Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, Basel, Switzerland.
Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York.
JAMA Psychiatry. 2016 Jul 1;73(7):675-84. doi: 10.1001/jamapsychiatry.2016.0838.
Antagonism of the postsynaptic metabotropic glutamate subtype 5 receptor is a novel approach to modulate glutamatergic function and has proven efficacy in a number of preclinical behavioral models of depression.
To evaluate the safety and efficacy of basimglurant modified-release (MR) vs placebo as adjunctive therapy to ongoing antidepressant medication therapy in patients with MDD who had inadequate response within the current episode.
DESIGN, SETTING, AND PARTICIPANTS: In this phase 2b, double blind, randomized clinical trial of 333 adult patients with a DSM-IV-TR diagnosis of MDD across 59 research clinics globally, patients were assigned to 1 of 2 doses of basimglurant MR (0.5 or 1.5 mg) or placebo once daily, adjunctive to ongoing antidepressant medication therapy (selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor). Patients were enrolled from October 5, 2011, through July 26, 2013.
Six-week treatment with 0.5 mg of basimglurant MR, 1.5-mg basimglurant MR, or placebo once daily, adjunctive to ongoing antidepressant medication therapy.
The primary end point was the mean change from baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS), as rated by the clinician at week 6. Other measures included patient-rated MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, Clinical Global Impression-Improvement, Patient Global Impression-Improvement, and Clinical Global Impression-Severity Scales and adverse events.
A total of 596 patients were screened, and 333 were randomized into the study (mean [SD] age, 47 [11.2] years; 216 female [65.1%]). The primary end point (mean change in clinician-rated MADRS score from baseline to end of treatment) was not met (effect size [ES] = 0.16, P = .42; intent-to-treat [ITT] mixed-effects model for repeated measures [MMRM] analysis for comparing 1.5-mg basimglurant MR and placebo). Across secondary and exploratory end points, 1.5-mg basimglurant MR revealed larger improvements vs placebo on the patient-rated MADRS (-16.2 vs -13.3, ES = 0.28, nominal P = .04), Quick Inventory of Depressive Symptomatology-Self-Report (-7.5 vs -5.8; ES = 0.37, nominal P = .009), Clinical Global Impression-Improvement mean score, and Patient Global Impression-Improvement mean score. Improvements were also seen in the patient-rated MADRS remission rate (36.0% vs 22.0%; nominal P = .03) and response rate (50.5% vs 40.4%; nominal P = .13), A 0.5-mg dose of basimglurant MR had no benefit over placebo in any of these measures. The most common adverse event was dizziness, which was mostly transient and of mild intensity.
No difference was observed on the study's primary outcome measure, the clinician-rated MADRS change from baseline to end of treatment, between adjunctive basimglurant MR vs placebo. Adjunctive 1.5-mg basimglurant MR daily revealed, however, an antidepressant effect across secondary end points, particularly in patient-rated measures. These findings combined with good tolerability warrant further investigation with this compound in depressive disorders.
clinicaltrials.gov Identifier: NCT01437657.
重要性： 代谢型谷氨酸受体 5 型（mGlu5）的突触后拮抗剂是调节谷氨酸能功能的一种新方法，已在许多抑郁症的临床前行为模型中证明了其疗效。
目的： 评估 basimglurant 缓释（MR）与安慰剂作为正在进行的抗抑郁药物治疗的辅助治疗，用于当前发作内反应不足的 MDD 患者。
设计、地点和参与者： 这是一项全球性 59 个研究诊所的 333 名成年患者参与的 2b 期、双盲、随机临床试验，这些患者根据 DSM-IV-TR 诊断为 MDD，被分配到 2 种剂量的 basimglurant MR（0.5 或 1.5mg）或安慰剂，每日一次，与正在进行的抗抑郁药物治疗联合使用（选择性 5-羟色胺再摄取抑制剂或 5-羟色胺和去甲肾上腺素再摄取抑制剂）。患者于 2011 年 10 月 5 日至 2013 年 7 月 26 日入组。
干预措施： 为期 6 周的治疗，给予 0.5mg 的 basimglurant MR、1.5mg 的 basimglurant MR 或安慰剂，每日一次，与正在进行的抗抑郁药物治疗联合使用。
主要终点和措施： 主要终点是由临床医生在第 6 周评定的基线蒙哥马利-阿斯伯格抑郁评定量表（MADRS）的平均变化。其他措施包括患者自评 MADRS、抑郁症状自评快速清单、临床总体印象-改善、患者总体印象-改善、临床总体印象-严重程度量表和不良事件。
结果： 共有 596 名患者接受了筛选，333 名患者被随机分为研究组（平均年龄[标准差]为 47[11.2]岁；216 名女性[65.1%]）。主要终点（从基线到治疗结束时临床医生评定的 MADRS 评分的平均变化）未达到（效应量[ES]为 0.16，P=0.42；意向治疗[ITT]重复测量混合效应模型[MMRM]分析比较 1.5mg 的 basimglurant MR 和安慰剂）。在次要和探索性终点方面，1.5mg 的 basimglurant MR 在患者自评 MADRS（-16.2 比-13.3，ES=0.28，名义 P=0.04）、快速抑郁症状自评清单（-7.5 比-5.8；ES=0.37，名义 P=0.009）、临床总体印象-改善平均分和患者总体印象-改善平均分上显示出更大的改善。患者自评 MADRS 缓解率（36.0%比 22.0%；名义 P=0.03）和反应率（50.5%比 40.4%；名义 P=0.13）也有所提高。在这些指标中，0.5mg 的 basimglurant MR 剂量与安慰剂相比没有任何益处。最常见的不良事件是头晕，主要是短暂的轻度。
结论和相关性： 在研究的主要结局指标（基线至治疗结束时临床医生评定的 MADRS 变化）中，附加 basimglurant MR 与安慰剂之间没有差异。然而，每日 1.5mg 的附加 basimglurant MR 在次要终点上显示出抗抑郁作用，特别是在患者自评的测量中。这些发现结合良好的耐受性，因此有必要进一步研究这种化合物在抑郁症中的应用。
试验注册： clinicaltrials.gov 标识符：NCT01437657。
