Before Auvelity earned approval, Nuedexta paved the way
STUDY: Cummings JL et al, JAMA 2015;314(12):1242–1254
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: Avanir Pharmaceuticals
Background
There are two branded versions of dextromethorphan, a glutamatergic cough medicine that treats depression, agitation, and possibly schizophrenia. Both are combination pills that pair dextro with another med to extend its notoriously short 2-4 hour half-life:
- Nuedexta (dextromethorphan-quinidine): Approved for pseudobulbar palsy, a syndrome of emotional outbursts (laughing/crying), speech impairment (dysarthria), and swallowing difficulties (dysphagia) seen in people with brain injuries.
- Auvelity (dextromethorphan-quinidine): A rapid-acting medication approved for major depressive disorder.
On April 30, 2026, the FDA approved Auvelity for agitation in dementia, but Nuedexta showed promise ten years earlier in this large, randomized trial.
The Study
The study progressed in two stages, of which stage one was the most important:
- 5-week multicenter, double-blind trial
- 220 adults with probable Alzheimer’s and moderate-to-severe agitation
- Randomized to dextromethorphan-quinidine or placebo
- Primary outcome = change in the agitation/aggression domain of the Neuropsychiatric Inventory (NPI)
- Titration: Week 1: 20/10 mg qam; Week 2-3: 20/10 mg bid; Week 4-5: 30/10 mg bid
Stage 2 covered another month (weeks 6-10). Those on the med stayed on it, while those on placebo were divided into placebo-responders and non-responders. Each of those groups were than randomized to receive the med or to stay on placebo.
In both stages, the drug separated from placebo (effect size 0.5 in stage-1, 0.3 in stage-2). The difference was detectable by one week.
Mean NPI agitation scores fell from 7.1 to 3.8 with the drug versus 7.0 to 5.3 with placebo at five weeks. By 10 weeks, patients who remained on their original treatment saw a 50% reduction in agitation (vs 26% on placebo). Caregiver distress and strain also improved significantly.
Risks: Falls were more common with the drug (8.6% vs 3.9%), though most who fell had a pre-existing fall history. Cognition, daily functioning, and QTc interval were not meaningfully affected.
Practice Implications
- This trial suggests dextromethorphan can treat agitation without the bupropion in the FDA-approved Auvelity.
- But before you reach for Nuedexta in dementia, know that the company failed in subsequent trials involving a modified form of the drug (deudextromethorphan). Learn more about why deudextromethorphan failed and how it compares to Auvelity.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
