Preskorn Sheldon H
Department ofPsychiatry, University of Kansas School of Medicine-Wichita, USA.
J Psychiatr Pract. 2012 Jan;18(1):38-45. doi: 10.1097/01.pra.0000410986.61593.46.
This column reviews why signal detection in psychiatric research has been problematic, how the use of biomarkers can help, how and why fixed dose studies are done, and how these studies differ from what clinicians do in practice. The fixed dose studies done with selective serotonin reuptake inhibitors (SSRIs) are used to illustrate general points about clinical trial research methodology relevant to clinical practice. Studies with SSRIs have yielded flat dose-response curves with regard to efficacy but ascending dose-response curves with regard to discontinuation due to adverse effects. These clinical trial findings are explained by studies using serotonin transporter inhibition or occupancy as a surrogate marker for SSRI efficacy and tolerability. Initially, these studies were conducted ex vivo using human platelets as the model system; however, they have now been extended to in vivo measurement of serotonin transporter occupancy in patients using positron emission tomography. The conclusion from this work is that the usually effective, minimum dose of each marketed SSRI produces 70%-80% inhibition or occupancy (depending on the methodology used) of the serotonin transporter; higher rates of inhibition or occupancy do not on average increase efficacy but instead increase early discontinuation rates due to adverse effects. These increased discontinuation rates offset any gain in efficacy when the results are analyzed using the last-observation-carried-forward approach. An understanding of these principles also provides an explanation for what initially may appear to be a conundrum: why some patients can benefit from a dose increase even though, in fixed dose clinical trials, the drug had a flat dose-efficacy curve.
本专栏回顾了为何精神病学研究中的信号检测一直存在问题，生物标志物的使用如何提供帮助，固定剂量研究的开展方式及原因，以及这些研究与临床医生实际操作的差异。以选择性5-羟色胺再摄取抑制剂（SSRI）进行的固定剂量研究，被用于阐释与临床实践相关的临床试验研究方法的一般要点。关于疗效，SSRI的研究得出了平坦的剂量反应曲线，但关于因不良反应导致停药的情况，则得出了上升的剂量反应曲线。这些临床试验结果通过使用5-羟色胺转运体抑制或占有率作为SSRI疗效和耐受性的替代标志物的研究得到了解释。最初，这些研究是在体外以人血小板作为模型系统进行的；然而，现在已扩展到使用正电子发射断层扫描在体内测量患者的5-羟色胺转运体占有率。这项工作得出的结论是，每种上市的SSRI通常有效的最小剂量会产生70%-80%的5-羟色胺转运体抑制或占有率（取决于所使用的方法）；更高的抑制率或占有率平均不会提高疗效，反而会增加因不良反应导致的早期停药率。当使用末次观察结转法分析结果时，这些增加的停药率抵消了疗效上的任何增益。对这些原则的理解也为最初看似矛盾的问题提供了解释：为什么有些患者即使在固定剂量临床试验中药物的剂量-疗效曲线是平坦的，仍能从增加剂量中获益。
