Rickels K, Schweizer E, Case W G, DeMartinis N, Greenblatt D J, Mandos L A, Garcia España F G
Department of Psychiatry, University of Pennsylvania, Philadelphia 19194-2649, USA.
J Clin Psychopharmacol. 1998 Apr;18(2):145-53. doi: 10.1097/00004714-199804000-00007.
One hundred sixty-six patients suffering from major depressive disorders were treated for 8 weeks with nefazodone in an open study in dosage ranges from 200 to 600 mg. This report focuses primarily on the first week of therapy and on the concomitant use of several benzodiazepines, one of which is not metabolized by the cytochrome system (temazepam). Triazolam response was further evaluated as a function of two nefazodone dosage regimens provided during the first week of therapy, one group receiving nefazodone 200 mg/day for 7 days, and another group receiving nefazodone 200 mg/day for 3 days, followed by 4 days with 400 mg/day. Finally, a comparison of three different nefazodone dosages, the third being 400 mg from day 1 on, was also carried out. Outcome measures included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as well as global improvement, a daily completed sleep questionnaire, and adverse event assessment. A combination of nefazodone with a benzodiazepine (BZ) caused more sedation than nefazodone alone; triazolam, the BZ with the shortest half-life and the highest dependence on the cytochrome 450 system for its metabolism, caused the least amount of sedation, and alprazolam and diazepam, the two daytime benzodiazepines, caused the most sedation. Triazolam caused significant and identical reduction of insomnia in both nefazodone groups. Compared with nefazodone 200 mg given as monotherapy, insomnia was significantly improved--not only by triazolam, but also alprazolam and diazepam, but not temazepam. The addition of nefazodone raised triazolam plasma levels to almost 500%, the plasma level of desmethyl-diazepam 87%, and that of alprazolam 34%. Temazepam plasma levels remained unchanged. When prescribing nefazodone with a benzodiazepine, one should expect an improved sleep pattern initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytochrome mechanism for metabolism, should be the least sedating, and triazolam, because of its cytochromic metabolism interference with nefazodone should be the most sedating, could not be confirmed. In fact, triazolam 0.25 mg capsules seem to be the safest treatment of choice when one has to combine a benzodiazepine with nefazodone in initial stages of therapy, at least of the four benzodiazepines tested in this study.
在一项开放性研究中，166名重度抑郁症患者接受了为期8周的奈法唑酮治疗，剂量范围为200至600毫克。本报告主要关注治疗的第一周以及几种苯二氮䓬类药物的联合使用情况，其中一种（替马西泮）不由细胞色素系统代谢。作为治疗第一周提供的两种奈法唑酮给药方案的函数，对三唑仑的反应进行了进一步评估，一组连续7天每天服用200毫克奈法唑酮，另一组前3天每天服用200毫克奈法唑酮，随后4天每天服用400毫克。最后，还对三种不同的奈法唑酮剂量进行了比较，第三种是从第1天起每天400毫克。结果指标包括汉密尔顿抑郁量表总分、汉密尔顿抑郁量表失眠项目的三项总分、整体改善情况、每日完成的睡眠问卷以及不良事件评估。奈法唑酮与苯二氮䓬类药物（BZ）联合使用比单独使用奈法唑酮引起更多的镇静作用；三唑仑，半衰期最短且其代谢对细胞色素450系统依赖性最高的BZ，引起的镇静作用最少，而两种日间使用的苯二氮䓬类药物阿普唑仑和地西泮引起的镇静作用最强。三唑仑在两个奈法唑酮组中均导致失眠显著且相同程度的减轻。与单独使用200毫克奈法唑酮作为单一疗法相比，不仅三唑仑，阿普唑仑和地西泮也能显著改善失眠，但替马西泮不能。添加奈法唑酮使三唑仑血浆水平升高至近500%，去甲基地西泮血浆水平升高87%，阿普唑仑血浆水平升高34%。替马西泮血浆水平保持不变。当开具奈法唑酮与苯二氮䓬类药物的联合处方时，最初应预期睡眠模式会得到改善，但代价是临床上相关的日间镇静作用。关于替马西泮（唯一不依赖细胞色素机制代谢的BZ，应是镇静作用最小的）以及三唑仑（因其细胞色素代谢会干扰奈法唑酮，应是镇静作用最强的）的预测未得到证实。事实上，当在治疗初期必须将苯二氮䓬类药物与奈法唑酮联合使用时，至少在本研究中测试的四种苯二氮䓬类药物中，0.25毫克胶囊的三唑仑似乎是最安全的治疗选择。
