BackgroundLurasidone is approved for the treatment of bipolar depression both as monotherapy and adjunctive therapy with lithium or valproate (Li/VPA). The aim of these analyses was to evaluate the prevalence of treatment-emergent mania (TEM) and worsening of mania symptom severity in clinical trials of both adult and pediatric patients with bipolar depression treated with lurasidone.MethodIn these post-hoc analyses, TEM and change in manic symptom severity as measured by the Young Mania Rating Scale (YMRS) were evaluated in two double-blind (DB), 6-week studies in adults of lurasidone monotherapy, 20–60 mg/d (n=161) and 80–120 mg/d (n=162) vs. placebo (n=162), and adjunctive therapy of lurasidone 20–120 mg/d + Li/VPA (n=179) vs. placebo + Li/VPA (n=161). Prevalence of TEM was also evaluated in a 6-month, open-label (OL) extension study of adults treated with lurasidone monotherapy (n=316) or adjunctive therapy (n=497). In pediatric patients (ages 10–17) TEM and change in manic symptoms was evaluated in a DB 6-week study of lurasidone monotherapy (n=173) vs. placebo (n=170) and in a 24-month OL extension study. TEM was defined as an adverse event of mania or hypomania and/or having a YMRS score =16 at 2 consecutive post-baseline weekly visits (or the final assessment) in short-term studies or 1 post-baseline monthly visit in long-term studies.ResultsAdult studies: In short-term studies, TEM rates were comparable in patients treated with lurasidone monotherapy 20–60 mg/d (3.7%) and 80–120 mg/d (1.9%) vs. placebo (1.9%). TEM rates were also comparable in patients treated with lurasidone 20–120 mg/d (1.1%) adjunctive to Li/VPA vs. placebo + Li/VPA (1.2%). In the monotherapy study, significant reduction in YMRS score was observed at study endpoint for the 20–60 mg/d group compared to placebo (−1.9 vs. −1.3; p<0.05) with similar improvement relative to placebo in the 80–120 mg/d group. Change for YMRS score was comparable for lurasidone and placebo in the adjunctive study. In long-term studies, 1.3% of adult patients treated with lurasidone monotherapy (n=316) met criteria for mania, and 3.8% of patients on adjunctive lurasidone therapy (n=497) met TEM criteria. Pediatric studies: TEM rates were comparable in patients treated with lurasidone vs. placebo (1.7% vs. 2.3%). LS mean reduction in symptoms of mania from baseline to week 6 was significantly greater for lurasidone vs. placebo on YMRS score (−2.0 vs. −1.1; p<0.05). Pediatric long-term studies: After two years of OL treatment with lurasidone, 5.2% of patients met TEM criteria. Mean change in YMRS total score from DB baseline to Month 24 continued to improve (−2.0).ConclusionsShort-term and long-term treatment with lurasidone demonstrated significant improvement in manic symptoms and was not associated with an increased risk of TEM in either adult or pediatric patient populations compared to rates reported in clinical populations of patients.FundingSunovion Pharmaceuticals Inc.

中文翻译：

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鲁拉西酮对双相抑郁症成人和儿童人群躁狂症状和治疗突发躁狂症的影响

背景鲁拉西酮被批准用于双相抑郁症的治疗，既可以作为单一疗法，也可以作为锂或丙戊酸盐 (Li/VPA) 的辅助疗法。这些分析的目的是评估在使用鲁拉西酮治疗的双相抑郁症成人和儿童患者的临床试验中，治疗出现躁狂症 (TEM) 的患病率和躁狂症症状严重程度的恶化。方法在这些事后分析中，TEM 和变化在两项双盲 (DB)、为期 6 周的成人鲁拉西酮单药治疗研究中评估了通过年轻躁狂评定量表 (YMRS) 测量的躁狂症状严重程度，20-60 mg/d (n=161) 和 80- 120 mg/d (n=162) 对比安慰剂 (n=162)，以及鲁拉西酮 20–120 mg/d + Li/VPA (n=179) 对比安慰剂 + Li/VPA (n=161) 的辅助治疗. TEM 的患病率也在 6 个月内进行了评估，对接受鲁拉西酮单药治疗 (n=316) 或辅助治疗 (n=497) 的成人进行的开放标签 (OL) 扩展研究。在一项为期 6 周的鲁拉西酮单药治疗（n=173）与安慰剂（n=170）的 DB 研究和一项为期 24 个月的 OL 扩展研究中，评估了儿科患者（10-17 岁）的 TEM 和躁狂症状的变化。TEM 被定义为躁狂或轻躁狂的不良事件和/或在短期研究中连续 2 次基线后每周访问（或最终评估）或 1 次长期基线后每月访问时 YMRS 评分 = 16研究。结果成人研究：在短期研究中，接受鲁拉西酮单药治疗 20-60 mg/d (3.7%) 和 80-120 mg/d (1.9%) 与安慰剂 (1.9%) 治疗的患者的 TEM 率相当。使用 Lurasidone 20–120 mg/d (1.1%) 辅助 Li/VPA 与安慰剂 + Li/VPA 治疗的患者的 TEM 率也相当（1. 2%）。在单药治疗研究中，与安慰剂相比，20-60 mg/d 组在研究终点观察到 YMRS 评分显着降低（-1.9 对 -1.3；p<0.05），在 80-120 组中与安慰剂相比有类似改善毫克/天组。在辅助研究中，鲁拉西酮和安慰剂的 YMRS 评分变化相当。在长期研究中，1.3% 接受鲁拉西酮单药治疗的成年患者 (n=316) 符合躁狂标准，3.8% 接受鲁拉西酮辅助治疗的患者 (n=497) 符合 TEM 标准。儿科研究：鲁拉西酮组与安慰剂组的 TEM 发生率相当（1.7% 与 2.3%）。在 YMRS 评分上，鲁拉西酮与安慰剂相比，从基线到第 6 周的躁狂症状的 LS 平均减少显着更大（-2.0 对 -1.1；p<0.05）。儿科长期研究：在使用 lurasidone 进行 OL 治疗两年后，5.2% 的患者符合 TEM 标准。从 DB 基线到第 24 个月，YMRS 总分的平均变化继续改善 (-2.0)。结论短期和长期鲁拉西酮治疗显示躁狂症状显着改善，并且与成人或成人 TEM 风险增加无关儿科患者人群与临床患者人群中报告的比率相比。资金 Sunovion Pharmaceuticals Inc.