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 New Alternative Drug Combo To Antipsychotics May Alleviate Aggression In Alzheimer’s Patients, Says Study

A pervasive yet elusive symptom among patients with Alzheimer’s disease—aggression—may soon have a targeted drug combo that works just as well as antipsychotics but without their dire side effects, reports a study in this week’s edition of the Journal of the American Medical Association.

Nearly half of all people with dementia have agitation symptoms every month,according to the oft-cited LASER-AD​ study. Because it is a behavior, aggression comes in many forms (verbal, physical), thus making it hard to pinpoint the exact culprit in the brain. The behavior is also difficult for the patient, caregiver, and family members to handle, observers note. Patients with this symptom face a greater risk of being institutionalized as well as a faster decline in disease severity and death.

Nonpharmacological interventions—social interaction and pleasant activities—are recommended as first-line approaches, but many patients fail to respond and end up on medication.

Off-label use of antipsychotics (risperidone, olanzapine, aripiprazole) are often used to treat aggression, but are linked to serious side effects, such as cognitive impairment, falls, and facial tics (tardive dyskinesia).

Recent trials have shown that citalopram, a selective serotonin reuptake inhibitor and popular antidepressant, improved the lashing out in patients with Alzheimer’s disease, but is linked with erratic heart beats and mild cognitive decline.

Currently used in the United States and Europe to treat pseudobulbar effect (uncontrollable laughing and crying in patients with brain traumas), dextromethorphan hydrobromide and quinidine sulfate have been shown anecdotally to calm agitated patients with dementia. Dextromethorphan works on many of the brain’s messenger chemicals—NMDA, serotonin, and norepinephrine, to name a few.

Jeffrey Cummings, MD, at the Cleveland Clinic Lou Ruvo Center for Brain Health, in Las Vegas, and his colleagues conducted a Phase 2 randomized clinical trial—the gold standard in research—using this drug combination but with a twist. The 10-week study in 42 U.S. sites, including outpatient Alzheimer’s disease clinics and assisted living and nursing facilities, employed 220 patients aged 50 to 90 years with mild to moderate forms of Alzheimer’s but split the trial into two five-week stages. For the first five weeks, three-quarters of the patients received placebo while the rest got the drug duo. After five weeks, those on the drug combo continued on it while those on placebo were split so that half now also started the experimental drugs while the other half remained on placebo.

In stage 1 of the trial, patients on the drugs had their aggression score drop by nearly three points on an internationally recognized neuropsychiatric test. The control group only dropped by one point. In stage 2, the group that switched from the placebo to the experimental drugs saw its scores decrease by two points. Those that remained on placebo saw a dip of almost one point.

Importantly, patients on these drugs did not experience cognitive impairment, sedation, or heart issues. A few, however, did suffer from falls, diarrhea, and urinary tract infections.

In an accompanying editorial to the article, neuroscientist Anne Corbett, at King’s College London, and her group wrote that these results indicate “a reasonably strong case to prioritize dextromethorphan-quinidine as an off-label treatment for agitation, possibly as a safer alternative to atypical antipsychotics.”

The Centers for Medicare & Medicaid Services (CMS) has led a push to lower the use of antipsychotics in nursing care centers. Anywhere from one in five to two in five nursing facility patients take daily antipsychotic doses that are higher than recommended levels, the agency’s statistics show.

CMS reports that the off-label use of antipsychotics for those suffering from dementia fell nearly 22 percent between the fourth quarter of 2011 and the first quarter of 2015.  A leading advocacy group for the long term and post-acute provider field, the American Health Care Association/National Center for Assisted Living, has made this goal part of its Quality Initiative. The group reports that its members have reduced improper antipsychotic use by 23 percent.

Jackie Oberst is Provider’s managing editor. Email her at joberst@providermagazine.com. Follow the magazine on Twitter @ProviderMag and @ProviderMyers.​

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