Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Bldg 1/Room 16.N655, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
J Clin Psychiatry. 2020 Jul 14;81(4):18m12470. doi: 10.4088/JCP.18m12470.
To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria.
This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters.
Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events.
Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects.
ClinicalTrials.gov identifier: NCT01457677.
评估作为选择性 5-羟色胺再摄取抑制剂和/或 5-羟色胺去甲肾上腺素再摄取抑制剂（SSRIs/SNRIs）的辅助治疗药物，谷氨酸 2/3 型代谢型谷氨酸受体 2/3（mGlu2/3）负变构调节剂 decoglurant 对部分难治性重性抑郁障碍（MDD）患者的潜在抗抑郁和认知作用，这些患者使用 DSM-IV-TR 标准诊断。
这是一项随机、安慰剂对照、双盲、多中心的 2 期临床试验，于 2011 年 9 月至 2014 年 6 月进行，包括 4 周的筛选期、6 周的治疗期和 8 周的随访期。入选患者的蒙哥马利-阿斯伯格抑郁评定量表（MADRS）评分≥25 分，临床总体印象-疾病严重程度量表（CGI-S）评分≥4 分，尽管接受了多达 2 次充分的 SSRI/SNRI 治疗，且通过 SSRI/SNRI 血药浓度阳性证实了依从性，将其随机分为 decoglurant 5mg（n=101）、15mg（n=102）或 30mg（n=55）每日一次或安慰剂（n=99），作为正在进行的 SSRI/SNRI 治疗的辅助治疗。采用适应性设计，每组 30 例患者接受 6 周治疗后进行中期分析。主要观察变量为基线至治疗结束时 MADRS 总分的变化。主要评估由完全盲法中心评估者进行。
在 357 名参与者中，有 310 名完成了 6 周的治疗。在 6 周时，与安慰剂相比，任何一种活性治疗组在降低 MADRS 总分或反应率或缓解率方面均未显示出显著差异。Decoglurant 对剑桥神经心理学测试自动化电池认知准确性和认知速度综合评分或情绪和功能的次要测量指标没有显著影响。观察到相对较高的安慰剂反应，这可能限制了检测治疗效果的能力。没有死亡发生；少数患者报告了严重不良事件。
总体而言，Decoglurant 耐受良好，但没有显示出任何抗抑郁或认知作用。
ClinicalTrials.gov 标识符：NCT01457677。
