What data are available for sublingual dexmedetomidine in the treatment of acute agitation related to schizophrenia or bipolar disorder?
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Background
Agitation is broadly defined as abnormal, excessive motor and verbal activity; acutely agitated patients may experience feelings of restlessness, inner tension, anxiety, hypervigilance, hyperarousal, and irritability.1-3 Agitation can be caused by a wide variety of psychiatric and medical conditions, including substance intoxication or withdrawal, dementia, neurologic or metabolic conditions, traumatic brain injury, delirium, anxiety, personality disorders, bipolar disorder, and schizophrenia.1 It is a common presenting or comorbid condition in emergency settings, occurring in an estimated 2.6% of emergency department presentations and up to 10% of psychiatric emergency department presentations.1,4,5
Schizophrenia and bipolar disorder are some of the most common underlying causes for acute agitation, accounting for an estimated 21% and 13%, respectively, of emergency department presentations for agitation.1 Patients with schizophrenia may become agitated due to persecutory delusions, hallucinations urging them to harm others, limited coping skills, irritability, and/or low frustration tolerance. Patients with bipolar disorder may develop agitation secondary to emotional lability, impulsivity, irritability, or fluctuations in energy levels. Manifestations of agitation can range from mild to extreme; if left unchecked, agitation may escalate to aggression and violent behaviors directed at things, other people, or the patient themselves.2,3 Risk factors for aggressive behaviors in agitated patients can include prior history of aggression, younger age, male sex, history of substance abuse, and behavioral warning signs like hostile mood or verbal threats.2 Consequences of aggressive agitation can include self-injury, injury to others (such as staff members), prolonged hospital courses, increased rates of readmission, and greater healthcare utilization costs.1 The goals of treatment in acute agitation are therefore to rapidly reduce patient distress, prevent the persistence or escalation of agitation, and allow for timely assessment and triage of the underlying cause.6-8
Guideline recommendations for management of acute agitation
The 2012 American Association for Emergency Psychiatry Project BETA consensus statement provides recommendations for the management of acute agitation in the emergency setting.7 These recommendations state that, when possible, nonpharmacologic approaches such as verbal de-escalation and environmental modifications (eg, dimming lights, moving the patient to a quiet room) should be tried before pharmacologic treatment is administered. The goal of pharmacologic treatment should not be to induce sleep or restrain the patient; rather, medication should be used to calm patients and facilitate a provisional diagnosis of the underlying cause of agitation. Treatment should always target the underlying cause of agitation when possible. When medication is administered to treat agitation, the patient should be involved in selecting the medication to whatever extent possible. If the patient is able to cooperate with taking oral medications, these should be considered before injectable preparations. For patients with agitation due to an underlying psychiatric illness, antipsychotics are preferred over benzodiazepines because they address the underlying cause of agitation. Second generation antipsychotics are preferred over haloperidol; if the patient can take oral medications, oral risperidone is preferred. Other options include oral olanzapine, intramuscular olanzapine, or intramuscular ziprasidone. If the initial dose of antipsychotic is insufficient to control agitation, adding a benzodiazepine (eg, lorazepam) is preferred over repeating a dose of the same antipsychotic or using a different antipsychotic.
Several international organizations have published updated guidelines on the management of acute agitation secondary to psychiatric conditions. A 2016 expert consensus echoes many of the recommendations from the BETA project, stating that nonpharmacologic measures should be tried first and, if medication is to be considered, the agitated patient should be involved in medication and administration route selection when possible.9 When choosing a medication and route, it is important to consider the anticipated onset of effect and reliability of delivery. For mildly agitated patients, oral medications are recommended over intramuscular medications; inhaled medications can also be considered for mild to moderate agitation. Specific medication recommendations are not provided.
A 2018 joint consensus guideline from the British Association for Psychopharmacology (BAP) and the National Association of Psychiatric Intensive Care and Low Secure Units (NAPICU) recommends various medications for the treatment of acute agitation, regardless of etiology.10 Oral options recommended by the guideline include aripiprazole, olanzapine, risperidone, haloperidol, quetiapine, inhaled loxapine, or buccal midazolam. Recommended intramuscular options include droperidol and olanzapine.
Finally, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) published a joint guideline on bipolar disorder in 2018 that addresses management of acute agitation.8 When possible, antimanic medications with rapid onset of efficacy should be considered first for patients whose agitation is secondary to a manic episode. If agitation persists despite antimanic treatment, additional rapidly acting pharmacotherapy is often needed. First-line options for additional pharmacotherapy include intramuscular lorazepam, inhaled loxapine, or intramuscular olanzapine. Second-line choices for additional pharmacotherapy include sublingual asenapine, risperidone orally dissolving tablets (ODT), intramuscular haloperidol, intramuscular haloperidol plus midazolam, intramuscular haloperidol plus promethazine, or intramuscular ziprasidone.
Although oral medication administration is frequently recommended by guidelines, there are limitations associated with this route; the onset of action may be slow, and some agitated patients with underlying psychiatric disorders may indicate that they will accept oral treatment but then “cheek” the medication, preventing effective therapy.1,8,9 In order to overcome these limitations, some medications have been made available as ODTs, oral liquids, sublingual formulations, or inhaled formulations.8 Sublingual formulations and inhaled formulations are thought to be useful in a certain subset of acutely agitated patients, specifically those that are significantly but not severely agitated, able to accept oral medication assistance, and able to cooperate with an unfamiliar route of medication delivery.11
In April of 2022, the United States Food and Drug Administration (FDA) approved a sublingual formulation of dexmedetomidine for the acute treatment of agitation associated with schizophrenia or bipolar disorder in adults.12,13 The remainder of this article will review the evidence associated with this medication and discuss the potential place in therapy.
Sublingual dexmedetomidine for acute agitation
Dexmedetomidine is a selective alpha-2 receptor agonist, previously approved in an intravenous formulation for use as a sedative in mechanically ventilated patients and patients undergoing medical procedures.1,14 The mechanism of action in acute agitation is thought to be related to the activation of alpha-2 receptors in the locus coeruleus; activation of these receptors decreases the firing of neurons in the locus coeruleus, resulting in decreased norepinephrine release in brain circuits driving the agitated behavior.1
Dexmedetomidine for acute agitation associated with schizophrenia or bipolar disorder is formulated as a film for buccal or sublingual administration.13 It should be administered under the supervision of a healthcare provider; vital signs and level of sedation should be monitored following administration to prevent falls and syncope. The film is available in 2 dosage strengths: 120 mcg and 180 mcg. Films may be cut in half to administer lower dosages of 60 mcg or 90 mcg, respectively. The recommended dosing depends on the patient’s age, agitation severity, and level of hepatic function (Table 1). Patients should not eat or drink for 15 minutes following sublingual administration or 1 hour following buccal administration. If agitation persists after the initial dose, up to 2 additional doses can be administered at least 2 hours apart. Vital signs should be assessed prior to subsequent doses; additional doses are not recommended in patients with systolic blood pressure (SBP) <90 mm Hg, diastolic blood pressure (DBP) <60 mm Hg, heart rate <60 beats per minute, or postural decreases in SBP ≥20 mm Hg or in DBP ≥10 mm Hg.
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| Table 1. Recommended dosing for dexmedetomidine sublingual film.13 |
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|---|---|---|---|---|
| Patient population | Agitation severity | Initial dose | Optional second or third doses | Maximum recommended total daily dosage |
| Adults | Mild or moderate | 120 mcg | 60 mcg | 240 mcg |
| Severe | 180 mcg | 90 mcg | 360 mcg |
|
| Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) | Mild or moderate | 90 mcg | 60 mcg | 210 mcg |
| Severe | 120 mcg | 60 mcg | 240 mcg |
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| Patients with severe hepatic impairment (Child-Pugh class C) | Mild or moderate | 60 mcg | 60 mcg | 180 mcg |
| Severe | 90 mcg | 60 mcg | 210 mcg |
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| Patients aged ≥65 years | Any severity | 120 mcg | 60 mcg | 240 mcg |
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Summary of clinical evidence
Two randomized controlled trials (RCTs) have examined the efficacy of sublingual dexmedetomidine for acute agitation (Table 2); one RCT enrolled only patients with agitation secondary to schizophrenia or schizoaffective disorder, while the other enrolled only patients with agitation secondary to bipolar disorder.15,16 The primary outcome for both studies was the total Positive and Negative Syndrome Scale (PANSS)-excited component (PEC) score at 2 hours post-dose. The PEC scale includes 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement.15 Each item is rated from 1 to 7; the total PEC score thus ranges from 5 (absence of agitation) to 35 (extremely severe). Both studies found that sublingual dexmedetomidine significantly decreased total PEC scores at 2 hours compared to placebo.15,16 Somnolence was the most common adverse effect, and decreases in blood pressure and heart rate were observed with sublingual dexmedetomidine; a small number of patients in each trial experienced bradycardia, but no clinically meaningful changes in electrocardiogram parameters (eg, PR interval, QRS duration, QTc interval) were observed. Of note, many patient populations at increased risk for hypotension and bradycardia were excluded from clinical trials: these populations included patients who had been treated with alpha-1 antagonists, benzodiazepines, or other hypnotics or antipsychotic drugs within 4 hours prior to study drug administration; patients with a history of syncope or syncopal attacks; patients with SBP <110 mm Hg, DBP <70 mm Hg, or heart rate <55 beats per minute; and patients with evidence of hypovolemia or orthostatic hypotension.13 The prescribing information recommends avoiding use of sublingual dexmedetomidine in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. Additionally, although clinically important QTc prolongation was not observed in clinical trials, the prescribing information cautions against the use of sublingual dexmedetomidine in patients with known QT prolongation, a history of arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, or concomitant use of other drugs known to prolong the QT interval.
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| Table 2. Overview of RCTs examining sublingual dexmedetomidine for acute agitation in schizophrenia or bipolar disorder.15,16 |
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| Study design and duration | Subjects | Interventions | Results | Conclusions |
| Citrome 202215 MC, DB, PC, RCT Follow-up: 7 days | N=380 patients aged 18 to 75 years with schizophrenia or schizoaffective disorder presenting with acute agitation (total PEC score ≥14 with a score of ≥4 on at least 1 of the 5 PEC items) Mean age: 45.6 years Mean PEC score at baseline: 17.6 Patients were identified from the following settings: outpatient clinics; mental health, psychiatric, or medical emergency services including medical or psychiatric observation units; or patients newly admitted to a hospital setting for acute agitation or already hospitalized for underlying chronic conditions | Dexmedetomidine film 180 mcg sublingually (n=125) Dexmedetomidine film 120 mcg sublingually (n=129) Placebo (n=126) Study drug was self-administered; for persistent or recurrent agitation, a repeat dose of 90 mcg or 60 mcg (half the initial dose) could be given 2 hours after the first dose, at the investigators’ discretion, if the change from baseline on the PEC scale was <40% and there were no safety concerns Maximum of 3 total doses of study drug (1 initial dose and up to 2 repeat doses) Most patients received 1 dose of study medication. 4%, 12.4%, and 23% of patients in the dexmedetomidine 180 mcg, dexmedetomidine 120 mcg, and placebo groups respectively received 2 doses, and 0%, 9.3%, and 19% respectively received 3 doses | Primary: Absolute change from baseline in PEC total score at 2 hours post-administration: ‑10.3, ‑8.5, and -4.8 with dexmedetomidine 180 mcg, dexmedetomidine 120 mcg, and placebo, respectively; LSM difference from placebo, ‑5.5 (97.5% CI, ‑6.7 to ‑4.3; p<0.001) for dexmedetomidine 180 mcg and -3.7 (97.5% CI, ‑4.9 to -2.5; p<0.001) for dexmedetomidine 120 mcg Other: Treatment effects were first observed 20 minutes after patients were treated with dexmedetomidine 180 mcg and 30 minutes after patients were treated with dexmedetomidine 120 mcg; patients in both dexmedetomidine groups showed greater improvements in PEC total score compared to placebo at all subsequent time points through 90 minutes after treatment At 2 hours post-treatment, the percentage of patients with a PEC response (defined as a reduction of ≥40% from baseline) was 88.8% in the dexmedetomidine 180 mcg group, 79.1% in the dexmedetomidine 120 mcg group, and 40.5% with placebo At 2 hours post-treatment, the percentage of patients with a CGI-I response (defined as a score of 1 or 2) was 86.9% in the dexmedetomidine 180 mcg group, 76.2% in the dexmedetomidine 120 mcg group, and 50% in the placebo group Safety: Treatment-emergent AEs occurred in 37.3%, 39.5%, and 15.1% of patients receiving dexmedetomidine 180 mcg, dexmedetomidine 120 mcg, and placebo, respectively No serious or severe AEs were observed The most common AEs with dexmedetomidine 180 mcg and 120 mcg respectively were somnolence (23% and 21.7% vs. 7.9% with placebo), dizziness (6.3% and 2.3% vs. 0.8% with placebo), headache (3.2% and 4.7% vs. 4.8% with placebo), oral hypoesthesia (5.6% and 3.9% vs. 0% with placebo), hypotension (4% and 6.2% vs. 0% with placebo), orthostatic hypotension (5.6% and 1.6% vs. 0% with placebo), and dry mouth (4% and 7.8% vs. 1.6% with placebo) Sinus bradycardia occurred in 2 patients receiving dexmedetomidine 120 mcg; both cases resolved without medical intervention At 2 hours post-treatment, mean decrease in SBP from baseline was -16.8 mm Hg with dexmedetomidine 180 mcg and -12.8 mm Hg with dexmedetomidine 120 mcg | Sublingual dexmedetomidine at a dose of 120 mcg or 180 mcg reduced the severity of agitation in participants with mild to moderate agitation secondary to schizophrenia or schizoaffective disorder. |
| Preskorn 202216 MC, DB, PC, RCT Follow-up: 7 days | N=378 patients aged 18 to 75 years with acute agitation associated with bipolar I or II disorder (total PEC score ≥14 with a score of ≥4 on at least 1 of the 5 PEC items) Mean age: 45.6 years Mean PEC score at baseline: 18 Patients were identified from the following settings: outpatient clinics; mental health, psychiatric, or medical emergency services including medical or psychiatric observation units; or patients newly admitted to a hospital setting for acute agitation or already hospitalized for underlying chronic conditions | Dexmedetomidine film 180 mcg sublingually (n=126) Dexmedetomidine film 120 mcg sublingually (n=126) Placebo (n=126) Study drug was self-administered; for persistent or recurrent agitation, a repeat dose of 90 mcg or 60 mcg could be given 2 hours after the first dose, at the investigators’ discretion, if the change from baseline on the PEC scale was <40% and there were no safety concerns Maximum of 2 repeat doses during the 12 hours after the first dose Most patients received 1 dose of study medication. 10.3%, 23.8%, and 46% of patients in the dexmedetomidine 180 mcg, dexmedetomidine 120 mcg, and placebo groups respectively received ≥2 doses | Primary: Absolute change from baseline in PEC total score at 2 hours post-administration: ‑10.4, ‑9, and -4.9 with dexmedetomidine 180 mcg, dexmedetomidine 120 mcg, and placebo, respectively; LSM difference from placebo, -5.4 (97.5% CI, -6.6 to ‑4.2; p<0.001) for dexmedetomidine 180 mcg and -4.1 (97.5% CI, -5.3 to -2.9; p<0.001) for dexmedetomidine 120 mcg Other: Treatment effects were first observed 20 minutes after patients were treated with sublingual dexmedetomidine; patients in both dexmedetomidine groups showed greater improvements in PEC total score compared to placebo at all subsequent time points through 90 minutes after treatment At 2 hours post-treatment, the percentage of patients with a PEC response (defined as a reduction of ≥40% from baseline) was 90.5% in the dexmedetomidine 180 mcg group, 77% in the dexmedetomidine 120 mcg group, and 46% with placebo (p<0.001 for both groups vs. placebo) At 2 hours post-treatment, the percentage of patients with a CGI-I response (defined as a score of 1 or 2) was 86.5% in the dexmedetomidine 180 mcg group, 69.8% in the dexmedetomidine 120 mcg group, and 38.1% in the placebo group (p<0.001 for both groups vs. placebo) Safety: Treatment-emergent AEs occurred in 35.7%, 34.9%, and 17.5% of patients receiving dexmedetomidine 180 mcg, dexmedetomidine 120 mcg, and placebo, respectively No treatment-related serious or severe AEs were observed The most common AEs with dexmedetomidine 180 mcg and 120 mcg respectively were somnolence (21.4% and 20.6% vs. 4.8% with placebo), dry mouth (4.8% and 7.1% vs. 0.8% with placebo), hypotension (6.3% and 4.8% vs. 0% with placebo), and dizziness (5.6% and 5.6% vs. 0.8% with placebo) Clinically meaningful bradycardia occurred in 1 patient receiving dexmedetomidine 180 mcg and 2 patients receiving dexmedetomidine 120 mcg At 2 hours post-treatment, mean decrease in standing SBP after 1 minute was ‑18.1 mm Hg with dexmedetomidine 180 mcg and -14.8 mm Hg with dexmedetomidine 120 mcg | Sublingual dexmedetomidine at a dose of 120 mcg or 180 mcg reduced the severity of agitation in participants with mild to moderate agitation associated with bipolar disorder. |
| Abbreviations: AE=adverse event; CGI-I= Clinical Global Impression-Improvement; CI=confidence interval; DB=double-blind; LSM=least-squares mean; MC=multicenter; PANSS=Positive and Negative Syndrome Scale; PC=placebo-controlled; PEC=PANSS excited component; RCT=randomized controlled trial; SBP=systolic blood pressure. |
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Conclusion
Sublingual dexmedetomidine is an effective new option for the treatment of mild to moderate acute agitation in patients with schizophrenia or bipolar disorder; however, there are some significant practical considerations that may limit its use. Sublingual dexmedetomidine is self-administered; therefore, it would not be a viable option for more severely agitated or uncooperative patients. Additionally, it has the potential to cause hypotension, orthostatic hypotension, and bradycardia. It is important to consider any pre-existing conditions that may increase the risk of these adverse effects, and ensure appropriate monitoring of hemodynamic parameters as well as implementation of fall prevention measures.
References
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- Citrome L. Agitation in schizophrenia: origins and evidence-based treatment. Curr Opin Psychiatry. 2021;34(3):216-221. doi:10.1097/YCO.0000000000000685
- Preskorn SH. Treatment of agitation in individuals with bipolar disorder or schizophrenia: lessons learned for clinical psychiatry and psychiatric drug development. J Psychiatr Pract. 2022;28(4):319-323. doi:10.1097/PRA.0000000000000647
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- Zagorski N. FDA approves Igalmi for agitation. Psychiatric News. April 25, 2022. Accessed March 23, 2023. https://psychnews.psychiatryonline.org/doi/10.1176/appi.pn.2022.05.5.10
- Igalmi. Package insert. BioXcel Therapeutics; 2022.
- Precedex. Package insert. Hospira; 2022.
- Citrome L, Preskorn SH, Lauriello J, et al. Sublingual dexmedetomidine for the treatment of acute agitation in adults with schizophrenia or schizoaffective disorder: a randomized placebo-controlled trial. J Clin Psychiatry. 2022;83(6):22m14447. doi:10.4088/JCP.22m14447
- Preskorn SH, Zeller S, Citrome L, et al. Effect of sublingual dexmedetomidine vs placebo on acute agitation associated with bipolar disorder: a randomized clinical trial. JAMA. 2022;327(8):727-736. doi:10.1001/jama.2022.0799
Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
April 2023
The information presented is current as of March 2, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.