September 22, 2015

Combination Drug Reduces Agitation for Patients With Probable Alzheimer Disease

CHICAGO -- September 22, 2015 -- In a preliminary 10-week randomised trial, patients with probable Alzheimer disease who received the combination medication dextromethorphan-quinidine demonstrated less occurrences and severity of agitation, compared with patients who received placebo, according to a study published in the September 22/29 issue of JAMA.

Nonpharmacological interventions are recommended as first-line therapy for agitation and aggression in patients with dementia, but many patients fail to respond. Although many classes of psychotropic drugs are prescribed for agitation, safety concerns and modest or unproven efficacy limit their use.

The combination of the drugs dextromethorphan hydrobromide and quinidine sulfate is approved for the treatment of pseudobulbar affect and there is evidence suggesting a potential benefit of these drugs for agitation.

Jeffrey L. Cummings, MD, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, and colleagues randomised 220 patients to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127) in stage 1. In stage 2, patients receiving dextromethorphan-quinidine continued and those receiving placebo were stratified by response and re-randomised to dextromethorphan-quinidine (n = 59) or placebo (n = 60). The 10-week trial was conducted at 42 study sites.

A total of 194 patients (88%) completed the study. Analysis combining stages 1 (all patients) and 2 (re-randomised placebo non-responders) showed significantly reduced measures of agitation (occurrence and severity of symptoms).

Patients treated with only dextromethorphan-quinidine had an average 51% reduction in the measure of agitation from baseline to week 10, compared with 26% for those treated with only placebo.

Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhoea (5.9% vs 3.1%, respectively), and urinary tract infection (5.3% vs 3.9%, respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine versus 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment or sedation.

“These preliminary findings require confirmation in additional clinical trials with longer treatment duration,” the authors wrote.

Pending further evidence, there is a reasonably strong case to prioritise dextromethorphan-quinidine as an off-label treatment for agitation, possibly as a safer alternative to atypical antipsychotics, wrote Anne Corbett, PhD, King’s College London, London, United Kingdom, in an accompanying editorial.

“However, while further studies are conducted to verify the efficacy and safety of this approach, it will be important to achieve a robust international expert consensus regarding the prioritisation of potential treatments for agitation in patients with dementia to improve the consistency of clinical practice,” she wrote. “This approach also must understand and incorporate patient and caregiver views regarding the evaluation of risk and benefits in relation to these treatments.”

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