Drug Combo May Reduce Aggressive Outbursts in Alzheimer’s

angry woman
angry woman
The drug was not associated with cognitive impairment or sedation in patients with probable Alzheimer's.

Beyond dealing with a loved one who may no longer recognize them, many caregivers of patients with Alzheimer’s also have to fight through bouts of agitation and aggression from the patient, which can be equally distressing for both parties, and in some cases could result in the patient being institutionalized.

Addressing these problems with non-pharmacological interventions is recommended as first-line therapy, however many Alzheimer’s dementia patients fail to respond. Now, preliminary research indicates that a combination pharmacological therapy may help curb the frequency and severity of these outbursts.

Jeffrey L. Cummings, MD, ScD, of the Cleveland Clinic Lou Ruvo Center for Brain Health, and colleagues conducted a preliminary 10-week randomized trial of dextromethorphan hydrobromide and quinidine sulfate in patients with probable Alzheimer’s. In previous research, the drug combination — which is approved to treat pseudobulbar effect — showed promise for treatment of agitation.

“Dextromethorphan, the neurologically active component of the dextromethorphan-quinidine combination, has activity at receptors involved in modulating glutamate, serotonin, norepinephrine, and potentially other neurotransmitters, although the exact mechanism of action responsible for the reduction of dementia-associated agitation is not known,” the authors wrote. “In earlier clinical studies, agitation in the context of dementia has been improved with drugs acting on serotonin (citalopram) or glutamate (memantine) receptors, lending support to the hypothesis that dextromethorphan exerts therapeutic effects on dementia-associated agitation through these and perhaps other central nervous system receptors.”

Cummings and colleagues randomly assigned 220 patients to receive either dextromethorphan-quinidine (n = 93) or placebo (n = 127) for stage 1 of the study. In stage 2, those who received dextromethorphan-quinidine continued while those who received placebo were stratified based on response and re-randomized to dextromethorphan-quinidine (n=59) or placebo (n=60).

In total, 194 patients (88.2%) completed the study. In combined analysis of stages 1 and 2, results showed a significant reduction in NPI Agitation/Aggression scores (0-12) in patients who received dextromethorphan-quinidine compared to placebo. During stage 1, mean NPI Agitation/Agression scores were reduced from 7.1 to 3.8 in the dextromethorphan-quinidine group and from 7.0 to 5.3 in the placebo group. In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 in the dextromethorphan-quinidine group and from 6.7 to 5.8 in the placebo group. Overall, a 51% reduction and 26% reduction in NPI Agitation/Aggression scores were observed from baseline to week 10 in the dextromethorphan-quinidine and placebo groups, respectively. Between-group differences were significant in both stage 1 and stage 2.

During the trial, adverse events included falls (8.6% of the dextromethorphan-quinidine group vs. 3.9% of the placebo group), diarrhea (5.9% vs. 3.1%), and urinary tract infection (5.3% vs. 3.9%). Serious adverse events were observed in 7.9% of the dextromethorphan-quinidine group and 4.7% of the placebo group; however dextromethorphan-quinidine was not associated with cognitive impairment or sedation.

The authors recommended that the results be confirmed in larger, long-term clinical trials.


  1. Cummings JL et al. JAMA. 2015; doi:10.1001/jama.2015.10214.