For a study, researchers sought to determine how orally absorbed, sublingual dexmedetomidine, a selective 2A-adrenergic receptor agonist, affected symptoms of acute agitation in patients with bipolar illness. A phase 3 randomized, double-blind, placebo-controlled study was undertaken at 15 US sites between February 24, 2020, and April 27, 2020, with a final follow-up on May 21, 2020. A total of 380 persons with bipolar I or II illness were randomly assigned to the trial, with 362 completing it. Participants were randomly assigned to one of three groups: 180 g sublingual dexmedetomidine (n=127), 120 g sublingual dexmedetomidine (n=127), or placebo (n=126). The primary effectiveness end goal was the mean difference from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours. The potential total scores range from 5 (no agitation) to 35. (extremely severe). The secondary endpoint was the earliest period when the medication vs placebo caused a statistically significant change in PEC total score from baseline. To account for the multiplicity associated with comparing two sublingual dexmedetomidine doses with placebo, the two-sided significance threshold for each dosage vs placebo was established at.025.
About 378 (99.5%) of the 380 participants randomized (mean age, 45.6; 54.8% women; and 56.1% Black adults) self-administered the study drug and finished the trial. The baseline agitation level was mild to moderate, with a mean PEC total score of 18.0. The mean increases from baseline in PEC total score two hours after taking the medicine were 10.4 for sublingual dexmedetomidine 180 g, 9.0 for sublingual dexmedetomidine 120 g, and 4.9 for placebo. The sublingual dexmedetomidine groups’ least-square mean differences from placebo at 2 hours were 5.4 (97.5% CI, 6.6 to 4.2) for 180 g and 4.1 (97.5% CI, 5.3 to 2.9) for 120 g (both dosages P<.001 versus placebo). Patients in the sublingual dexmedetomidine groups saw treatment effects 20 minutes after taking the medicine (least-square mean difference for 180 g, 1.1 [97.5% CI, 2.0 to 0.2]; P=.007; for 120 g, 1.0 [97.5% CI, 1.9 to 0.1]; =.009). Adverse events occurred in 35.7% of patients receiving 180 g of dexmedetomidine, 34.9% receiving 120 g, and 17.5% receiving placebo. The most common adverse events (5%) in the 180 g, 120 g, 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% ).
Treatment with a sublingual film formulation of dexmedetomidine 120 g or 180 g, compared to placebo, resulted in a significantly greater reduction in agitation score at 2 hours in patients with mild to moderate agitation associated with bipolar disorder. More study was needed to determine the patient population for whom this treatment would be beneficial and practicable, as well as the clinical significance of the reported effect magnitude.