Pharmacology

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

Psilocybin paired with psychotherapy is associated with a robust and sustained decrease in drinking among adults with alcohol use disorder (AUD), new research suggests.

Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.

In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.

The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.

If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.

The findings were published online in JAMA Psychiatry.

83% reduction in drinking days

The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.

Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.

The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.

The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.

The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).

“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.

During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.

“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.

Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.

‘Encouraged and hopeful’

Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.

However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.

A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.

This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.

Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.

Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.

“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.

Urgent need

The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”

Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”

They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.

“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.

The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Psilocybin paired with psychotherapy is associated with a robust and sustained decrease in drinking among adults with alcohol use disorder (AUD), new research suggests.

Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.

In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.

The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.

If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.

The findings were published online in JAMA Psychiatry.

83% reduction in drinking days

The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.

Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.

The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.

The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.

The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).

“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.

During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.

“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.

Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.

‘Encouraged and hopeful’

Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.

However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.

A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.

This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.

Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.

Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.

“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.

Urgent need

The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”

Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”

They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.

“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.

The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Psilocybin paired with psychotherapy is associated with a robust and sustained decrease in drinking among adults with alcohol use disorder (AUD), new research suggests.

Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.

In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.

The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.

If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.

The findings were published online in JAMA Psychiatry.

83% reduction in drinking days

The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.

Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.

The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.

The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.

The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).

“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.

During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.

“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.

Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.

‘Encouraged and hopeful’

Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.

However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.

A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.

This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.

Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.

Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.

“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.

Urgent need

The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”

Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”

They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.

“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.

The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Use of the epidermal growth-factor receptor inhibitor erlotinib led to about a 30% reduction in duodenal polyp burden after 6 months of once-weekly treatment for patients with familial adenomatous polyposis (FAP) in a phase 2 clinical trial.

“If existing data are confirmed and extended through future research, this strategy has the potential for substantial impact on clinical practice by decreasing, delaying, or augmenting endoscopic and surgical interventions as the mainstay for duodenal cancer prevention in this high-risk patient population,” the study team says.

FAP is a rare genetic condition that markedly raises the risk for colorectal polyps and cancer.

“The biological pathway that leads to the development of polyps and colon cancer in patients with FAP is the same biological pathway as patients in the general population,” study investigator Niloy Jewel Samadder, MD, with the Mayo Clinic, Rochester, Minn., said in a news release.

“Our trial looked at opportunities to use chemoprevention agents in patients with FAP to inhibit the development of precancerous polyps in the small bowel and colorectum,” Dr. Samadder explains.

In an earlier study, the researchers found that the combination of the COX-2 inhibitor sulindac (150 mg twice daily) and erlotinib (75 mg daily) reduced duodenal polyp burden.

However, the dual-drug strategy was associated with a relatively high adverse event (AE) rate, which may limit use of the combination for chemoprevention, as reported previously.

This phase 2 study tested whether erlotinib’s AE profile would be improved with a once-weekly dosing schedule while still reducing polyp burden.

The study was first published online in the journal Gut.

In the single-arm, multicenter study, 46 adults with FAP (mean age, 44 years; 48% women) self-administered 350 mg of erlotinib by mouth one time per week for 6 months. All but four participants completed the 6-month study.

After 6 months of weekly erlotinib, duodenal polyp burden was significantly reduced, with a mean percent reduction of 29.6% (95% confidence interval: –39.6% to –19.7%; P < .0001).

The benefit was observed in patients with either Spigelman 2 or Spigelman 3 duodenal polyp burden.

“Though only 12% of patients noted a decrease in Spigelman stage from 3 to 2 associated with therapy, the majority of patients (86%) had stable disease while on treatment,” the study team reports.

GI polyp number (a secondary outcome) was also decreased after 6 months of treatment with erlotinib (median decrease of 30.8%; P = .0256).

While once-weekly erlotinib was “generally” well tolerated, grade 2 or 3 AEs were reported in 72% of patients; two suffered grade 3 toxicity. Nonetheless, the AE rate was significantly more than the expected null hypothesis rate of 50%, the study team states.

Four patients withdrew from the study because of drug-induced AEs, which included grade 3 rash acneiform, grade 2 infections (hand, foot, and mouth disease), grade 1 fatigue, and grade 1 rash acneiform. No grade 4 AEs were reported.

The most common AE was an erlotinib-induced acneiform-like rash, which occurred in 56.5% of study patients. The rash was managed with topical cortisone and/or clindamycin. Additional erlotinib-induced AEs included oral mucositis (6.5%), diarrhea (50%), and nausea (26.1%).

Summing up, Dr. Samadder and colleagues note that FAP “portends a heritable, systemic predisposition to cancer, and the ultimate goal of cancer preventive intervention is to interrupt the development of neoplasia, need for surgery, and ultimately death from cancer, with an acceptable AE profile.”

The findings from this phase 2 trial support further study of erlotinib as “an effective, acceptable cancer preventive agent for FAP-associated gastrointestinal polyposis,” they conclude.

The study was sponsored by the National Cancer Institute. Dr. Samadder is a consultant for Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals.

A version of this article first appeared on Medscape.com.

Use of the epidermal growth-factor receptor inhibitor erlotinib led to about a 30% reduction in duodenal polyp burden after 6 months of once-weekly treatment for patients with familial adenomatous polyposis (FAP) in a phase 2 clinical trial.

“If existing data are confirmed and extended through future research, this strategy has the potential for substantial impact on clinical practice by decreasing, delaying, or augmenting endoscopic and surgical interventions as the mainstay for duodenal cancer prevention in this high-risk patient population,” the study team says.

FAP is a rare genetic condition that markedly raises the risk for colorectal polyps and cancer.

“The biological pathway that leads to the development of polyps and colon cancer in patients with FAP is the same biological pathway as patients in the general population,” study investigator Niloy Jewel Samadder, MD, with the Mayo Clinic, Rochester, Minn., said in a news release.

“Our trial looked at opportunities to use chemoprevention agents in patients with FAP to inhibit the development of precancerous polyps in the small bowel and colorectum,” Dr. Samadder explains.

In an earlier study, the researchers found that the combination of the COX-2 inhibitor sulindac (150 mg twice daily) and erlotinib (75 mg daily) reduced duodenal polyp burden.

However, the dual-drug strategy was associated with a relatively high adverse event (AE) rate, which may limit use of the combination for chemoprevention, as reported previously.

This phase 2 study tested whether erlotinib’s AE profile would be improved with a once-weekly dosing schedule while still reducing polyp burden.

The study was first published online in the journal Gut.

In the single-arm, multicenter study, 46 adults with FAP (mean age, 44 years; 48% women) self-administered 350 mg of erlotinib by mouth one time per week for 6 months. All but four participants completed the 6-month study.

After 6 months of weekly erlotinib, duodenal polyp burden was significantly reduced, with a mean percent reduction of 29.6% (95% confidence interval: –39.6% to –19.7%; P < .0001).

The benefit was observed in patients with either Spigelman 2 or Spigelman 3 duodenal polyp burden.

“Though only 12% of patients noted a decrease in Spigelman stage from 3 to 2 associated with therapy, the majority of patients (86%) had stable disease while on treatment,” the study team reports.

GI polyp number (a secondary outcome) was also decreased after 6 months of treatment with erlotinib (median decrease of 30.8%; P = .0256).

While once-weekly erlotinib was “generally” well tolerated, grade 2 or 3 AEs were reported in 72% of patients; two suffered grade 3 toxicity. Nonetheless, the AE rate was significantly more than the expected null hypothesis rate of 50%, the study team states.

Four patients withdrew from the study because of drug-induced AEs, which included grade 3 rash acneiform, grade 2 infections (hand, foot, and mouth disease), grade 1 fatigue, and grade 1 rash acneiform. No grade 4 AEs were reported.

The most common AE was an erlotinib-induced acneiform-like rash, which occurred in 56.5% of study patients. The rash was managed with topical cortisone and/or clindamycin. Additional erlotinib-induced AEs included oral mucositis (6.5%), diarrhea (50%), and nausea (26.1%).

Summing up, Dr. Samadder and colleagues note that FAP “portends a heritable, systemic predisposition to cancer, and the ultimate goal of cancer preventive intervention is to interrupt the development of neoplasia, need for surgery, and ultimately death from cancer, with an acceptable AE profile.”

The findings from this phase 2 trial support further study of erlotinib as “an effective, acceptable cancer preventive agent for FAP-associated gastrointestinal polyposis,” they conclude.

The study was sponsored by the National Cancer Institute. Dr. Samadder is a consultant for Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals.

A version of this article first appeared on Medscape.com.

Use of the epidermal growth-factor receptor inhibitor erlotinib led to about a 30% reduction in duodenal polyp burden after 6 months of once-weekly treatment for patients with familial adenomatous polyposis (FAP) in a phase 2 clinical trial.

“If existing data are confirmed and extended through future research, this strategy has the potential for substantial impact on clinical practice by decreasing, delaying, or augmenting endoscopic and surgical interventions as the mainstay for duodenal cancer prevention in this high-risk patient population,” the study team says.

FAP is a rare genetic condition that markedly raises the risk for colorectal polyps and cancer.

“The biological pathway that leads to the development of polyps and colon cancer in patients with FAP is the same biological pathway as patients in the general population,” study investigator Niloy Jewel Samadder, MD, with the Mayo Clinic, Rochester, Minn., said in a news release.

“Our trial looked at opportunities to use chemoprevention agents in patients with FAP to inhibit the development of precancerous polyps in the small bowel and colorectum,” Dr. Samadder explains.

In an earlier study, the researchers found that the combination of the COX-2 inhibitor sulindac (150 mg twice daily) and erlotinib (75 mg daily) reduced duodenal polyp burden.

However, the dual-drug strategy was associated with a relatively high adverse event (AE) rate, which may limit use of the combination for chemoprevention, as reported previously.

This phase 2 study tested whether erlotinib’s AE profile would be improved with a once-weekly dosing schedule while still reducing polyp burden.

The study was first published online in the journal Gut.

In the single-arm, multicenter study, 46 adults with FAP (mean age, 44 years; 48% women) self-administered 350 mg of erlotinib by mouth one time per week for 6 months. All but four participants completed the 6-month study.

After 6 months of weekly erlotinib, duodenal polyp burden was significantly reduced, with a mean percent reduction of 29.6% (95% confidence interval: –39.6% to –19.7%; P < .0001).

The benefit was observed in patients with either Spigelman 2 or Spigelman 3 duodenal polyp burden.

“Though only 12% of patients noted a decrease in Spigelman stage from 3 to 2 associated with therapy, the majority of patients (86%) had stable disease while on treatment,” the study team reports.

GI polyp number (a secondary outcome) was also decreased after 6 months of treatment with erlotinib (median decrease of 30.8%; P = .0256).

While once-weekly erlotinib was “generally” well tolerated, grade 2 or 3 AEs were reported in 72% of patients; two suffered grade 3 toxicity. Nonetheless, the AE rate was significantly more than the expected null hypothesis rate of 50%, the study team states.

Four patients withdrew from the study because of drug-induced AEs, which included grade 3 rash acneiform, grade 2 infections (hand, foot, and mouth disease), grade 1 fatigue, and grade 1 rash acneiform. No grade 4 AEs were reported.

The most common AE was an erlotinib-induced acneiform-like rash, which occurred in 56.5% of study patients. The rash was managed with topical cortisone and/or clindamycin. Additional erlotinib-induced AEs included oral mucositis (6.5%), diarrhea (50%), and nausea (26.1%).

Summing up, Dr. Samadder and colleagues note that FAP “portends a heritable, systemic predisposition to cancer, and the ultimate goal of cancer preventive intervention is to interrupt the development of neoplasia, need for surgery, and ultimately death from cancer, with an acceptable AE profile.”

The findings from this phase 2 trial support further study of erlotinib as “an effective, acceptable cancer preventive agent for FAP-associated gastrointestinal polyposis,” they conclude.

The study was sponsored by the National Cancer Institute. Dr. Samadder is a consultant for Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals.

A version of this article first appeared on Medscape.com.

PORTLAND, ORE. – For those who hesitate to prescribe Janus kinase inhibitors for patients with moderate to severe atopic dermatitis (AD) because of the boxed warnings on currently approved agents, it’s time to reconsider, according to Andrew Blauvelt, MD, MBA.

“In dermatology, you need to know about JAK inhibitors, and you need to know how to use them,” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the annual meeting of the Pacific Dermatologic Association. “Making the choice, ‘I’m not going to use those drugs because of safety concerns,’ may be okay in 2022, but we are going to be getting a lot more indications for these drugs. So instead of avoiding JAK inhibitors, I would say try to learn [about] them, understand them, and get your messaging out on safety.”

It’s difficult to imagine a clinician-researcher who has more experience with the use of biologics and JAK inhibitors in AD than Dr. Blauvelt, who has been the international investigator on several important trials of treatments that include dupilumab, tralokinumab, abrocitinib, and upadacitinib for AD such as CHRONOS, ECZTEND, JADE REGIMEN, and HEADS UP. At the meeting, he discussed his clinical approach to selecting systemic agents for AD and shared prescribing tips. He began by noting that the approval of dupilumab for moderate to severe AD in 2017 ushered in a new era of treating the disease systemically.

“When it was approved, experts went right to dupilumab if they could, and avoided the use of cyclosporine or methotrexate,” said Dr. Blauvelt, who is also an elected member of the American Society for Clinical Investigation and the International Eczema Council. “I still think that dupilumab is a great agent to start with. We’ve had a bit of difficulty improving upon it.”

Following dupilumab’s approval, three other systemic options became available for patients with moderate to severe AD: the human IgG4 monoclonal antibody tralokinumab that binds to interleukin-13, which is administered subcutaneously; and, more recently, the oral JAK inhibitors abrocitinib and upadacitinib, approved in January for moderate to severe AD.

“I’m a big fan of JAK inhibitors because I think they offer things that biologic and topical therapies can’t offer,” Dr. Blauvelt said. “Patients like the pills versus shots. They also like the speed; JAK inhibitors work faster than dupilumab and tralokinumab. So, if you have a patient with bad AD who wants to get better quickly, that would be a reason to choose a JAK inhibitor over a biologic if you can.”

When Dr. Blauvelt has asked AD clinical trial participants if they’d rather be treated with a biologic agent or with a JAK inhibitor, about half choose one over the other.

“Patients who shy away from the safety issues would choose the biologic trial while the ones who wanted the fast relief would choose the JAK trial,” he said. “But if you present both options and the patients prefer a pill, I think the JAK inhibitors do better with a rapid control of inflammation as well as pruritus – the latter within 2 days of taking the pills.”

When counseling patients initiating a JAK inhibitor, Dr. Blauvelt mentioned three advantages, compared with biologics: the pill formulation, the rapidity of response in pruritus control, and better efficacy. “The downside is the safety,” he said. “Safety is the elephant in the room for the JAK inhibitors.”

The risks listed in the boxed warning in the labeling for JAK inhibitors include: an increased risk of serious bacterial, fungal, and opportunistic infections such as TB; a higher rate of all-cause mortality, including cardiovascular death; a higher rate of MACE (major adverse cardiovascular events, defined as cardiovascular death, MI, and stroke); the potential for malignancy, including lymphoma; and the potential for thrombosis, including an increased incidence of pulmonary embolism (PE).

“Risk of thrombosis seems to be a class effect for all JAK inhibitors,” Dr. Blauvelt said. “As far as I know, it’s idiosyncratic. For nearly all the DVT [deep vein thrombosis] cases that have been reported, patients had baseline risk factors for DVT and PE, which are obesity, smoking, and use of oral contraceptives.”

Dr. Blauvelt pointed out that the boxed warning related to mortality, malignancies, and MACE stemmed from a long-term trial of the JAK inhibitor tofacitinib in RA patients. “Those patients had to be at least 50 years old, 75% of them were on concomitant methotrexate and/or prednisone, and they had to have at least one cardiac risk factor to get into the trial,” he said.

“I’m not saying those things can’t happen in dermatology patients, but if you look at the safety data of JAK inhibitors in the AD studies and in the alopecia areata studies, we are seeing a few cases of these things here and there, but not major signals,” he said. To date, “they look safer in dermatologic diseases compared to tofacitinib in RA data in older populations.”

He emphasized the importance of discussing each of the risks in the boxed warning with patients who are candidates for JAK inhibitor therapy.

Dr. Blauvelt likened the lab monitoring required for JAK inhibitors to that required for methotrexate. This means ordering at baseline, a CBC with differential, a chem-20, a lipid panel, and a QuantiFERON-TB Gold test. The JAK inhibitor labels do not include information on the frequency of monitoring, “but I have a distinct opinion on this because of my blood test monitoring experience in the trials for many years,” he said.

“I think it’s good to do follow-up testing at 1 month, then every 3 months in the first year. In my experience, the people who drop blood cell counts or increase their lipids tend to do it in the first year.”

After 1 year of treatment, he continued, follow-up testing once every 6 months is reasonable. “If CPK [creatine phosphokinase] goes up, I don’t worry about it; it’s not clinically relevant. There is no recommendation for CPK monitoring, so if you’re getting that on your chem-20, I’d say don’t worry about it.”

Dr. Blauvelt reported that he is an investigator and a scientific adviser for several pharmaceutical companies developing treatments for AD, including companies that are evaluating or marketing JAK inhibitors for AD, including AbbVie, Incyte, and Pfizer, as well as dupilumab’s joint developers Sanofi and Regeneron.

PORTLAND, ORE. – For those who hesitate to prescribe Janus kinase inhibitors for patients with moderate to severe atopic dermatitis (AD) because of the boxed warnings on currently approved agents, it’s time to reconsider, according to Andrew Blauvelt, MD, MBA.

“In dermatology, you need to know about JAK inhibitors, and you need to know how to use them,” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the annual meeting of the Pacific Dermatologic Association. “Making the choice, ‘I’m not going to use those drugs because of safety concerns,’ may be okay in 2022, but we are going to be getting a lot more indications for these drugs. So instead of avoiding JAK inhibitors, I would say try to learn [about] them, understand them, and get your messaging out on safety.”

It’s difficult to imagine a clinician-researcher who has more experience with the use of biologics and JAK inhibitors in AD than Dr. Blauvelt, who has been the international investigator on several important trials of treatments that include dupilumab, tralokinumab, abrocitinib, and upadacitinib for AD such as CHRONOS, ECZTEND, JADE REGIMEN, and HEADS UP. At the meeting, he discussed his clinical approach to selecting systemic agents for AD and shared prescribing tips. He began by noting that the approval of dupilumab for moderate to severe AD in 2017 ushered in a new era of treating the disease systemically.

“When it was approved, experts went right to dupilumab if they could, and avoided the use of cyclosporine or methotrexate,” said Dr. Blauvelt, who is also an elected member of the American Society for Clinical Investigation and the International Eczema Council. “I still think that dupilumab is a great agent to start with. We’ve had a bit of difficulty improving upon it.”

Following dupilumab’s approval, three other systemic options became available for patients with moderate to severe AD: the human IgG4 monoclonal antibody tralokinumab that binds to interleukin-13, which is administered subcutaneously; and, more recently, the oral JAK inhibitors abrocitinib and upadacitinib, approved in January for moderate to severe AD.

“I’m a big fan of JAK inhibitors because I think they offer things that biologic and topical therapies can’t offer,” Dr. Blauvelt said. “Patients like the pills versus shots. They also like the speed; JAK inhibitors work faster than dupilumab and tralokinumab. So, if you have a patient with bad AD who wants to get better quickly, that would be a reason to choose a JAK inhibitor over a biologic if you can.”

When Dr. Blauvelt has asked AD clinical trial participants if they’d rather be treated with a biologic agent or with a JAK inhibitor, about half choose one over the other.

“Patients who shy away from the safety issues would choose the biologic trial while the ones who wanted the fast relief would choose the JAK trial,” he said. “But if you present both options and the patients prefer a pill, I think the JAK inhibitors do better with a rapid control of inflammation as well as pruritus – the latter within 2 days of taking the pills.”

When counseling patients initiating a JAK inhibitor, Dr. Blauvelt mentioned three advantages, compared with biologics: the pill formulation, the rapidity of response in pruritus control, and better efficacy. “The downside is the safety,” he said. “Safety is the elephant in the room for the JAK inhibitors.”

The risks listed in the boxed warning in the labeling for JAK inhibitors include: an increased risk of serious bacterial, fungal, and opportunistic infections such as TB; a higher rate of all-cause mortality, including cardiovascular death; a higher rate of MACE (major adverse cardiovascular events, defined as cardiovascular death, MI, and stroke); the potential for malignancy, including lymphoma; and the potential for thrombosis, including an increased incidence of pulmonary embolism (PE).

“Risk of thrombosis seems to be a class effect for all JAK inhibitors,” Dr. Blauvelt said. “As far as I know, it’s idiosyncratic. For nearly all the DVT [deep vein thrombosis] cases that have been reported, patients had baseline risk factors for DVT and PE, which are obesity, smoking, and use of oral contraceptives.”

Dr. Blauvelt pointed out that the boxed warning related to mortality, malignancies, and MACE stemmed from a long-term trial of the JAK inhibitor tofacitinib in RA patients. “Those patients had to be at least 50 years old, 75% of them were on concomitant methotrexate and/or prednisone, and they had to have at least one cardiac risk factor to get into the trial,” he said.

“I’m not saying those things can’t happen in dermatology patients, but if you look at the safety data of JAK inhibitors in the AD studies and in the alopecia areata studies, we are seeing a few cases of these things here and there, but not major signals,” he said. To date, “they look safer in dermatologic diseases compared to tofacitinib in RA data in older populations.”

He emphasized the importance of discussing each of the risks in the boxed warning with patients who are candidates for JAK inhibitor therapy.

Dr. Blauvelt likened the lab monitoring required for JAK inhibitors to that required for methotrexate. This means ordering at baseline, a CBC with differential, a chem-20, a lipid panel, and a QuantiFERON-TB Gold test. The JAK inhibitor labels do not include information on the frequency of monitoring, “but I have a distinct opinion on this because of my blood test monitoring experience in the trials for many years,” he said.

“I think it’s good to do follow-up testing at 1 month, then every 3 months in the first year. In my experience, the people who drop blood cell counts or increase their lipids tend to do it in the first year.”

After 1 year of treatment, he continued, follow-up testing once every 6 months is reasonable. “If CPK [creatine phosphokinase] goes up, I don’t worry about it; it’s not clinically relevant. There is no recommendation for CPK monitoring, so if you’re getting that on your chem-20, I’d say don’t worry about it.”

Dr. Blauvelt reported that he is an investigator and a scientific adviser for several pharmaceutical companies developing treatments for AD, including companies that are evaluating or marketing JAK inhibitors for AD, including AbbVie, Incyte, and Pfizer, as well as dupilumab’s joint developers Sanofi and Regeneron.

PORTLAND, ORE. – For those who hesitate to prescribe Janus kinase inhibitors for patients with moderate to severe atopic dermatitis (AD) because of the boxed warnings on currently approved agents, it’s time to reconsider, according to Andrew Blauvelt, MD, MBA.

“In dermatology, you need to know about JAK inhibitors, and you need to know how to use them,” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the annual meeting of the Pacific Dermatologic Association. “Making the choice, ‘I’m not going to use those drugs because of safety concerns,’ may be okay in 2022, but we are going to be getting a lot more indications for these drugs. So instead of avoiding JAK inhibitors, I would say try to learn [about] them, understand them, and get your messaging out on safety.”

It’s difficult to imagine a clinician-researcher who has more experience with the use of biologics and JAK inhibitors in AD than Dr. Blauvelt, who has been the international investigator on several important trials of treatments that include dupilumab, tralokinumab, abrocitinib, and upadacitinib for AD such as CHRONOS, ECZTEND, JADE REGIMEN, and HEADS UP. At the meeting, he discussed his clinical approach to selecting systemic agents for AD and shared prescribing tips. He began by noting that the approval of dupilumab for moderate to severe AD in 2017 ushered in a new era of treating the disease systemically.

“When it was approved, experts went right to dupilumab if they could, and avoided the use of cyclosporine or methotrexate,” said Dr. Blauvelt, who is also an elected member of the American Society for Clinical Investigation and the International Eczema Council. “I still think that dupilumab is a great agent to start with. We’ve had a bit of difficulty improving upon it.”

Following dupilumab’s approval, three other systemic options became available for patients with moderate to severe AD: the human IgG4 monoclonal antibody tralokinumab that binds to interleukin-13, which is administered subcutaneously; and, more recently, the oral JAK inhibitors abrocitinib and upadacitinib, approved in January for moderate to severe AD.

“I’m a big fan of JAK inhibitors because I think they offer things that biologic and topical therapies can’t offer,” Dr. Blauvelt said. “Patients like the pills versus shots. They also like the speed; JAK inhibitors work faster than dupilumab and tralokinumab. So, if you have a patient with bad AD who wants to get better quickly, that would be a reason to choose a JAK inhibitor over a biologic if you can.”

When Dr. Blauvelt has asked AD clinical trial participants if they’d rather be treated with a biologic agent or with a JAK inhibitor, about half choose one over the other.

“Patients who shy away from the safety issues would choose the biologic trial while the ones who wanted the fast relief would choose the JAK trial,” he said. “But if you present both options and the patients prefer a pill, I think the JAK inhibitors do better with a rapid control of inflammation as well as pruritus – the latter within 2 days of taking the pills.”

When counseling patients initiating a JAK inhibitor, Dr. Blauvelt mentioned three advantages, compared with biologics: the pill formulation, the rapidity of response in pruritus control, and better efficacy. “The downside is the safety,” he said. “Safety is the elephant in the room for the JAK inhibitors.”

The risks listed in the boxed warning in the labeling for JAK inhibitors include: an increased risk of serious bacterial, fungal, and opportunistic infections such as TB; a higher rate of all-cause mortality, including cardiovascular death; a higher rate of MACE (major adverse cardiovascular events, defined as cardiovascular death, MI, and stroke); the potential for malignancy, including lymphoma; and the potential for thrombosis, including an increased incidence of pulmonary embolism (PE).

“Risk of thrombosis seems to be a class effect for all JAK inhibitors,” Dr. Blauvelt said. “As far as I know, it’s idiosyncratic. For nearly all the DVT [deep vein thrombosis] cases that have been reported, patients had baseline risk factors for DVT and PE, which are obesity, smoking, and use of oral contraceptives.”

Dr. Blauvelt pointed out that the boxed warning related to mortality, malignancies, and MACE stemmed from a long-term trial of the JAK inhibitor tofacitinib in RA patients. “Those patients had to be at least 50 years old, 75% of them were on concomitant methotrexate and/or prednisone, and they had to have at least one cardiac risk factor to get into the trial,” he said.

“I’m not saying those things can’t happen in dermatology patients, but if you look at the safety data of JAK inhibitors in the AD studies and in the alopecia areata studies, we are seeing a few cases of these things here and there, but not major signals,” he said. To date, “they look safer in dermatologic diseases compared to tofacitinib in RA data in older populations.”

He emphasized the importance of discussing each of the risks in the boxed warning with patients who are candidates for JAK inhibitor therapy.

Dr. Blauvelt likened the lab monitoring required for JAK inhibitors to that required for methotrexate. This means ordering at baseline, a CBC with differential, a chem-20, a lipid panel, and a QuantiFERON-TB Gold test. The JAK inhibitor labels do not include information on the frequency of monitoring, “but I have a distinct opinion on this because of my blood test monitoring experience in the trials for many years,” he said.

“I think it’s good to do follow-up testing at 1 month, then every 3 months in the first year. In my experience, the people who drop blood cell counts or increase their lipids tend to do it in the first year.”

After 1 year of treatment, he continued, follow-up testing once every 6 months is reasonable. “If CPK [creatine phosphokinase] goes up, I don’t worry about it; it’s not clinically relevant. There is no recommendation for CPK monitoring, so if you’re getting that on your chem-20, I’d say don’t worry about it.”

Dr. Blauvelt reported that he is an investigator and a scientific adviser for several pharmaceutical companies developing treatments for AD, including companies that are evaluating or marketing JAK inhibitors for AD, including AbbVie, Incyte, and Pfizer, as well as dupilumab’s joint developers Sanofi and Regeneron.

The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.

Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).

It is the “first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week,” the company said in a news release.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release. 
 

‘Milestone’ in depression treatment?

Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.

“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.

The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.

The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which  compared it with bupropion sustained-release tablets.

Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.

The full prescribing information and medication guide are available online.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.

Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).

It is the “first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week,” the company said in a news release.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release. 
 

‘Milestone’ in depression treatment?

Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.

“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.

The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.

The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which  compared it with bupropion sustained-release tablets.

Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.

The full prescribing information and medication guide are available online.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.

Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).

It is the “first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week,” the company said in a news release.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release. 
 

‘Milestone’ in depression treatment?

Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.

“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.

The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.

The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which  compared it with bupropion sustained-release tablets.

Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.

The full prescribing information and medication guide are available online.

A version of this article first appeared on Medscape.com.

The strongest evidence yet to support clinical guidelines that recommend that people at high risk of endocarditis, such as those who’ve had previous episode the disease or who have a prosthetic cardiac valve, should take antibiotics before they have a tooth pulled or other types of oral surgery, comes from a new study that used two methodologies.

But it also pointed out that two-thirds of the time they aren’t getting that type of antibiotic coverage.

RobertoDavid/iStock/Getty Images Plus

The researchers conducted a cohort study of almost 8 million retirees with employer-paid Medicare supplemental prescription benefits and dental benefits, then conducted a case-crossover study of 3,774 people from the cohort who’d been hospitalized with infectious endocarditis (IE) and who had invasive dental procedures. The bottom line is that the study supports the clinical guidelines from the American Heart Association and the European Society of Cardiology that recommend antibiotic prophylaxis (AP) before dental procedures for patients at high-risk of IE.

Likewise, lead author Martin Thornhill, MBBS, BDS, PhD, said in an interview, the findings also suggest that existing guidelines in the United Kingdom, which recommend against AP in these patients, “should be reconsidered.”

Those AHA and ESC guidelines, however,  are “based on no good quality evidence,” said Dr. Thornhill, professor of translational research in dentistry at the University of Sheffield (England) School of Clinical Dentistry. “Other studies have looked at this, but we’ve done the largest study that has shown the clear association between invasive dental procedures and subsequent development of infective endocarditis.”

In the entire cohort of 7.95 million patients, 3,774 had cases of IE that required hospitalization. The study defined highest risk of IE as meeting one of these six criteria: a previous case of IE; a prosthetic cardiac valve or a valve repair that used prosthetic material; cyanotic congenital heart disease; palliative shunts or conduits to treat CHD; or a congenital heart defect that had been fully repaired, either by  surgery or a transcatheter procedure, with prosthetic material or device – the latter within 6 months of the procedure.

Moderate IE risk included patients who had rheumatic heart disease, nonrheumatic valve disease or congenital valve anomalies—including mitral valve prolapse or aortic stenosis—or hypertrophic cardiomyopathy.

 

Risk classification and poor compliance

Highest-risk patients had significantly higher rates of IE a month after a dental procedure than lower-risk groups:  467.6 cases per 1 million procedures vs. 24.2 for moderate risk and 3.8 for low or unknown risk. A subanalysis found that the odds of IE were significantly increased for two specific dental procedures: extractions, with an odds ratio of 9.22 (95% confidence interval [CI], 5.54-15.88; P < .0001); and other oral surgical procedures, with an OR of 20.18 (95% CI, 11.22-37.74; P < .0001).

The study also found that 32.6% of the high-risk patients undergoing dental procedures got AP. “Clearly that shows a low level of compliance with the guidelines in the U.S.,” Dr. Thornhill said. “That’s something that needs to be addressed.”

The study was unique in that it used both a population cohort study and the case-crossover study. “It didn’t matter which of the two methods we used; we essentially came to the same result, which I think adds further weight to the findings,” Dr. Thornhill said.

This may be the best evidence to support the guidelines that clinicians may get. While the observational nature of this study has its limitations, conducting a randomized clinical trial to further validate the findings would be “logistically impossible,” he said, in that it would require an “absolutely enormous” cohort and coordination between medical and dental databases covering thousands of lives. An RCT would also require not using AP for some patients. “It’s not ethical to keep somebody off of antibiotic prophylaxis when there’s such a high risk of death and severe outcomes,” Dr. Thornhill said.

Ann Bolger, MD, emeritus professor of medicine at the University of California, San Francisco, and coauthor of an editorial comment on the study, said in an interview that this study is noteworthy not only for its dual methodology, but for the quality of the data that matched patients at high risk for IE with prescription and dental records. “The fact that they were able to have those details in enough granularity that they knew whether a dental procedure was likely to meet the criteria for these more invasive exposures really broke it open from my perspective,” she said.

She called the low compliance rate with AHA guidelines “one of the most sobering points of this,” and said it should put clinicians on notice that they must do more to educate and engage with high-risk patients. “The lines of communication here are somewhat fraught; it’s a little bit of a hot potato,” she said. “It’s a really great communications opportunity to get the provider’s attention back on this. You’re a cardiologist; you have to have this conversation when you see your patient with a prosthetic valve or who’s had endocarditis every time they come in. There’s a whole litany, and it takes 3 minutes, but you have to do it.”

The study received funding from Delta Dental of Michigan Research Committee and Renaissance Health Service Corp., and Dr. Thornhill received support from Delta Dental Research and Data Institute for the study. Dr. Bolger participated in the 2007 and 2021 AHA statements on AP to prevent IE.

The strongest evidence yet to support clinical guidelines that recommend that people at high risk of endocarditis, such as those who’ve had previous episode the disease or who have a prosthetic cardiac valve, should take antibiotics before they have a tooth pulled or other types of oral surgery, comes from a new study that used two methodologies.

But it also pointed out that two-thirds of the time they aren’t getting that type of antibiotic coverage.

RobertoDavid/iStock/Getty Images Plus

The researchers conducted a cohort study of almost 8 million retirees with employer-paid Medicare supplemental prescription benefits and dental benefits, then conducted a case-crossover study of 3,774 people from the cohort who’d been hospitalized with infectious endocarditis (IE) and who had invasive dental procedures. The bottom line is that the study supports the clinical guidelines from the American Heart Association and the European Society of Cardiology that recommend antibiotic prophylaxis (AP) before dental procedures for patients at high-risk of IE.

Likewise, lead author Martin Thornhill, MBBS, BDS, PhD, said in an interview, the findings also suggest that existing guidelines in the United Kingdom, which recommend against AP in these patients, “should be reconsidered.”

Those AHA and ESC guidelines, however,  are “based on no good quality evidence,” said Dr. Thornhill, professor of translational research in dentistry at the University of Sheffield (England) School of Clinical Dentistry. “Other studies have looked at this, but we’ve done the largest study that has shown the clear association between invasive dental procedures and subsequent development of infective endocarditis.”

In the entire cohort of 7.95 million patients, 3,774 had cases of IE that required hospitalization. The study defined highest risk of IE as meeting one of these six criteria: a previous case of IE; a prosthetic cardiac valve or a valve repair that used prosthetic material; cyanotic congenital heart disease; palliative shunts or conduits to treat CHD; or a congenital heart defect that had been fully repaired, either by  surgery or a transcatheter procedure, with prosthetic material or device – the latter within 6 months of the procedure.

Moderate IE risk included patients who had rheumatic heart disease, nonrheumatic valve disease or congenital valve anomalies—including mitral valve prolapse or aortic stenosis—or hypertrophic cardiomyopathy.

 

Risk classification and poor compliance

Highest-risk patients had significantly higher rates of IE a month after a dental procedure than lower-risk groups:  467.6 cases per 1 million procedures vs. 24.2 for moderate risk and 3.8 for low or unknown risk. A subanalysis found that the odds of IE were significantly increased for two specific dental procedures: extractions, with an odds ratio of 9.22 (95% confidence interval [CI], 5.54-15.88; P < .0001); and other oral surgical procedures, with an OR of 20.18 (95% CI, 11.22-37.74; P < .0001).

The study also found that 32.6% of the high-risk patients undergoing dental procedures got AP. “Clearly that shows a low level of compliance with the guidelines in the U.S.,” Dr. Thornhill said. “That’s something that needs to be addressed.”

The study was unique in that it used both a population cohort study and the case-crossover study. “It didn’t matter which of the two methods we used; we essentially came to the same result, which I think adds further weight to the findings,” Dr. Thornhill said.

This may be the best evidence to support the guidelines that clinicians may get. While the observational nature of this study has its limitations, conducting a randomized clinical trial to further validate the findings would be “logistically impossible,” he said, in that it would require an “absolutely enormous” cohort and coordination between medical and dental databases covering thousands of lives. An RCT would also require not using AP for some patients. “It’s not ethical to keep somebody off of antibiotic prophylaxis when there’s such a high risk of death and severe outcomes,” Dr. Thornhill said.

Ann Bolger, MD, emeritus professor of medicine at the University of California, San Francisco, and coauthor of an editorial comment on the study, said in an interview that this study is noteworthy not only for its dual methodology, but for the quality of the data that matched patients at high risk for IE with prescription and dental records. “The fact that they were able to have those details in enough granularity that they knew whether a dental procedure was likely to meet the criteria for these more invasive exposures really broke it open from my perspective,” she said.

She called the low compliance rate with AHA guidelines “one of the most sobering points of this,” and said it should put clinicians on notice that they must do more to educate and engage with high-risk patients. “The lines of communication here are somewhat fraught; it’s a little bit of a hot potato,” she said. “It’s a really great communications opportunity to get the provider’s attention back on this. You’re a cardiologist; you have to have this conversation when you see your patient with a prosthetic valve or who’s had endocarditis every time they come in. There’s a whole litany, and it takes 3 minutes, but you have to do it.”

The study received funding from Delta Dental of Michigan Research Committee and Renaissance Health Service Corp., and Dr. Thornhill received support from Delta Dental Research and Data Institute for the study. Dr. Bolger participated in the 2007 and 2021 AHA statements on AP to prevent IE.

The strongest evidence yet to support clinical guidelines that recommend that people at high risk of endocarditis, such as those who’ve had previous episode the disease or who have a prosthetic cardiac valve, should take antibiotics before they have a tooth pulled or other types of oral surgery, comes from a new study that used two methodologies.

But it also pointed out that two-thirds of the time they aren’t getting that type of antibiotic coverage.

RobertoDavid/iStock/Getty Images Plus

The researchers conducted a cohort study of almost 8 million retirees with employer-paid Medicare supplemental prescription benefits and dental benefits, then conducted a case-crossover study of 3,774 people from the cohort who’d been hospitalized with infectious endocarditis (IE) and who had invasive dental procedures. The bottom line is that the study supports the clinical guidelines from the American Heart Association and the European Society of Cardiology that recommend antibiotic prophylaxis (AP) before dental procedures for patients at high-risk of IE.

Likewise, lead author Martin Thornhill, MBBS, BDS, PhD, said in an interview, the findings also suggest that existing guidelines in the United Kingdom, which recommend against AP in these patients, “should be reconsidered.”

Those AHA and ESC guidelines, however,  are “based on no good quality evidence,” said Dr. Thornhill, professor of translational research in dentistry at the University of Sheffield (England) School of Clinical Dentistry. “Other studies have looked at this, but we’ve done the largest study that has shown the clear association between invasive dental procedures and subsequent development of infective endocarditis.”

In the entire cohort of 7.95 million patients, 3,774 had cases of IE that required hospitalization. The study defined highest risk of IE as meeting one of these six criteria: a previous case of IE; a prosthetic cardiac valve or a valve repair that used prosthetic material; cyanotic congenital heart disease; palliative shunts or conduits to treat CHD; or a congenital heart defect that had been fully repaired, either by  surgery or a transcatheter procedure, with prosthetic material or device – the latter within 6 months of the procedure.

Moderate IE risk included patients who had rheumatic heart disease, nonrheumatic valve disease or congenital valve anomalies—including mitral valve prolapse or aortic stenosis—or hypertrophic cardiomyopathy.

 

Risk classification and poor compliance

Highest-risk patients had significantly higher rates of IE a month after a dental procedure than lower-risk groups:  467.6 cases per 1 million procedures vs. 24.2 for moderate risk and 3.8 for low or unknown risk. A subanalysis found that the odds of IE were significantly increased for two specific dental procedures: extractions, with an odds ratio of 9.22 (95% confidence interval [CI], 5.54-15.88; P < .0001); and other oral surgical procedures, with an OR of 20.18 (95% CI, 11.22-37.74; P < .0001).

The study also found that 32.6% of the high-risk patients undergoing dental procedures got AP. “Clearly that shows a low level of compliance with the guidelines in the U.S.,” Dr. Thornhill said. “That’s something that needs to be addressed.”

The study was unique in that it used both a population cohort study and the case-crossover study. “It didn’t matter which of the two methods we used; we essentially came to the same result, which I think adds further weight to the findings,” Dr. Thornhill said.

This may be the best evidence to support the guidelines that clinicians may get. While the observational nature of this study has its limitations, conducting a randomized clinical trial to further validate the findings would be “logistically impossible,” he said, in that it would require an “absolutely enormous” cohort and coordination between medical and dental databases covering thousands of lives. An RCT would also require not using AP for some patients. “It’s not ethical to keep somebody off of antibiotic prophylaxis when there’s such a high risk of death and severe outcomes,” Dr. Thornhill said.

Ann Bolger, MD, emeritus professor of medicine at the University of California, San Francisco, and coauthor of an editorial comment on the study, said in an interview that this study is noteworthy not only for its dual methodology, but for the quality of the data that matched patients at high risk for IE with prescription and dental records. “The fact that they were able to have those details in enough granularity that they knew whether a dental procedure was likely to meet the criteria for these more invasive exposures really broke it open from my perspective,” she said.

She called the low compliance rate with AHA guidelines “one of the most sobering points of this,” and said it should put clinicians on notice that they must do more to educate and engage with high-risk patients. “The lines of communication here are somewhat fraught; it’s a little bit of a hot potato,” she said. “It’s a really great communications opportunity to get the provider’s attention back on this. You’re a cardiologist; you have to have this conversation when you see your patient with a prosthetic valve or who’s had endocarditis every time they come in. There’s a whole litany, and it takes 3 minutes, but you have to do it.”

The study received funding from Delta Dental of Michigan Research Committee and Renaissance Health Service Corp., and Dr. Thornhill received support from Delta Dental Research and Data Institute for the study. Dr. Bolger participated in the 2007 and 2021 AHA statements on AP to prevent IE.

Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.

Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.

New therapies sought

In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.

It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
 

Evoking emotions

A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.

Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).

Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.

Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.

Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).

These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.

In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.

Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
 

Ketamine’s effects

Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.

Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.

Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.

Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
 

Ketamine 2.0?

Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.

A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.

In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).

In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.

Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.

According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.

In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
 

Add-on psilocybin?

While ketamine is only suitable for acute intervention, owing to the short duration of effect, the effects of psilocybin can last for weeks or even months following administration, and this has been seen in more than just a few patients. What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.

The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.

The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
 

Two therapeutic settings

Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.

Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.

Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
 

Euphoria and disillusionment

The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.

“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.

“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
 

Outlook for psilocybin

Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.

“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”

In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.

Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.

In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
 

Possible psilocybin improvement?

Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.

In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.

When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.

A version of this article first appeared on Medscape.com.

Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.

Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.

New therapies sought

In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.

It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
 

Evoking emotions

A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.

Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).

Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.

Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.

Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).

These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.

In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.

Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
 

Ketamine’s effects

Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.

Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.

Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.

Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
 

Ketamine 2.0?

Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.

A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.

In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).

In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.

Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.

According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.

In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
 

Add-on psilocybin?

While ketamine is only suitable for acute intervention, owing to the short duration of effect, the effects of psilocybin can last for weeks or even months following administration, and this has been seen in more than just a few patients. What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.

The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.

The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
 

Two therapeutic settings

Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.

Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.

Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
 

Euphoria and disillusionment

The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.

“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.

“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
 

Outlook for psilocybin

Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.

“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”

In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.

Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.

In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
 

Possible psilocybin improvement?

Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.

In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.

When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.

A version of this article first appeared on Medscape.com.

Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.

Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.

New therapies sought

In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.

It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
 

Evoking emotions

A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.

Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).

Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.

Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.

Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).

These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.

In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.

Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
 

Ketamine’s effects

Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.

Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.

Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.

Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
 

Ketamine 2.0?

Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.

A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.

In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).

In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.

Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.

According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.

In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
 

Add-on psilocybin?

While ketamine is only suitable for acute intervention, owing to the short duration of effect, the effects of psilocybin can last for weeks or even months following administration, and this has been seen in more than just a few patients. What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.

The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.

The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
 

Two therapeutic settings

Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.

Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.

Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
 

Euphoria and disillusionment

The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.

“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.

“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
 

Outlook for psilocybin

Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.

“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”

In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.

Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.

In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
 

Possible psilocybin improvement?

Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.

In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.

When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.

A version of this article first appeared on Medscape.com.