Dextromethorphan/bupropion

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Dextromethorphan/bupropion
Dextromethorphan.svg
Dextromethorphan
Bupropion.svg
Bupropion
Combination of
Dextromethorphan NMDA receptor antagonist, σ1 receptor agonist, serotonin-norepinephrine reuptake inhibitor, nicotinic acetylcholine receptor negative allosteric modulator, and other actions
Bupropion Norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator
Clinical data
Trade names Auvelity
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]

Contents

Side effects of dextromethorphan/bupropion include dizziness, headache, diarrhea, somnolence, 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. 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. Antidepressant efficacy of dextromethorphan and bupropion (Auvelity) versus placebo in the GEMINI trial.png
Antidepressant efficacy of dextromethorphan/bupropion (Auvelity) versus placebo in the GEMINI clinical trial. 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.

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]

Side effects

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. [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 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.

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]

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]

Research

Dextromethorphan/bupropion is under development for the treatment of agitation in Alzheimer's disease and 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]

Related Research Articles

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Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.

<span class="mw-page-title-main">Sertraline</span> Antidepressant (SSRI class) medication

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder (GAD), and obsessive–compulsive disorder (OCD). However, for OCD, cognitive behavioral therapy, particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder (PTSD), sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder (PMDD) and can be used in sub-therapeutic doses or intermittently for its treatment.

<span class="mw-page-title-main">Bupropion</span> Substituted cathinone medication mainly used for depression and smoking cessation

Bupropion, sold under the brand name Wellbutrin among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cases of "incomplete response" to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue. Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder.

<span class="mw-page-title-main">Venlafaxine</span> Antidepressant medication

Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder. Studies have shown that Venlafaxine improves quality of life. It may also be used for chronic pain. It is taken by mouth. It is also available as the salt venlafaxine besylate in an extended-release formulation.

<span class="mw-page-title-main">Dextrorphan</span> Psychoactive cough suppressant medication

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<span class="mw-page-title-main">Dextromethorphan</span> Morphinan antitussive and dissociative drug

Dextromethorphan (DXM) is a cough suppressant used in many cough and cold medicines. It affects NMDA, and sigma-1 receptors in the brain, all of which have been implicated in the pathophysiology of depression. In 2022, the FDA approved a formulation of it combined with bupropion named Auvelity to serve as a rapid acting antidepressant in patients with major depressive disorder.

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<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

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<span class="mw-page-title-main">Gepirone</span> Medication used for major depressive disorder

Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally.

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<span class="mw-page-title-main">Vortioxetine</span> Serotonin modulator antidepressant

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<span class="mw-page-title-main">Levomilnacipran</span> SNRI antidepressant drug

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Dextromethorphan/quinidine, sold under the brand name Nuedexta, is a fixed-dose combination medication for the treatment of pseudobulbar affect (PBA). It contains dextromethorphan (DXM) and the class I antiarrhythmic agent quinidine.

<span class="mw-page-title-main">Rislenemdaz</span> Chemical compound

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<span class="mw-page-title-main">4-Chlorokynurenine</span> Chemical compound

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