FDA Approves Igalmi for Agitation

The Food and Drug Administration (FDA) in April approved a sublingual formulation of dexmedetomidine under the brand name of Igalmi for the treatment of agitation associated with schizophrenia or bipolar I or II disorder. Dexmedetomidine was previously approved in intravenous form for anesthesia.

The effectiveness of dexmedetomidine for the treatment of agitation associated with schizophrenia or bipolar I or II disorder was evaluated in two phase 3 randomized, controlled trials: SERENITY I and SERENITY II. Igalmi is manufactured by BioXcel.

Patients in both trials received either dexmedetomidine (120 mcg or 180 mcg) or placebo while they were experiencing agitation—as measured by the Positive and Negative Syndrome Scale, Excitatory Component (PEC). The PEC assesses patients on five agitation-associated behaviors: poor impulse control, tension, hostility, uncooperativeness, and excitement. SERENITY I included 381 patients with schizophrenia, and SERENITY II included 378 patients with bipolar disorder.

In both trials, participants who received dexmedetomidine had significantly greater improvements in PEC scores at two hours compared with those who received placebo, with observable improvements in agitation beginning as soon as 20 minutes after treatment.

The most common side effects reported by patients taking dexmedetomidine were drowsiness, dry mouth, hypotension, and dizziness. No serious adverse events were reported, and there was no indication of the problems sometimes encountered with antipsychotics (muscle tremors and spasms) or benzodiazepines (behavioral disinhibition).

“This medication could be a big deal in psychiatry,” said Roger McIntyre, M.D., a professor of psychiatry and pharmacology at the University of Toronto and head of the University’s Mood Disorders Psychopharmacology Unit. “We have a medication that is appealing on several fronts: It’s well tolerated, easy to administer, not oversedating, and not restricted by the DEA [Drug Enforcement Administration].”

Sheldon Preskorn, M.D., a professor of psychiatry and behavioral sciences at the Kansas University School of Medicine in Wichita and investigator on both SERENITY trials, noted that developing the medication as a rapidly dissolving film strip offers multiple advantages. “It makes the medication fast acting, but also allows patients to administer the drug themselves and thus participate in their treatment,” he said. Preskorn has received consulting fees and research support from BioXcel.

“It’s [also] nice to see things come full circle,” said Preskorn, whose early neuroscience research in the 1970s involved determining the role of the locus coeruleus (a region in the brain stem that synthesizes the stress hormone noradrenaline and regulates human arousal). Dexmedetomidine binds to alpha-2 receptors on noradrenaline-releasing cells and inhibits this hormone’s production, which induces calm.

Encouraging News for People Experiencing Bipolar Agitation

As of press time, the data from SERENITY I had yet to be published in a journal. The SERENITY II results appeared in JAMA at the end of February.

As described in JAMA, this trial involved 378 adults with bipolar disorder who presented with acute agitation in a clinical setting (such as an emergency room or mental health clinic). Adults who agreed to participate were given a rapidly dissolving film with either 120 mcg dexmedetomidine, 180 mcg dexmedetomidine, or placebo and then carefully monitored. After two hours, participants whose agitation had not significantly dropped could receive a second dose of drug at half strength (60 mcg or 90 mcg) if there were no safety concerns, such as low blood pressure or excess sedation.

At baseline, the participants had an average PEC score of 18 (on a scale of 5 to 35). There were no differences in PEC scores among the three participant groups after 10 minutes, but by 20 minutes the dexmedetomidine groups began to separate from the placebo group (3-point drop in PEC scores for both doses compared with a 2-point drop in the placebo group).

After two hours, 77% of the participants who took 120 mcg dexmedetomidine and 90.5% of participants who took 180 mcg achieved a clinically meaningful drop in agitation (defined as at least a 40% reduction in PEC score) compared with 46% of the placebo group. Just 17% of the participants who received dexmedetomidine needed a second dose.

Preskorn said that the improvements in PEC scores among participants who received placebo was not surprising, given that these patients also received careful monitoring and de-escalation techniques such as talking to someone if they wanted or being placed in a quiet environment.

McIntyre, who is not involved with BioXcel, believes Igalmi could have widespread use since agitation occurs in the context of multiple mental health conditions and multiple inpatient and outpatient settings. But he said that he thinks this new approval could be especially meaningful for bipolar patients.

Though several antipsychotic formulations have been approved by the FDA for agitation associated with schizophrenia, only two of them are also approved for agitation associated with bipolar I disorder: inhaled loxapine powder and injectable olanzapine.

“We typically associate agitation with someone with schizophrenia, or maybe an elderly individual with dementia, but agitation is one of the most common reasons why people with bipolar disorder need to visit the health care system,” McIntyre told Psychiatric News. He added that bipolar-related agitation can affect patients during periods of mania, depression, and mixed states. He noted that the SERENITY II trial was careful to include people in all three mood states when agitated.

Though no studies comparing the effectiveness of dexmedetomidine with other medications have been conducted, McIntyre said the ability of dexmedetomidine to achieve a strong calming effect in one to two hours is on par with existing agitation therapies.

Preskorn told Psychiatric News that in addition to these two completed trials, BioXcel is currently conducting a trial of sublingual dexmedetomidine for agitation related to dementia. ■