Kevin Kunzmann

Investigative therapy dextromethorphan-bupropion (AXS-05) provided significantly improved 

 versus lone sustained-release bupropion while remaining tolerable in adult patients over 6 weeks, according to new phase 2 trial findings.

In a randomized, double-blind, multi center, parallel-group study of the NMDA/sigma-1 receptor antagonist combination therapy, investigators observed significant improvements in the Montgomery-Asberg Depression Rating Scale (MADRS) of adults with major depression treated with dextromethorphan-bupropion versus those treated with lone antidepressant bupropion.

The new findings from the ASCEND trial contribute to the clinical profile of the Axsome Therapeutics agent, which previously received breakthrough therapy designation by the US Food and Drug Administration (FDA). They also offer differentiated outcomes for clinical assessment of depression—a field which due to increasing rates of placebo-controlled assessments has reported an approximate 50% clinical trial signal response rate in the last 25 years, according to the investigators.

Led by chief executive officer Herriot Tabuteau, MD, the Axsome research team sought to compare mean MADS score change in patients randomized to either dextromethorphan-bupropion or bupropion from baseline to each week of treatment through 6 weeks.

“Currently approved oral antidepressants work primarily via monoamine pathways,” investigators explained. “Partial or inadequate response is common with these agents, and they typically take several weeks to produce clinically meaningful effects.”

Their assessment included patients aged 18-65 years old with a diagnosis of major depressive disorder of moderate to greater severity. Patients were randomized to either 45 mg/105 mg dextromethorphan-bupropion tablet or 105 mg bupropion, taken once-daily for the first 3 days then twice daily thereafter, for 6 weeks.

Patient diagnoses and disease severity were confirmed by an independent assessor, and all patients received ≥1 study medication dose and ≥1 post-baseline assessment.

Of the 97 patients randomized in the trial, 17 did not have a confirmed diagnosis and severity based on the independent assessment—leaving 80 patients randomized to either dextromethorphan-bupropion (n = 43) or bupropion (n = 37).

The MADRS is a 10-item clinician-led questionnaire that scores patients on a scale from 0 - 60, with greater scores representing more severe depression. Tabuteau and colleagues sought secondary endpoints including ≥50% reduction from baseline in MADRS total score, representing clinical response, and MADRS total scores of ≤10, representing remission.

At 6 weeks, investigators observed a mean reduction of 13.7 points in MADRS score from baseline among patients treated with dextromethorphan-bupropion, versus just 8.8 points in the comparator group—a mean difference of 4.9 points (95% CI, -3.1 to -6.8). In fact, patients treated with the investigative drug reported significantly greater MADRS reductions starting at week 2 and every week thereafter.

Patients treated with dextromethorphan-bupropion also reported significantly greater remission rates beginning at week 2 and continuing through the study (46.5% vs 16.2%; mean difference, 30.3; 95% CI, 11.2 - 49.3). Another 60.5% of patients treated with dextromethorphan-bupropion achieved the response rate, versus 40.5% of patients treated with bupropion (mean difference, 19.9; 95% CI, -1.6 to 41).

Commonly observed adverse events with the investigative drug included dizziness, nausea, dry mouth, decreased appetite and anxiety; investigators observed no associations with psychotomimetic effects, unlike other NMDA receptor antagonists.

Investigators described the benefit of care as “rapid, substantial, and statistically significant” in treating the primary endpoints of major depression symptoms in adults versus lone bupropion.

“Dextromethorphan-bupropion demonstrated a rapid onset of effect on depressive symptoms and global measures, with statistically significant improvements compared with bupropion observed starting at week 2 on several measures, despite the small sample size of the study,” they wrote. "The team concluded that ASCEND, the first controlled trial for dextromethorphan-bupropion in patients with depression, showed clinically meaningful improvements against the active comparator.

"ASCEND is one of the pivotal efficacy trials that forms the basis of our (New Drug Application) for AXS-05 in depression, which is currently under review by the FDA,” Tabuteau said in a 

. “Axsome is positioned to move expeditiously to make this product available to patients as quickly as possible, should it be approved."

Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial

Articles

The first controlled trial of the combination therapy shows its benefit in 6-week depressive symptom improvement versus lone bupropion.

Dextromethorphan-Bupropion Significantly Improves Major Depression Symptoms in Phase 2 ASCEND

Investigators observed that nearly half of all 

tests conducted at a Korean teaching hospital were done so inappropriately, according to a new study that highlights continued need for improved and communicated diagnostic stewardship for the gastric infection.

In new retrospective analysis data from Seoul National University College of Medicine, investigators reported significant differences in rates of inappropriate 

testing based on the clinical setting and prescribing clinician’s profession. The team additionally observed via questionnaire that physicians’ confidence in ordering an appropriate 

Led by Dr. Hee Bum Jo, of the division of infectious diseases in the department of internal medicine at Seoul National University Bundang Hospital, the research team conducted a retrospective review of patient medical records at a 1300-bed tertiary-care teaching hospital who were tested for 

infection from September - November 2019. They additionally conducted a physician survey to assess the knowledge and ordering patterns of testing for such infections.

As the most common healthcare-associated infection, 

prevalence in Korea alone had increased more than 3-fold from 2008 to 2011—while nations including the US have reported increasing greater management of the infection. Investigators cited the 2017 Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) guideline updates recommending testing in relevant clinical settings, defined as instances of unexplained and new-onset ≥3 unformed stools within 24 hours, to improve the reliability of the various available 

“Although asymptomatic colonization is not an indication for treatment, the 

 nucleic acid amplification test (NAAT) and glutamate dehydrogenase (GDH), the currently used methods cannot discriminate between CDI and asymptomatic colonization with 

, which results in overdiagnosis and overtreatment,” they wrote. Therefore, there is a need to consider the relevant clinical situations and symptoms for effective CDI diagnosis.”

Jo and colleagues’ analysis included 715 tests from 520 patients. They classified testing as either hospital-onset or community-onset, and they used an algorithmic method to define appropriate or inappropriate testing. Patients were ≥18 years old, did not receive outpatient testing, and did not have colostomies.

A total of 576 tests were hospital-onset, having occurred >3 days after admission or transfer from another hospital; the remaining 139 were community-onset. Of the hospital-onset tests, nearly two-thirds (n = 355 [61.6%]) were conducted having met IDSA and SHEA’s ≥3 unformed stools in 24-hour criteria, and the remaining 221 (38.4%) did not.

Of the tests of patients with ≥3 unformed stools, 282 (49.0%) did not include laxative use in patients; 73 (12.7%) included laxative use <48 hours prior to the test. Just 15 tests (2.6%) were conducted when patient had shock or were positive for ileus.

The team concluded that 297 tests (51.6%) for 

were conducted appropriately based on the recommended in-hospital guidelines, while 279 (48.4%) were conducted inappropriately.

The appropriately tested group was equally conducted in the hospital’s general ward (81.8%) as the inappropriately tested group (86.7%; 

 = .1.06). But the former group were far less conducted in the emergency room (0.3%) than the latter group (5.0%; 

The appropriately tested group additionally had greater proportions of internal medicine physicians ordering the test than the inappropriately testing group (72.4% vs 63.4%; 

 = .021). Investigators observed no differences in the 2 groups’ median number of days between admission and testing.

The team observed a significantly increased risk of inappropriate testing conducted in the emergency room (odds ratio [OR], 20.06; 95% CI, 2.60 - 154.78; 

< .004), and a decreased risk in the intensive care unit (OR, 0.33; 95% CI, 0.18 - 0.61; 

In their survey of 61 physicians, investigators observed significantly higher mean scores on the 10-point score among internal medicine physicians (7.1) versus other physicians (5.7; 

“Specifically, the question regarding repeat testing had the lowest correct answer rate (36.7% in internal medicine physicians; 38.7% in non-internal medicine physicians; 37.7% in total population),” investigators noted. “There was a significant between-speciality difference in questions regarding culture testing, toxin EIA with GDH EIA testing, GDH EIA with culture testing, and requirement of test of cure.”

The team concluded that this assessment—potentially the first to assess the appropriateness and physician practice patterns in a country with a growing burden of 

—showed institution-specific lanes of improvement for diagnostic stewardship.

“Diagnostic stewardship for CDI should be implemented, particularly through educational interventions for those working in the emergency room and for non-internal medicine physicians,” they wrote. “Prospective multicentre studies on the effectiveness of diagnostic stewardship are warranted.”

Prevalence of and factors associated with inappropriate Clostridioides difficile testing in a teaching hospital in Korea

,” was published online in Antimicrocial Resistance & Infection Control.

A South Korea in-hospital assessment found that approximately half of all ordered CDI tests did not meet recommendation standards.

Appropriate C Difficile Testing May Vary by Hospital Setting, Physician

A new assessment observed an association between rheumatic disease and 

Systematic review and meta analysis data from a team of investigators in China showed a correlation of potentially nonspecific, shared alterations of gut microbes in patients with either dysbiosis or rheumatic diseases including arthritis and systemic lupus erythematosus (SLE).

The findings contribute further evidence to a proposed link between the 2 disease group pathologies, and provide clearer paths for follow-up research.

Led by Yilun Wang, of the department of orthopedics at Xiangya Hospital in Changsha, the investigators noted prior research suggests dysbiosis may playing a contributing role to the occurrence, or even development, of various rheumatic diseases. The gut microbiota has an established association with various disease conditions including obesity, growth disorders, metabolic diseases, and mental illness.

“The emerging evidence in the past decades suggests that dysbiosis in gut microbiota and its impact on the balance between pro- and anti-inflammatory immune responses may contribute to the occurrence or development of several rheumatic diseases,” investigators wrote. “Since gut microbiota dysbiosis is potentially modifiable, it has been postulated to be a promising preventive or therapeutic target for rheumatic diseases.”

Wang and colleagues analyzed observational studies evaluating associations between dysbiosis and rheumatic disease via PubMed, Embase and Cochrane Library. They estimated a standardized mean difference (SMD) of α-diversity indices between prevalence of rheumatic disease versus control, while also qualitatively summarizing β-diversity indices and relative abundance of gut microbes.

Their assessment included 92 trials with 11,998 participants; eventually 68 provided data for α-diversity.

The team found consistent α-diversity index decreases for rheumatic diseases overall (SMD, -0.36; 95% CI, -0.63 to -0.09). However, when observing specific diseases, investigators only observed decreases in the following 4 conditions:

Rheumatoid arthritis (SMD, -0.51; 95% CI, -0.78 to -0.24)

Gout (SMD, -0.64; 95% CI, -1.07 to -0.22)

Fibromyalgia (SMD, -0.28; 95% CI, -0.44 to -0.11)

Interestingly, investigators observed an associated increase in α-diversity indices with systemic sclerosis (SMD, 1.25; 95% CI, 0.09 - 2.41).

Ankylosing spondylitis and immunoglobulin G4 (IgG4) related diseases were associated with statistically-significant differences in β-diversity.

—an anti-inflammatory butyrate-producing microbe—and enrichment of 

—a pro-inflammatory microbe—were observed in instances of rheumatoid arthritis, Sjorgen’s syndrome, and SLE. However, whenever the gut microbes merited specificity, investigators observed weaker reproductions, meaning that disease-specific alterations of gut microbes are still uncertain without further research.

Though they caution interpreting the findings—as the observed microbial associations may indicate a shared alteration to multiple rheumatic disease instead a disease-specific biologic difference—the team concluded the observed altered microbes and their metabolites could be used as “general targets for innovative preventive or therapeutic tools for different rheumatic diseases.”

“Finally, little evidence of distinct disease-specific alterations in gut microbes was evident,” they concluded. “This suggests that gut microbes serving as diagnostics for specific rheumatic diseases warrants further investigations.”

Gut dysbiosis in rheumatic diseases: A systematic review and meta-analysis of 92 observational studies

Developing research into the specific alterations of dysbiosis and diseases like arthritis suggest possibly novel pathways to therapy development.

Gut Microbiota Dybiosis May Be Linked to Rheumatic Disease

A 29-host-mRNA response classifier showed ability to detect bacterial co-infections, as well as superinfections, among patients with confirmed COVID-19.

In new abstract presented at the Society of Advanced Emergency Medicine (SAEM) 2022 Meeting in New Orleans this week, a team of academic and industry investigators reported that the dynamic host response platform may help emergency and acute care setting clinicians address various infection risks at once, particularly 

Led by Nikhil Ram Mohan, PhD, of the Stanford University School of Medicine’s emergency medicine department, investigators sought to assess the accuracy of the IMX-BVN-3 and IMX-SEV-3 host response classifiers in detecting SARS-CoV-2 infection, bacterial co-infections and superinfections, and predicting severity of COVID-19 disease in confirmed patients.

The team, supported by diagnostic company Inflammatix Inc., emphasized the potential significance of platforms being capable of providing such accuracy for coinciding risks during the ongoing pandemic. The 2 classifiers included in the study have been reported, they wrote, to help accurately determine both the likelihood of bacterial and viral infection—from very unlikely to very likely—and severity of illness—from low to high—in patients without COVID-19.

“The major clinical challenges currently faced by emergency department (ED) clinicians assessing patients with suspected infection include accurate identification of COVID-19, detection of bacterial co- or superinfection, and determination of severity of illness,” Mohan and colleagues wrote. “Currently no single biomarker or clinical algorithm can perform all 3 critical roles.”

Their assessment included 161 patients with PCR-confirmed COVID-19 infection who were enrolled through the Stanford University Medical Center. Median patient age was 50.0 years old; 52.2% were female. Approximately half (51.0%) were hospitalized during the assessment, and 9 had died.

Investigators extracted RNA via 2.5 mL whole blood samples assayed through PAXgene Blood RNA, and 29 host mRNAs were quantified via Nanostring nCounter. COVID-19 and bacterial co-infection or superinfection risks were defined as very unlikely, unlikely, likely, or very likely. Disease severity risks were defined as low, moderate, or high.

Nearly all patients (n = 151 [93.8%]) were allocated into the Very Likely or Likely viral bands; 5 patients each were placed into the Unlikely and Very Unlikely viral bands. Of the latter 10 patients, 6 had positive COVID-19 tests >9 days prior to admission; the remaining 4 had results oscillating between positive or negative, or were asymptomatic.

Regarding bacterial infection risk, 155 (96.3%) were classified in the Unlikely or Very Unlikely groups; 6 were classified as Likely. Of the latter 6, clinical adjudication confirmed that 4 (66.7%) had either bacterial coinfection 

colitis, fecal pathogens in urine, or clinically suspected bacterial superinfections. All 9 patients to die during hospitalization came from either the Low (n = 2 [2.8%]) or Moderate (n = 7 [11.7%]) severity disease classifications.

“In conclusion, IMX-BVN-3/SEV-3 accurately identified patients with COVID-19, bacterial co/ superinfections, and stratified clinical outcomes,” investigators wrote. “Such a multifaceted host response-based platform could improve ED patient management, accurate diagnoses, and optimized resource utilization.”

The study, “29-mRNA Host Response Classifier Detects Bacterial Co-infection and Superinfection and Predicts Outcomes in COVID-19 Patients,” was presented at SAEM 2022.

New data suggest prediction of SARS-CoV-2 and bacterial co-infection or superinfection could be provided for hospitalized patients.