Safety, Dosing, and Drug Interactions for Dextromethorphan-Bupropion in Agitation

This episode, "Safety, Dosing, and Drug Interactions for Dextromethorphan-Bupropion in Agitation," features the panel comparing safety data and detailing the practical dosing of a newer agitation therapy.

The panel compares the safety profile of the newer, non-antipsychotic combination therapy with older off-label antipsychotics. In its short-term trial, discontinuation for side effects like dizziness and dyspepsia stayed under 2%, and unlike antipsychotics, it carries no black-box warning for mortality in dementia-related psychosis. Brexpiprazole does carry that warning, though it remains labeled specifically for agitation associated with Alzheimer's disease. Reassuringly, the panel notes an absence of signals for falls, infections, or death with the newer combination, along with no signal for akathisia, notable given how restless this population already tends to be.

Discussing a mortality black-box warning with families is described as an uncomfortable but necessary conversation, made more complicated by families researching medications online before or after a visit, sometimes arriving anxious about a warning they only partly understand. For the newer combination therapy, roughly 9% of patients experienced dizziness and about 3% experienced dyspepsia in trials.

Dosing for this indication differs meaningfully from the drug's existing major depressive disorder indication: 30 milligrams of dextromethorphan with 105 milligrams of bupropion SR once daily in week one, moving to twice daily, separated by at least eight hours, in week two, and reaching the familiar maintenance dose of 45 and 105 milligrams twice daily from week three onward. Clinicians should check baseline blood pressure given norepinephrine reuptake effects and adjust dosing for renal impairment or interacting medications. Relevant interactions include CYP2D6, affecting mainly antidepressants and beta-blockers, and CYP3A4, relevant to brexpiprazole and affecting certain antibiotics, statins, and blood thinners, along with watching for activation of mania in patients with a bipolar history.

Our next episode, "Mechanism and Trial Data for an Antipsychotic Agitation Therapy," turns to the second on-label option for agitation and the trials that supported its approval.