 Dextromethorphan | |
 Bupropion | |
| Combination of | |
|---|---|
| Dextromethorphan | NMDA receptor antagonist,σ1 receptoragonist,serotonin-norepinephrine reuptake inhibitor,nicotinic acetylcholine receptornegative allosteric modulator, and other actions |
| Bupropion | Norepinephrine–dopamine reuptake inhibitor andnicotinic acetylcholine receptornegative allosteric modulator |
| Clinical data | |
| Trade names | Auvelity |
| Other names | DXM/BUP; AXS-05 |
| License data | |
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| KEGG | |
Dextromethorphan/bupropion (DXM/BUP), sold under the brand nameAuvelity, is acombination medication for the treatment ofmajor depressive disorder (MDD).[1] Its active components aredextromethorphan (DXM) andbupropion.[1] Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial.[2][3] It is taken as atabletby mouth.[1]
Side effects of dextromethorphan/bupropion includedizziness,headache,diarrhea,somnolence,dry mouth,sexual dysfunction, andhyperhidrosis, among others.[1] Themechanism of action of dextromethorphan/bupropion in the treatment of depression is unknown.[1]
Dextromethorphan/bupropion was developed by Axsome Therapeutics and was approved for the treatment of major depressive disorder in the United States in August 2022.[1]
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Dextromethorphan/bupropion is approved for the treatment ofmajor depressive disorder.[1] Dextromethorphan and bupropion have both individually been reported to be effective for the treatment of this condition.[6][7][8] Theeffect 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 regulatoryclinical trials.[1]
In Study 1 (GEMINI), a six-weekrandomized controlled trial of dextromethorphan/bupropion versusplacebo in people with major depressive disorder, scores on theMontgomery–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 aleast-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 six to eight weeks duration recorded in theFood 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 notclinically 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]
Side effects of dextromethorphan/bupropion includedizziness,nausea,headache,diarrhea,somnolence,dry mouth,sexual dysfunction (includingabnormal orgasm,erectile dysfunction,decreased libido, andanorgasmia),hyperhidrosis,anxiety,constipation,decreased appetite,insomnia,arthralgia,fatigue,paresthesia, andblurred vision.[1] These side effects occurred at rates ≥2% and to a greater extent than with placebo inclinical trials.[1]
Auvelity is contraindicated for these indications
Anybody with a seizure disorder. Auvelity may decrease the seizure threshold.[13]
Anybody with bulimia or anorexia. These disorders can lower the seizure threshold, and it may make food avoidance worse.[13]
Anybody undergoing an abrupt discontinuation of aCNS depressant likealcohol,benzodiazepines, orbarbiturates. Discontinuation of these severely lowers the seizure threshold and significantly increase the risk of having a seizure.[13]
Anybody with hypertension. Auvelity may worsen hypertension, especially when Auvelity is combined with other drugs that also worsen hypertension.[13]
Bupropion may lower the seizure threshold.[14] Therefore, caution is advised when combining Auvelity (which contains bupropion) with other medications that also lower the seizure threshold, such asalcohol,tramadol,clozapine, and CNS stimulants likeamphetamine,cocaine, andmethylphenidate.
Dextromethorphan (a component of Auvelity) increases serotonin; this can lead to a life threatening complication known asserotonin syndrome (especially serotonergic drugs are combined). Therefore, caution should be used when combining dextromethorphan with other drugs that increase serotonin. Certain drugs that increase serotonin include CNS stimulants likeamphetamine andcocaine,selective serotonin reuptake inhibitors, andtriptans.[15]
Bupropion (a component of Auvelity) may increase blood pressure and lead to hypertension. Therefore, combining Auvelity with other drugs that increase blood pressure may result in hypertension. Some examples of drugs that increase blood pressure are stimulants likecocaine,amphetamine,caffeine,methylphenidate, andpseudoephedrine,monoamine oxidase inhibitors, and certain NSAIDs likeibuprofen.
Because Auvelity is aCYP2D6 inhibitor, it can increase the plasma concentrations of drugs metabolized by this enzyme.[13][16] Examples of such drugs arerisperidone,aripiprazole,codeine,metoprolol, andtamoxifen.
Dextromethorphan acts as anNMDA receptor antagonist,σ1 receptoragonist, andserotonin–norepinephrine reuptake inhibitor, among other actions, while bupropion acts as anorepinephrine–dopamine reuptake inhibitor andnicotinic acetylcholine receptornegative allosteric modulator.[1][17] Bupropion is also apotentinhibitor ofCYP2D6, and thereby inhibits themetabolism of dextromethorphan.[17] Dextromethorphan/bupropion has less activity as an NMDA receptor antagonist than dextromethorphan alone.[11] This is because bupropion is apotentCYP2D6inhibitor and prevents thebioactivation of dextromethorphan intodextrorphan, a much more potent NMDA receptor antagonist and weaker serotonin reuptake inhibitor than dextromethorphan itself.[11] Themechanism 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, theelimination half-life of dextromethorphan is 22 hours and the elimination half-life of bupropion is 15 hours.[1] The elimination half-lives of bupropionactive metabolites are 35 hours forhydroxybupropion, 44 hours forerythrohydrobupropion, and 33 hours forthreohydrobupropion.[1] Bupropion inhibits themetabolism of dextromethorphan by inhibiting theenzymeCYP2D6, the major enzyme responsible for the metabolism of dextromethorphan.[1] This in turn improves thebioavailability of dextromethorphan, prolongs its half-life, prevents its metabolism intodextrorphan, and increases the ratio of dextromethorphan to dextrorphan in the body.[1][17][18][6][19]
Dextromethorphan/bupropion was developed by Axsome Therapeutics.[20] It was approved for the treatment of major depressive disorder by the USFood and Drug Administration in August 2022.[1]
Dextromethorphan/bupropion is sold under the brand name Auvelity.[1]
Dextromethorphan/bupropion is not acontrolled substance in the United States.[1] Themisuse potential of dextromethorphan and bupropion has not been systematically studied.[1] However, both dextromethorphan and bupropion may have misuse liability atsupratherapeutic doses.[1][21][22][23] Despite the known misuse potential of dextromethorphan, it is available widely as anover-the-counter drug.[22] Conversely, bupropion is aprescription-only medication.[24]
Dextromethorphan/bupropion is under development for the treatment ofagitation inAlzheimer's disease andsmoking withdrawal.[20][25][26] As of August 2022, it is inphase IIIclinical trials for agitation andphase II trials for smoking withdrawal.[20]