Kasper Siegfried, Sacher Julia, Klein Nikolas, Mossaheb Nilufar, Attarbaschi-Steiner Trawat, Lanzenberger Rupert, Spindelegger Christoph, Asenbaum Susanne, Holik Alexander, Dudczak Robert
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
Int Clin Psychopharmacol. 2009 May;24(3):119-25. doi: 10.1097/YIC.0b013e32832a8ec8.
Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.
艾司西酞普兰是消旋体西酞普兰的S-对映体，在治疗重度抑郁症方面临床上比西酞普兰更有效。然而，艾司西酞普兰优于西酞普兰的确切机制尚未确定。据推测，治疗上无活性的R-对映体在5-羟色胺再摄取转运体（SERTs）上的低亲和力变构位点与增强5-羟色胺的S-对映体竞争，并降低S-对映体在主要的高亲和力5-羟色胺结合位点的有效性。本研究总结了两项最近的单光子发射计算机断层扫描研究的结果，这些研究测量了单次给药和多次给药后（即在稳态条件下），接受西酞普兰治疗和艾司西酞普兰治疗的健康志愿者的SERT占有率。单剂量研究显示R-西酞普兰没有减弱作用。然而，多次给药后，在存在R-西酞普兰的情况下，SERT占有率显著降低。在稳态条件下，由于R-西酞普兰清除较慢，R-对映体浓度高于S-对映体。一项汇总分析表明，重复服用西酞普兰后R-对映体的积累可能导致对SERT上S-对映体占有率的抑制增加。这篇综述增加了越来越多关于SERT占有率动力学差异的证据，即艾司西酞普兰在重度抑郁症中通常观察到的优于西酞普兰的临床疗效的分子机制。
