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Clinician Article

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.



  • Cummings JL
  • Lyketsos CG
  • Peskind ER
  • Porsteinsson AP
  • Mintzer JE
  • Scharre DW, et al.
JAMA. 2015 Sep 22-29;314(12):1242-54. doi: 10.1001/jama.2015.10214. (Original)
PMID: 26393847
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Disciplines
  • Geriatrics
    Relevance - 7/7
    Newsworthiness - 7/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 6/7
  • Neurology
    Relevance - 6/7
    Newsworthiness - 6/7
  • Hospital Doctor/Hospitalists
    Relevance - 5/7
    Newsworthiness - 5/7
  • Internal Medicine
    Relevance - 5/7
    Newsworthiness - 5/7

Abstract

IMPORTANCE: Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking.

OBJECTIVE: To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation.

DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score =4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed.

INTERVENTIONS: In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60).

MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]).

RESULTS: A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (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 vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation.

CONCLUSIONS AND RELEVANCE: In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01584440.


Clinical Comments

Geriatrics

This is a yet unknown pharmatherapeutic approach to agitation in dementia with highest promise to improve treatment in the future.

Neurology

Management of agitation/aggression in Alzheimer disease patients is a difficult problem. Patients are elderly and are often on multiple drugs. The hazards of tranquilizers are of concern. The results of the dextromethorphan trial, while modest, offer hope for a reasonably safe and effective therapy. The accompanying editorial suggests off label use of dextromethorphan-quinine for problem patients -- I think this is reasonable.

Neurology

The employment of the sequential parallel comparison design which intends to increase the study power by minimizing the effect of placebo response is quite interesting and might be efficacious for these kind of subject. Placebo responders always bother us in the estimation of pharmaceutical efficacy research. Adopting the caregiver distress and strain is also the prominent feature of this study, which surely supports our practical needs as a clinician.

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