Dextromethorphan/Bupropion: A Novel Treatment for Patients With Major Depressive Disorder

Abstract

Background: Major depressive disorder (MDD) affects millions of people and is the leading cause of disability worldwide. Patients report decreased quality of life and ability to perform activities of daily living. It is estimated that the current standard of care, which includes pharmacologic therapy with a selective serotonin reuptake inhibitor, is effective in 40%–60%. Additional treatment options are warranted. The combination of dextromethorphan (DEX) and bupropion (BUP) (Auveulty) was approved for treatment in 2022. This unique combination offers an interesting mechanism of action and favorable onset of action for patients with MDD. Pharmacodynamics and Pharmacokinetics: The mechanism of action of DEX–BUP when used in combination is unique. DEX is a noncompetitive N-methyl-d-aspartate receptor antagonist rapidly metabolized through the CYP450 2D6. BUP is an aminoketone and CYP2D6 inhibitor, which results in increased plasma levels of DEX through competitive CYP2D6 inhibition. Clinical Trials: In a phase 2 clinical study, the efficacy of DEX-BUP was compared with BUP alone in patients with clinically diagnosed MDD. At baseline, participants had moderate-to-severe depression using the Montgomery–Asberg Depression Rating Scale (MADRS) and Clinical Global Impressions Severity (CGI-S) scales. There was a significant overall reduction in MADRS and CGI-S scores in the treatment group compared with the BUP monotherapy with improvement observed as early as week 1 of treatment. Later, a phase 3 study was conducted comparing DEX-BUP 45 mg/105 mg with placebo in patients with moderate-to-severe MDD. Similarly, MADRS and CGI-S scores were significantly reduced in the treatment group. Adverse effects were similar in all groups. Therapeutic Advance: Clinical response to first line treatment options for MDD are reported to be 40%–60%. Availability of additional treatment options, particularly those with reduced time to efficacy, may improve overall treatment and patient quality of life. DEX–BUP is a combination option that has been shown to improve depression symptoms as early as 1 week after initiation.

Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate

“…Dextromethorphan was first reported in 1953 as a nonopioid cough suppressant and has been one of the most widely used antitussives due to its excellent efficacy and safety. − In addition, dextromethorphan alone or combination with other agents can also be used for the treatment of depression, , pain, , and pseudobulbar affect. , ( S )-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (( S )-1-(4-methoxybenzyl)-OHIQ, ( S )- 2a ) as a molecular scaffold for the synthesis of dextromethorphan has attracted much attention in terms of synthetic methods and industrial applications (Scheme ). Kinetic resolution of racemic 2a has been used to prepare ( S )- 2a with a maximum theoretical yield of 50%. , The enantioselective transfer hydrogenation of iminium salts or ( Z )-enamide to ( S )- 2a using iridium or ruthenium − complexes has also been achieved in 86–98% ee values but it required harsh conditions such as high hydrogen pressure.…”