dextromethorphan/bupropion

File:Antidepressant efficacy of dextromethorphan and bupropion (Auvelity) versus placebo in the GEMINI trial.png

Dextromethorphan/bupropion is approved for the treatment of major depressive disorder. Dextromethorphan and bupropion have both individually been reported to be effective for the treatment of this condition.{{cite journal | vauthors = Majeed A, Xiong J, Teopiz KM, Ng J, Ho R, Rosenblat JD, Phan L, Cao B, McIntyre RS | display-authors = 6 | title = Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials | journal = Expert Opin Emerg Drugs | volume = 26 | issue = 1 | pages = 63–74 | date = March 2021 | pmid = 33682569 | doi = 10.1080/14728214.2021.1898588| issn=1472-8214 | s2cid = 232141396 }}{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 | url = }}{{cite journal | vauthors = Monden R, Roest AM, van Ravenzwaaij D, Wagenmakers EJ, Morey R, Wardenaar KJ, de Jonge P | title = The comparative evidence basis for the efficacy of second-generation antidepressants in the treatment of depression in the US: A Bayesian meta-analysis of Food and Drug Administration reviews | journal = J Affect Disord | volume = 235 | issue = | pages = 393–398 | date = August 2018 | pmid = 29677603 | doi = 10.1016/j.jad.2018.04.040 | s2cid = 5011570 | url = https://pure.rug.nl/ws/files/58350957/The_comparative_evidence_basis_for_the_efficacy_of_second_generation_antidepressants_in_the_treatment_of_depression_in_the_US_A_Bayesian_meta_analysis_of_Food_and_Drug_Administration_reviews.pdf}} The effect size of bupropion alone relative to placebo for depression is small, whereas only limited evidence exists for dextromethorphan alone. The combination was approved in the US on the basis of two regulatory clinical trials.

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{{nbsp}}points—decreased with dextromethorphan/bupropion by 15.9{{nbsp}}points from a baseline score of 33.6{{nbsp}}points (an approximate 47% reduction) and decreased with placebo by 12.1{{nbsp}}points from a baseline score of 33.2{{nbsp}}points (an approximate 36% reduction).{{cite journal | vauthors = Iosifescu DV, Jones A, O'Gorman C, Streicher C, Feliz S, Fava M, Tabuteau H | display-authors = 6 | title = Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI) | journal = J Clin Psychiatry | volume = 83 | issue = 4 | pages = | date = May 2022 | pmid = 35649167 | doi = 10.4088/JCP.21m14345 | s2cid = 249104681 | doi-access = free }} This resulted in a least-squares mean difference in reduction of depression scores between dextromethorphan/bupropion and placebo of 3.9{{nbsp}}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. In antidepressant trials of 6 to 8{{nbsp}}weeks duration recorded in the Food and Drug Administration (FDA) database, the average difference from placebo with other antidepressants was 2.5{{nbsp}}points. The mean improvement in scores with dextromethorphan/bupropion was statistically significant but not clinically significant{{cite journal | vauthors = Turkoz I, Alphs L, Singh J, Jamieson C, Daly E, Shawi M, Sheehan J, Trivedi M, Rush A | title = Clinically meaningful changes on depressive symptom measures and patient-reported outcomes in patients with treatment-resistant depression | journal = Acta Psychiatrica Scandinavica | year = 2021 | volume = 143 | issue = 3 | pages = 253–263 | doi = 10.1111/acps.13260| pmid = 33249552 | pmc = 7986932 }} 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.

In Study 2 (STRIDE-1), dextromethorphan/bupropion was compared with bupropion alone in another randomized controlled trial. The dose of bupropion in the study was lower than the target dose recommended for clinical practice.{{cite journal | vauthors = Fava M, Rush A, Thase M, Clayton A, Stahl S, Pradko J, Johnston J | title = 15 Years of Clinical Experience With Bupropion HCl: From Bupropion to Bupropion SR to Bupropion XL | journal = The Primary Care Companion to the Journal of Clinical Psychiatry | year = 2005 | volume = 7 | issue = 3 | pages = 106–113 | pmid = 16027765 | doi = 10.4088/pcc.v07n0305| pmc = 1163271 }} 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.{{cite journal | vauthors = Sakurai H, Yonezawa K, Tani H, Mimura M, Bauer M, Uchida H | title = Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry | journal = Pharmacopsychiatry | volume = 55 | issue = 4 | pages = 193–202 | date = July 2022 | pmid = 35045580 | pmc = 9259184 | doi = 10.1055/a-1714-9097 }} The baseline scores were 33.4{{nbsp}}points with dextromethorphan/placebo and 33.2{{nbsp}}points with placebo, while the score reductions at week 1 were 5.2{{nbsp}}points on the MADRS with dextromethorphan/bupropion and 3.6{{nbsp}}points with bupropion (a 1.6-point difference), at week 2 were 8.0{{nbsp}}points with dextromethorphan/bupropion and 6.1{{nbsp}}points with bupropion (a 1.9-point difference), and at week 6 were 11.6{{nbsp}}points with dextromethorphan/bupropion and 9.4{{nbsp}}points with bupropion (a 2.2-point difference).{{cite web | author = Axsome Therapeutics | title = STRIDE-1 Phase 3 Trial of AXS-05 in TRD Topline Results Conference Call | date = 30 March 2020 | format = PDF | url = https://axsometherapeuticsinc.gcs-web.com/static-files/ea125d9e-1b04-447f-80f3-f4cd7ad1f248}} On the basis of this trial, the FDA concluded that dextromethorphan contributes to the apparent antidepressant effects of dextromethorphan/bupropion.

Side effects of dextromethorphan/bupropion include dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction (including abnormal orgasm, erectile dysfunction, decreased libido, and anorgasmia), hyperhidrosis, anxiety, constipation, decreased appetite, insomnia, arthralgia, fatigue, paresthesia, and blurred vision. These side effects occurred at rates ≥2% and to a greater extent than with placebo in clinical trials.

Auvelity is contraindicated for these indications

Anybody with a seizure disorder. As Auvelity may decrease the seizure threshold.{{Cite web |website=FDA |title=Auvelity Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215430s000lblCorrect3.pdf}}

Anybody with bullmia or anorexia. As these disorders can lower the seizure threshold, and it may make food avoidance worse.

Anybody undergoing an abrupt discontinuation of a CNS depressant like alcohol, benzodiazepines, or barbiturates. As these severely lower the seizure threshold and significantly increase the risk of having a seizure.

Anybody with hypertension. As Auvelity may worsen hypertension, especially when Auvelity is combined with other drugs that also worsen hypertension.

Bupropion may lower the seizure threshold.{{Cite web |first=FDA |title=Wellbutrin prescribing information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018644s039s040.pdf}} Therefore, caution is advised when combining Auvelity (which contains bupropion) with other medications that also lower the seizure threshold, such as alcohol, tramadol, clozapine, and CNS stimulants like amphetamine, cocaine, and methylphenidate.

Dextromethorphan (a component of Auvelity) increases serotonin which can lead to a life threatening complication known as serotonin 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 like amphetamine and cocaine, selective serotonin reuptake inhibitors, and triptans.{{Cite web |last=Indiana |first=Charles H. Brown, MS Pharm, RPh, CACP Professor Emeritus of Clinical Pharmacy Purdue University College of Pharmacy West Lafayette |title=Drug-Induced Serotonin Syndrome |url=https://www.uspharmacist.com/article/drug-induced-serotonin-syndrome |access-date=2025-04-20 |website=www.uspharmacist.com |language=en}}

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 like cocaine, amphetamine, caffeine and, methylphenidate, monoamine oxidase inhibitors, certain NSAIDs like Ibuprofen, and pseudoephedrine.

Because Auvelity is a CYP2D6 inhibitor, it can increase the plasma concentrations of drugs metabolized by this enzyme.{{Cite journal |last=Kotlyar |first=Michael |last2=Brauer |first2=Lisa H. |last3=Tracy |first3=Timothy S. |last4=Hatsukami |first4=Dorothy K. |last5=Harris |first5=Jennifer |last6=Bronars |first6=Carrie A. |last7=Adson |first7=David E. |date=June 2005 |title=Inhibition of CYP2D6 activity by bupropion |url=https://pubmed.ncbi.nlm.nih.gov/15876900 |journal=Journal of Clinical Psychopharmacology |volume=25 |issue=3 |pages=226–229 |doi=10.1097/01.jcp.0000162805.46453.e3 |issn=0271-0749 |pmid=15876900}} Examples of such drugs include risperidone, aripiprazole, codeine, metoprolol, and tamoxifen

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.{{cite journal | vauthors = Jefferson JW, Pradko JF, Muir KT | title = Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations | journal = Clin Ther | volume = 27 | issue = 11 | pages = 1685–95 | date = November 2005 | pmid = 16368442 | doi = 10.1016/j.clinthera.2005.11.011 | url = }} Bupropion is also a potent inhibitor of CYP2D6, and thereby inhibits the metabolism of dextromethorphan. Dextromethorphan/bupropion has less activity as an NMDA receptor antagonist than dextromethorphan alone. 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. 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{{nbsp}}hours and the elimination half-life of bupropion is 15{{nbsp}}hours. The elimination half-lives of bupropion active metabolites are 35{{nbsp}}hours for hydroxybupropion, 44{{nbsp}}hours for erythrohydrobupropion, and 33{{nbsp}}hours for threohydrobupropion. Bupropion inhibits the metabolism of dextromethorphan by inhibiting the enzyme CYP2D6, the major enzyme responsible for the metabolism of dextromethorphan. 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.{{cite journal | vauthors = Stahl SM | title = Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity | journal = CNS Spectr | volume = 24 | issue = 5 | pages = 461–466 | date = October 2019 | pmid = 31566163 | doi = 10.1017/S1092852919001470 | s2cid = 203607617 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Schoedel KA, Morrow SA, Sellers EM | title = Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect | journal = Neuropsychiatr Dis Treat | volume = 10 | issue = | pages = 1161–74 | date = 2014 | pmid = 25061302 | pmc = 4079824 | doi = 10.2147/NDT.S30713 | doi-access = free }}

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

Dextromethorphan/bupropion is sold under the brand name Auvelity.

Dextromethorphan/bupropion is not a controlled substance in the United States. The misuse potential of dextromethorphan and bupropion has not been systematically studied. However, both dextromethorphan and bupropion may have misuse liability at supratherapeutic doses.{{cite journal | vauthors = Silva AR, Dinis-Oliveira RJ | title = Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects | journal = Drug Metab Rev | volume = 52 | issue = 2 | pages = 258–282 | date = May 2020 | pmid = 32393072 | doi = 10.1080/03602532.2020.1758712 | s2cid = 218599441 | url = }}{{cite journal | vauthors = Stanciu CN, Penders TM, Rouse EM | title = Recreational use of dextromethorphan, "Robotripping"-A brief review | journal = Am J Addict | volume = 25 | issue = 5 | pages = 374–7 | date = August 2016 | pmid = 27288091 | doi = 10.1111/ajad.12389 | url = }}{{cite journal | vauthors = Costa R, Oliveira NG, Dinis-Oliveira RJ | title = Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects | journal = Drug Metab Rev | volume = 51 | issue = 3 | pages = 293–313 | date = August 2019 | pmid = 31124380 | doi = 10.1080/03602532.2019.1620763 | s2cid = 163167323 | url = }} Despite the known misuse potential of dextromethorphan, it is available widely as an over-the-counter drug. Conversely, bupropion is a prescription-only medication.{{cite web | url=https://www.drugs.com/bupropion.html | title=Bupropion: Drug Uses, Dosage, Side Effects }}

Dextromethorphan/bupropion is under development for the treatment of agitation in Alzheimer's disease and smoking withdrawal.{{cite web | title = Bupropion/dextromethorphan | url = https://adisinsight.springer.com/drugs/800044221 | work = Adis Insight | access-date = 16 December 2019 | archive-date = 21 September 2021 | archive-url = https://web.archive.org/web/20210921025848/https://adisinsight.springer.com/drugs/800044221 | url-status = live }}{{cite journal | vauthors = Wilkinson ST, Sanacora G | title = A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems | journal = Drug Discovery Today | volume = 24 | issue = 2 | pages = 606–615 | date = February 2019 | pmid = 30447328 | pmc = 6397075 | doi = 10.1016/j.drudis.2018.11.007 }}{{cite news|title=Axsome depression drug meets late-stage study goal, shares soar 56%|url=https://www.reuters.com/article/us-axsome-study-idUSKBN1YK0ZG|publisher=Reuters|date=16 December 2019|access-date=16 December 2019|archive-date=16 December 2019|archive-url=https://web.archive.org/web/20191216162552/https://www.reuters.com/article/us-axsome-study-idUSKBN1YK0ZG|url-status=live}} As of August 2022, it is in phase III clinical trials for agitation and phase II trials for smoking withdrawal.

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Category:Antidepressants

Category:Combination psychiatric drugs