Dextromethorphan/bupropion

Antidepressant efficacy of dextromethorphan/bupropion (Auvelity) versus placebo in the GEMINI clinical trial.[1][3][4][5] The scores shown are the mean total depression scores on the MADRS over 6 weeks. Only 124/156 patients completed 6 weeks of Auvelity while 150/162 patients completed 6 weeks of placebo, consistent with a high rate of adverse reactions.[4][5][2]

Dextromethorphan/bupropion is approved for the treatment of major depressive disorder.[1] Dextromethorphan and bupropion have both individually been reported to be effective for the treatment of this condition.[6][7][8] The effect size of bupropion alone relative to placebo for depression is small,[7][8] whereas only limited evidence exists for dextromethorphan alone.[6] The combination was approved in the US on the basis of two regulatory clinical trials.[1]

In Study 1 (GEMINI), a 6-week randomized controlled trial of dextromethorphan/bupropion versus placebo in people with major depressive disorder, scores on the Montgomery–Åsberg Depression Rating Scale (MADRS)—a scale with a range of 0 to 60 points—decreased with dextromethorphan/bupropion by 15.9 points from a baseline score of 33.6 points (an approximate 47% reduction) and decreased with placebo by 12.1 points from a baseline score of 33.2 points (an approximate 36% reduction).[1][3] This resulted in a least-squares mean difference in reduction of depression scores between dextromethorphan/bupropion and placebo of 3.9 points, with the placebo group showing approximately 76% of the improvement in depression scores as the dextromethorphan/bupropion group and with depression scores at baseline improving overall about 11% more with the medication than with placebo.[1][3] In antidepressant trials of 6 to 8 weeks duration recorded in the Food and Drug Administration (FDA) database, the average difference from placebo with other antidepressants was 2.5 points.[3] The mean improvement in scores with dextromethorphan/bupropion was statistically significant but not clinically significant[9] relative to placebo at all assessed timepoints including at the end of week 1, although at the end of the study some patients did have clinically significant improvement.[1][3]

In Study 2 (STRIDE-1), dextromethorphan/bupropion was compared with bupropion alone in another randomized controlled trial.[1] The dose of bupropion in the study was lower than the target dose recommended for clinical practice.[10] In this study, dextromethorphan/bupropion showed significantly greater improvement than bupropion alone in the first two weeks of treatment but not by week 6 of treatment in people with major depressive disorder.[1][11] The baseline scores were 33.4 points with dextromethorphan/placebo and 33.2 points with placebo, while the score reductions at week 1 were 5.2 points on the MADRS with dextromethorphan/bupropion and 3.6 points with bupropion (a 1.6-point difference), at week 2 were 8.0 points with dextromethorphan/bupropion and 6.1 points with bupropion (a 1.9-point difference), and at week 6 were 11.6 points with dextromethorphan/bupropion and 9.4 points with bupropion (a 2.2-point difference).[11][12] On the basis of this trial, the FDA concluded that dextromethorphan contributes to the apparent antidepressant effects of dextromethorphan/bupropion.[1]

Dextromethorphan acts as an NMDA receptor antagonist, σ₁ receptor agonist, and serotonin–norepinephrine reuptake inhibitor, among other actions, while bupropion acts as a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator.[1][13] Bupropion is also a potent inhibitor of CYP2D6, and thereby inhibits the metabolism of dextromethorphan.[13] Dextromethorphan/bupropion has less activity as an NMDA receptor antagonist than dextromethorphan alone.[11] This is because bupropion is a potent CYP2D6 inhibitor and prevents the bioactivation of dextromethorphan into dextrorphan, a much more potent NMDA receptor antagonist and weaker serotonin reuptake inhibitor than dextromethorphan itself.[11] The mechanism of action of dextromethorphan/bupropion in the treatment of depression is unknown, although the preceding pharmacological actions are assumed to be involved.

When administered together as dextromethorphan/bupropion, the elimination half-life of dextromethorphan is 22 hours and the elimination half-life of bupropion is 15 hours.[1] The elimination half-lives of bupropion active metabolites are 35 hours for hydroxybupropion, 44 hours for erythrohydrobupropion, and 33 hours for threohydrobupropion.[1] Bupropion inhibits the metabolism of dextromethorphan by inhibiting the enzyme CYP2D6, the major enzyme responsible for the metabolism of dextromethorphan.[1] This in turn improves the bioavailability of dextromethorphan, prolongs its half-life, prevents its metabolism into dextrorphan, and increases the ratio of dextromethorphan to dextrorphan in the body.[1][13][14][6][15]

Dextromethorphan/bupropion is sold under the brand name Auvelity.[1]

Dextromethorphan/bupropion is not a controlled substance in the United States.[1] The misuse potential of dextromethorphan and bupropion has not been systematically studied.[1] However, both dextromethorphan and bupropion may have misuse liability at supratherapeutic doses.[1][17][18][19] Despite the known misuse potential of dextromethorphan, it is available widely as an over-the-counter drug.[18] Conversely, bupropion is a prescription-only medication.[20]