PHARMACOLOGY ― Dextromethorphan is an uncompetitive antagonist of the N-methyl D-aspartate (NMDA) receptor (an ionotropic glutamate receptor). Its mechanism of action for treatment of agitation in patients with AD dementia is unclear. Dextromethorphan is rapidly absorbed from the GI tract and undergoes extensive first-pass metabolism, mainly via CYP2D6. Bupropion increases serum concentrations of dextromethorphan by inhibiting CYP2D6.

THE DISORDER ― Agitation is common in patients with AD dementia. It is associated with decreased quality of life, greater caregiver burden, institutionalization, and increased morbidity and mortality. Symptoms include emotional distress, excessive motor activity (e.g., pacing, restlessness), and verbal and physical aggression.3

PHARMACOLOGIC TREATMENT ― Antidepressants, such as the selective serotonin reuptake inhibitor (SSRI) citalopram (Celexa, and generics), can be effective for treatment of agitation and other behavioral symptoms in patients with AD. Brexpiprazole and older second-generation antipsychotic drugs, such as quetiapine (Seroquel, and generics; off-label use), can also improve agitation symptoms, but their use has been associated with an increased risk of death in older patients with dementia-related psychosis. Nuedexta, a fixed-dose combination of dextromethorphan and quinidine that is FDA-approved for treatment of pseudobulbar affect, and pimavanserin (Nuplazid, and generics), a second-generation antipsychotic drug that is FDA-approved for treatment of hallucinations and delusions associated with Parkinson's disease, are modestly effective for treatment of agitation associated with dementia due to AD.4 Limited evidence suggests that the beta blocker propranolol can also improve behavioral and psychological symptoms of dementia, including agitation.5,6 Sedative/hypnotics, anxiolytics, antiseizure drugs, and cannabinoids have been used off label for this indication, but data supporting their efficacy and safety are lacking.

CLINICAL STUDIES ― FDA approval of dextromethorphan/bupropion for the new indication was based on the results of two unpublished double-blind trials (summarized in the package insert) in patients with agitation associated with AD dementia.

In the first trial (ADVANCE-1), 308 patients were randomized to receive the combination (titrated to a dose of dextromethorphan 45 mg/bupropion 105 mg) or placebo twice daily. The least-squares mean change from baseline to week 5 in the Cohen-Mansfield Agitation Inventory (CMAI) total score (29-item questionnaire used to assess agitated behavior severity and frequency; scores range from 29-203 [baseline score was ~60 in both arms], with lower scores indicating less severe disease) was significantly greater with the combination than with placebo (-14.9 vs -11.6).

In the second trial (ACCORD-2), patients who had a sustained clinical response to dextromethorphan 45 mg/bupropion 105 mg twice daily during an open-label treatment period of up to 52 weeks were randomized to continue the combination or switch to placebo for up to 24 additional weeks. Compared to placebo, the combination significantly delayed the time to relapse of agitation symptoms.

ADVERSE EFFECTS ― The most common adverse effects (occurring in ≥5% of patients and more often than with placebo) of dextromethorphan/bupropion in patients with AD dementia were dizziness, somnolence, dyspepsia, fatigue, and nausea. Bupropion monotherapy (at doses higher than in Auvelity) has caused hypertension, angle-closure glaucoma, dose-related seizures, and neuropsychiatric reactions, including psychosis. All antidepressants can induce mania in patients with bipolar disorder.

DRUG INTERACTIONS — Dextromethorphan has serotonergic effects; concomitant use of other serotonergic drugs, such as monoamine oxidase (MAO) inhibitors and SSRIs, can result in serotonin syndrome. Use of Auvelity within 14 days of a MAO inhibitor can cause hypertensive crisis and is contraindicated.

Bupropion inhibits CYP2D6 and can increase serum concentrations of drugs that are substrates of CYP2D6 and reduce the efficacy of drugs that require activation by CYP2D6. Use of Auvelity with strong CYP2D6 inhibitors can further increase serum concentrations of dextromethorphan and the risk of adverse effects. Coadministration of strong CYP2B6 inducers can decrease serum concentrations of both bupropion and dextromethorphan and should be avoided.7 Auvelity may decrease plasma levels of digoxin. CNS toxicity has occurred when bupropion was coadministered with levodopa or amantadine. Auvelity should be used with caution in patients who are taking dopaminergic agents or drugs that lower the seizure threshold.

DOSAGE, ADMINISTRATION, AND COST — Auvelity is available in extended-release tablets containing dextromethorphan/bupropion 30 mg/105 mg or 45 mg/105 mg. The recommended starting dosage for the new indication is 30 mg/105 mg taken once daily in the morning for 7 days. The dosage should be increased to 30 mg/105 mg twice daily on day 8 and to 45 mg/105 mg twice daily on day 15. The doses should be separated by at least 8 hours. In patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m²) and in those who are CYP2D6 poor metabolizers or are concomitantly taking a strong CYP2D6 inhibitor, the recommended maintenance dosage is 45 mg/105 mg once daily. Auvelity is not recommended for use in patients with severe renal impairment. The wholesale acquisition cost of a 30-day supply of Auvelity 45 mg/105 mg taken twice daily is about $1248.8

CONCLUSION ― The fixed-dose combination of dextromethorphan and bupropion (Auvelity) appears to be a moderately effective alternative to antipsychotic drugs for treatment of agitation associated with dementia due to Alzheimer's disease. Direct comparisons with brexpiprazole (Rexulti), the second-generation antipsychotic drug FDA-approved for this indication, are lacking.

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