Dextromethorphan/bupropion
Dextromethorphan/bupropion, sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder. Its active components are dextromethorphan and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.
Side effects of dextromethorphan/bupropion include dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis, among others. The mechanism of action of dextromethorphan/bupropion in the treatment of depression is unknown.
Dextromethorphan/bupropion was developed by Axsome Therapeutics and was approved for the treatment of major depressive disorder in the United States in August 2022.
Medical uses
Depression
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. 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, 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 —a scale with a range of 0 to 60points—decreased with dextromethorphan/bupropion by 15.9points from a baseline score of 33.6points and decreased with placebo by 12.1points from a baseline score of 33.2points. This resulted in a least-squares mean difference in reduction of depression scores between dextromethorphan/bupropion and placebo of 3.9points, 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 six to eight weeks duration recorded in the Food and Drug Administration database, the average difference from placebo with other antidepressants was 2.5points. The mean improvement in scores with dextromethorphan/bupropion was statistically significant but not clinically significant 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, 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. 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. The baseline scores were 33.4points with dextromethorphan/placebo and 33.2points with placebo, while the score reductions at week 1 were 5.2points on the MADRS with dextromethorphan/bupropion and 3.6points with bupropion, at week 2 were 8.0points with dextromethorphan/bupropion and 6.1points with bupropion, and at week 6 were 11.6points with dextromethorphan/bupropion and 9.4points with bupropion. On the basis of this trial, the FDA concluded that dextromethorphan contributes to the apparent antidepressant effects of dextromethorphan/bupropion.
Side effects
Side effects of dextromethorphan/bupropion include dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, 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.Contraindications
Auvelity is contraindicated for these indicationsAnybody with a seizure disorder. Auvelity may decrease the seizure threshold.
Anybody with bulimia or anorexia. 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. Discontinuation of these severely lowers the seizure threshold and significantly increase the risk of having a seizure.
Anybody with hypertension. Auvelity may worsen hypertension, especially when Auvelity is combined with other drugs that also worsen hypertension.
Interactions
Bupropion may lower the seizure threshold. Therefore, caution is advised when combining Auvelity with other medications that also lower the seizure threshold, such as alcohol, tramadol, clozapine, and CNS stimulants like amphetamine, cocaine, and methylphenidate.Dextromethorphan increases serotonin; this can lead to a life threatening complication known as serotonin syndrome. 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.
Bupropion 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, methylphenidate, and pseudoephedrine, monoamine oxidase inhibitors, and certain NSAIDs like ibuprofen.
Because Auvelity is a CYP2D6 inhibitor, it can increase the plasma concentrations of drugs metabolized by this enzyme. Examples of such drugs are risperidone, aripiprazole, codeine, metoprolol, and tamoxifen.