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

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.

Trial registration: ClinicalTrials.gov Identifier: NCT04276883.

Figure 1.. Recruitment, Randomization, and Follow-up of Patients^a

^aThis was a single-dose study, and the safety, full analysis, and per-protocol data sets all contained 378 patients—126 in each group. There were no missing data for the primary or secondary outcome measures. One patient each from 180 μg and 120 μg groups did not receive a dose of medication, but all other discontinuations occurred after dosing and primary and secondary end point assessments. ^bOne hundred thirteen patients (89.7%) received only 1 dose; 5 (4%), 2 doses; and 8 (6.3%), 3 doses. ^cNinety-six patients (76.2%) received only 1 dose; 18 (14.7%), 2 doses; and 12 (9.5%), 3 doses. ^dSixty-eight patients (54%) received only 1 dose; 29 (23.0%), 2 doses; and 29 (23%), 3 doses. ^eDue to acute agitation on day 7 that was judged to be unrelated to study drug.

Figure 2.. Mean Change From Baseline in the Positive and Negative Syndrome Scale-Excited Component Total Score Through 2 Hours

Dark squares in boxes indicate the mean; the top box lines, upper quartile; the bottom box line, lower quartile; bars in boxes, median; whiskers, data falling within 1.5 times the interquartile range; dots, values outside the range indicated by the whiskers; and PEC, Positive and Negative Syndrome Scale-Excited Component.