Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response
Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response
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DOI：
10.1016/j.biopsych.2018.01.008
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发表时间：
2018-07-01
影响因子：
10.6
通讯作者：
Schatzberg, Alan
中科院分区：
文献类型：
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作者：
Block, Thaddeus S.;Kushner, Harvey;Schatzberg, Alan
背景：精神病性抑郁症患者的皮质醇水平升高。用米非司酮竞争性拮抗糖皮质激素受体上的皮质醇，在精神病抑郁患者的早期研究中显示出治疗的益处。我们对所有对照的2期和3期研究进行了联合分析，以报告米非司酮和安慰剂治疗之间的抗精神病药物差异，并评估在治疗过程中达到预先定义的高米非司酮血浆水平和糖皮质激素受体拮抗标记物(促肾上腺皮质激素和皮质醇增加)对反应的相对贡献。方法：收集5项类似设计的双盲2期或3期研究的数据，评估米非司酮7天治疗精神病抑郁症的有效性和安全性(米非司酮n=833；安慰剂n=627)。在基线以及第7、14、28、42和56天进行临床评估。在基线和第7天收集米非司酮、促肾上腺皮质激素和皮质醇样本。结果：综合结果显示，米非司酮在减少精神病症状方面有显著疗效(p<；004)，且安全裕度很大。预先定义的高米非司酮血药浓度组(>；=1637 ng/mL)的患者显示出比安慰剂更显著的治疗效果(p=.0004)。高米非司酮组和低米非司酮组需要治疗的人数分别为7人和48人。服用米非司酮和服用安慰剂的患者不良反应相似。结论：高水平的米非司酮血浆水平与反应密切相关，其次是促肾上腺皮质激素和皮质醇的变化。米非司酮1200毫克/天的剂量最有可能达到治疗性血药浓度。
BACKGROUND: Patients with psychotic depression exhibit elevated cortisol levels. Competitively antagonizing cortisol at the glucocorticoid receptor with mifepristone demonstrated therapeutic benefit in early studies of patients with psychotic depression. We present a combined analysis of all controlled phase 2 and 3 studies to report antipsychotic differences between treatment with mifepristone or placebo and to evaluate the relative contributions to response of attaining an a priori-defined, high mifepristone plasma level and markers of glucocorticoid receptor antagonism (increases in adrenocorticotropin hormone and cortisol) with treatment.METHODS: Data from five similarly designed double-blind phase 2 or 3 studies evaluating the efficacy and safety of 7-day treatment with mifepristone for the psychotic symptoms of psychotic depression were pooled for analysis (mifepristone n = 833; placebo n = 627). Clinical assessments were performed at baseline and on days 7, 14, 28, 42, and 56. Mifepristone, adrenocorticotropin hormone, and cortisol samples were collected at baseline and day 7.RESULTS: Combined results demonstrated meaningful efficacy (p < 004) for mifepristone in reducing psychotic symptoms with wide safety margins. Patients in the a priori-defined, high mifepristone plasma level group (>= 1637 ng/mL) demonstrated a more significant treatment effect over placebo (p = .0004). A number needed to treat of 7 and 48 was observed in the high and low mifepristone plasma level groups, respectively. Adverse events were similar in mifepristone-and placebo-treated patients.CONCLUSIONS: A high mifepristone plasma level carried the strongest association with response, followed by changes in adrenocorticotropin hormone and cortisol. Therapeutic plasma levels of mifepristone were most likely to be achieved with the 1200 mg/day dose.