Correll Christoph U, Jain Rakesh, Meyer Jonathan M, Periclou Antonia, Carrothers Timothy, Barabássy Ágota, Patel Mehul, Earley Willie
Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
Neuropsychiatr Dis Treat. 2019 Aug 30;15:2537-2550. doi: 10.2147/NDT.S210340. eCollection 2019.
To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs).
Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan-Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves.
The Kaplan-Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6-7 weeks after randomization, compared to the Kaplan-Meier curves for the other AAPs, which showed earlier separation at 1-4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8-34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at 2-4 weeks after last dose.
Discontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other AAPs, which may be due to the longer half-life of cariprazine and its active metabolites.
通过比较卡立普唑随机、安慰剂对照撤药研究的数据与其他口服非典型抗精神病药（AAPs）设计和实施相似的随机对照试验的数据，探讨停药后复发的时间及其与估计血浆水平和消除半衰期的关系。
分析了一项针对精神分裂症患者的长期、随机、双盲、安慰剂对照预防复发研究（NCT01412060）的数据。使用其他AAPs设计相似的已发表研究进行比较。从Kaplan-Meier曲线估计药物-安慰剂复发分离时间和复发率，并进行描述性评估。分离定义为AAP和安慰剂曲线之间复发发生率持续差异≥5%。
卡立普唑的Kaplan-Meier曲线显示随机分组后6-7周出现药物-安慰剂复发分离，而其他AAPs的Kaplan-Meier曲线显示在1-4周出现更早的分离。随机分组后4周，卡立普唑的安慰剂复发率为5%，其他AAPs为8%-34%。停药后2周和4周时，卡立普唑总活性部分（卡立普唑、去甲基卡立普唑和双去甲基卡立普唑之和）模型预测血浆浓度的几何平均值分别为20.0和6.1 nM。其他AAPs及其活性代谢物的消除半衰期（<4天）表明，末次给药后2-4周血浆浓度将很低或可忽略不计。
与其他AAPs相比，停用卡立普唑治疗似乎与复发发生率延迟有关，这可能归因于卡立普唑及其活性代谢物的半衰期更长。
