Dextromethorphan/bupropion

Depression

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 six-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][2] 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][2] In antidepressant trials of six to eight weeks duration recorded in the Food and Drug Administration (FDA) database, the average difference from placebo with other antidepressants was 2.5 points.^[2] 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][2]

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]

Pharmacodynamics

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][17] Bupropion is also a potent inhibitor of CYP2D6, and thereby inhibits the metabolism of dextromethorphan.^[17] 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.

Because dextromethorphan (DXM) acts predominantly as the parent compound rather than through dextrorphan in Auvelity,^[1] the contribution of the active metabolite can largely be disregarded when analyzing Auvelity's pharmacological effects. Dextrorphan primarily provides NMDA channel blockade. However, DXM itself exhibits its strongest activity as a serotonin transporter (SERT) inhibitor and σ1 receptor agonist,^[19] while its NMDA antagonism is actually quite weak.^[19] In Auvelity, the conversion of DXM to dextrorphan by the CYP2D6 enzyme is substantially inhibited by bupropion, resulting in extremely high plasma concentrations of the parent DXM.^[1] Consequently, Auvelity's NMDA receptor antagonism is clinically quite limited, whereas σ1 receptor agonism and SERT inhibition become the dominant pharmacological actions. Based on pharmacokinetic data, it can be inferred that DXM in Auvelity may achieve approximately 60–85% whole-brain SERT occupancy, a level comparable to that of most SSRIs (selective serotonin reuptake inhibitors). In addition, σ1 receptor agonism, which was previously investigated as a target for antidepressant development, likely contributes to Auvelity's therapeutic efficacy.

Bupropion produces relatively strong inhibition of the norepinephrine transporter (NET)^[22] and achieves approximately 14–28% dopamine transporter (DAT)^[22] occupancy, making it an NDRI (norepinephrine-dopamine reuptake inhibitor).^[22] Bupropion also antagonizes nicotinic acetylcholine receptors, acts as a weak positive allosteric modulator of the σ1 receptor,^[23][24] and inhibits 5-HT3 receptors. The significance of these additional actions for Auvelity's antidepressant effects remains unclear. The combined pharmacological actions of DXM and bupropion make Auvelity function similarly to an SNDRI (serotonin-norepinephrine-dopamine reuptake inhibitor), simultaneously enhancing all three monoamine neurotransmitter systems. This characteristic may contribute to its relatively rapid antidepressant onset.

The role of NMDA antagonism in Auvelity appears to be relatively limited. Ketamine and related compounds do indeed owe their rapid antidepressant effects to NMDA receptor antagonism. However, subsequent studies of numerous NMDA antagonists have found that most do not exhibit antidepressant efficacy. The reason appears to be that antidepressant activity requires exceptionally stringent molecular properties for NMDA receptor antagonism, particularly highly specific receptor-binding kinetics. In practice, neither DXM nor dextrorphan fulfills these requirements. This likely explains why Auvelity requires approximately 8 days to produce antidepressant effects,^[1][2][11] whereas esketamine can begin working within only a few hours. Therefore, although Auvelity substantially shortens the onset of action compared with conventional oral antidepressants, its mechanism underlying the accelerated antidepressant response appears to have only a limited relationship to the rapid antidepressant mechanism of ketamine.

Pharmacokinetics

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][17][25][6][26]}

Brand names

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

Legal status

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][28][29][22]} Despite the known misuse potential of dextromethorphan, it is available widely as an over-the-counter drug.^[29] Conversely, bupropion is a prescription-only medication.^[30]