Sublingual dexmedetomidine reduces agitation in patients with bipolar disorder

A sublingual film form of the selective alpha-2a-adrenergic receptor agonist dexmedetomidine significantly reduced mild to moderate agitation in patients with bipolar disorder, a phase 3 randomized trial showed.

“Recent guidance for the management of agitation recommends patient-centered approaches, in which verbal and non-verbal de-escalation techniques are used and less invasive treatments are preferred when possible,” Sheldon H. Preskorn, MD, a professor of psychiatry and behavioral science at the University of Kansas Medical Center, and colleagues wrote in JAMA.

“When pharmacotherapy is needed, antipsychotics, benzodiazepines, and ketamine are commonly used, although only intramuscular olanzapine and inhaled loxapine are formally indicated for the treatment of agitation associated with bipolar disorder. However, none of these is a panacea, and each has limitations,” the researchers wrote. “The goal of pharmacological treatment should be to induce calm without oversedation, which can prevent timely assessment and triage.”

Preskorn and colleagues randomly assigned 380 adults (mean age, 45.6 years; 54.8% women; 56.1% Black) with either bipolar 1 or bipolar 2 disorder in an approximate 1:1:1 ratio to receive either 180 g of sublingual dexmedetomidine, 120 g of sublingual dexmedetomidine or placebo. Among all participants, the mean total Positive and Negative Syndrome Scale-Excited Component (PEC) score was 18 points. According to the researchers, a total PEC score ranges from 5 (indicating the absence of agitation) to 35 (indicating extremely severe agitation).

The researchers reported that 2 hours after patients were administered their respective medication, the total PEC score declined 10.4 points from baseline in the 180 g sublingual dexmedetomidine cohort, 9 points from baseline in the 120 g sublingual dexmedetomidine cohort and 4.9 points from baseline in the placebo cohort.

In addition, 2 hours after treatment, the least-square mean difference from placebo was a decline of 5.4 (97.5% CI, –6.6 to –4.2) in the 180 g cohort and a decline of 4.1 (97.5% CI, –5.3 to –2.9) in the 120 g cohort (both doses P < .001 compared with placebo). The effects of dexmedetomidine were observed 20 minutes after administration (least-squares mean difference for 180 g = –1.1; 97.5% CI, –2 to –0.2; least-squares mean difference for 120 g = –1; 97.5% CI, 1.9 to –0.1), according to the researchers.

Adverse events were reported in 37.5% of patients who received 180 g of dexmedetomidine, 34.9% of patients who received 120 g of dexmedetomidine and 17.5% of patients who received placebo. The most common adverse events were somnolence (21.4%, 20.6%, 4.8%), dry mouth (4.8%, 7.1%, 0.8%), hypotension (6.3%, 4.8%, 0%) and dizziness (5.6%, 5.6%, 0.8%) in the 180 g, 120 g, and placebo cohorts, respectively.

Limitations to the study include the lack of universal agreement on what represents a “minimal clinically important difference” in PEC score and a large placebo effect among trial participants, the researchers wrote.

“Although in this study dexmedetomidine did not cause extrapyramidal adverse effects, unarousable sedation or QTc prolongation, the study was not powered to assess these endpoints,” Preskorn and colleagues wrote.

In a related editorial, John Hsiao, MD, the director of dementia diagnosis and biomarkers at the National Institute on Aging, noted that sublingual dexmedetomidine has yet to be approved by the FDA, but the current findings suggest that dexmedetomidine is well absorbed via mucosal administration. He added that Preskorn and colleagues’ study “both introduces and provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation.”

“The results from this clinical trial call attention to novel-use cases for dexmedetomidine outside the critical care setting and beyond sedation for procedures,” Hsiao wrote. “More research in diverse settings with different formulations of dexmedetomidine is needed to define how this unique noradrenergic sedative might best be used in clinical management of agitated patients.”

References:

Hsiao J. JAMA. 2022;doi: 10.1001/jama.2021.21313.

Preskorn SH, et al. JAMA. 2022;doi:10.1001/jama.2022.079.