(122) Sublingual Dexmedetomidine for the Treatment of Acute Agitation Associated with Schizophrenia or Bipolar Disorder: Effect Size and Pooled Efficacy

Abstract: Episodes of acute agitation are frequently managed in psychiatric and emergency care settings. Nonpharmacological techniques such as verbal de-escalation, environment management, and collaborative care are recommended to improve patient outcomes. When needed, pharmacological treatment should ideally be noninvasive, have rapid onset, and produce calming without oversedation. Cohen’s d effect sizes and pooled efficacy data are presented from two clinical trials evaluating a single dose of dexmedetomidine sublingual film for the treatment of acute agitation associated with schizophrenia (Serenity I) or bipolar disorder (Serenity II).

Two similarly designed US multicenter, randomized, double-blind, placebo-controlled, Phase 3 clinical trials included adults (18-75 years) with acute agitation and DSM-5 diagnosis of either schizophrenia, schizoaffective disorder, or bipolar disorder. Acute agitation was defined as a score of ³14 on the PANSS-Excited Component (PEC) scale and ³4 on at least 1 of 5 PEC items. Participants were randomized to dexmedetomidine sublingual film 120 mcg or 180 mcg or matching placebo. All participants self-administered study drug. The primary endpoint was the 2-hour change from baseline in total PEC score. The secondary endpoint was the earliest time of a statistically significant separation of active drug from placebo. Cohen’s effect sizes for active treatment versus placebo were calculated for both doses in each trial.

380 patients were randomized in each trial (N=760). Both dexmedetomidine doses met the primary endpoint of change in PEC total score at 2 hours (P< .001). Pooled PEC change from baseline scores, [mean (standard deviation)], were -10.4 (4.39) at 180 mcg and -8.7 (5.05) at 120 mcg versus -4.8 (4.67) for placebo. In the pooled data statistically significant improvement on the PEC occurred as early as 10 minutes at the 180 mcg dose and 20 minutes at the 120 mcg dose. Cohen’s effect sizes for the 180 mcg doses in Serenity 1 and Serenity 2 were 1.25 and 1.21, respectively, and for the 120 mcg doses in Serenity 1 and Serenity 2 were 0.78 and 0.83, respectively.

There were no serious or severe treatment-related adverse events (TEAEs), and no participant was unarousable. The most common treatment emergent adverse events were somnolence (21.5%), dry mouth (5.9%), hypotension (5.3%), dizziness (4.9%), orthostatic hypotension (4.0%), oral hypoesthesia (3.8%), headache (3.6%), nausea (2.8%), and oral paresthesia (2.6%). None of the cardiovascular TEAEs required medical intervention.

Sublingual dexmedetomidine effectively treated symptoms of acute agitation associated with schizophrenia or bipolar disorder, had an onset of action as early as 10 minutes at the 180 mcg dose, and produced a calming effect without excess sedation. Cohen’s effect sizes for both doses in each trial were in the range generally considered large. There were no serious or severe treatment-related adverse effects, and mild or moderate somnolence was the most common AE.