Evidence for using dextromethorphan-quinidine for the treatment of agitation in dementia

Table 3 Results summary from included studies

Ref.	Outcomes	Tolerability	Limitations
Cummings et al[8], 2015	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, P < 0.001. In stage 2, mean NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo, P = 0.02. The prespecified comparison of NPI Agitation/Aggression scores between patients who were randomized to receive only dextromethorphan-quinidine vs only placebo for the entire 10 weeks of the trial also favored dextromethorphan-quinidine over placebo, P = 0.003. Response to dextromethorphan-quinidine compared with placebo did not appear to differ by disease stage. The additional prespecified analysis that included both placebo responders and non-responders who were rerandomized in stage 2 did not alter the significance or magnitude of effect of the primary analysis. Sequential parallel comparison design analysis of prespecified secondary outcomes showed significant improvement favoring dextromethorphan-quinidine on global rating scores. Results for changes in the quality of life–Alzheimer disease score, ADCS activities of daily living Inventory, MMSE, and ADAS-Cog were not significant vs placebo. Post hoc analyses showed similar improvement in NPI Agitation/Aggression scores with dextromethorphan-quinidine in patients taking concomitant acetylcholinesterase inhibitors, memantine, antidepressants, or antipsychotics n when compared with those not receiving these agents. Lorazepam rescue medication was used by 6.6% of patients in the dextromethorphan-quinidine group during treatment and by 10.4% during treatment with placebo	Treatment-emergent adverse events were reported by 61.2% of patients in the dextromethorphan -quinidine group and 43.3% with placebo group. The most commonly occurring treatment-emergent adverse events 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%). Serious adverse events occurred in 7.9% patients receiving dextromethorphan-quinidine and in 4.7% of patients receiving placebo. Serious adverse events in patients receiving dextromethorphan-quinidine included chest pain (n = 2), anemia, acute myocardial infarction, bradycardia, kidney infection, femur fracture, dehydration, colon cancer, cerebrovascular accident, aggression, and hematuria. Serious adverse events in patients receiving placebo included idiopathic thrombocytopenic purpura, vertigo, pneumonia, gastroenteritis, contusion, transient ischemic attack, and agitation. Eight patients (5.3%) receiving dextromethorphan-quinidine and 4 (3.1%) receiving placebo discontinued treatment owing to adverse events. No deaths occurred during the study. No clinically meaningful between-group differences in electrocardiographic findings were observed	The duration was limited to 10 wk. The dose-escalation schedule limited evaluation of dose-response relationships. Exclusion of concomitant drugs related to quinidine and specific electrocardiographic/cardiac parameters that restricted patient enrollment, may limit the generalizability of study findings. Treatment at experienced trial sites by specialized clinicians under a clinical protocol prescribing frequent assessments may not reflect general practice. The patient sample consisted predominantly of outpatients; agitation in nursing home residents was underrepresented

NPI: Neuropsychiatric inventory; ADCS: Alzheimer’s disease cooperative study; MMSE: Mini mental state examination; ADAS-Cog: Alzheimer disease assessment scale–cognitive subscale.