Crawford A M, Beasley C M, Tollefson G D
Olanzapine Development Team, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Schizophr Res. 1997 Jul 25;26(1):41-54. doi: 10.1016/S0920-9964(97)00036-4.
Prolactin elevation is both a common and a persistent event with the currently marketed antipsychotics, excluding clozapine. Elevations have been associated with both acute (galactorrhea, amenorrhea) and chronic (predisposition to osteoporosis) treatment-emergent adverse events. One of the defining criteria for an atypical antipsychotic is the relative lack of persistent prolactinemia. A double-blind, placebo- (N = 68) and haloperidol- (Hal: 15 +/- 5 mg/day, N = 69) controlled trial of three dose ranges of olanzapine (Olz-L: 5 +/- 2.5 mg/day, N = 65; Olz-M: 10 +/- 2.5 mg/day, N = 64; Olz-H: 15 +/- 2.5 mg/day, N = 69) in the treatment of schizophrenia afforded the opportunity to assess the temporal course of the influence of olanzapine and haloperidol on serum prolactin concentration. Consistent with its potent D2 antagonism, haloperidol was associated with a statistically significantly higher incidence of treatment-emergent prolactin elevation (72%) than seen with placebo (8%; p < 0.001) at week 2 of therapy. Expectedly, this elevation was also persistent at weeks 4 and 6. In contrast, olanzapine-associated treatment-emergent prolactin elevations were both lower in magnitude and transient. At week 2, 38% of the Olz-H, 24% of the Olz-M, and 13% of the Olz-L treatment groups exhibited a treatment-emergent prolactin elevation, with a mean increase of 0.35, 0.52, and 0.61 nmol/l, respectively; for haloperidol the mean increase was 1.23 nmol/l. For only the Olz-M and the Olz-H treatment groups did the week 2 incidence of treatment-emergent prolactin elevations differ statistically significantly from placebo. Both the incidence of elevations and the mean increase, in prolactin concentration were less than that seen with haloperidol. Furthermore, by treatment week 6, all three olanzapine groups exhibited incidences of treatment-emergent prolactin elevation that were comparable to placebo and were statistically significantly less than observed with haloperidol. Rapid adaptation was observed in the temporal course of prolactin elevations associated with olanzapine based on both the categorical analysis of treatment-emergent high values and the analyses of temporal change in mean concentrations. In contrast to haloperidol, the magnitudes of the treatment-emergent elevations associated with olanzapine were minimal. The rates of elevation were approximately one-half to one-third those observed with haloperidol and were significantly more transient. Olanzapine, even at the highest doses (15 +/- 2.5 mg/day) used, was not associated with persistent elevations of prolactin, consistent with an 'atypical' pharmacologic profile.
除氯氮平外，目前市售的抗精神病药物都会导致催乳素升高，这是一个常见且持续存在的现象。催乳素升高与急性（溢乳、闭经）和慢性（易患骨质疏松症）治疗中出现的不良事件均有关联。非典型抗精神病药物的一个决定性标准是相对缺乏持续性高催乳素血症。一项双盲试验，以安慰剂（N = 68）和氟哌啶醇（Hal：15±5毫克/天，N = 69）作为对照，对三个剂量范围的奥氮平（Olz-L：5±2.5毫克/天，N = 65；Olz-M：10±2.5毫克/天，N = 64；Olz-H：15±2.5毫克/天，N = 69）治疗精神分裂症进行研究，该试验提供了评估奥氮平和氟哌啶醇对血清催乳素浓度影响的时间进程的机会。与氟哌啶醇强效的D2拮抗作用一致，在治疗第2周时，氟哌啶醇导致治疗中出现催乳素升高的发生率（72%）在统计学上显著高于安慰剂组（8%；p < 0.001）。不出所料，这种升高在第4周和第6周时也持续存在。相比之下，奥氮平导致治疗中出现的催乳素升高幅度较小且是短暂的。在第2周时，Olz-H治疗组的38%、Olz-M治疗组的24%和Olz-L治疗组的13%出现了治疗中出现的催乳素升高，平均升高分别为0.35、0.52和0.61纳摩尔/升；氟哌啶醇的平均升高为1.23纳摩尔/升。仅Olz-M和Olz-H治疗组在第2周时治疗中出现催乳素升高的发生率与安慰剂组在统计学上有显著差异。升高的发生率和催乳素浓度的平均升高均低于氟哌啶醇组。此外，到治疗第6周时，所有三个奥氮平组出现治疗中出现催乳素升高的发生率与安慰剂组相当，且在统计学上显著低于氟哌啶醇组。基于对治疗中出现的高值的分类分析以及平均浓度的时间变化分析，观察到奥氮平相关的催乳素升高在时间进程上有快速适应性。与氟哌啶醇不同，奥氮平导致治疗中出现的升高幅度最小。升高速率约为氟哌啶醇观察值的二分之一到三分之一，且明显更短暂。即使使用最高剂量（15±2.5毫克/天）的奥氮平，也不会导致催乳素持续升高，这与“非典型”药理学特征一致。
