On April 30, the FDA granted approval for a combination medication of dextromethorphan and bupropion for the treatment of agitation in Alzheimer’s disease. The medication (Auvelity; Axsome Therapeutics) was previously approved for major depression and is a unique combination of two drugs—burproprion and dextromethorphan. The approval for agitation was based on two randomized trials of the medication. The first was a five-week placebo controlled trial that demonstrated statistical benefit of the drug compared to placebo on a measure of 29 agitated behaviors that occur in AD. The second was a relapse prevention study, where all participants with agitated behaviors were treated with the active drug for nine weeks; those who responded to treatment were then randomized to either continue taking the drug or cross-over to placebo. Over a 6-month followup period, 8% of those who stayed on active drug experienced a relapse in agitation, compared to 29% of those who were switched to placebo. Two additional studies have supported these findings although in one trial, the magnitude of benefit was not statistically significant.
These results represent a significant new opportunity for those with Alzheimer’s disease and agitated behaviors. These behaviors often occur as the illness advances and contribute notably to caregiver burden, institutionalization, and accelerated cognitive decline. Despite the significant burden, few pharmacologic options have been approved for dementia-related agitation – almost all are used off-label. In the unique two-drug formulation of Auvelity, bupropion is an approved antidepressant but also slows the elimination of dextromethorphan that is thought to contribute much of the anti-agitation effect. Dextromethorphan has effects on NMDA, sigma-1, and other receptors in the brain, which distinguish it from the commonly prescribed antipsychotic medications—such as quetiapine and risperidone and the newly FDA-approved medication brexpiprazole—that all share effects on brain dopamine receptors. These dopamine effects are largely responsible for many of the side effects of antipsychotic drugs such as parkinsonism. Such effects were not seen in the Auvelity trials, which did show some adverse consequences such as diarrhea, dizziness, falls, and sedation although these were not common nor particularly serious. Importantly, no deaths were seen in the Auvelity trials in people with Alzheimer’s disease, contrasting with the small increased risk for death associated with antipsychotic treatment that is specified in an FDA warning for those drugs.
So, what do these trial results and the new FDA approval mean for people with Alzheimer’s disease? Most importantly, it represents a second approved treatment and an alternative to antipsychotic drugs to treat agitation. The side effect profile appears to be significantly better and those who are particularly sensitive to adverse antipsychotic drug effects now have other options. For example, Auvelity does not hold the same black box warning indicating an increased risk of mortality for those with dementia-related psychosis that Rexulti and other antipsychotics retain. However, longer-term experience will help to confirm this, head-to-head comparisons have not been studied, and the trial results have not been fully released for review in the scientific community. Of note, the magnitude of agitation improvement seen in the Auvelity trials was not overwhelming on average and, while some will certainly benefit, there’s more work to be done to understand optimal use of this new treatment. But having a non-antipsychotic drug available to aid treatment of agitation is a good first step and several other drugs targeting alternative brain mechanisms involved in these behaviors are currently advancing through the clinical trials process. So we can look forward to better benefit/risk balance when treating these challenging behaviors, pending future strategies to prevent them altogether.
