Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder

Abstract

IMPORTANCEAcute 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 α 2A -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 MEASURESThe 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. RESULTSOf 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 (Ն5%) 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...

Sublingual Dexmedetomidine for Agitation Associated with Schizophrenia or Bipolar Disorder: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed

“…Data were taken from two similarly designed, randomized, double-blind, placebo-controlled studies that evaluated the effects of sublingual dexmedetomidine on acute agitation in patients with schizophrenia (NCT04268303) or bipolar disorder (NCT04276883) [ 19 , 20 ]. The studies were conducted between January and May 2020 at clinical sites in the United States.…”

“…The efficacy and tolerability of 120-µg and 180-µg doses of sublingual dexmedetomidine were evaluated in two similarly designed, randomized, double-blind, placebo-controlled, phase 3 trials in the treatment of acute agitation associated with schizophrenia [ 19 ] and bipolar disorder [ 20 ]. Efficacy in both studies was measured from 10 min through 24 h post-dose using the 5-item Positive and Negative Syndrome Scale-Excited Component (PEC), a validated and commonly used research instrument for evaluating acute agitation and aggression in patients with different psychiatric pathologies [ 21 ].…”

“…Efficacy in both studies was measured from 10 min through 24 h post-dose using the 5-item Positive and Negative Syndrome Scale-Excited Component (PEC), a validated and commonly used research instrument for evaluating acute agitation and aggression in patients with different psychiatric pathologies [ 21 ]. Participants with schizophrenia or bipolar disorder who were treated with sublingual dexmedetomidine, 120 µg or 180 µg, had symptomatic improvements from baseline to 2 h post-dose compared to placebo, and treatment effects began at 20 or 30 min post-dose [ 19 , 20 , 22 ]. Sublingual dexmedetomidine was well tolerated, with mild or moderate somnolence as the most common AE [ 16 ].…”

How an Understanding of the Function of the Locus Coeruleus Led to Use of Dexmedetomidine to Treat Agitation in Bipolar Disorder: Example of Rational Development of Psychiatric Medications

“…That prediction was successfully tested in agitated patients with bipolar disorder. 1 This column also complements multiple previous columns that have discussed how novel central nervous system drugs can be developed based on an understanding of the circuitry underlying the target indications. [35][36][37][38][39] These columns also illustrate how specific forms of psychopharmacology can be tied to specific brain mechanisms and circuits, allowing for a more sophisticated way of conceptualizing and utilizing various psychopharmacological therapies.…”

Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents

“…Dexmedetomidine, a lipophilic imidazole derivative, is a potent and selective agonist of α 2 -adrenergic receptors [ 13 ]. This drug has been disclosed to exert a variety of actions on the human brain such as sedation, anesthetic sparing effects, and analgesia [ 13 , 14 ]. A recent investigation has shown that dexmedetomidine could perturb on the non-equilibrium property of I h in response to triangular V ramp found in GH 3 cells [ 15 ].…”