Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.

Objective: Determine if sublingual dexmedetomidine, a selective α2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder. Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 μg, 120 μg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose. Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 μg, -8.5 (0.4) for 120 μg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 μg and -3.7 (-4.9 to -2.5) for 120 μg (both P < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 μg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 μg dose. Conclusions: Treatment with sublingual dexmedetomidine 180 μg or 120 μg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose. Trial Registration: ClinicalTrials.gov identifier: NCT04268303.