Study ObjectiveApproved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.MethodPatients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.ResultsIn this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (least squares mean difference [LSMD]=-4.6; 95% confidence interval [CI]=-6.34, −2.83; effect size vs placebo [ES]=-0.56; P<.0001). Lumateperone treatment was associated with significant MADRS improvement in both patients with bipolar I (LSMD=-4.0; 95% CI=-5.92, −1.99; ES=-0.49; P<.0001) and bipolar II (LSMD=-7.0; 95% CI=-10.92, −3.16; ES=-0.81; P=.0004). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.ConclusionsLumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.FundingIntra-Cellular Therapies, Inc.

中文翻译：

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Lumateperone (ITI-007) 治疗双相抑郁症：随机临床试验的结果

研究目标双相抑郁症的批准治疗是有限的，并且与一系列不良副作用有关。Lumateperone (lumateperone tosylate, ITI-007) 是一种机制新颖的抗精神病药，可同时调节血清素、多巴胺和谷氨酸神经传递，已获 FDA 批准用于治疗精神分裂症。Lumateperone 目前正在研究用于治疗双相抑郁症（与双相 I 和双相 II 障碍相关的重度抑郁发作 [MDE]）。这项 3 期随机、双盲、平行组、安慰剂对照多国研究 (NCT03249376) 调查了 lumateperone 在患有 MDE 的双相 I 或双相 II 障碍患者中的​​疗效和安全性。方法临床诊断为双相 I 或双相 II 障碍的患者（18 75 岁）正在经历 MDE（Montgomery-Åsberg 抑郁评定量表 [MADRS] 总分 =20 和临床总体印象量表-双相版本-严重性 [CGI- BP-S] 评分 = 4 在筛选和基线）被随机分配到 lumateperone 42mg 或安慰剂治疗 6 周。主要和关键次要疗效终点分别是 MADRS 总分和 CGI​​-BP-S 评分从基线到第 43 天的变化。次要疗效结果包括第 43 天的缓解（MADRS 改善 = 50%）和缓解（MADRS 总分 = 12）。安全性评估包括治疗中出现的不良事件、实验室参数、生命体征、锥体外系症状 (EPS) 和自杀。结果在此研究中，377 名患者接受了治疗（安慰剂，n=189；lumateperone 42mg，n = 188）和333完成治疗。与安慰剂相比，lumateperone 42-mg 组患者从基线到第 43 天的 MADRS 总分变化的平均改善明显更大（最小二乘平均差 [LSMD]=-4.6；95% 置信区间 [CI]=-6.34，- 2.83；效应量与安慰剂[ES]=-0.56；P<.0001）。Lumateperone 治疗与双相 I（LSMD=-4.0；95% CI=-5.92，-1.99；ES=-0.49；P<.0001）和双相 II（LSMD=-7.0；95）患者的 MADRS 显着改善相关% CI=-10.92，-3.16；ES=-0.81；P=.0004）。与安慰剂相比，lumateperone 42 mg 组的 CGI-BP-S 总分平均改善也显着更大（LSMD=-0.9；95% CI=-1.37，-0.51；ES=-0.46；P<.001）。与安慰剂相比，Lumateperone 的 MADRS 反应率显着提高（51.1% vs 36.7%；优势比=2.98；P<. 001) 和第 43 天的缓解率 (P=.02)。Lumateperone 治疗耐受性良好，EPS、代谢和催乳素副作用的风险最小。结论 Lumateperone 42 mg 显着改善双相 I 和双相 II 患者的抑郁症状沮丧。Lumateperone 通常耐受性良好。这些结果表明，lumateperone 42 mg 可能是治疗与双相 I 或双相 II 障碍相关的双相抑郁症的有希望的新疗法。FundingIntra-Cellular Therapies, Inc.