Dextromethorphan/bupropion

Source: Wikipedia, the free encyclopedia.

Dextromethorphan/bupropion
negative allosteric modulator
Clinical data
Trade namesAuvelity
Other namesDXM/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 name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD).[1] Its active components are dextromethorphan (DXM) and bupropion.[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 a tablet by mouth.[1]

dry mouth, sexual dysfunction, and hyperhidrosis, among others.[1] The mechanism 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]

Medical uses

Depression

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

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]

Side effects

Side effects of dextromethorphan/bupropion include

fatigue, paresthesia, and blurred vision.[1] These side effects occurred at rates ≥2% and to a greater extent than with placebo in clinical trials.[1]

Pharmacology

Pharmacodynamics

Dextromethorphan acts as an

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.

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][13][14][6][15]

History

Dextromethorphan/bupropion was developed by Axsome Therapeutics.[16] It was approved for the treatment of major depressive disorder by the US Food and Drug Administration in August 2022.[1]

Society and culture

Brand names

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

Legal status

Dextromethorphan/bupropion is not a

prescription-only medication.[20]

Research

Dextromethorphan/bupropion is under development for the treatment of

smoking withdrawal.[16][21][22] As of August 2022, it is in phase III clinical trials for agitation and phase II trials for smoking withdrawal.[16]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab "Auvelity- dextromethorphan hydrobromide, bupropion hydrochloride tablet, multilayer, extended release". DailyMed. 15 December 2022. Retrieved 21 January 2023.
  2. ^ a b "AUVELITY (dextromethorphan hydrobromide and bupropion hydrochloride) extended-release tablets, for oral use" (PDF). October 2022.
  3. ^
    S2CID 249104681
    .
  4. ^ a b O'Gorman C, Jones A, Thomas Z, Iosifescu DV, Tabuteau H (June 2021). "W19 Rapid Effects of AXS-05, an Oral NMDA Receptor Antagonist, in Major Depressive Disorder: Results from Two Randomized, Double-Blind, Controlled Trials" (PDF). American Society of Clinical Psychopharmacology, Annual Meeting 2021, 1-4 June 2021 (PDF).
  5. ^ a b O'Gorman C, Feliz S, Jones A, Streicher C, Thomas Z, Tabuteau H (June 2021). "W20 Effects of AXS-05, an Oral NMDA Receptor Antagonist with Multimodal Activity, on Patient Reported Depressive Symptoms in Major Depressive Disorder: Results from the GEMINI Phase 3 Double-Blind, Placebo-Controlled Trial" (PDF) (PDF).
  6. ^
    S2CID 232141396
    .
  7. ^
    PMID 29477251
    .
  8. ^
    S2CID 5011570
    .
  9. PMID 33249552
    .
  10. PMID 16027765
    .
  11. ^
    PMID 35045580
    .
  12. ^ Axsome Therapeutics (30 March 2020). "STRIDE-1 Phase 3 Trial of AXS-05 in TRD Topline Results Conference Call" (PDF).
  13. ^
    PMID 16368442
    .
  14. S2CID 203607617
    .
  15. PMID 25061302
    .
  16. ^ a b c "Bupropion/dextromethorphan". Adis Insight. Archived from the original on 21 September 2021. Retrieved 16 December 2019.
  17. S2CID 218599441
    .
  18. ^
    PMID 27288091
    .
  19. S2CID 163167323
    .
  20. ^ "Bupropion: Drug Uses, Dosage, Side Effects".
  21. PMID 30447328
    .
  22. ^ "Axsome depression drug meets late-stage study goal, shares soar 56%". Reuters. 16 December 2019. Archived from the original on 16 December 2019. Retrieved 16 December 2019.