美国BioXcel Therapeutics公司Robert Risinger团队联合堪萨斯大学威奇托医学院Sheldon H. Preskorn团队比较了舌下含服右美托咪定与安慰剂对双相情感障碍相关急性躁动的影响。2022年2月22日出版的《美国医学会杂志》发表了这项成果。

急性躁动在双相情感障碍患者中很常见，需要紧急处理以缓解痛苦，防止升级为攻击性行为。

为了评价选择性α2A-肾上腺素能受体激动剂右美托咪定舌下给药经口吸收对双相情感障碍患者急性躁动症的影响，2020年2月24日至2020年4月27日，研究组在美国15个机构进行了一项临床3期、随机、双盲、安慰剂对照试验，最终随访时间为2020年5月21日。

共招募了380名患有双相I型或II型障碍的成年人，将其随机分为3组，其中362名完成了这项研究。127名舌下含右美托咪定180 μg，127名舌下含右美托咪定120 μg，126名舌下含安慰剂。

主要疗效终点是阳性和阴性综合征量表兴奋因子（PEC）总分在2小时后与基线检查相比的平均变化。可能的总分范围为5分（无躁动）至35分（极度严重）。次要终点是药物与安慰剂的PEC总分与基线相比发生统计学显著变化的最早时间。在主要疗效终点，为了解释与比较2种舌下含右美托咪定剂量与安慰剂相关的多重性，每种剂量与安慰剂的双侧显著性水平设定为0.025。

380名患者的平均年龄为45.6岁，54.8%为女性，56.1%为黑人，378名（99.5%）自行服用研究药物并完成了研究。基线检查时的躁动程度为轻度至中度，PEC总分的总体平均值为18.0。

服药两小时后，舌下含右美托咪定180 μg组患者的PEC总分与基线相比平均降低10.4，舌下含右美托咪定120 μg组降低9.0，安慰剂组降低4.9。 舌下含右美托咪定180 μg组和120 μg组与安慰剂组的最小均数差异分别为−5.4和-4.1，组间差异均显著。舌下含右美托咪定组的患者在服药20分钟后开始出现疗效。

舌下含右美托咪定180 μg组患者中有35.7%发生不良事件，舌下含右美托咪定120 μg组有34.9%，安慰剂组有17.5%。舌下含右美托咪定180 μg组、120 μg组和安慰剂组最常见的不良事件（发生率超过5%）分别为嗜睡（21.4%、20.6%、4.8%）、口干（4.8%、7.1%、0.8%）、低血压（6.3%、4.8%、0%）和头晕（5.6%、5.6%、0.8%）。

研究结果表明，在与双相情感障碍相关的轻中度躁动患者中，与安慰剂相比，使用120 μg或180 μg右美托咪定舌下贴膜制剂治疗2小时后，躁动评分显著降低。仍需进一步的研究来了解这种治疗对哪些患者有效和可行。

附：英文原文

Title: Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder: A Randomized Clinical Trial

Author: Sheldon H. Preskorn, Scott Zeller, Leslie Citrome, Jeffrey Finman, Joseph F. Goldberg, Maurizio Fava, Rishi Kakar, Michael De Vivo, Frank D. Yocca, Robert Risinger

Issue&Volume: 2022/02/22

Abstract:

Importance  Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior.

Objective  To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder.

Design, Setting, and Participants  Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study.

Interventions  Participants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n=127), sublingual dexmedetomidine 120 μg (n=127), or placebo (n=126).

Main Outcomes and Measures  The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025.

Results  Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were 10.4 for sublingual dexmedetomidine 180 μg, 9.0 for sublingual dexmedetomidine 120 μg, and 4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were 5.4 (97.5% CI, 6.6 to 4.2) for 180 μg and 4.1 (97.5% CI, 5.3 to 2.9) for 120 μg (both doses P<.001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 μg, 1.1 [97.5% CI, 2.0 to 0.2]; P=.007; for 120 μg, 1.0 [97.5% CI, 1.9 to 0.1]; P=.009). Adverse events occurred in 35.7% of patients taking 180 μg of dexmedetomidine, 34.9% taking 120 μg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 μg, 120 μg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%).

Conclusions and Relevance  Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 μg or 180 μg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size.

DOI: 10.1001/jama.2022.0799

Source: https://jamanetwork.com/journals/jama/article-abstract/2789315