Combination of Dextromethorphan, Quinidine Reduces Agitation in Alzheimer’s Patients

A medication approved to treat pseudobulbar affect (PBA)—a condition characterized by uncontrolled laughing or crying that sometimes arises in people with neurological problems—could prove to be one of the first approved specifically to reduce agitation in patients with Alzheimer’s disease without inducing any adverse effect on cognition, according to a study presented last month at the 2015 Alzheimer’s Association International Conference in Washington, D.C.

Agitation is a common neuropsychiatric symptom associated with Alzheimer’s disease. Because of its impact on patients and their caregivers, it is one of the major reasons for transferring a patient to a care facility.

“There are currently no FDA-approved medications designed to treat these severe symptoms,” said Jeffrey Cummings, M.D., director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, who presented the study. “And the current approaches we do have all come with a cognitive cost.”

A potential treatment for Alzheimer’s-associated agitation with less compromise to cognitive function may be AVP-923, a single dose combination of dextromethorphan and quinidine, which was recently approved as a therapy for PBA in patients with multiple sclerosis (MS) or amyloid lateral sclerosis (ALS).

During the PBA clinical trials of AVP-923, researchers noticed that patients taking the medication also experienced reduced agitation. Alzheimer’s can also manifest PBA symptoms in addition to agitation; thus, testing the drug in patients presenting with Alzheimer’s-related agitation seemed like a logical step.

During a 10-week trial of more than 150 patients with Alzheimer’s-related agitation, Cummings and colleagues observed that participants who received AVP-923 (30 mg of dextromethorphan/10 mg of quinidine) twice daily showed a significant improvement in scores on the Neuropsychiatric Inventory relating to aggression/agitation from baseline to study endpoint (3.6 point decrease) compared with those taking placebo (1.9 point decrease). Noticeable differences were seen between the two groups after just one week of treatment.

The AVP-923 cohort also displayed improvements in other symptoms, including depression, irritability, anxiety, and sleep behaviors.

There were no statistically significant differences in dementia ratings between the two groups, as measured by the Mini-Mental State Exam, which suggests AVP-923 does not adversely affect cognition.

However, there were some increased risks associated with AVP-293—the biggest being an increased risk of falling. A total of 8.6 percent of the participants on AVP-923 experienced falls over the course of the trial compared with 3.9 percent in placebo group. Cummings acknowledged concern over this rate, but noted that previous clinical studies testing this medication as a PBA therapy had not been associated with any increase in incidence of falls.

“During the randomization process for this study, the AVP-923 group did have a slightly higher rate of people with a prior history of falling, and that may account for the difference,” he said in his presentation. “However, this will be closely monitored in an upcoming phase 3 trial, which will begin later this year and follow patients for six months.”

The current study was funded by Avanir Pharmaceuticals, makers of AVP-923. Cummings is a paid consultant for Avanir. More details on the study are available here. ■