Deborah Brauser

For years, electroconvulsive therapy (ECT) has been a lifesaving treatment for patients with treatment-resistant depression (TRD), yet exactly how it works has largely remained a mystery. Now researchers believe they have uncovered the underlying mechanisms behind its therapeutic effects — a discovery that may help clinicians better predict treatment response in individual patients and quell much of the fear and stigma associated with one of psychiatry’s most effective, yet misunderstood, treatments.

Two recent papers published in Translational Psychiatry have highlighted the significance of aperiodic neural activity. The first study showed this activity increased following ECT treatment. The second study expanded on these data by demonstrating a significant increase in aperiodic activity after patients received either ECT or magnetic seizure therapy (MST), which has a better side-effect profile than ECT but lower efficacy.

Aperiodic activity is “like the brain’s background noise, and for years scientists treated it that way and didn’t pay much attention to it,” first author Sydney E. Smith, a PhD candidate at the Voytek Lab in the Neuroscience Graduate Program at the University of California San Diego (UCSD), said in a press release.

However, aperiodic activity boosts inhibitory activity in the brain, effectively slowing it down,” the investigators noted.

In an interview with this news organization, Ms. Smith used a car analogy to explain the mechanism behind ECT. “ECT might be increasing the activity levels in the brain cells that help calm it down. It taps on the brakes that tend to malfunction in depression. By restoring the balance between the gas and the brakes in the brain, some of those depressive symptoms are alleviated,” she said.

Ms. Smith added her team’s research helps demystify one of the most effective yet stigmatized treatments for severe depression.

“Aperiodic activity as a physiologically interpretable EEG metric could be a really valuable new predictive indicator for treatment response,” she added.
 

Fear and Stigma

ECT is primarily used for TRD and is effective in up to 80% of patients, yet it remains one of the least prescribed treatments.

Although it’s been around for almost 90 years, fear and concern about its potential cognitive side effects have contributed to its poor uptake. It is estimated that less than 1% of patients with TRD receive ECT.

Smith noted that the 1970s movie One Flew Over the Cuckoo’s Nest still contributes to ECT’s stigma. In the film, actor Jack Nicholson’s character is forced to undergo ECT as a punishment.

It’s important for clinicians to acknowledge the stigma while advising patients that “the actual treatment doesn’t look anything like what’s in the movies,” noted Ms. Smith. Patients must give informed consent for the procedure, and it’s delivered with the lowest level of effective stimulation.

“So many steps are taken to consider comfort and efficacy for patients and to minimize how scary it can be,” she said.

ECT uses an electrical current to induce a seizure that spreads to deep subcortical structures. MST, which was developed as an alternative to ECT, uses a magnetic field to induce a more focal seizure primarily confined to the cortex.

Although MST has a better side-effect profile, experts noted it has remission rates of 30%-60% compared with ECT. Even one of MST’s inventors, Harold Sackeim, PhD, professor in the Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, is skeptical about its efficacy for TRD.

“I don’t think it works,” Dr. Sackeim, founding editor of Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, told this news organization.

In addition to being more expensive, MST produces a peak electrical intensity at one-tenth of what a typical ECT stimulus produces. “We’re limited by electrical engineering at this point with MST. That’s my view; others are more optimistic,” he said.
 

A Lifesaving Treatment

One of the reasons ECT isn’t more popular is because for many patients, it’s easier and more convenient to just take a pill, senior investigator Bradley Voytek, PhD, professor of cognitive science at UCSD, said in the release.

“However, in people for whom medications don’t work, [ECT] can be lifesaving. Understanding how it works will help us discover ways to increase the benefits while minimizing side effects,” he added.

In the first study, which included nine patients with major depressive disorder (MDD), EEG results showed an increase in aperiodic activity following ECT.

The investigators then wanted to test whether these findings could be replicated in a larger study. They retrospectively assessed two previous datasets — 1 of 22 patients with MDD who received ECT and 1 of 23 patients who received MST. After treatment, both groups showed increased aperiodic activity.

“Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST,” the investigators wrote.

The researchers noted that this increase in aperiodic activity is a more parsimonious explanation for observations of clinical slowing than delta band power or delta oscillations for both ECT and MST.”

So why is it important to know exactly how ECT works, and is there any clinical utility to these research findings?

“It’s important for clinicians to give a patient who has questions, a meaningful understanding of what the treatment is going to do, especially with something so scary and stigmatized. The ability to tell a patient why this treatment is working could provide a level of comfort that can assuage some of these fears,” Ms. Smith said.
 

A New Predictor of Response?

In addition, she noted that psychiatry is becoming more focused on predictive indicators for treatment.

“It’s asking: Are there any biological measures that can be used to predict whether someone is going to respond to a treatment or not?” said Ms. Smith.

“Aperiodic activity might be a valuable asset to add to that arsenal. Maybe we can better predict which patients might respond to ECT by using this as an additional biological indicator,” she added.

Smith noted that while more studies are needed, it’s exciting that some investigators are already starting to include aperiodic activity as a variable in their research analyses on a variety of topics, such as pharmacological intervention and transcranial magnetic stimulation.

“I don’t know exactly how much utility aperiodic activity is going to have in terms of being a great biological indicator, but I hope that the research will start to play out and reveal a little bit more,” she said.

Dr. Sackeim noted that ECT is one of the most misunderstood, controversial, and infrequently used treatments in psychiatry.

“But there’s also no doubt that when you look at ECT, it saves the lives of people with psychiatric illness. Period, full stop,” he said.

He added that although restarting a patient’s heart doesn’t seem to cause unease in the public, the idea of applying electricity to the brain under anesthesia in order to provoke a seizure for therapeutic purpose causes anxiety.

Still, the benefits and harms of a treatment are more important than how it looks, Sackeim said. “If it was only about how it looks, we’d never have surgery,” he added.
 

‘A Huge Success Story’

ECT was first introduced by Hungarian neuropsychiatrist László Meduna in 1935, and today clinicians “know where the current goes in the brain, at what dosage, and with what path you can get 70%, 80% fully remitted,” said Dr. Sackeim.

He noted that in a randomized study published in JAMA Psychiatry, investigators compared the outcomes of MST vs ECT for major depressive episodes in 73 patients. They reported that although depression symptom scores decreased for both treatments, there was “no significant difference” between the two in response or remission rates.

However, in an opinion letter the journal published in April, Dr. Sackeim and colleagues Mark S. George, MD, Medical University of South Carolina, and William V. McCall, MD, Augusta University, Augusta, Georgia, strongly questioned the findings.

At less than 30%, “the ECT remission rate after acute treatment was exceptionally low, limiting confidence in the validity and/or generalizability of the findings,” they wrote.

“It’s undoubtedly the case that either if you recruited a sample from whom the treatment may not be as efficacious or if there are issues in delivering them, then you may be finding equivalence” between ECT and MST, Dr. Sackeim said.

In addition, he noted that although there have been concerns about cognitive side effects with ECT, they have improved over the years. Sackeim reported that when he entered the field, the average time for a patient to remember their name or the day of the week was 6 hours after receiving unilateral ECT and 8 hours after bilateral ECT. “With modern methods, that’s now down to 10 minutes,” he said.

“The fundamental knowledge is that this treatment can be administered far softer than it ever was in the past. Impressions from the 50s and 60s and portrayed in movies have very little to do with modern practice and with the real effects of the treatment,” Dr. Sackeim said.

As for the new studies about aperiodic activity, the investigators are “essentially saying, ‘We have a better marker’ of the process. That way of thinking had in many ways been left behind in the run to study connectivity,” Dr. Sackeim said.

He noted that years ago, while he was with Columbia University, his team found that patients who had frontal inhibition were more likely to get well after ECT.

“And that’s essentially the same thing you’re hearing from the UCSD group. They’re saying that the aperiodic measure is hopefully of clearer physiological significance than simply delta [waves] in the EEG,” Dr. Sackeim said.

“The idea that inhibition was the key to its efficacy has been around. This is saying it’s a better measure of that, and that may be true. It’s certainly an interesting contribution,” he added.

Dr. Sackeim said the takeaway message for clinicians regarding ECT today is that it can be lifesaving but is still often only used as a last resort and reserved for those who have run out of options.

However, he said, ECT is “a huge success story: Maintaining its efficacy, reducing its side effects, getting an understanding as to what the physics of it are. We have some compelling stories about ECT, but even more so, we know what’s not true. And what’s not true are most of the assumptions people have about the treatment,” he concluded.

Ms. Smith and Dr. Voytek reported no relevant conflicts of interest. Dr. Sackeim reported holding patents in ECT technology and consulting with the MECTA Corporation and SigmaStim LLC and other neuromodulation companies.
 

A version of this article appeared on Medscape.com.

For years, electroconvulsive therapy (ECT) has been a lifesaving treatment for patients with treatment-resistant depression (TRD), yet exactly how it works has largely remained a mystery. Now researchers believe they have uncovered the underlying mechanisms behind its therapeutic effects — a discovery that may help clinicians better predict treatment response in individual patients and quell much of the fear and stigma associated with one of psychiatry’s most effective, yet misunderstood, treatments.

Two recent papers published in Translational Psychiatry have highlighted the significance of aperiodic neural activity. The first study showed this activity increased following ECT treatment. The second study expanded on these data by demonstrating a significant increase in aperiodic activity after patients received either ECT or magnetic seizure therapy (MST), which has a better side-effect profile than ECT but lower efficacy.

Aperiodic activity is “like the brain’s background noise, and for years scientists treated it that way and didn’t pay much attention to it,” first author Sydney E. Smith, a PhD candidate at the Voytek Lab in the Neuroscience Graduate Program at the University of California San Diego (UCSD), said in a press release.

However, aperiodic activity boosts inhibitory activity in the brain, effectively slowing it down,” the investigators noted.

In an interview with this news organization, Ms. Smith used a car analogy to explain the mechanism behind ECT. “ECT might be increasing the activity levels in the brain cells that help calm it down. It taps on the brakes that tend to malfunction in depression. By restoring the balance between the gas and the brakes in the brain, some of those depressive symptoms are alleviated,” she said.

Ms. Smith added her team’s research helps demystify one of the most effective yet stigmatized treatments for severe depression.

“Aperiodic activity as a physiologically interpretable EEG metric could be a really valuable new predictive indicator for treatment response,” she added.
 

Fear and Stigma

ECT is primarily used for TRD and is effective in up to 80% of patients, yet it remains one of the least prescribed treatments.

Although it’s been around for almost 90 years, fear and concern about its potential cognitive side effects have contributed to its poor uptake. It is estimated that less than 1% of patients with TRD receive ECT.

Smith noted that the 1970s movie One Flew Over the Cuckoo’s Nest still contributes to ECT’s stigma. In the film, actor Jack Nicholson’s character is forced to undergo ECT as a punishment.

It’s important for clinicians to acknowledge the stigma while advising patients that “the actual treatment doesn’t look anything like what’s in the movies,” noted Ms. Smith. Patients must give informed consent for the procedure, and it’s delivered with the lowest level of effective stimulation.

“So many steps are taken to consider comfort and efficacy for patients and to minimize how scary it can be,” she said.

ECT uses an electrical current to induce a seizure that spreads to deep subcortical structures. MST, which was developed as an alternative to ECT, uses a magnetic field to induce a more focal seizure primarily confined to the cortex.

Although MST has a better side-effect profile, experts noted it has remission rates of 30%-60% compared with ECT. Even one of MST’s inventors, Harold Sackeim, PhD, professor in the Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, is skeptical about its efficacy for TRD.

“I don’t think it works,” Dr. Sackeim, founding editor of Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, told this news organization.

In addition to being more expensive, MST produces a peak electrical intensity at one-tenth of what a typical ECT stimulus produces. “We’re limited by electrical engineering at this point with MST. That’s my view; others are more optimistic,” he said.
 

A Lifesaving Treatment

One of the reasons ECT isn’t more popular is because for many patients, it’s easier and more convenient to just take a pill, senior investigator Bradley Voytek, PhD, professor of cognitive science at UCSD, said in the release.

“However, in people for whom medications don’t work, [ECT] can be lifesaving. Understanding how it works will help us discover ways to increase the benefits while minimizing side effects,” he added.

In the first study, which included nine patients with major depressive disorder (MDD), EEG results showed an increase in aperiodic activity following ECT.

The investigators then wanted to test whether these findings could be replicated in a larger study. They retrospectively assessed two previous datasets — 1 of 22 patients with MDD who received ECT and 1 of 23 patients who received MST. After treatment, both groups showed increased aperiodic activity.

“Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST,” the investigators wrote.

The researchers noted that this increase in aperiodic activity is a more parsimonious explanation for observations of clinical slowing than delta band power or delta oscillations for both ECT and MST.”

So why is it important to know exactly how ECT works, and is there any clinical utility to these research findings?

“It’s important for clinicians to give a patient who has questions, a meaningful understanding of what the treatment is going to do, especially with something so scary and stigmatized. The ability to tell a patient why this treatment is working could provide a level of comfort that can assuage some of these fears,” Ms. Smith said.
 

A New Predictor of Response?

In addition, she noted that psychiatry is becoming more focused on predictive indicators for treatment.

“It’s asking: Are there any biological measures that can be used to predict whether someone is going to respond to a treatment or not?” said Ms. Smith.

“Aperiodic activity might be a valuable asset to add to that arsenal. Maybe we can better predict which patients might respond to ECT by using this as an additional biological indicator,” she added.

Smith noted that while more studies are needed, it’s exciting that some investigators are already starting to include aperiodic activity as a variable in their research analyses on a variety of topics, such as pharmacological intervention and transcranial magnetic stimulation.

“I don’t know exactly how much utility aperiodic activity is going to have in terms of being a great biological indicator, but I hope that the research will start to play out and reveal a little bit more,” she said.

Dr. Sackeim noted that ECT is one of the most misunderstood, controversial, and infrequently used treatments in psychiatry.

“But there’s also no doubt that when you look at ECT, it saves the lives of people with psychiatric illness. Period, full stop,” he said.

He added that although restarting a patient’s heart doesn’t seem to cause unease in the public, the idea of applying electricity to the brain under anesthesia in order to provoke a seizure for therapeutic purpose causes anxiety.

Still, the benefits and harms of a treatment are more important than how it looks, Sackeim said. “If it was only about how it looks, we’d never have surgery,” he added.
 

‘A Huge Success Story’

ECT was first introduced by Hungarian neuropsychiatrist László Meduna in 1935, and today clinicians “know where the current goes in the brain, at what dosage, and with what path you can get 70%, 80% fully remitted,” said Dr. Sackeim.

He noted that in a randomized study published in JAMA Psychiatry, investigators compared the outcomes of MST vs ECT for major depressive episodes in 73 patients. They reported that although depression symptom scores decreased for both treatments, there was “no significant difference” between the two in response or remission rates.

However, in an opinion letter the journal published in April, Dr. Sackeim and colleagues Mark S. George, MD, Medical University of South Carolina, and William V. McCall, MD, Augusta University, Augusta, Georgia, strongly questioned the findings.

At less than 30%, “the ECT remission rate after acute treatment was exceptionally low, limiting confidence in the validity and/or generalizability of the findings,” they wrote.

“It’s undoubtedly the case that either if you recruited a sample from whom the treatment may not be as efficacious or if there are issues in delivering them, then you may be finding equivalence” between ECT and MST, Dr. Sackeim said.

In addition, he noted that although there have been concerns about cognitive side effects with ECT, they have improved over the years. Sackeim reported that when he entered the field, the average time for a patient to remember their name or the day of the week was 6 hours after receiving unilateral ECT and 8 hours after bilateral ECT. “With modern methods, that’s now down to 10 minutes,” he said.

“The fundamental knowledge is that this treatment can be administered far softer than it ever was in the past. Impressions from the 50s and 60s and portrayed in movies have very little to do with modern practice and with the real effects of the treatment,” Dr. Sackeim said.

As for the new studies about aperiodic activity, the investigators are “essentially saying, ‘We have a better marker’ of the process. That way of thinking had in many ways been left behind in the run to study connectivity,” Dr. Sackeim said.

He noted that years ago, while he was with Columbia University, his team found that patients who had frontal inhibition were more likely to get well after ECT.

“And that’s essentially the same thing you’re hearing from the UCSD group. They’re saying that the aperiodic measure is hopefully of clearer physiological significance than simply delta [waves] in the EEG,” Dr. Sackeim said.

“The idea that inhibition was the key to its efficacy has been around. This is saying it’s a better measure of that, and that may be true. It’s certainly an interesting contribution,” he added.

Dr. Sackeim said the takeaway message for clinicians regarding ECT today is that it can be lifesaving but is still often only used as a last resort and reserved for those who have run out of options.

However, he said, ECT is “a huge success story: Maintaining its efficacy, reducing its side effects, getting an understanding as to what the physics of it are. We have some compelling stories about ECT, but even more so, we know what’s not true. And what’s not true are most of the assumptions people have about the treatment,” he concluded.

Ms. Smith and Dr. Voytek reported no relevant conflicts of interest. Dr. Sackeim reported holding patents in ECT technology and consulting with the MECTA Corporation and SigmaStim LLC and other neuromodulation companies.
 

A version of this article appeared on Medscape.com.

For years, electroconvulsive therapy (ECT) has been a lifesaving treatment for patients with treatment-resistant depression (TRD), yet exactly how it works has largely remained a mystery. Now researchers believe they have uncovered the underlying mechanisms behind its therapeutic effects — a discovery that may help clinicians better predict treatment response in individual patients and quell much of the fear and stigma associated with one of psychiatry’s most effective, yet misunderstood, treatments.

Two recent papers published in Translational Psychiatry have highlighted the significance of aperiodic neural activity. The first study showed this activity increased following ECT treatment. The second study expanded on these data by demonstrating a significant increase in aperiodic activity after patients received either ECT or magnetic seizure therapy (MST), which has a better side-effect profile than ECT but lower efficacy.

Aperiodic activity is “like the brain’s background noise, and for years scientists treated it that way and didn’t pay much attention to it,” first author Sydney E. Smith, a PhD candidate at the Voytek Lab in the Neuroscience Graduate Program at the University of California San Diego (UCSD), said in a press release.

However, aperiodic activity boosts inhibitory activity in the brain, effectively slowing it down,” the investigators noted.

In an interview with this news organization, Ms. Smith used a car analogy to explain the mechanism behind ECT. “ECT might be increasing the activity levels in the brain cells that help calm it down. It taps on the brakes that tend to malfunction in depression. By restoring the balance between the gas and the brakes in the brain, some of those depressive symptoms are alleviated,” she said.

Ms. Smith added her team’s research helps demystify one of the most effective yet stigmatized treatments for severe depression.

“Aperiodic activity as a physiologically interpretable EEG metric could be a really valuable new predictive indicator for treatment response,” she added.
 

Fear and Stigma

ECT is primarily used for TRD and is effective in up to 80% of patients, yet it remains one of the least prescribed treatments.

Although it’s been around for almost 90 years, fear and concern about its potential cognitive side effects have contributed to its poor uptake. It is estimated that less than 1% of patients with TRD receive ECT.

Smith noted that the 1970s movie One Flew Over the Cuckoo’s Nest still contributes to ECT’s stigma. In the film, actor Jack Nicholson’s character is forced to undergo ECT as a punishment.

It’s important for clinicians to acknowledge the stigma while advising patients that “the actual treatment doesn’t look anything like what’s in the movies,” noted Ms. Smith. Patients must give informed consent for the procedure, and it’s delivered with the lowest level of effective stimulation.

“So many steps are taken to consider comfort and efficacy for patients and to minimize how scary it can be,” she said.

ECT uses an electrical current to induce a seizure that spreads to deep subcortical structures. MST, which was developed as an alternative to ECT, uses a magnetic field to induce a more focal seizure primarily confined to the cortex.

Although MST has a better side-effect profile, experts noted it has remission rates of 30%-60% compared with ECT. Even one of MST’s inventors, Harold Sackeim, PhD, professor in the Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, is skeptical about its efficacy for TRD.

“I don’t think it works,” Dr. Sackeim, founding editor of Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, told this news organization.

In addition to being more expensive, MST produces a peak electrical intensity at one-tenth of what a typical ECT stimulus produces. “We’re limited by electrical engineering at this point with MST. That’s my view; others are more optimistic,” he said.
 

A Lifesaving Treatment

One of the reasons ECT isn’t more popular is because for many patients, it’s easier and more convenient to just take a pill, senior investigator Bradley Voytek, PhD, professor of cognitive science at UCSD, said in the release.

“However, in people for whom medications don’t work, [ECT] can be lifesaving. Understanding how it works will help us discover ways to increase the benefits while minimizing side effects,” he added.

In the first study, which included nine patients with major depressive disorder (MDD), EEG results showed an increase in aperiodic activity following ECT.

The investigators then wanted to test whether these findings could be replicated in a larger study. They retrospectively assessed two previous datasets — 1 of 22 patients with MDD who received ECT and 1 of 23 patients who received MST. After treatment, both groups showed increased aperiodic activity.

“Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST,” the investigators wrote.

The researchers noted that this increase in aperiodic activity is a more parsimonious explanation for observations of clinical slowing than delta band power or delta oscillations for both ECT and MST.”

So why is it important to know exactly how ECT works, and is there any clinical utility to these research findings?

“It’s important for clinicians to give a patient who has questions, a meaningful understanding of what the treatment is going to do, especially with something so scary and stigmatized. The ability to tell a patient why this treatment is working could provide a level of comfort that can assuage some of these fears,” Ms. Smith said.
 

A New Predictor of Response?

In addition, she noted that psychiatry is becoming more focused on predictive indicators for treatment.

“It’s asking: Are there any biological measures that can be used to predict whether someone is going to respond to a treatment or not?” said Ms. Smith.

“Aperiodic activity might be a valuable asset to add to that arsenal. Maybe we can better predict which patients might respond to ECT by using this as an additional biological indicator,” she added.

Smith noted that while more studies are needed, it’s exciting that some investigators are already starting to include aperiodic activity as a variable in their research analyses on a variety of topics, such as pharmacological intervention and transcranial magnetic stimulation.

“I don’t know exactly how much utility aperiodic activity is going to have in terms of being a great biological indicator, but I hope that the research will start to play out and reveal a little bit more,” she said.

Dr. Sackeim noted that ECT is one of the most misunderstood, controversial, and infrequently used treatments in psychiatry.

“But there’s also no doubt that when you look at ECT, it saves the lives of people with psychiatric illness. Period, full stop,” he said.

He added that although restarting a patient’s heart doesn’t seem to cause unease in the public, the idea of applying electricity to the brain under anesthesia in order to provoke a seizure for therapeutic purpose causes anxiety.

Still, the benefits and harms of a treatment are more important than how it looks, Sackeim said. “If it was only about how it looks, we’d never have surgery,” he added.
 

‘A Huge Success Story’

ECT was first introduced by Hungarian neuropsychiatrist László Meduna in 1935, and today clinicians “know where the current goes in the brain, at what dosage, and with what path you can get 70%, 80% fully remitted,” said Dr. Sackeim.

He noted that in a randomized study published in JAMA Psychiatry, investigators compared the outcomes of MST vs ECT for major depressive episodes in 73 patients. They reported that although depression symptom scores decreased for both treatments, there was “no significant difference” between the two in response or remission rates.

However, in an opinion letter the journal published in April, Dr. Sackeim and colleagues Mark S. George, MD, Medical University of South Carolina, and William V. McCall, MD, Augusta University, Augusta, Georgia, strongly questioned the findings.

At less than 30%, “the ECT remission rate after acute treatment was exceptionally low, limiting confidence in the validity and/or generalizability of the findings,” they wrote.

“It’s undoubtedly the case that either if you recruited a sample from whom the treatment may not be as efficacious or if there are issues in delivering them, then you may be finding equivalence” between ECT and MST, Dr. Sackeim said.

In addition, he noted that although there have been concerns about cognitive side effects with ECT, they have improved over the years. Sackeim reported that when he entered the field, the average time for a patient to remember their name or the day of the week was 6 hours after receiving unilateral ECT and 8 hours after bilateral ECT. “With modern methods, that’s now down to 10 minutes,” he said.

“The fundamental knowledge is that this treatment can be administered far softer than it ever was in the past. Impressions from the 50s and 60s and portrayed in movies have very little to do with modern practice and with the real effects of the treatment,” Dr. Sackeim said.

As for the new studies about aperiodic activity, the investigators are “essentially saying, ‘We have a better marker’ of the process. That way of thinking had in many ways been left behind in the run to study connectivity,” Dr. Sackeim said.

He noted that years ago, while he was with Columbia University, his team found that patients who had frontal inhibition were more likely to get well after ECT.

“And that’s essentially the same thing you’re hearing from the UCSD group. They’re saying that the aperiodic measure is hopefully of clearer physiological significance than simply delta [waves] in the EEG,” Dr. Sackeim said.

“The idea that inhibition was the key to its efficacy has been around. This is saying it’s a better measure of that, and that may be true. It’s certainly an interesting contribution,” he added.

Dr. Sackeim said the takeaway message for clinicians regarding ECT today is that it can be lifesaving but is still often only used as a last resort and reserved for those who have run out of options.

However, he said, ECT is “a huge success story: Maintaining its efficacy, reducing its side effects, getting an understanding as to what the physics of it are. We have some compelling stories about ECT, but even more so, we know what’s not true. And what’s not true are most of the assumptions people have about the treatment,” he concluded.

Ms. Smith and Dr. Voytek reported no relevant conflicts of interest. Dr. Sackeim reported holding patents in ECT technology and consulting with the MECTA Corporation and SigmaStim LLC and other neuromodulation companies.
 

A version of this article appeared on Medscape.com.

High plasma concentrations of buprenorphine may reduce fentanyl-induced respiratory depression, new research suggests.

The primary endpoint measure in a small “proof of principal” pharmacology study was effect of escalating fentanyl dosing on respiratory depression by way of decreased isohypercapnic minute ventilation (VE) – or volume of gas inhaled or exhaled per minute from the lungs.

sdominick/iStock/Getty Images

Results showed the maximum decrease in highest-dose fentanyl-induced VE was almost 50% less for opioid-tolerant patients receiving a 2.0 ng/mL concentration of steady-state plasma buprenorphine than when receiving matching placebo.

Risk for apnea requiring stimulation after fentanyl dosing was also significantly lower with buprenorphine.

“Even though the study is small, a lot of data were collected which will allow us to very accurately predict which plasma concentrations, and therefore drug doses, are needed to protect people adequately in practice,” study coinvestigator Geert Jan Groeneveld, MD, PhD, neurologist and clinical pharmacologist at the Centre for Human Drug Research, Leiden, the Netherlands, and professor of clinical neuropharmacology at Leiden University Medical Center, told this news organization.

He added the “beautiful results” were in line with what the researchers expected and although further research is needed, the study provides a lot of useful information for clinicians.

“I think this is an approach that works, and this study makes that clear,” Dr. Groeneveld added.

The findings were published online Jan. 27, 2022, in PLoS One.
 

High death rate from synthetic opioids

A recent report from the Centers for Disease Control and Prevention noted that, between June 2020 and June 2021, there were more than 100,000 drug overdose deaths in the United States. Of these, more than 73,000 were attributed to opioids and more than 60,000 to synthetic opioids such as fentanyl.

Most opioid-related overdose deaths in the United States are attributable to synthetic opioids “that can unexpectedly cause respiratory depression by being ingested as a substitute for heroin or with [other] drugs,” Indivior noted in a press release.

Buprenorphine is a partial agonist that “binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects,” the investigators wrote.

As reported by this news organization, the Food and Drug Administration approved buprenorphine extended release (Sublocade, Indivior) in 2017 as the first once-monthly injection for the treatment of opioid use disorder.

In the current study, which was conducted in Leiden, the Netherlands, the investigators used continuous intravenous buprenorphine in order to “mimic” the sustained plasma concentrations of the drug that can be delivered with the long-acting injectable, noted Christian Heidbreder, PhD, chief scientific officer at Indivior.

“This was an experimental medicine study, whereby we used intravenous buprenorphine to really understand the interaction with escalating doses of fentanyl” on respiratory depression, he told this news organization.
 

Two-part, two-period study

In part A, period one of the two-period crossover study, 14 healthy volunteers were randomly assigned to receive for 360 minutes continuous infusion of 0.02 or 0.05 mg/70 kg per hour of buprenorphine to target plasma concentrations of 0.2 or 0.5 ng/mL, respectively, or matching placebo. In the second period, participants received the alternative infusion – either placebo or the active drug.

In part B, eight opioid-tolerant patients who had used high-dose opioids for at least 3 months prior received a higher infusion rate of 0.1, 0.2, or 0.5 mg/70 kg per hour to target plasma concentrations of 1, 2, or 5 ng/mL, respectively.

The 2 ng/mL “is a very important threshold for us” and the result from several previous experiments, Dr. Heidbreder noted. So the investigators targeted that concentration as well as one below and one “much higher” in the current study.

“Because tolerance to opioid effects is poorly characterized in patients receiving long-term opioids, opioid-tolerant participants in part B had a fixed treatment sequence, receiving placebo infusion plus fentanyl challenges in period 1 to optimize the fentanyl dose escalation before buprenorphine and fentanyl were coadministered in period 2,” the investigators reported.

All participants received up to four escalating doses of intravenous fentanyl after reaching target buprenorphine plasma concentrations.

For healthy volunteers, the planned fentanyl doses were 0.075, 0.15, 0.25, and 0.35 mg/70 kg. For the opioid-tolerant patients, the doses were 0.25, 0.35, 0.5, and 0.7 mg/70 kg.

The infusions began after baseline VE had stabilized at 20 plus or minus 2 L/min, which is about four times above normal resting VE.
 

First clinical evidence?

Results showed fentanyl-induced adverse changes in VE were less at higher concentrations of buprenorphine plasma.

Opioid-tolerant patients receiving the 2.0 ng/mL concentration of buprenorphine had a 33.7% decrease in highest dose fentanyl-induced VE versus an 82.3% decrease when receiving placebo.

In addition, fentanyl reduced VE up to 49% (95% confidence interval, 21%-76%) in opioid-tolerant patients in all buprenorphine concentration groups combined versus reducing VE up to 100% (95% CI, 68%-132%) during placebo infusion (P = .006).

In addition, buprenorphine was associated with a lower risk versus placebo for apnea requiring verbal stimulation after fentanyl dosing (odds ratio, 0.07; P = .001).

For the healthy volunteers, the first fentanyl bolus reduced VE by 26% for those at target buprenorphine concentration of 0.5 ng/mL versus 51% when receiving placebo (P = .001). The second bolus reduced VE by 47% versus 79%, respectively (P < .001).

“Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection,” the investigators reported.

Overall, the findings “provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids,” they added.

Additional research is now “warranted to assess the competitive interaction of buprenorphine and fentanyl (as well as other illicitly manufactured fentanyl analogs) as we continue to deepen our understanding of buprenorphine as an evidence-based treatment for patients struggling with opioid use disorder,” Dr. Heidbreder said in a press release.

It’s unclear whether the study’s findings are generalizable to other populations, said Dr. Heidbreder.

“So what we are going to do next is to see what is actually happening in a real world, much broader patient population; and for that we’ll be using [the injectable] Sublocade as the medication of choice,” said Dr. Heidbreder.

“Conceptually, we feel confident about these data, but now we need to demonstrate what is happening in the real world,” he added.

The study was funded by Indivior. Dr. Groeneveld has reported no relevant financial relationships. Dr. Heidbreder is an employee of Indivior.

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

High plasma concentrations of buprenorphine may reduce fentanyl-induced respiratory depression, new research suggests.

The primary endpoint measure in a small “proof of principal” pharmacology study was effect of escalating fentanyl dosing on respiratory depression by way of decreased isohypercapnic minute ventilation (VE) – or volume of gas inhaled or exhaled per minute from the lungs.

sdominick/iStock/Getty Images

Results showed the maximum decrease in highest-dose fentanyl-induced VE was almost 50% less for opioid-tolerant patients receiving a 2.0 ng/mL concentration of steady-state plasma buprenorphine than when receiving matching placebo.

Risk for apnea requiring stimulation after fentanyl dosing was also significantly lower with buprenorphine.

“Even though the study is small, a lot of data were collected which will allow us to very accurately predict which plasma concentrations, and therefore drug doses, are needed to protect people adequately in practice,” study coinvestigator Geert Jan Groeneveld, MD, PhD, neurologist and clinical pharmacologist at the Centre for Human Drug Research, Leiden, the Netherlands, and professor of clinical neuropharmacology at Leiden University Medical Center, told this news organization.

He added the “beautiful results” were in line with what the researchers expected and although further research is needed, the study provides a lot of useful information for clinicians.

“I think this is an approach that works, and this study makes that clear,” Dr. Groeneveld added.

The findings were published online Jan. 27, 2022, in PLoS One.
 

High death rate from synthetic opioids

A recent report from the Centers for Disease Control and Prevention noted that, between June 2020 and June 2021, there were more than 100,000 drug overdose deaths in the United States. Of these, more than 73,000 were attributed to opioids and more than 60,000 to synthetic opioids such as fentanyl.

Most opioid-related overdose deaths in the United States are attributable to synthetic opioids “that can unexpectedly cause respiratory depression by being ingested as a substitute for heroin or with [other] drugs,” Indivior noted in a press release.

Buprenorphine is a partial agonist that “binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects,” the investigators wrote.

As reported by this news organization, the Food and Drug Administration approved buprenorphine extended release (Sublocade, Indivior) in 2017 as the first once-monthly injection for the treatment of opioid use disorder.

In the current study, which was conducted in Leiden, the Netherlands, the investigators used continuous intravenous buprenorphine in order to “mimic” the sustained plasma concentrations of the drug that can be delivered with the long-acting injectable, noted Christian Heidbreder, PhD, chief scientific officer at Indivior.

“This was an experimental medicine study, whereby we used intravenous buprenorphine to really understand the interaction with escalating doses of fentanyl” on respiratory depression, he told this news organization.
 

Two-part, two-period study

In part A, period one of the two-period crossover study, 14 healthy volunteers were randomly assigned to receive for 360 minutes continuous infusion of 0.02 or 0.05 mg/70 kg per hour of buprenorphine to target plasma concentrations of 0.2 or 0.5 ng/mL, respectively, or matching placebo. In the second period, participants received the alternative infusion – either placebo or the active drug.

In part B, eight opioid-tolerant patients who had used high-dose opioids for at least 3 months prior received a higher infusion rate of 0.1, 0.2, or 0.5 mg/70 kg per hour to target plasma concentrations of 1, 2, or 5 ng/mL, respectively.

The 2 ng/mL “is a very important threshold for us” and the result from several previous experiments, Dr. Heidbreder noted. So the investigators targeted that concentration as well as one below and one “much higher” in the current study.

“Because tolerance to opioid effects is poorly characterized in patients receiving long-term opioids, opioid-tolerant participants in part B had a fixed treatment sequence, receiving placebo infusion plus fentanyl challenges in period 1 to optimize the fentanyl dose escalation before buprenorphine and fentanyl were coadministered in period 2,” the investigators reported.

All participants received up to four escalating doses of intravenous fentanyl after reaching target buprenorphine plasma concentrations.

For healthy volunteers, the planned fentanyl doses were 0.075, 0.15, 0.25, and 0.35 mg/70 kg. For the opioid-tolerant patients, the doses were 0.25, 0.35, 0.5, and 0.7 mg/70 kg.

The infusions began after baseline VE had stabilized at 20 plus or minus 2 L/min, which is about four times above normal resting VE.
 

First clinical evidence?

Results showed fentanyl-induced adverse changes in VE were less at higher concentrations of buprenorphine plasma.

Opioid-tolerant patients receiving the 2.0 ng/mL concentration of buprenorphine had a 33.7% decrease in highest dose fentanyl-induced VE versus an 82.3% decrease when receiving placebo.

In addition, fentanyl reduced VE up to 49% (95% confidence interval, 21%-76%) in opioid-tolerant patients in all buprenorphine concentration groups combined versus reducing VE up to 100% (95% CI, 68%-132%) during placebo infusion (P = .006).

In addition, buprenorphine was associated with a lower risk versus placebo for apnea requiring verbal stimulation after fentanyl dosing (odds ratio, 0.07; P = .001).

For the healthy volunteers, the first fentanyl bolus reduced VE by 26% for those at target buprenorphine concentration of 0.5 ng/mL versus 51% when receiving placebo (P = .001). The second bolus reduced VE by 47% versus 79%, respectively (P < .001).

“Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection,” the investigators reported.

Overall, the findings “provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids,” they added.

Additional research is now “warranted to assess the competitive interaction of buprenorphine and fentanyl (as well as other illicitly manufactured fentanyl analogs) as we continue to deepen our understanding of buprenorphine as an evidence-based treatment for patients struggling with opioid use disorder,” Dr. Heidbreder said in a press release.

It’s unclear whether the study’s findings are generalizable to other populations, said Dr. Heidbreder.

“So what we are going to do next is to see what is actually happening in a real world, much broader patient population; and for that we’ll be using [the injectable] Sublocade as the medication of choice,” said Dr. Heidbreder.

“Conceptually, we feel confident about these data, but now we need to demonstrate what is happening in the real world,” he added.

The study was funded by Indivior. Dr. Groeneveld has reported no relevant financial relationships. Dr. Heidbreder is an employee of Indivior.

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

High plasma concentrations of buprenorphine may reduce fentanyl-induced respiratory depression, new research suggests.

The primary endpoint measure in a small “proof of principal” pharmacology study was effect of escalating fentanyl dosing on respiratory depression by way of decreased isohypercapnic minute ventilation (VE) – or volume of gas inhaled or exhaled per minute from the lungs.

sdominick/iStock/Getty Images

Results showed the maximum decrease in highest-dose fentanyl-induced VE was almost 50% less for opioid-tolerant patients receiving a 2.0 ng/mL concentration of steady-state plasma buprenorphine than when receiving matching placebo.

Risk for apnea requiring stimulation after fentanyl dosing was also significantly lower with buprenorphine.

“Even though the study is small, a lot of data were collected which will allow us to very accurately predict which plasma concentrations, and therefore drug doses, are needed to protect people adequately in practice,” study coinvestigator Geert Jan Groeneveld, MD, PhD, neurologist and clinical pharmacologist at the Centre for Human Drug Research, Leiden, the Netherlands, and professor of clinical neuropharmacology at Leiden University Medical Center, told this news organization.

He added the “beautiful results” were in line with what the researchers expected and although further research is needed, the study provides a lot of useful information for clinicians.

“I think this is an approach that works, and this study makes that clear,” Dr. Groeneveld added.

The findings were published online Jan. 27, 2022, in PLoS One.
 

High death rate from synthetic opioids

A recent report from the Centers for Disease Control and Prevention noted that, between June 2020 and June 2021, there were more than 100,000 drug overdose deaths in the United States. Of these, more than 73,000 were attributed to opioids and more than 60,000 to synthetic opioids such as fentanyl.

Most opioid-related overdose deaths in the United States are attributable to synthetic opioids “that can unexpectedly cause respiratory depression by being ingested as a substitute for heroin or with [other] drugs,” Indivior noted in a press release.

Buprenorphine is a partial agonist that “binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects,” the investigators wrote.

As reported by this news organization, the Food and Drug Administration approved buprenorphine extended release (Sublocade, Indivior) in 2017 as the first once-monthly injection for the treatment of opioid use disorder.

In the current study, which was conducted in Leiden, the Netherlands, the investigators used continuous intravenous buprenorphine in order to “mimic” the sustained plasma concentrations of the drug that can be delivered with the long-acting injectable, noted Christian Heidbreder, PhD, chief scientific officer at Indivior.

“This was an experimental medicine study, whereby we used intravenous buprenorphine to really understand the interaction with escalating doses of fentanyl” on respiratory depression, he told this news organization.
 

Two-part, two-period study

In part A, period one of the two-period crossover study, 14 healthy volunteers were randomly assigned to receive for 360 minutes continuous infusion of 0.02 or 0.05 mg/70 kg per hour of buprenorphine to target plasma concentrations of 0.2 or 0.5 ng/mL, respectively, or matching placebo. In the second period, participants received the alternative infusion – either placebo or the active drug.

In part B, eight opioid-tolerant patients who had used high-dose opioids for at least 3 months prior received a higher infusion rate of 0.1, 0.2, or 0.5 mg/70 kg per hour to target plasma concentrations of 1, 2, or 5 ng/mL, respectively.

The 2 ng/mL “is a very important threshold for us” and the result from several previous experiments, Dr. Heidbreder noted. So the investigators targeted that concentration as well as one below and one “much higher” in the current study.

“Because tolerance to opioid effects is poorly characterized in patients receiving long-term opioids, opioid-tolerant participants in part B had a fixed treatment sequence, receiving placebo infusion plus fentanyl challenges in period 1 to optimize the fentanyl dose escalation before buprenorphine and fentanyl were coadministered in period 2,” the investigators reported.

All participants received up to four escalating doses of intravenous fentanyl after reaching target buprenorphine plasma concentrations.

For healthy volunteers, the planned fentanyl doses were 0.075, 0.15, 0.25, and 0.35 mg/70 kg. For the opioid-tolerant patients, the doses were 0.25, 0.35, 0.5, and 0.7 mg/70 kg.

The infusions began after baseline VE had stabilized at 20 plus or minus 2 L/min, which is about four times above normal resting VE.
 

First clinical evidence?

Results showed fentanyl-induced adverse changes in VE were less at higher concentrations of buprenorphine plasma.

Opioid-tolerant patients receiving the 2.0 ng/mL concentration of buprenorphine had a 33.7% decrease in highest dose fentanyl-induced VE versus an 82.3% decrease when receiving placebo.

In addition, fentanyl reduced VE up to 49% (95% confidence interval, 21%-76%) in opioid-tolerant patients in all buprenorphine concentration groups combined versus reducing VE up to 100% (95% CI, 68%-132%) during placebo infusion (P = .006).

In addition, buprenorphine was associated with a lower risk versus placebo for apnea requiring verbal stimulation after fentanyl dosing (odds ratio, 0.07; P = .001).

For the healthy volunteers, the first fentanyl bolus reduced VE by 26% for those at target buprenorphine concentration of 0.5 ng/mL versus 51% when receiving placebo (P = .001). The second bolus reduced VE by 47% versus 79%, respectively (P < .001).

“Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection,” the investigators reported.

Overall, the findings “provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids,” they added.

Additional research is now “warranted to assess the competitive interaction of buprenorphine and fentanyl (as well as other illicitly manufactured fentanyl analogs) as we continue to deepen our understanding of buprenorphine as an evidence-based treatment for patients struggling with opioid use disorder,” Dr. Heidbreder said in a press release.

It’s unclear whether the study’s findings are generalizable to other populations, said Dr. Heidbreder.

“So what we are going to do next is to see what is actually happening in a real world, much broader patient population; and for that we’ll be using [the injectable] Sublocade as the medication of choice,” said Dr. Heidbreder.

“Conceptually, we feel confident about these data, but now we need to demonstrate what is happening in the real world,” he added.

The study was funded by Indivior. Dr. Groeneveld has reported no relevant financial relationships. Dr. Heidbreder is an employee of Indivior.

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

The U.S. Food and Drug Administration has expanded the indication for the noninvasive BrainsWay Deep Transcranial Magnetic Stimulation (Deep TMS) System to include treatment of comorbid anxiety symptoms in adult patients with depression, the company has announced.

As reported by this news organization, the neurostimulation system has previously received FDA approval for treatment-resistant major depression, obsessive-compulsive disorder, and smoking addiction.

In the August 18 announcement, BrainsWay reported that it has also received 510(k) clearance from the FDA to market its TMS system for the reduction of anxious depression symptoms.

“This clearance is confirmation of what many have believed anecdotally for years – that Deep TMS is a unique form of therapy that can address comorbid anxiety symptoms using the same depression treatment protocol,” Aron Tendler, MD, chief medical officer at BrainsWay, said in a press release.

‘Consistent, robust’ effect

Before receiving approval, the company submitted data on 573 patients who underwent this treatment while participating in 11 studies, which included both randomized controlled trials and open-label studies.

“The data demonstrated a treatment effect that was consistent, robust, and clinically meaningful for decreasing anxiety symptoms in adult patients suffering from major depressive disorder [MDD],” the company said in its release.

Data from three of the randomized trials showed an effect size of 0.3 when compared with a sham device and an effect size of 0.9 when compared with medication. The overall, weighted, pooled effect size was 0.55.

The company noted that in more than 70 published studies with about 16,000 total participants, effect sizes have ranged from 0.2-0.37 for drug-based anxiety treatments.

“The expanded FDA labeling now allows BrainsWay to market its Deep TMS System for the treatment of depressive episodes and for decreasing anxiety symptoms for those who may exhibit comorbid anxiety symptoms in adult patients suffering from [MDD] and who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode,” the company said.

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

The U.S. Food and Drug Administration has expanded the indication for the noninvasive BrainsWay Deep Transcranial Magnetic Stimulation (Deep TMS) System to include treatment of comorbid anxiety symptoms in adult patients with depression, the company has announced.

As reported by this news organization, the neurostimulation system has previously received FDA approval for treatment-resistant major depression, obsessive-compulsive disorder, and smoking addiction.

In the August 18 announcement, BrainsWay reported that it has also received 510(k) clearance from the FDA to market its TMS system for the reduction of anxious depression symptoms.

“This clearance is confirmation of what many have believed anecdotally for years – that Deep TMS is a unique form of therapy that can address comorbid anxiety symptoms using the same depression treatment protocol,” Aron Tendler, MD, chief medical officer at BrainsWay, said in a press release.

‘Consistent, robust’ effect

Before receiving approval, the company submitted data on 573 patients who underwent this treatment while participating in 11 studies, which included both randomized controlled trials and open-label studies.

“The data demonstrated a treatment effect that was consistent, robust, and clinically meaningful for decreasing anxiety symptoms in adult patients suffering from major depressive disorder [MDD],” the company said in its release.

Data from three of the randomized trials showed an effect size of 0.3 when compared with a sham device and an effect size of 0.9 when compared with medication. The overall, weighted, pooled effect size was 0.55.

The company noted that in more than 70 published studies with about 16,000 total participants, effect sizes have ranged from 0.2-0.37 for drug-based anxiety treatments.

“The expanded FDA labeling now allows BrainsWay to market its Deep TMS System for the treatment of depressive episodes and for decreasing anxiety symptoms for those who may exhibit comorbid anxiety symptoms in adult patients suffering from [MDD] and who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode,” the company said.

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

The U.S. Food and Drug Administration has expanded the indication for the noninvasive BrainsWay Deep Transcranial Magnetic Stimulation (Deep TMS) System to include treatment of comorbid anxiety symptoms in adult patients with depression, the company has announced.

As reported by this news organization, the neurostimulation system has previously received FDA approval for treatment-resistant major depression, obsessive-compulsive disorder, and smoking addiction.

In the August 18 announcement, BrainsWay reported that it has also received 510(k) clearance from the FDA to market its TMS system for the reduction of anxious depression symptoms.

“This clearance is confirmation of what many have believed anecdotally for years – that Deep TMS is a unique form of therapy that can address comorbid anxiety symptoms using the same depression treatment protocol,” Aron Tendler, MD, chief medical officer at BrainsWay, said in a press release.

‘Consistent, robust’ effect

Before receiving approval, the company submitted data on 573 patients who underwent this treatment while participating in 11 studies, which included both randomized controlled trials and open-label studies.

“The data demonstrated a treatment effect that was consistent, robust, and clinically meaningful for decreasing anxiety symptoms in adult patients suffering from major depressive disorder [MDD],” the company said in its release.

Data from three of the randomized trials showed an effect size of 0.3 when compared with a sham device and an effect size of 0.9 when compared with medication. The overall, weighted, pooled effect size was 0.55.

The company noted that in more than 70 published studies with about 16,000 total participants, effect sizes have ranged from 0.2-0.37 for drug-based anxiety treatments.

“The expanded FDA labeling now allows BrainsWay to market its Deep TMS System for the treatment of depressive episodes and for decreasing anxiety symptoms for those who may exhibit comorbid anxiety symptoms in adult patients suffering from [MDD] and who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode,” the company said.

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

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

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

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

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

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

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

After several weeks of outcry and heated debate over the Food and Drug Administration’s controversial approval of the Alzheimer’s drug aducanumab (Aduhelm), the head of the agency is now calling for a federal investigation into its own approval proceedings.

Janet Woodcock, MD, the FDA’s acting commissioner, sent a letter to the Office of the Inspector General on July 9, she announced in a tweet.

Dr. Woodcock is asking for an investigation into questionable meetings and other interactions between Biogen and FDA staff members prior to the drug’s approval that “may have occurred outside of the formal correspondence process.”

The letter explains that concerns around these issues “could undermine the public’s confidence in the FDA’s decision.” Therefore, an independent investigation is needed to determine whether anything occurred that was “inconsistent with FDA policies and procedures.”

Dr. Woodcock noted that she has “tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research” involved in the review process.

However, “FDA is dedicated to scientific integrity, to reviewing data without bias, and to basing its regulatory decisions on data,” she wrote. “You have my personal commitment that the Agency will fully cooperate should your office undertake a review.”

Dr. Woodcock concluded by urging that a review be conducted as soon as possible, noting that “should such a review result in actionable items, you also have my commitment to addressing these issues.”

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

After several weeks of outcry and heated debate over the Food and Drug Administration’s controversial approval of the Alzheimer’s drug aducanumab (Aduhelm), the head of the agency is now calling for a federal investigation into its own approval proceedings.

Janet Woodcock, MD, the FDA’s acting commissioner, sent a letter to the Office of the Inspector General on July 9, she announced in a tweet.

Dr. Woodcock is asking for an investigation into questionable meetings and other interactions between Biogen and FDA staff members prior to the drug’s approval that “may have occurred outside of the formal correspondence process.”

The letter explains that concerns around these issues “could undermine the public’s confidence in the FDA’s decision.” Therefore, an independent investigation is needed to determine whether anything occurred that was “inconsistent with FDA policies and procedures.”

Dr. Woodcock noted that she has “tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research” involved in the review process.

However, “FDA is dedicated to scientific integrity, to reviewing data without bias, and to basing its regulatory decisions on data,” she wrote. “You have my personal commitment that the Agency will fully cooperate should your office undertake a review.”

Dr. Woodcock concluded by urging that a review be conducted as soon as possible, noting that “should such a review result in actionable items, you also have my commitment to addressing these issues.”

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

After several weeks of outcry and heated debate over the Food and Drug Administration’s controversial approval of the Alzheimer’s drug aducanumab (Aduhelm), the head of the agency is now calling for a federal investigation into its own approval proceedings.

Janet Woodcock, MD, the FDA’s acting commissioner, sent a letter to the Office of the Inspector General on July 9, she announced in a tweet.

Dr. Woodcock is asking for an investigation into questionable meetings and other interactions between Biogen and FDA staff members prior to the drug’s approval that “may have occurred outside of the formal correspondence process.”

The letter explains that concerns around these issues “could undermine the public’s confidence in the FDA’s decision.” Therefore, an independent investigation is needed to determine whether anything occurred that was “inconsistent with FDA policies and procedures.”

Dr. Woodcock noted that she has “tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research” involved in the review process.

However, “FDA is dedicated to scientific integrity, to reviewing data without bias, and to basing its regulatory decisions on data,” she wrote. “You have my personal commitment that the Agency will fully cooperate should your office undertake a review.”

Dr. Woodcock concluded by urging that a review be conducted as soon as possible, noting that “should such a review result in actionable items, you also have my commitment to addressing these issues.”

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

The U.S. Food and Drug Administration has provided a detailed and documented account of how it arrived at its decision to approve the controversial Alzheimer’s drug aducanumab (Aduhelm, Biogen/Eisai), including the release of several internal documents.

In a letter sent to members of the FDA’s Center for Drug Evaluation Research (CDER), CDER Director Patrizia Cavazzoni, MD, noted that in view of the “fierce public debate” that erupted immediately following the drug’s approval, she felt compelled to explain how the agency came to its decision.

Also publicly released today on the FDA’s updated aducanumab landing page was “the first set of review memos,” for the drug.

“We’re releasing these documents with the intent of informing public discourse – providing interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni wrote. “The rest of the approval package will be released over the next several days,” she added.
 

Immediate backlash

The FDA’s June 7 approval of aducanumab was met with instant backlash. In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted nearly unanimously to not vote in favor of approval because of a lack of evidence proving its efficacy.

Since the drug was approved, three of the advisory committee’s members resigned in protest. In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.

In its letter, the group noted that the FDA’s decision “showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”

Even the Alzheimer’s Association, which was a staunch supporter of the drug throughout its development process and applauded its approval, expressed outrage over its more than $56,000-a-year cost to patients and called the price “simply unacceptable” in a statement.

In the June 23 letter, the CDER director noted, “this was one of the most complex applications in recent history” and admitted that deliberations were lengthy and difficult.

“It’s also not surprising, in fact it was to be expected, that there would be different viewpoints about the data, including dissenting opinions about the approval decision,” Dr. Cavazzoni wrote.

However, this “is what scientific debate is all about, and while difficult at times, it should be celebrated,” she added. “Please know that every opinion was heard, and the approval is a direct reflection of this open and robust scientific and regulatory debate.”
 

Accelerated approval pathway

Documents newly posted to the FDA’s aducanumab landing page include CDER’s Office of Neurology’s Summary Review Memorandum, which includes details on the basis for the approval; the Concurrence Memorandum from the director of CDER’s Office of New Drugs; and the Concurrence Memorandum from Dr. Cavazzoni.

“The remaining scientific review documents in the Aduhelm action package are not yet available but will be made available to the public as soon as the internal process of review and redaction is complete,” the FDA noted on its site.

In the document FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, Dr. Cavazzoni noted that the “highly complex” data included in the submission package for the drug “left residual uncertainties regarding clinical benefit.”

However, after listening to the patient community and reviewing all the data, the FDA chose to use the Accelerated Approval pathway, deciding that the potential benefit to patients outweighed the drug’s risks.

Of two phase 3 trials, only one met its primary endpoint. However, in all trials, including earlier studies, “Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Dr. Cavazzoni wrote.

“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” she added.

Dr. Cavazzoni noted that although the Advisory Committee did not agree that clinical benefit from one trial meeting its primary endpoint was enough for approval, “the option of Accelerated Approval was not discussed” at that time.

This type of approval “is based on a surrogate or intermediate clinical endpoint, in this case reduction of amyloid plaque in the brain” and requires post-approval studies to verify clinical benefit.

Dr. Cavazzoni added that the drug could still be removed from the market if its confirmatory trial does not verify this type of benefit.

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

The U.S. Food and Drug Administration has provided a detailed and documented account of how it arrived at its decision to approve the controversial Alzheimer’s drug aducanumab (Aduhelm, Biogen/Eisai), including the release of several internal documents.

In a letter sent to members of the FDA’s Center for Drug Evaluation Research (CDER), CDER Director Patrizia Cavazzoni, MD, noted that in view of the “fierce public debate” that erupted immediately following the drug’s approval, she felt compelled to explain how the agency came to its decision.

Also publicly released today on the FDA’s updated aducanumab landing page was “the first set of review memos,” for the drug.

“We’re releasing these documents with the intent of informing public discourse – providing interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni wrote. “The rest of the approval package will be released over the next several days,” she added.
 

Immediate backlash

The FDA’s June 7 approval of aducanumab was met with instant backlash. In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted nearly unanimously to not vote in favor of approval because of a lack of evidence proving its efficacy.

Since the drug was approved, three of the advisory committee’s members resigned in protest. In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.

In its letter, the group noted that the FDA’s decision “showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”

Even the Alzheimer’s Association, which was a staunch supporter of the drug throughout its development process and applauded its approval, expressed outrage over its more than $56,000-a-year cost to patients and called the price “simply unacceptable” in a statement.

In the June 23 letter, the CDER director noted, “this was one of the most complex applications in recent history” and admitted that deliberations were lengthy and difficult.

“It’s also not surprising, in fact it was to be expected, that there would be different viewpoints about the data, including dissenting opinions about the approval decision,” Dr. Cavazzoni wrote.

However, this “is what scientific debate is all about, and while difficult at times, it should be celebrated,” she added. “Please know that every opinion was heard, and the approval is a direct reflection of this open and robust scientific and regulatory debate.”
 

Accelerated approval pathway

Documents newly posted to the FDA’s aducanumab landing page include CDER’s Office of Neurology’s Summary Review Memorandum, which includes details on the basis for the approval; the Concurrence Memorandum from the director of CDER’s Office of New Drugs; and the Concurrence Memorandum from Dr. Cavazzoni.

“The remaining scientific review documents in the Aduhelm action package are not yet available but will be made available to the public as soon as the internal process of review and redaction is complete,” the FDA noted on its site.

In the document FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, Dr. Cavazzoni noted that the “highly complex” data included in the submission package for the drug “left residual uncertainties regarding clinical benefit.”

However, after listening to the patient community and reviewing all the data, the FDA chose to use the Accelerated Approval pathway, deciding that the potential benefit to patients outweighed the drug’s risks.

Of two phase 3 trials, only one met its primary endpoint. However, in all trials, including earlier studies, “Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Dr. Cavazzoni wrote.

“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” she added.

Dr. Cavazzoni noted that although the Advisory Committee did not agree that clinical benefit from one trial meeting its primary endpoint was enough for approval, “the option of Accelerated Approval was not discussed” at that time.

This type of approval “is based on a surrogate or intermediate clinical endpoint, in this case reduction of amyloid plaque in the brain” and requires post-approval studies to verify clinical benefit.

Dr. Cavazzoni added that the drug could still be removed from the market if its confirmatory trial does not verify this type of benefit.

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

The U.S. Food and Drug Administration has provided a detailed and documented account of how it arrived at its decision to approve the controversial Alzheimer’s drug aducanumab (Aduhelm, Biogen/Eisai), including the release of several internal documents.

In a letter sent to members of the FDA’s Center for Drug Evaluation Research (CDER), CDER Director Patrizia Cavazzoni, MD, noted that in view of the “fierce public debate” that erupted immediately following the drug’s approval, she felt compelled to explain how the agency came to its decision.

Also publicly released today on the FDA’s updated aducanumab landing page was “the first set of review memos,” for the drug.

“We’re releasing these documents with the intent of informing public discourse – providing interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni wrote. “The rest of the approval package will be released over the next several days,” she added.
 

Immediate backlash

The FDA’s June 7 approval of aducanumab was met with instant backlash. In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted nearly unanimously to not vote in favor of approval because of a lack of evidence proving its efficacy.

Since the drug was approved, three of the advisory committee’s members resigned in protest. In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.

In its letter, the group noted that the FDA’s decision “showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”

Even the Alzheimer’s Association, which was a staunch supporter of the drug throughout its development process and applauded its approval, expressed outrage over its more than $56,000-a-year cost to patients and called the price “simply unacceptable” in a statement.

In the June 23 letter, the CDER director noted, “this was one of the most complex applications in recent history” and admitted that deliberations were lengthy and difficult.

“It’s also not surprising, in fact it was to be expected, that there would be different viewpoints about the data, including dissenting opinions about the approval decision,” Dr. Cavazzoni wrote.

However, this “is what scientific debate is all about, and while difficult at times, it should be celebrated,” she added. “Please know that every opinion was heard, and the approval is a direct reflection of this open and robust scientific and regulatory debate.”
 

Accelerated approval pathway

Documents newly posted to the FDA’s aducanumab landing page include CDER’s Office of Neurology’s Summary Review Memorandum, which includes details on the basis for the approval; the Concurrence Memorandum from the director of CDER’s Office of New Drugs; and the Concurrence Memorandum from Dr. Cavazzoni.

“The remaining scientific review documents in the Aduhelm action package are not yet available but will be made available to the public as soon as the internal process of review and redaction is complete,” the FDA noted on its site.

In the document FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, Dr. Cavazzoni noted that the “highly complex” data included in the submission package for the drug “left residual uncertainties regarding clinical benefit.”

However, after listening to the patient community and reviewing all the data, the FDA chose to use the Accelerated Approval pathway, deciding that the potential benefit to patients outweighed the drug’s risks.

Of two phase 3 trials, only one met its primary endpoint. However, in all trials, including earlier studies, “Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Dr. Cavazzoni wrote.

“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” she added.

Dr. Cavazzoni noted that although the Advisory Committee did not agree that clinical benefit from one trial meeting its primary endpoint was enough for approval, “the option of Accelerated Approval was not discussed” at that time.

This type of approval “is based on a surrogate or intermediate clinical endpoint, in this case reduction of amyloid plaque in the brain” and requires post-approval studies to verify clinical benefit.

Dr. Cavazzoni added that the drug could still be removed from the market if its confirmatory trial does not verify this type of benefit.

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

Amid significant controversy, the U.S. Food and Drug Administration (FDA) has approved the anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug.

In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.

In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
 

Rocky road

The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.

As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.

However, in an about-face 7 months later, Biogen and Eisai announced that a  new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.

Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.

However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.

As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.

“There is no persuasive evidence to support approval of aducanumab at this time,” they write.

Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.

On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
 

Alzheimer association weighs in

The Alzheimer’s Association has been a proponent of the drug throughout its development.

Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.

“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.

Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.

“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.

“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.

Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.

In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.

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

Amid significant controversy, the U.S. Food and Drug Administration (FDA) has approved the anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug.

In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.

In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
 

Rocky road

The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.

As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.

However, in an about-face 7 months later, Biogen and Eisai announced that a  new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.

Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.

However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.

As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.

“There is no persuasive evidence to support approval of aducanumab at this time,” they write.

Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.

On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
 

Alzheimer association weighs in

The Alzheimer’s Association has been a proponent of the drug throughout its development.

Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.

“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.

Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.

“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.

“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.

Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.

In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.

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

Amid significant controversy, the U.S. Food and Drug Administration (FDA) has approved the anti-amyloid agent aducanumab (Biogen, Eisai) for the treatment of Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug.

In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.

In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
 

Rocky road

The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.

As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.

However, in an about-face 7 months later, Biogen and Eisai announced that a  new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.

Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.

However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.

As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.

“There is no persuasive evidence to support approval of aducanumab at this time,” they write.

Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.

On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
 

Alzheimer association weighs in

The Alzheimer’s Association has been a proponent of the drug throughout its development.

Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.

“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.

Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.

“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.

“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.

Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.

In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.

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

A novel, once-nightly formulation of sodium oxybate is safe and effective for treating both subjective and objective symptoms of narcolepsy, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.

The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).

Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”

“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.

Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.

Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.

FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.

Forced awakening

Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.

“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.

FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.

It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.

The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.

Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.

Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.

Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.

Improvement across doses

Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).

The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).

All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).

There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.

Generally well tolerated

The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”

Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.

Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.

The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.

Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.

Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.

Benefits ‘sleep architecture’

Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”

Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.

Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.

“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.

He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”

“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.

The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.

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

A novel, once-nightly formulation of sodium oxybate is safe and effective for treating both subjective and objective symptoms of narcolepsy, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.

The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).

Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”

“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.

Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.

Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.

FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.

Forced awakening

Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.

“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.

FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.

It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.

The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.

Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.

Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.

Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.

Improvement across doses

Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).

The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).

All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).

There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.

Generally well tolerated

The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”

Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.

Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.

The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.

Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.

Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.

Benefits ‘sleep architecture’

Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”

Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.

Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.

“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.

He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”

“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.

The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.

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

A novel, once-nightly formulation of sodium oxybate is safe and effective for treating both subjective and objective symptoms of narcolepsy, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.

The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).

Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”

“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.

Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.

Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.

FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.

Forced awakening

Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.

“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.

FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.

It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.

The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.

Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.

Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.

Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.

Improvement across doses

Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).

The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).

All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).

There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.

Generally well tolerated

The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”

Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.

Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.

The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.

Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.

Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.

Benefits ‘sleep architecture’

Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”

Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.

Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.

“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.

He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”

“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.

The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.

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

A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.

The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.

That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.

However, the new report noted that these conditions are very rare.

“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.

“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”

The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
 

Assessing 81 million patients

In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.

Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.

Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.

Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.

For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.

“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected. 
 

Rare events

The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.

An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.

An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.

A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.

“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”

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

A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.

The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.

That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.

However, the new report noted that these conditions are very rare.

“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.

“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”

The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
 

Assessing 81 million patients

In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.

Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.

Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.

Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.

For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.

“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected. 
 

Rare events

The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.

An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.

An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.

A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.

“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”

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

A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.

The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.

That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.

However, the new report noted that these conditions are very rare.

“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.

“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”

The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
 

Assessing 81 million patients

In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.

Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.

Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.

Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.

For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.

“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected. 
 

Rare events

The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.

An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.

An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.

A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.

“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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