Schizophrenia and bipolar disorder are commonly associated with acute episodes of agitation in emergency settings [1]. Of the 1.7 million emergency department visits per year involving agitation, approximately 21% are due to schizophrenia and 13% are due to bipolar disorder [2-4]. Given that agitation can result in injury to patients and staff, safe and effective treatment of patients presenting with agitation is essential.

Guidelines for acute agitation management are heterogenous, but recommend prioritizing safety, behavioral interventions, and verbal deescalation as first line interventions and contend that physical restraint should be used as a last resort. Psychopharmacological therapy should be reserved for when behavioral interventions fail to prevent physical restraint. For acute agitation as a result of schizophrenia or bipolar disorder, oral antipsychotics and/or oral benzodiazepines are first line, followed by intramuscular antipsychotics and/or benzodiazepines [5-10]. With high prevalence of acute agitation in emergency care settings, combined with recent shortages of medications commonly used for agitation and concerns related to current therapies, there has been an increasing interest in new treatment options for acute agitation management [11,12].

A sublingual formulation of dexmedetomidine (Igalmi), a novel therapeutic, was approved by the U.S. Food and Drug Administration (FDA) in 2022 for the treatment of acute agitation associated with schizophrenia or bipolar I or II disorder in adults [13]. In this article, we review the safety and efficacy of sublingual dexmedetomidine in the treatment of agitation of these patient populations.

Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, is thought to treat acute agitation associated with schizophrenia or bipolar disorder by activating presynaptic α2-adrenergic receptors to suppress the hypersympathetic activity and decrease the firing of locus coeruleus neurons [14]. The mucoadhesive film is rapidly absorbed into the bloodstream via the sublingual or buccal route. In pharmacokinetic studies after a single dose of dexmedetomidine, the absolute bioavailability of the sublingual and buccal administration was 72% and 82% respectively and plasma concentrations were quantifiable 5 to 20 minutes after oral administration [13]. Tables 1 and 2 provide key pharmacodynamic and pharmacokinetic properties and dosing in special populations.

Sublingual dexmedetomidine was assessed for efficacy in treating acute agitation in two phase 3 randomized, double-blind, placebo-controlled trials [15,16]. One study evaluated its use in patients with bipolar I or II disorder (n = 378), while the other included patients with schizophrenia or schizoaffective disorder (n = 381). For both trials, patients were between the ages of 18−75 and had a diagnosis of one of the aforementioned disorders, respective for the trial they were enrolled in, along with current agitation. After screening, patients were assessed beginning on the day of treatment (day 1) through day 3, as well as an end of study visit on day 7. Patients had a baseline score of ≥ 14 on the 5 items of the Positive and Negative Syndrome Scale-Excited Component (PEC) and a score of ≥ 4 on at least one of the 5 PEC items. Patients were recruited from a variety of settings including hospitals; outpatient clinics; and mental health, psychiatric, or emergency medical services. Common medications that patients were on at baseline include second generation antipsychotics, antidepressants, and sedatives/hypnotics/ anxiolytics. Key baseline demographics for both studies are found in Table 3. Notable exclusion criteria were the use of antipsychotics or benzodiazepines within 4 hours of treatment, intoxication with alcohol or other drugs of abuse, current use of α1-blockers, and pregnancy or breastfeeding.

The primary endpoint was the change from baseline in PEC total score 2 hours after receiving a single dose of the study medication. Two strengths of sublingual dexmedetomidine (180 mg and 120 mg) were compared to placebo; patients were randomized in both studies in a 1-1-1 fashion and stratified based on age < 65 or ≥ 65 years old. In the trials, both doses of sublingual dexmedetomidine significantly reduced PEC scores at 2 hours post-dose compared to placebo; the magnitude of effect was greatest with the 180 mg dose. In the schizophrenia and schizoaffective disorder trial, 180 mg produced significantly reduced agitation within 20 minutes compared to 30 minutes with 120 mg, while both doses produced this effect within 20 minutes in the bipolar disorder study. Table 4 contains results for the primary endpoint.

The bipolar disorder study had one secondary endpoint which was the earliest point at which the change in PEC score from baseline statistically significantly separated from placebo, the results of which are mentioned above. The secondary endpoint for the schizophrenia study was the absolute change from baseline in PEC total score at 10, 20, 30, 45, 60, and 90 minutes post dose. In both treatment groups, PEC scores continuously decreased from baseline at all of these time points. Redosing of sublingual dexmedetomidine 2 hours after initial treatment was permitted at half of the first dose (90 mg or 60 mg) if necessary. Patients could receive a maximum of 2 subsequent doses in the 12 hours following the initial dose. In the bipolar disorder study, the number of patients requiring more than one dose were as follows: 10.3% of the 180 mg group, 23.8% of the 120 mg group, and 46% of the placebo group. In the schizophrenia study, the amount of patients requiring redosing were: 4% of the 180 mg group, 21.7% of the 120 mg group, and 42% of the placebo group. Rescue medication was also permitted for persistent agitation, defined as oral or intramuscular lorazepam 0.5−5 mg. For the bipolar disorder study, rescue medication was needed in 2.4% of the 180 mg group and 1.6% of both the 120 mg and placebo groups. For the schizophrenia study, rescue medication was needed in 0.8% of the 180 mg group, 3.1% of the 120 mg group, and 0.8% of the placebo group.

The authors of both studies investigated numerous prespecified post dose exploratory endpoints focused on agitation including Agitation-Calmness Evaluation Scale (ACES) scores at 15 minutes, 2, 4, and 8 hours; and PEC response rate defined as a ≥ 40% reduction in total score from baseline at or before 2 hours. In both trials, there was a greater percentage of patients whose agitation was resolved (ACES score ≥ 4 at 2, 4, and 8 hours) in the 180 mg and 120 mg groups than in the placebo group. In the bipolar disorder study, PEC response rates were 90.5% for the 180 mg group, 77% for the 120 mg group, and 46% for the placebo group. In the schizophrenia study, PEC response rates were 88.8% for the 180 mg group, 79.1% for the 120 mg group, and 40.5% for the placebo group.

Adverse events were minimal across the studies, with the most common side effect being somnolence that was rated as mild in many cases (Table 5). No patients were unarousable. Other adverse effects included hypotension, dizziness, and dry mouth. Only one serious adverse event occurred in the 120 mg group of the bipolar disorder study, though this was determined to not be related to dexmedetomidine. In the bipolar disorder study, two patients - one in each sublingual dexmedetomidine group - experienced suicidal ideation lasting for one day. One patient in the schizophrenia study, belonging to the 120 mg group, experienced this adverse event. All patients reporting suicidal ideation completed the study. Overall, 3 patients dropped out of the study due to adverse events, all of which belonged to the 120 mg group.

Instances of hypotension, orthostatic hypotension, and bradycardia were reviewed by an external board-certified cardiologist. Generally, these events occurred more frequently in the 180 mg group than in the 120 mg group. Most of these cases were rated as mild. Patients were monitored via ECG through 24 hours post dose, and no relevant findings were noted.

A post hoc analysis of the two phase 3 trials with sublingual dexmedetomidine was conducted to calculate the numbers needed to treat (NNT), numbers needed to harm (NNH), and likelihood to be helped or harmed (LHH) [17]. The NNT was calculated based on the PEC response rate defined as a 40% or greater reduction in PEC score from baseline. The LHH metric is found by dividing NNH by NNT. A value of greater than 1 indicates the treatment is more likely to help than to harm. The authors’ intent with this analysis was to translate the findings from the two phase 3 studies into clinically meaningful metrics of the efficacy and tolerability.

In the schizophrenia and schizoaffective disorder study, the NNT versus placebo was 3 for the 180 mg and 120 mg doses, while in bipolar disorder study it was 3 for the 180 mg dose and 4 for the 120 mg dose. In both studies, the NNH values were greater than 10 for all adverse events except a NNH of 7 for somnolence. The LHH values were greater than 1 for all adverse effects. The calculated NNT, NNH, and LHH provide values indicating a favorable benefit-risk profile of sublingual dexmedetomidine in the treatment of acute agitation in the studied patient populations. A limitation of this post hoc analysis is the NNT of PEC response was an exploratory endpoint and was not adjusted for multiplicity.

Sublingual dexmedetomidine represents the first drug approved by the FDA in the last decade for the treatment of acute agitation in people with schizophrenia or bipolar I disorder and the first approved for agitation associate with bipolar II disorder [18]. Emerging evidence suggests that this novel drug has a role in agitation management in these patient populations.

There are several potential advantages to sublingual dexmedetomidine as a treatment option in the management of acute agitation in people with schizophrenia and bipolar disorders. First, sublingual medications are inherently less coercive and more collaborative than the intramuscular options that have been commonly used in agitation management despite recommendations to first offer oral alternatives [19]. Sublingual formulations pose less physical and psychological risk to patients experiencing agitation, leading to improved patient experience [20, 21]. Second, sublingual dexmedetomidine lacks dopamine receptor activity, avoiding extrapyramidal side effects including dystonia, akathisia, and tremor resulting from antipsychotic use [22]. Third, the use of sublingual dexmedetomidine avoids the potential stigma associated with antipsychotic use [23]. Finally, dexmedetomidine is familiar to those in the field of psychopharmacology given its unique sedative and anxiolytic properties. Although the intravenous formulation was first approved by the FDA in 1999 for sedation and analgesia in intensive care settings [24], it has since been used by some psychiatrists in the management of agitation in delirium [25], alcohol withdrawal [26,27], and catatonia [28].

Despite the potential unique advantages of sublingual dexmedetomidine, there are several concerns that may affect its clinical utility in acute agitation management. First, the primary α2-adrenergic receptor agonist activity may not address the underlying mechanism of illness in either schizophrenia or bipolar disorders, as the pathophysiology of these disease states is currently understood, which is the primary reason antipsychotics are used as first line for this population [20]. Second, the safety and effectiveness for the drug has not been evaluated beyond 24 hours of first use [13]. Ten percent (10%) or less and approximately 20% of patients in the clinical trials (180 mg and 120 mg respectively) required a second dose of sublingual dexmedetomidine. Third, medications delivered sublingu-ally limit their use in patients who are severely agitated requiring involuntary medication. Indeed, one criticism of the available data on sublingual dexmedetomidine is that participants may not represent the full spectrum and severity of patients presenting with acute agitation since participants were able to consent to and self-administer treatment [29]. The wholesaler acquisition cost (WAC) in the United States is $105 per dose. The WAC price represents a published list price, but may not represent an actual transactional price for this medication [30].

Taken together, the available evidence suggests that sublingual dexmedetomidine is a safe and effective treatment for acute agitation in patients with schizophrenia or bipolar I and II disorder. Sublingual dexmedetomidine represents a novel medication in the agitation treatment armamentarium due to its quick onset of action, minimal need for repeat dosing, and a favorable side effect profile that is unique from current treatments, namely extrapyramidal side effects from antipsychotics and excessive sedation with benzodiazepines. Future studies will need to assess the clinical utility of sublingual dexmedetomidine in the real world setting and its impact on important healthcare outcomes including hospital admission rates, hospital length of stay, concomitant medication use for agitation, and restraint use. Studies exploring the use of sublingual dexmedetomidine for treatment of agitation in other patient populations will be useful to clinicians.

The views expressed are those of the authors and do not necessarily represent those of the United States Government or the Indian Health Service.

No potential conflict of interest relevant to this article was reported.

None.

Conceptualization: Colin M. Smith, Morgan Santalucia, Hannah Bunn, Andrew Muzyk. Formal analysis: Colin M. Smith, Morgan Santalucia, Hannah Bunn, Andrew Muzyk. Writing—original draft: Colin M. Smith, Morgan Santalucia, Hannah Bunn, Andrew Muzyk. Writing—review & editing: all authors.