In this post, I link to and excerpt from Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI) [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Clin Psychiatry. 2022 May 30;83(4):21m14345
All that follows is from the above resource.
Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD).
Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. 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. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. 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.
Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. 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 [CI], −1.39 to −6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 (P = .007) and week 2 (P < .001). 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. 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). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.
Conclusions: 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.
Trial Registration: ClinicalTrials.gov Identifier: NCT04019704
Major depressive disorder (MDD) is a prevalent, disabling, chronic, biologically based disorder, which impairs social, occupational, and educational functioning.1 It is the leading cause of disability worldwide and is associated with increased suicide risk, morbidity, and mortality.2,3 Currently approved oral antidepressants work primarily via monoamine pathways.4 Partial or inadequate response is common with these agents, and they typically take several weeks to produce clinically meaningful effects.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.6
Involvement of the glutamatergic system in the pathogenesis of depression is suggested by data from neuroimaging, cellular, and clinical studies. 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.9,10
TRIAL DESIGN AND OVERSIGHT
The GEMINI (Glutamatergic and Monoaminergic Modulation in Depression) study was a phase 3, randomized, double-blind, placebo-controlled, 6-week trial conducted at 40 centers in the United States from June 2019 to December 2019.
Patients were men or women 18–65 years of age with a primary diagnosis of MDD, experiencing a major depressive episode of at least 4 weeks in duration, and having a Montgomery-Asberg Depression Rating Scale (MADRS)18 total score of 25 or higher, corresponding to moderate or greater severity, with higher scores indicating more severe depression. Patients were also required to have a score on the Clinician Global Impression-Severity (CGI-S)19 scale of 4 or higher (range, 1 to 7, with higher scores indicating greater severity of illness). The diagnosis of depression was established using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), criteria for MDD without psychotic features, based on the Structured Clinical Interview,20 which has been shown to diagnose MDD more conservatively than other structured interviews.21 As part of the screening process, an independent assessor confirmed the eligibility and symptom severity of each patient. The assessment consisted of a clinical review of all available documentation including complete medical history, and clinician- and patient-reported outcome measures.
Key exclusion criteria included bipolar disorder, psychotic disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (defined as ≥ 2 adequate failed antidepressant treatments in the current major depressive episode), alcohol/substance use disorder within the past year, clinically significant risk of suicide, and history of seizure disorder.
The primary endpoint was the change from baseline to week 6 in the MADRS total score. The MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores representing more severe depression. The key secondary endpoints were the change from baseline in the MADRS total score at week 1; change from baseline in the MADRS total score at week 2; remission, defined as MADRS total score ≤ 10, at week 2; and clinical response, defined as ≥ 50% reduction in MADRS total score, at week 6.
Other secondary endpoints included the Clinician Global Impression-Improvement (CGI-I; scores range from 1 [very much improved] to 7 [very much worse])19; CGI-S (scores range from 1 [normal state] to 7 [among the most extremely ill])19; Patient Global Impression-Improvement (PGI-I; scores range from 1 [very much improved] to 7 [very much worse])19; Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR-16; scores range from 0 to 27 with higher scores representing more severe depression)22; Sheehan Disability Scale (SDS; scores range from 0 to 30 with higher scores indicating more severe disability)23; the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; scores are based on the percentage of the maximum total score with higher percentages indicating greater satisfaction)24; and the MADRS-6 (a subscale of the 10-item MADRS evaluating the core symptoms of depression [apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thought]).25,26
Safety was assessed based on the incidence of adverse events; changes in vital signs, clinical laboratory measurements, physical examinations, and electrocardiograms; assessment of suicidal ideation and behavior, with the use of the Columbia-Suicide Severity Rating Scale (C-SSRS); and assessment for withdrawal-related symptoms, using the Physician Withdrawal Checklist. Adverse events during the treatment period were defined as adverse events occurring from the time of administration of the first dose of dextromethorphan-bupropion or placebo until 7 days after the last dose.
In this randomized, placebo-controlled trial, dextromethorphan-bupropion (AXS-05) demonstrated statistically significant antidepressant efficacy on the primary endpoint and the majority of secondary endpoints across multiple symptom-specific and global measures. Treatment with dextromethorphan-bupropion resulted in statistically significantly greater reductions in MADRS total score than placebo starting at week 1 and continuing at every time point thereafter. The medication-placebo difference for dextromethorphan-bupropion on the change in MADRS was substantial at all time points, being approximately 2–3 points at weeks 1 and 2 and increasing to approximately 4–5 points at weeks 4 and 6. This treatment effect compares favorably to the approximately 2.5-point mean difference from placebo seen at 6 to 8 weeks in antidepressant studies in the FDA database.27–29
Symptom remission is considered a desired goal in depression treatment because it is associated with better daily functioning and better long-term prognosis.30 Dextromethorphan-bupropion treatment resulted in early and substantial achievement of remission on the MADRS (total score ≤ 10), with statistically significant separation from placebo demonstrated at week 2 and at every subsequent time point. At week 6, the percentage of patients achieving remission was 39.5% in the dextromethorphan-bupropion group compared to 17.3% in the placebo group (P = .004). Clinical response on the MADRS (≥ 50% reduction from baseline) was also early and substantial with statistical significance versus placebo observed at week 1 and at every subsequent time point. At week 6, the percentage of patients achieving clinical response was 54.0% in the dextromethorphan-bupropion group compared to 34.0% in the placebo group (P < .001).
The early efficacy of dextromethorphan-bupropion was further evidenced by statistically significant benefits versus placebo at week 1 and at all subsequent time points on numerous other clinically relevant measures including MADRS-6, CGI-S, CGI-I, PGI-I, QIDS-SR-16, and Q-LES-Q-SF. Improvement in functional disability was also observed early with statistical significance on the SDS achieved at week 2 and at every time point thereafter.
Dextromethorphan-bupropion was safe and well tolerated in this trial, with low rates of discontinuations due to adverse events. The magnitude of the differences in the rates of adverse events and discontinuations due to adverse events between the two treatment groups in the trial likely reflects the much lower-than-expected rate of these events in the placebo group. For example, the 61.7% overall rate of adverse events in the dextromethorphan-bupropion group is in line with the average of 76.4% reported for antidepressant arms in a large meta-analysis of placebo-controlled depression trials.31 In comparison, the 45.1% rate of adverse events for placebo in this trial is lower than the 63.0% average reported for the placebo arms in the same meta-analysis. Similarly, the 6.2% rate of discontinuations due to adverse events in the dextromethorphan-bupropion group is in line with the average of 7% reported for antidepressant arms in another large meta-analysis of placebo-controlled depression trials.32 In contrast, the 0.6% rate of discontinuations due to adverse events for placebo in our trial is substantially lower than the 4% average reported for the placebo arms in that same meta-analysis. Unlike other NMDA receptor antagonists, dextromethorphan-bupropion was not associated with psychotomimetic effects. This tolerability profile could be related to the significantly faster rate of unblocking of the NMDA receptor channel reported for dextromethorphan as compared to other NMDA antagonists.11 Dextromethorphan-bupropion was not associated with weight gain or increased sexual dysfunction.
Limitations of this trial include exclusion of patients with psychotic or other psychiatric disorders, alcohol/substance use disorders, clinically significant risk of suicide, or significant medical comorbidities. These exclusions along with prohibition of certain concomitant medications may limit the generalizability of the study findings. In addition, treatment at experienced trial sites by specialized clinicians under a trial protocol with frequent clinical assessments may not reflect general practice. The dropout rate of 24.1% in the dextromethorphan-bupropion group is approximately twice that of placebo. However, this rate is in line with the average of 24.3% reported for antidepressant arms in a large meta-analysis of published placebo-controlled depression trials.32 In contrast, the 10.4% dropout rate for placebo in this trial is substantially lower than the 24.0% average reported for placebo arms in the same meta-analysis. Multiplicity adjustments were only applied to the key secondary efficacy endpoints; however, the nominal P values for most other secondary endpoints were < .05. Finally, the trial duration was limited to 6 weeks. The effect of long-term treatment with dextromethorphan-bupropion has been evaluated in a separate study.
In conclusion, this study demonstrated that treatment with dextromethorphan-bupropion (AXS-05) resulted in clinically meaningful and statistically significant improvements in depressive symptoms compared to placebo starting at week 1 in patients with MDD and was well tolerated. The efficacy of dextromethorphan-bupropion was supported by significant improvements compared to placebo on multiple clinically relevant endpoints across symptom-specific and global measures, demonstrating internal consistency of the study results.
Submitted: December 3, 2021; accepted May 5, 2022.
Published online: May 30, 2022.