Dextromethorphan-Bupropion-Esketamine Triadic Pharmacology: Molecular Targets, Enzymatic Interactions, and Risk-Benefit Assessment of a Three-Agent Combination for Treatment-Resistant Depression

Dextromethorphan is extensively O-demethylated by cytochrome P450 2D6 (CYP2D6) to dextrorphan, and the two molecules do not share a target profile. Dextrorphan is the more potent N-methyl-D-aspartate (NMDA) channel blocker; the parent compound is the more potent serotonin transporter inhibitor; their sigma-1 affinities are comparable, so differences in sigma-1 engagement depend on exposure rather than intrinsic affinity. CYP2D6 activity therefore does not scale exposure to a fixed pharmacology; it determines which pharmacology is expressed. This review develops that principle and extends it to a three-agent system. From published unbound concentrations and functional potencies, we calculate a model-derived fractional-target-engagement index. Under the base-case inputs, CYP2D6 inhibition raises the serotonergic index approximately fourfold while reducing the NMDA channel index; deterministic sensitivity analysis shows that the direction is robust to one-at-a-time 0.5-fold to 2-fold perturbations but not to all joint extreme assumptions. Quinidine and bupropion are analyzed as mechanistically distinct proofs of concept, and quinidine-derived exposure estimates are not treated as quantitative surrogates for the dextromethorphan–bupropion steady state. The framework is then applied to the untested question of whether a boosted dextromethorphan combination and esketamine are redundant or complementary. The agents share an NMDA channel mechanism, while CYP2B6 pathway overlap remains a hypothesis-generating observation rather than evidence of clinically relevant competition. No controlled data on the three-agent combination exist, and no therapeutic recommendation is made.