13,14 The clinical utility of dextromethorphan has been limited in humans by its rapid and extensive metabolism through cytochrome P450 (CYP)2D6 yielding subtherapeutic plasma levels. 12 Blockade of the NMDA receptor and agonism of the σ 1 receptor modulate glutamate signaling in the central nervous system. 9,10ĭextromethorphan is an uncompetitive antagonist of the NMDA receptor (an ionotropic glutamate receptor) 11 and a σ 1 receptor agonist. This evidence includes findings of abnormal glutamate levels in the cortex of depressed patients using magnetic resonance spectroscopy, 7 observations of abnormal N-methyl- D-aspartate (NMDA) receptor expression and signaling in postmortem cortical preparations from depressed patients, 8 and demonstration of antidepressant efficacy in studies with parenteral administration of the NMDA receptor antagonist ketamine. Involvement of the glutamatergic system in the pathogenesis of depression is suggested by data from neuroimaging, cellular, and clinical studies. 5 In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, about two thirds of depression patients failed to achieve remission with first-line treatment, and of those who experienced a clinical response, approximately 60% did so only at or after 8 weeks of treatment. 4 Partial or inadequate response is common with these agents, and they typically take several weeks to produce clinically meaningful effects. 2,3 Currently approved oral antidepressants work primarily via monoamine pathways. 1 It is the leading cause of disability worldwide and is associated with increased suicide risk, morbidity, and mortality. Major depressive disorder (MDD) is a prevalent, disabling, chronic, biologically based disorder, which impairs social, occupational, and educational functioning. Trial Registration: Identifier: NCT04019704 Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.Ĭonclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, −0.48 95% CI, −0.48 to −0.79 P = .002). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2 95% CI, 11.7 to 32.7 P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0% 95% CI, 8.4%, 31.6% P < .001), at week 6. Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 ( P = .007) and week 2 ( P < .001). The least-squares mean change from baseline to week 6 in MADRS total score was −15.9 points in the dextromethorphan-bupropion group and −12.0 points in the placebo group (least-squares mean difference, −3.87 95% confidence interval, −1.39 to −6.36 P = .002). Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1–3, twice daily thereafter) for 6 weeks. Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl- D-aspartate (NMDA) receptor antagonist and σ 1 receptor agonist, in the treatment of major depressive disorder (MDD). Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression.
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