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

Susan Kellum, Mercer University College of Pharmacy

The Alzheimer’s Association states that agitation and aggression are highly prevalent in patients with dementia and may be caused by numerous conditions or medications, but are most likely a direct result of the disease.1 Currently most patients with dementia receive antipsychotic medications for the treatment of agitation and aggression.2 Guidelines suggest that nonpharmacological interventions be used as first-line therapy, and to avoid antipsychotics if possible due to their increased risk of severe side effects. 3

The combination of dextromethorphan hydrobromide and quinidine sulfate is approved, in the United States and European Union, for the treatment of pseudobulbar affect. Evidence from a controlled clinical trial suggests potential for using dextromethorphan-quinidine for agitation in non-demented patients with pseudobulbar affect. This trial aims to assess the efficacy of dextromethorphan-quinidine for moderate to severe agitation associated with Alzheimer disease. 4

Title: Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial [4]
Design Phase II, randomized, multicenter, double-blind, placebo-controlled
Objective To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide–quinidine sulfate for Alzheimer disease–related agitation.
Study Groups Stage I: dextromethorphan-quinidine (n = 93) or placebo (n = 127)

Stage II: dextromethorphan-quinidine continued; those receiving placebo were stratified and randomized in a 1:1 ratio to dextromethorphan-quinidine (n =59) or placebo (n = 60)

Methods In stage one, dextromethorphan-quinidine was dosed as 20/10 mg once daily in the morning (with placebo in the evening) for week one. Dextromethorphan-quinidine was increased to twice daily for weeks two and three and then increased to 30/10 mg twice daily for weeks four and five.

In stage two, patients receiving dextromethorphan-quinidine continued to receive 30/10 mg twice daily. Patients who received placebo during stage one were randomized in a 1:1 ratio to receive dextromethorphan-quinidine (dose escalated as described above) or matching placebo.

Patients were considered responders at the end of stage 1 if their clinical global impressions score (CGIS) score for agitation was 3 (mildly ill) or lower and their Neuropsychiatric Inventory (NPI) Agitation/Aggression domain score decreased by 25% or more from baseline.

Duration August 2012 – August 2014
Primary Outcome Measure 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]).
Baseline Characteristics Baseline characteristics were similar with regard to average age (77.8), race, history of falls, neuropsychiatric inventory, caregiver strain index, quality of life, mini-mental state examination, and Alzheimer disease assessment scale. Concomitant medications and residence varied between the dextromethorphan-quinidine and placebo groups.

No. of Participants

Change from Baseline, Mean (95% CI) P Value by stage
dextromethorphan-quinidine Placebo dextromethorphan-quinidine Placebo  
NPI Agitation/Aggression Domain
Stage 1 93 125 -3.3 -1.7 <0.001
10 wk 93 66 -3.6 -1.9 0.001
NPI total score
Stage 1 93 125 -13.5 -8.5 0.03
10 wk 93 66 -16.0 -10.1 0.02
ADCS Clinical Global Impression of Change score for agitation
Stage 1 88 123 3.0 3.6 <0.001
10 wk 82 59 2.7 3.3 0.02
Above is a summary of efficacy outcome measures, please refer to article for the entire table.
Adverse Events Common Adverse Events: The most commonly occurring treatment-emergent adverse events (>3% and greater than placebo) were falls (8.6% vs 3.9%), diarrhea (5.9% vs 3.1%), urinary tract infection (5.3% vs 3.9%), and dizziness (4.6% vs 2.4%) for dextromethorphan-quinidine vs placebo, respectively.
Serious Adverse Events: Occurred in 12 patients (7.9%) receiving dextromethorphan-quinidine and in 6 (4.7%) receiving placebo
Percentage that Discontinued due to Adverse Events: 5.3% in dextromethorphan-quinidine group and 3.1% in placebo group
Study Author Conclusions 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.


In this study, eligible patients had behavioral symptoms that interfered with daily routine, were severe enough to warrant pharmacological treatment, scored 4 or higher (moderately ill) on the Clinical Global Impressions–Severity (CGIS) scale for agitation, and had a Mini-Mental State Examination (MMSE) score of 8 to 28. Oral lorazepam (maximum dosage of 1.5 mg/d and maximum of 3 days in a 7-day period) was allowed as rescue medication for agitation if deemed necessary by the study investigator. In this study, patients treated with only dextromethorphan-quinidine had a mean 50.7% reduction in the NPI Agitation/Aggression scores from baseline to week 10 compared with 26.4% treated with only placebo (P = .001); this placebo response would not be deemed clinically meaningful. 4


1] Alzheimer’s Association. http://www.alz.org/alzheimers_disease. Accessed September 23, 2015.

2] Chen Y, Briesacher BA, Field TS, Tjia J, Lau DT, Gurwitz JH: Unexplained variation across US nursing homes in antipsychotic prescribing rates. Arch Intern Med 2010; 170:89-95.

3] Cummings JL, Frank JC, Cherry D, et al. Guidelines for managing Alzheimer’s disease: Part II. Treatment. Am Fam Physician. 2002;65(12):2525-34.

4] Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA. 2015;314(12):1242-1254.


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