that influence its blood concentrations. Relevant articles reporting duloxetine blood concentrations in relation to i) clinical effects/adverse effects, ii) pharmacokinetics and iii) receptor occupancy were analyzed. Out of 340 articles, 11 studies were selected for qualitative synthesis, with seven being included in the quantitative analysis. Three studies showed a positive correlation between duloxetine blood concentrations and antidepressant effects. The adverse event irritability/anxiety was found to be concentration-dependent in one study. Across four studies (n = 223), the 25%-75% interquartile concentration range was 22-72 ng/mL. Two studies reported interquartile ranges of responders (72-116 ng/mL and 65-123 ng/mL), with one of them identifying a threshold concentration for clinical response (58 ng/mL). Neuroimaging studies indicated that 80% serotonin transporter occupancy is reached with blood concentrations above 10-15 ng/mL, while 50% norepinephrine transporter occupancy is observed at 58 ng/mL. We suggest a therapeutic reference range between 20 and 120 ng/mL to achieve optimal antidepressant effects during duloxetine treatment in adults. Due to duloxetine's inhibition of both serotonin and norepinephrine receptors, some patients benefit from low duloxetine concentrations, while others may need higher concentrations to benefit from norepinephrine transporter blockage. In case of non-response at low to medium concentrations (i.e. < 60 ng/mL), we recommend dose titration within the proposed reference range. Blood concentrations can be affected by smoking and certain medications. Hence, therapeutic drug monitoring of duloxetine is strongly recommended for dose titration, particularly with initial prescription.
5-羟色胺和去甲肾上腺素再摄取抑制剂度洛西汀的浓度-效应关系构成了其治疗浓度参考范围的基础。然而，这方面缺乏系统研究，目前治疗药物监测指南中报告的范围只能视为初步范围。我们在四个数据库中进行了一项系统评价和荟萃分析，以确定度洛西汀产生抗抑郁作用的最佳目标浓度，并识别影响其血药浓度的因素。分析了报告度洛西汀血药浓度与以下方面相关的文章：i）临床疗效/不良反应，ii）药代动力学，以及iii）受体占有率。在340篇文章中，选取了11项研究进行定性综合分析，其中7项纳入定量分析。三项研究显示度洛西汀血药浓度与抗抑郁作用呈正相关。在一项研究中发现不良事件易怒/焦虑与浓度有关。在四项研究（n = 223）中，25%-75%四分位数浓度范围为22-72 ng/mL。两项研究报告了有反应者的四分位数范围（72-116 ng/mL和65-123 ng/mL），其中一项研究确定了临床反应的阈值浓度（58 ng/mL）。神经影像学研究表明，血药浓度高于10-15 ng/mL时可达到80%的5-羟色胺转运体占有率，而在58 ng/mL时可观察到50%的去甲肾上腺素转运体占有率。我们建议在成人度洛西汀治疗期间，治疗参考范围为20至120 ng/mL，以实现最佳抗抑郁效果。由于度洛西汀对5-羟色胺和去甲肾上腺素受体均有抑制作用，一些患者从低度洛西汀浓度中获益，而另一些患者可能需要更高浓度才能从去甲肾上腺素转运体阻断中获益。如果在低至中等浓度（即<60 ng/mL）时无反应，我们建议在建议的参考范围内进行剂量滴定。血药浓度会受到吸烟和某些药物的影响。因此，强烈建议对度洛西汀进行治疗药物监测以进行剂量滴定，尤其是在初始处方时。
