Among patients with Alzheimer disease,more than 90% experienceneuropsychiatric symptomsduring thecourseof their illness1 with agitation one of themost frequent and clinically important symptoms. Agitation isnotonlydistressing for the patient but often confers risk both to patients and to others (such as family members and caregivers). Agitation also represents a common trigger for institutionalization and presents a major management challenge for clinicians. Effective treatment options for agitation in patients with Alzheimer disease are limited, so clinical innovation in this area is a high priority. Currentpractice guidelines2-4 promotenonpharmacological interventionsas the first-lineapproach for treatmentof agitation, and an increasing evidence base supports the value of thisapproach.5-7Despiteconsiderablevariabilitybetweenstudies, a 2014 meta-analysis highlighted the benefit associated with interventions involvingsocial interactionandpleasantactivities, such as at least 60 minutes a week of enjoyable activities.7 However, implementation of nonpharmacological interventions can be difficult, especially for patients with severesymptoms, forwhompharmacological interventionsare often required. Someevidence supportsmodest symptomatic benefit associatedwith short-term treatmentof patientswith severe aggressionusing atypical antipsychotic agents,8 particularly risperidone, olanzapine, and aripiprazole.However, benefits for nonaggressive agitationand for longer-termtreatment are less clear.8-10 Moreover, the modest benefits must be balanced against significant safetyconcernsassociatedwith thesedrugs, including risks of accelerated cognitive decline, stroke, and death, particularly with longer-term use.8,9 Therefore, even though nonpharmacological strategies provide a useful firstline treatment approach, pharmacological interventions that are more effective, are safer, and confer longer-term benefits are needed. Thecombinationofdextromethorphanhydrobromideand quinidine sulfate has been proposed as a candidate treatmentof agitationamongpatientswithAlzheimerdisease. The treatment is approved in the United States and the European Union for the treatment of pseudobulbar affect, the involuntary oruncontrollable episodes of crying and/or laughingusually occurring secondary to a neurological disease or brain injury. Dextromethorphan-quinidine has several mechanistic actions that are potentially relevant for the treatment of agitation,11 including low-affinity N-methyl-D-aspartate antagonism, serotonin and norepinephrine reuptake inhibition, and nicotinic α3β4 receptor antagonism. Emerging evidence also suggests analgesic action,12 which may directly affect agitated behavior. However, it is unclear whether any of these actions occur at therapeutically relevant doses. Anecdotal observations of improvement in agitation among patients without dementia were the main rationale for the randomized clinical trial (RCT) by Cummings and colleagues13 reported in this issue of JAMA. Cummings et al conducted a parallel-group, phase 2, double-blind RCT to evaluate the effect of dextromethorphan hydrobromide–quinidine sulfate on clinically significant agitation among patients with mild to moderately severe Alzheimer disease. This 10-week study used a sequential parallel comparison design in which patients allocated to placebo were rerandomized after 5 weeks. With this design, 220 patients initially were randomized 3:4 to receive dextromethorphan/quinidine (n = 93) or placebo (n = 127). After 5 weeks, patients receiving dextromethorphanquinidine continued that therapy, whereas those receiving placebo were stratified by response and rerandomized 1:1 to receive dextromethorphan/quinidine (n = 59) or placebo (n = 60). The primary outcome was change from baseline in the Agitation/Aggression domain of the Neuropsychiatric Inventory (NPI; which ranges from a score of 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]), as rated by the patient’s caregiver. Of the 220 randomized patients, 194 completed the study, including a total of 152 patients who had received dextromethorphan-quinidine and 127 who had received placebo at some point during the study. In the primary sequential parallel comparison design analysis, dextromethorphanquinidine, comparedwithplacebo, significantly improved the NPI Agitation/Aggression score (ordinary least squares z statistic, −3.95; P < .001), and results for each stage of randomization also favored dextromethorphan-quinidine. In the analysis after the first randomization, mean NPI Agitation/Aggression scoreswere reduced from7.1 to 3.8with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo, for a least squares mean between-group treatment difference of −1.5 (95%CI, −2.3 to −0.7; P < .001). In the analysis includingplacebononresponderswhowere rerandomizedafter 5 weeks to either dextromethorphan-quinidine or placebo,meanNPIAgitation/Aggressionscoreswere reducedfrom 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo, for a least squares mean treatment difference of −1.6 (95% CI, −2.9 to −0.3; P = .02). Related article page 1242 Opinion
