REVIEW OF: Preskorn SH et al, JAMA 2022;327(8):727–736

STUDY TYPE: Randomized controlled trial

Acute agitation is common in patients with bipolar disorder. When we use pharmacotherapy, we typically use oral or parenteral antipsychotic medications (eg, haloperidol, olanzapine) and benzodiazepines (eg, lorazepam), but these do not always work quickly and are poorly tolerated by some patients. It would be helpful to have additional options for the management of acute agitation.

In April 2022, the FDA approved a sublingual film formulation of dexmedetomidine—an alpha2-adrenergic receptor agonist approved in intravenous form for procedural sedation and anesthesia—for the acute treatment of agitation in patients with bipolar disorder and schizophrenia. The sublingual formulation bypasses first-pass metabolism and is absorbed quickly.

This randomized, double-blind, placebo-controlled trial tested sublingual dexmedetomidine in patients with mild to moderate agitation associated with bipolar I and II disorder (n=380) across 15 clinical sites. The authors estimated baseline agitation by using the Positive and Negative Syndrome Scale–Excited Component (PEC) score, which includes five items (poor impulse control, tension, hostility, uncooperativeness, and excitement) each rated from 1 to 7. The PEC total score ranges from 5 (absence of agitation) to 35 (extremely severe). Mean total PEC score at baseline was 18. 

Patients were randomly assigned to receive a single dose of dexmedetomidine (180 µg or 120 µg) or placebo, self-administered under supervision of a staff member. A repeat dose of 60 µg or 90 µg could be given two hours after the first dose, at the investigators’ discretion, if the change from baseline on the PEC score was less than 40% and if there were no safety concerns. All patients also were continued on their current psychiatric medications.

Dexmedetomidine was significantly more effective than placebo in reducing agitation (both dosages p<0.001 vs placebo). The onset of effect began within 20 minutes for both dosages. Response rates (defined as a decrease of 40% or more in PEC score at two hours compared to baseline) were 91% (180 µg dose), 77% (120 µg), and 46% (placebo). Unfortunately, the study did not compare dexmedetomidine with any standard agitation medications. 

Dexmedetomidine produced no serious adverse events. The most common side effects were somnolence, dry mouth, hypotension, and dizziness. One patient in each dexmedetomidine group reported suicidal ideation lasting one day. 

Carlat Take

Sublingual dexmedetomidine appears to be a fast-acting, well-tolerated option for mild to moderate agitation in patients with bipolar disorder. The sublingual film requires self-administration, so it will not be an option for patients who are unwilling to cooperate. Until more safety data are available, minimize its use in the elderly, adolescents, and patients with comorbid health conditions.