MDedge Neurology

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

Proper care of teeth and gums may offer benefits beyond oral health, including improving brain health, new research suggests.

In a large observational study of middle-aged adults without stroke or dementia, poor oral health was strongly associated with multiple neuroimaging markers of white matter injury.

“Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health,” wrote the authors, led by Cyprien A. Rivier, MD, MS, with the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

The study was published online on December 20, 2023, in Neurology.

Research data came from 40,175 adults (mean age, 55 years; 53% women) with no history of stroke or dementia who enrolled in the UK Biobank from 2006 to 2010 and had brain MRI between 2014 and 2016.

Altogether, 5470 (14%) participants had poor oral health, defined as the presence of dentures or loose teeth. Those with poor (vs optimal) oral health were older, more likely to be male, and had higher prevalence of hypertension, hypercholesterolemia, diabetes, overweight/obesity, and current or past smoking history.

In a multivariable model, poor oral health was associated with a 9% increase in white matter hyperintensity (WMH) volume (P < .001), a well-established marker of clinically silent cerebrovascular disease.

Poor oral health was also associated with a 10% change in aggregate fractional anisotropy (FA) score (P < .001) and a 5% change in aggregate mean diffusivity (MD) score (P < .001), two diffusion tensor imaging metrics that accurately represent white matter disintegrity.

Genetic analyses using Mendelian randomization confirmed these associations. Individuals who were genetically prone to poor oral health had a 30% increase in WMH volume (P < .001), 43% change in aggregate FA score (P < .001), and 10% change in aggregate MD score (P < .01), the researchers reported.

These findings, they noted, add to prior epidemiologic evidence for an association between poor oral health and a higher risk for clinical outcomes related to brain health, including cognitive decline.

‘Huge Dividends’

The authors of an accompanying editorial praised the authors for looking at the consequences of poor oral health in a “new and powerful way by using as their outcome MRI-defined white matter injury, which is associated with, but antedates by many years, cognitive decline and stroke.”

“The fact that these imaging changes are seen in asymptomatic persons offers the hope that if the association is causal, interventions to improve oral health could pay huge dividends in subsequent brain health,” wrote Steven J. Kittner, MD, MPH, and Breana L. Taylor, MD, with the Department of Neurology, University of Maryland School of Medicine in Baltimore.

“The mechanisms mediating the relationship between the oral health genetic risk score and white matter injury are likely to be complex, but the authors have taken an important step forward in addressing a hypothesis of immense public health importance,” they added.

Data from the World Health Organization suggested that oral diseases, which are largely preventable, affect nearly 3.5 billion people globally, with three out of four people affected in middle-income countries.

Funding for the study was provided in part by grants from the National Institutes of Health, the American Heart Association, and the Neurocritical Care Society Research Fellowship. The authors and editorialists disclosed no relevant conflicts of interest.

Megan Brooks has disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Proper care of teeth and gums may offer benefits beyond oral health, including improving brain health, new research suggests.

In a large observational study of middle-aged adults without stroke or dementia, poor oral health was strongly associated with multiple neuroimaging markers of white matter injury.

“Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health,” wrote the authors, led by Cyprien A. Rivier, MD, MS, with the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

The study was published online on December 20, 2023, in Neurology.

Research data came from 40,175 adults (mean age, 55 years; 53% women) with no history of stroke or dementia who enrolled in the UK Biobank from 2006 to 2010 and had brain MRI between 2014 and 2016.

Altogether, 5470 (14%) participants had poor oral health, defined as the presence of dentures or loose teeth. Those with poor (vs optimal) oral health were older, more likely to be male, and had higher prevalence of hypertension, hypercholesterolemia, diabetes, overweight/obesity, and current or past smoking history.

In a multivariable model, poor oral health was associated with a 9% increase in white matter hyperintensity (WMH) volume (P < .001), a well-established marker of clinically silent cerebrovascular disease.

Poor oral health was also associated with a 10% change in aggregate fractional anisotropy (FA) score (P < .001) and a 5% change in aggregate mean diffusivity (MD) score (P < .001), two diffusion tensor imaging metrics that accurately represent white matter disintegrity.

Genetic analyses using Mendelian randomization confirmed these associations. Individuals who were genetically prone to poor oral health had a 30% increase in WMH volume (P < .001), 43% change in aggregate FA score (P < .001), and 10% change in aggregate MD score (P < .01), the researchers reported.

These findings, they noted, add to prior epidemiologic evidence for an association between poor oral health and a higher risk for clinical outcomes related to brain health, including cognitive decline.

‘Huge Dividends’

The authors of an accompanying editorial praised the authors for looking at the consequences of poor oral health in a “new and powerful way by using as their outcome MRI-defined white matter injury, which is associated with, but antedates by many years, cognitive decline and stroke.”

“The fact that these imaging changes are seen in asymptomatic persons offers the hope that if the association is causal, interventions to improve oral health could pay huge dividends in subsequent brain health,” wrote Steven J. Kittner, MD, MPH, and Breana L. Taylor, MD, with the Department of Neurology, University of Maryland School of Medicine in Baltimore.

“The mechanisms mediating the relationship between the oral health genetic risk score and white matter injury are likely to be complex, but the authors have taken an important step forward in addressing a hypothesis of immense public health importance,” they added.

Data from the World Health Organization suggested that oral diseases, which are largely preventable, affect nearly 3.5 billion people globally, with three out of four people affected in middle-income countries.

Funding for the study was provided in part by grants from the National Institutes of Health, the American Heart Association, and the Neurocritical Care Society Research Fellowship. The authors and editorialists disclosed no relevant conflicts of interest.

Megan Brooks has disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Proper care of teeth and gums may offer benefits beyond oral health, including improving brain health, new research suggests.

In a large observational study of middle-aged adults without stroke or dementia, poor oral health was strongly associated with multiple neuroimaging markers of white matter injury.

“Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health,” wrote the authors, led by Cyprien A. Rivier, MD, MS, with the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

The study was published online on December 20, 2023, in Neurology.

Research data came from 40,175 adults (mean age, 55 years; 53% women) with no history of stroke or dementia who enrolled in the UK Biobank from 2006 to 2010 and had brain MRI between 2014 and 2016.

Altogether, 5470 (14%) participants had poor oral health, defined as the presence of dentures or loose teeth. Those with poor (vs optimal) oral health were older, more likely to be male, and had higher prevalence of hypertension, hypercholesterolemia, diabetes, overweight/obesity, and current or past smoking history.

In a multivariable model, poor oral health was associated with a 9% increase in white matter hyperintensity (WMH) volume (P < .001), a well-established marker of clinically silent cerebrovascular disease.

Poor oral health was also associated with a 10% change in aggregate fractional anisotropy (FA) score (P < .001) and a 5% change in aggregate mean diffusivity (MD) score (P < .001), two diffusion tensor imaging metrics that accurately represent white matter disintegrity.

Genetic analyses using Mendelian randomization confirmed these associations. Individuals who were genetically prone to poor oral health had a 30% increase in WMH volume (P < .001), 43% change in aggregate FA score (P < .001), and 10% change in aggregate MD score (P < .01), the researchers reported.

These findings, they noted, add to prior epidemiologic evidence for an association between poor oral health and a higher risk for clinical outcomes related to brain health, including cognitive decline.

‘Huge Dividends’

The authors of an accompanying editorial praised the authors for looking at the consequences of poor oral health in a “new and powerful way by using as their outcome MRI-defined white matter injury, which is associated with, but antedates by many years, cognitive decline and stroke.”

“The fact that these imaging changes are seen in asymptomatic persons offers the hope that if the association is causal, interventions to improve oral health could pay huge dividends in subsequent brain health,” wrote Steven J. Kittner, MD, MPH, and Breana L. Taylor, MD, with the Department of Neurology, University of Maryland School of Medicine in Baltimore.

“The mechanisms mediating the relationship between the oral health genetic risk score and white matter injury are likely to be complex, but the authors have taken an important step forward in addressing a hypothesis of immense public health importance,” they added.

Data from the World Health Organization suggested that oral diseases, which are largely preventable, affect nearly 3.5 billion people globally, with three out of four people affected in middle-income countries.

Funding for the study was provided in part by grants from the National Institutes of Health, the American Heart Association, and the Neurocritical Care Society Research Fellowship. The authors and editorialists disclosed no relevant conflicts of interest.

Megan Brooks has disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The first time I saw a patient in the hospital was in 2004, twenty years ago, when I was a third-year med student. I mean, look at that guy. The things I could tell him.

Since that time, I have spent countless hours in the hospital as a resident, a renal fellow, and finally as an attending. And I’m sure many of you in the medical community feel the same thing I do, which is that patients are much more complicated now than they used to be. I’ll listen to an intern present a new case on rounds and she’ll have an assessment and plan that encompasses a dozen individual medical problems. Sometimes I have to literally be like, “Wait, why is this patient here again?”

But until now, I had no data to convince myself that this feeling was real — that hospitalized patients are getting more and more complicated, or that they only seem more complicated because I’m getting older. Maybe I was better able to keep track of things when I was an intern rather than now as an attending, spending just a couple months of the year in the hospital. I mean, after all, if patients were getting more complicated, surely hospitals would know this and allocate more resources to patient care, right?

Right?

It’s not an illusion. At least not according to this paper, Population-Based Trends in Complexity of Hospital Inpatients, appearing in JAMA Internal Medicine, which examines about 15 years of inpatient hospital admissions in British Columbia.

I like Canada for this study for two reasons: First, their electronic health record system is province-wide, so they don’t have issues of getting data from hospital A vs hospital B. All the data are there — in this case, more than 3 million nonelective hospital admissions from British Columbia. Second, there is universal healthcare. We don’t have to worry about insurance companies changing, or the start of a new program like the Affordable Care Act. It’s just a cleaner set-up.

Of course, complexity is hard to define, and the authors here decide to look at a variety of metrics I think we can agree are tied into complexity. These include things like patient age, comorbidities, medications, frequency of hospitalization, and so on. They also looked at outcomes associated with hospitalization: Did the patient require the ICU? Did they survive? Were they readmitted?

And the tale of the tape is as clear as that British Columbian air: Over the past 15 years, your average hospitalized patient is about 3 years older, is twice as likely to have kidney disease, 70% more likely to have diabetes, is on more medications (particularly anticoagulants), and is much more likely to be admitted through the emergency room. They’ve also spent more time in the hospital in the past year.

Given the increased complexity, you might expect that the outcomes for these patients are worse than years ago, but the data do not bear that out. In fact, inpatient mortality is lower now than it was 15 years ago, although 30-day postdischarge mortality is higher. Put those together and it turns out that death rates are pretty stable: 9% of people admitted for nonelective reasons to the hospital will die within 30 days. It’s just that nowadays, we tend to discharge them before that happens.

Why are our patients getting more complex? Some of it is demographics; the population is aging, after all. Some of it relates to the increasing burden of comorbidities like diabetes and kidney disease, which are associated with the obesity epidemic. But in some ways, we’re a victim of our own success. We have the ability to keep people alive today who would not have survived 15 years ago. We have better treatments for metastatic cancer, less-invasive therapies for heart disease, better protocolized ICU care.

Given all that, does it make any sense that many of our hospitals are at skeleton-crew staffing levels? That hospitalists report taking care of more patients than they ever have before?

There’s been so much talk about burnout in the health professions lately. Maybe something people need to start acknowledging — particularly those who haven’t practiced on the front lines for a decade or two — is that the job is, quite simply, harder now. As patients become more complex, we need more resources, human and otherwise, to care for them.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The first time I saw a patient in the hospital was in 2004, twenty years ago, when I was a third-year med student. I mean, look at that guy. The things I could tell him.

Since that time, I have spent countless hours in the hospital as a resident, a renal fellow, and finally as an attending. And I’m sure many of you in the medical community feel the same thing I do, which is that patients are much more complicated now than they used to be. I’ll listen to an intern present a new case on rounds and she’ll have an assessment and plan that encompasses a dozen individual medical problems. Sometimes I have to literally be like, “Wait, why is this patient here again?”

But until now, I had no data to convince myself that this feeling was real — that hospitalized patients are getting more and more complicated, or that they only seem more complicated because I’m getting older. Maybe I was better able to keep track of things when I was an intern rather than now as an attending, spending just a couple months of the year in the hospital. I mean, after all, if patients were getting more complicated, surely hospitals would know this and allocate more resources to patient care, right?

Right?

It’s not an illusion. At least not according to this paper, Population-Based Trends in Complexity of Hospital Inpatients, appearing in JAMA Internal Medicine, which examines about 15 years of inpatient hospital admissions in British Columbia.

I like Canada for this study for two reasons: First, their electronic health record system is province-wide, so they don’t have issues of getting data from hospital A vs hospital B. All the data are there — in this case, more than 3 million nonelective hospital admissions from British Columbia. Second, there is universal healthcare. We don’t have to worry about insurance companies changing, or the start of a new program like the Affordable Care Act. It’s just a cleaner set-up.

Of course, complexity is hard to define, and the authors here decide to look at a variety of metrics I think we can agree are tied into complexity. These include things like patient age, comorbidities, medications, frequency of hospitalization, and so on. They also looked at outcomes associated with hospitalization: Did the patient require the ICU? Did they survive? Were they readmitted?

And the tale of the tape is as clear as that British Columbian air: Over the past 15 years, your average hospitalized patient is about 3 years older, is twice as likely to have kidney disease, 70% more likely to have diabetes, is on more medications (particularly anticoagulants), and is much more likely to be admitted through the emergency room. They’ve also spent more time in the hospital in the past year.

Given the increased complexity, you might expect that the outcomes for these patients are worse than years ago, but the data do not bear that out. In fact, inpatient mortality is lower now than it was 15 years ago, although 30-day postdischarge mortality is higher. Put those together and it turns out that death rates are pretty stable: 9% of people admitted for nonelective reasons to the hospital will die within 30 days. It’s just that nowadays, we tend to discharge them before that happens.

Why are our patients getting more complex? Some of it is demographics; the population is aging, after all. Some of it relates to the increasing burden of comorbidities like diabetes and kidney disease, which are associated with the obesity epidemic. But in some ways, we’re a victim of our own success. We have the ability to keep people alive today who would not have survived 15 years ago. We have better treatments for metastatic cancer, less-invasive therapies for heart disease, better protocolized ICU care.

Given all that, does it make any sense that many of our hospitals are at skeleton-crew staffing levels? That hospitalists report taking care of more patients than they ever have before?

There’s been so much talk about burnout in the health professions lately. Maybe something people need to start acknowledging — particularly those who haven’t practiced on the front lines for a decade or two — is that the job is, quite simply, harder now. As patients become more complex, we need more resources, human and otherwise, to care for them.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The first time I saw a patient in the hospital was in 2004, twenty years ago, when I was a third-year med student. I mean, look at that guy. The things I could tell him.

Since that time, I have spent countless hours in the hospital as a resident, a renal fellow, and finally as an attending. And I’m sure many of you in the medical community feel the same thing I do, which is that patients are much more complicated now than they used to be. I’ll listen to an intern present a new case on rounds and she’ll have an assessment and plan that encompasses a dozen individual medical problems. Sometimes I have to literally be like, “Wait, why is this patient here again?”

But until now, I had no data to convince myself that this feeling was real — that hospitalized patients are getting more and more complicated, or that they only seem more complicated because I’m getting older. Maybe I was better able to keep track of things when I was an intern rather than now as an attending, spending just a couple months of the year in the hospital. I mean, after all, if patients were getting more complicated, surely hospitals would know this and allocate more resources to patient care, right?

Right?

It’s not an illusion. At least not according to this paper, Population-Based Trends in Complexity of Hospital Inpatients, appearing in JAMA Internal Medicine, which examines about 15 years of inpatient hospital admissions in British Columbia.

I like Canada for this study for two reasons: First, their electronic health record system is province-wide, so they don’t have issues of getting data from hospital A vs hospital B. All the data are there — in this case, more than 3 million nonelective hospital admissions from British Columbia. Second, there is universal healthcare. We don’t have to worry about insurance companies changing, or the start of a new program like the Affordable Care Act. It’s just a cleaner set-up.

Of course, complexity is hard to define, and the authors here decide to look at a variety of metrics I think we can agree are tied into complexity. These include things like patient age, comorbidities, medications, frequency of hospitalization, and so on. They also looked at outcomes associated with hospitalization: Did the patient require the ICU? Did they survive? Were they readmitted?

And the tale of the tape is as clear as that British Columbian air: Over the past 15 years, your average hospitalized patient is about 3 years older, is twice as likely to have kidney disease, 70% more likely to have diabetes, is on more medications (particularly anticoagulants), and is much more likely to be admitted through the emergency room. They’ve also spent more time in the hospital in the past year.

Given the increased complexity, you might expect that the outcomes for these patients are worse than years ago, but the data do not bear that out. In fact, inpatient mortality is lower now than it was 15 years ago, although 30-day postdischarge mortality is higher. Put those together and it turns out that death rates are pretty stable: 9% of people admitted for nonelective reasons to the hospital will die within 30 days. It’s just that nowadays, we tend to discharge them before that happens.

Why are our patients getting more complex? Some of it is demographics; the population is aging, after all. Some of it relates to the increasing burden of comorbidities like diabetes and kidney disease, which are associated with the obesity epidemic. But in some ways, we’re a victim of our own success. We have the ability to keep people alive today who would not have survived 15 years ago. We have better treatments for metastatic cancer, less-invasive therapies for heart disease, better protocolized ICU care.

Given all that, does it make any sense that many of our hospitals are at skeleton-crew staffing levels? That hospitalists report taking care of more patients than they ever have before?

There’s been so much talk about burnout in the health professions lately. Maybe something people need to start acknowledging — particularly those who haven’t practiced on the front lines for a decade or two — is that the job is, quite simply, harder now. As patients become more complex, we need more resources, human and otherwise, to care for them.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — “There are similarities between Alzheimer’s disease and epilepsy,” said Delia Marias Talos, MD, at a session of the annual meeting of the American Epilepsy Society (AES).

A Closer Look at the Brain

“Phosphorylated tau correlates with cognitive function and executive function recorded presurgery, but it looks like the generative changes are more associated with temporal lobe and aging.”

Alzheimer’s disease is a degenerative condition marked by progressive memory deficits and cognitive decline noted by amyloid plaques and a formation of neurofibrillary tangles resulting from tau hyperphosphorylation.

Epilepsy, on the other hand, is a multifactorial condition with causes ranging from metabolic disorders, structural defects, infections, genetic mutations, and autoimmune disorders. In addition, nearly 50% of all epileptic seizures are idiopathic in nature.

Dr. Talos, professor of neurology at the University of Pennsylvania Perlman School of Medicine in Philadelphia, and her team did not see neurofibrillary tangles in the presurgical brains of epilepsy patients they studied; however, they saw tau plaques. In the future, they seek to investigate the features that distinguish epilepsy from Alzheimer’s disease.

Toxic fragments are probably there because amyloid precursor protein is highly upregulated, she told conference attendees. “We hypothesized that amyloid plaque is cleared but not impaired in epilepsy.”

The prognosis looks comparatively worse for patients who have Alzheimer’s disease and comorbid epilepsy than for patients who have only epilepsy. In addition, Dr. Talos stated that seizures appear to have an additive effort on Alzheimer’s disease.
 

Fyn-disruptive Therapy

Marson Putra, MD, PhD, a neuroscientist and postdoctoral researcher at Iowa State in Ames, Iowa, presented on the potential impact of a novel fyn-tau interaction as an unexplored target for epileptogensis and epilepsy.

Dr. Putra studied whether fyn-tau interactions exist in epilepsy. In both Alzheimer’s disease and epilepsy, Fyn belongs to the Src family of nonreceptor tyrosine kinases (SFKs), which are involved in cell proliferation and migration. Fyn contains an SH3 domain, which serves as a target for tau’s proline-rich (PxxP) motif. Fyn phosphorylates tau, specifically at tyrosine residue Y18, making fyn-disruptive therapy worth exploring.

Dr. Putra shared several currently proposed mechanisms of action regarding the pathogenesis of the tau plaque. In the first theory, the tau protein assumes a closed conformation in its normal state, thereby concealing the PxxP motif. However, in the second theory, pathogenesis causes the tau protein to assume an open conformation in the disease state, exposing pAT8 sites and making them available to fyn phosphorylation. In the second scenario, which involves Alzheimer’s disease, the fyn-tau interaction still occurs in open conformation state and is thought to occur in the postsynaptic terminal of the dendritic spine.

To investigate the proposed disease-causing mechanisms, Dr. Putra and her team studied status epilepticus in a rodent model of status epilepticus (SE). They used proximity ligation assay to measure interactions between Fyn and tau. They found AT8 and Y18 Fyn and N-methyl-D-aspartate (NMDA) receptor activation in a rat model and increased Fyn interaction. In addition, neuronal nitric oxide synthase levels were elevated 24 hours post-status. When investigating the fyn activity and interactions in the human brain, they found fyn phosphorylation – something that had never been reported before.

From there, Dr. Putra’s team sought to answer whether manipulating fyn-tau interactions could modify epilepsy. To do so, they conducted an experiment using the pharmacological Fyn inhibitor sarcatinib (SAR) and found it modified dysregulated postsynaptic proteins 24 hours post-SE in rat models. Longer exposure also bore a positive effect on epileptic rats.

After treating epileptic rats with SAR for 7 weeks, Dr. Putra found that SAR therapy reduces convulsive seizures during 7 weeks post-SE in rats. Recruiting pharmacological Fyn inhibition sufficiently decreased Fyn-tau interaction, NR-PSD95 complex, and convulsive seizures in chronic epilepsy.

Ultimately, her findings showed that SE exacerbates fyn-tau interactions, with chronic epilepsy modeling showing sustained elevation. In addition, fyn-tau interactions mediate and sustain neuronal hyperexcitability in the epileptic population.

“The impact on clinical care will be bidirectional relevant therapeutic targets in epilepsy and Alzheimer’s disease,” Dr. Putra told the audience.
 

Trends in epilepsy comorbidity and mortality

The final presenter, University of Washington researcher Aaron del Pozo, PhD, explained the impact of early-onset Alzheimer’s disease on overall outcomes and epilepsy.

“Early-onset Alzheimer’s disease carries a high seizure risk that affects quality of life as well as mortality,” Dr. del Pozo said.

According to data published in the British Medical Journal in 2020, the number of patients with epilepsy who had degenerative disease of the central nervous system or vascular dementia and delirium increased by approximately 210% from 1999 to 2017. Cerebral palsy trailed in second place with malignant neoplasms increasing by 50%. Cerebrovascular disease­–related death in the epileptic population showed nearly negligible change, and ischemic heart disease and epilepsy decreased by approximately 25% and 15%, respectively. In addition, patients who have both epilepsy and Alzheimer’s disease are less likely to survive than patients who develop epilepsy after Alzheimer’s disease.

“We found that having epilepsy alone has decreased mortality, but having it in addition to other generative diseases of the central nervous system has a 200% increase in mortality,” Dr. del Pozo said.

ORLANDO — “There are similarities between Alzheimer’s disease and epilepsy,” said Delia Marias Talos, MD, at a session of the annual meeting of the American Epilepsy Society (AES).

A Closer Look at the Brain

“Phosphorylated tau correlates with cognitive function and executive function recorded presurgery, but it looks like the generative changes are more associated with temporal lobe and aging.”

Alzheimer’s disease is a degenerative condition marked by progressive memory deficits and cognitive decline noted by amyloid plaques and a formation of neurofibrillary tangles resulting from tau hyperphosphorylation.

Epilepsy, on the other hand, is a multifactorial condition with causes ranging from metabolic disorders, structural defects, infections, genetic mutations, and autoimmune disorders. In addition, nearly 50% of all epileptic seizures are idiopathic in nature.

Dr. Talos, professor of neurology at the University of Pennsylvania Perlman School of Medicine in Philadelphia, and her team did not see neurofibrillary tangles in the presurgical brains of epilepsy patients they studied; however, they saw tau plaques. In the future, they seek to investigate the features that distinguish epilepsy from Alzheimer’s disease.

Toxic fragments are probably there because amyloid precursor protein is highly upregulated, she told conference attendees. “We hypothesized that amyloid plaque is cleared but not impaired in epilepsy.”

The prognosis looks comparatively worse for patients who have Alzheimer’s disease and comorbid epilepsy than for patients who have only epilepsy. In addition, Dr. Talos stated that seizures appear to have an additive effort on Alzheimer’s disease.
 

Fyn-disruptive Therapy

Marson Putra, MD, PhD, a neuroscientist and postdoctoral researcher at Iowa State in Ames, Iowa, presented on the potential impact of a novel fyn-tau interaction as an unexplored target for epileptogensis and epilepsy.

Dr. Putra studied whether fyn-tau interactions exist in epilepsy. In both Alzheimer’s disease and epilepsy, Fyn belongs to the Src family of nonreceptor tyrosine kinases (SFKs), which are involved in cell proliferation and migration. Fyn contains an SH3 domain, which serves as a target for tau’s proline-rich (PxxP) motif. Fyn phosphorylates tau, specifically at tyrosine residue Y18, making fyn-disruptive therapy worth exploring.

Dr. Putra shared several currently proposed mechanisms of action regarding the pathogenesis of the tau plaque. In the first theory, the tau protein assumes a closed conformation in its normal state, thereby concealing the PxxP motif. However, in the second theory, pathogenesis causes the tau protein to assume an open conformation in the disease state, exposing pAT8 sites and making them available to fyn phosphorylation. In the second scenario, which involves Alzheimer’s disease, the fyn-tau interaction still occurs in open conformation state and is thought to occur in the postsynaptic terminal of the dendritic spine.

To investigate the proposed disease-causing mechanisms, Dr. Putra and her team studied status epilepticus in a rodent model of status epilepticus (SE). They used proximity ligation assay to measure interactions between Fyn and tau. They found AT8 and Y18 Fyn and N-methyl-D-aspartate (NMDA) receptor activation in a rat model and increased Fyn interaction. In addition, neuronal nitric oxide synthase levels were elevated 24 hours post-status. When investigating the fyn activity and interactions in the human brain, they found fyn phosphorylation – something that had never been reported before.

From there, Dr. Putra’s team sought to answer whether manipulating fyn-tau interactions could modify epilepsy. To do so, they conducted an experiment using the pharmacological Fyn inhibitor sarcatinib (SAR) and found it modified dysregulated postsynaptic proteins 24 hours post-SE in rat models. Longer exposure also bore a positive effect on epileptic rats.

After treating epileptic rats with SAR for 7 weeks, Dr. Putra found that SAR therapy reduces convulsive seizures during 7 weeks post-SE in rats. Recruiting pharmacological Fyn inhibition sufficiently decreased Fyn-tau interaction, NR-PSD95 complex, and convulsive seizures in chronic epilepsy.

Ultimately, her findings showed that SE exacerbates fyn-tau interactions, with chronic epilepsy modeling showing sustained elevation. In addition, fyn-tau interactions mediate and sustain neuronal hyperexcitability in the epileptic population.

“The impact on clinical care will be bidirectional relevant therapeutic targets in epilepsy and Alzheimer’s disease,” Dr. Putra told the audience.
 

Trends in epilepsy comorbidity and mortality

The final presenter, University of Washington researcher Aaron del Pozo, PhD, explained the impact of early-onset Alzheimer’s disease on overall outcomes and epilepsy.

“Early-onset Alzheimer’s disease carries a high seizure risk that affects quality of life as well as mortality,” Dr. del Pozo said.

According to data published in the British Medical Journal in 2020, the number of patients with epilepsy who had degenerative disease of the central nervous system or vascular dementia and delirium increased by approximately 210% from 1999 to 2017. Cerebral palsy trailed in second place with malignant neoplasms increasing by 50%. Cerebrovascular disease­–related death in the epileptic population showed nearly negligible change, and ischemic heart disease and epilepsy decreased by approximately 25% and 15%, respectively. In addition, patients who have both epilepsy and Alzheimer’s disease are less likely to survive than patients who develop epilepsy after Alzheimer’s disease.

“We found that having epilepsy alone has decreased mortality, but having it in addition to other generative diseases of the central nervous system has a 200% increase in mortality,” Dr. del Pozo said.

ORLANDO — “There are similarities between Alzheimer’s disease and epilepsy,” said Delia Marias Talos, MD, at a session of the annual meeting of the American Epilepsy Society (AES).

A Closer Look at the Brain

“Phosphorylated tau correlates with cognitive function and executive function recorded presurgery, but it looks like the generative changes are more associated with temporal lobe and aging.”

Alzheimer’s disease is a degenerative condition marked by progressive memory deficits and cognitive decline noted by amyloid plaques and a formation of neurofibrillary tangles resulting from tau hyperphosphorylation.

Epilepsy, on the other hand, is a multifactorial condition with causes ranging from metabolic disorders, structural defects, infections, genetic mutations, and autoimmune disorders. In addition, nearly 50% of all epileptic seizures are idiopathic in nature.

Dr. Talos, professor of neurology at the University of Pennsylvania Perlman School of Medicine in Philadelphia, and her team did not see neurofibrillary tangles in the presurgical brains of epilepsy patients they studied; however, they saw tau plaques. In the future, they seek to investigate the features that distinguish epilepsy from Alzheimer’s disease.

Toxic fragments are probably there because amyloid precursor protein is highly upregulated, she told conference attendees. “We hypothesized that amyloid plaque is cleared but not impaired in epilepsy.”

The prognosis looks comparatively worse for patients who have Alzheimer’s disease and comorbid epilepsy than for patients who have only epilepsy. In addition, Dr. Talos stated that seizures appear to have an additive effort on Alzheimer’s disease.
 

Fyn-disruptive Therapy

Marson Putra, MD, PhD, a neuroscientist and postdoctoral researcher at Iowa State in Ames, Iowa, presented on the potential impact of a novel fyn-tau interaction as an unexplored target for epileptogensis and epilepsy.

Dr. Putra studied whether fyn-tau interactions exist in epilepsy. In both Alzheimer’s disease and epilepsy, Fyn belongs to the Src family of nonreceptor tyrosine kinases (SFKs), which are involved in cell proliferation and migration. Fyn contains an SH3 domain, which serves as a target for tau’s proline-rich (PxxP) motif. Fyn phosphorylates tau, specifically at tyrosine residue Y18, making fyn-disruptive therapy worth exploring.

Dr. Putra shared several currently proposed mechanisms of action regarding the pathogenesis of the tau plaque. In the first theory, the tau protein assumes a closed conformation in its normal state, thereby concealing the PxxP motif. However, in the second theory, pathogenesis causes the tau protein to assume an open conformation in the disease state, exposing pAT8 sites and making them available to fyn phosphorylation. In the second scenario, which involves Alzheimer’s disease, the fyn-tau interaction still occurs in open conformation state and is thought to occur in the postsynaptic terminal of the dendritic spine.

To investigate the proposed disease-causing mechanisms, Dr. Putra and her team studied status epilepticus in a rodent model of status epilepticus (SE). They used proximity ligation assay to measure interactions between Fyn and tau. They found AT8 and Y18 Fyn and N-methyl-D-aspartate (NMDA) receptor activation in a rat model and increased Fyn interaction. In addition, neuronal nitric oxide synthase levels were elevated 24 hours post-status. When investigating the fyn activity and interactions in the human brain, they found fyn phosphorylation – something that had never been reported before.

From there, Dr. Putra’s team sought to answer whether manipulating fyn-tau interactions could modify epilepsy. To do so, they conducted an experiment using the pharmacological Fyn inhibitor sarcatinib (SAR) and found it modified dysregulated postsynaptic proteins 24 hours post-SE in rat models. Longer exposure also bore a positive effect on epileptic rats.

After treating epileptic rats with SAR for 7 weeks, Dr. Putra found that SAR therapy reduces convulsive seizures during 7 weeks post-SE in rats. Recruiting pharmacological Fyn inhibition sufficiently decreased Fyn-tau interaction, NR-PSD95 complex, and convulsive seizures in chronic epilepsy.

Ultimately, her findings showed that SE exacerbates fyn-tau interactions, with chronic epilepsy modeling showing sustained elevation. In addition, fyn-tau interactions mediate and sustain neuronal hyperexcitability in the epileptic population.

“The impact on clinical care will be bidirectional relevant therapeutic targets in epilepsy and Alzheimer’s disease,” Dr. Putra told the audience.
 

Trends in epilepsy comorbidity and mortality

The final presenter, University of Washington researcher Aaron del Pozo, PhD, explained the impact of early-onset Alzheimer’s disease on overall outcomes and epilepsy.

“Early-onset Alzheimer’s disease carries a high seizure risk that affects quality of life as well as mortality,” Dr. del Pozo said.

According to data published in the British Medical Journal in 2020, the number of patients with epilepsy who had degenerative disease of the central nervous system or vascular dementia and delirium increased by approximately 210% from 1999 to 2017. Cerebral palsy trailed in second place with malignant neoplasms increasing by 50%. Cerebrovascular disease­–related death in the epileptic population showed nearly negligible change, and ischemic heart disease and epilepsy decreased by approximately 25% and 15%, respectively. In addition, patients who have both epilepsy and Alzheimer’s disease are less likely to survive than patients who develop epilepsy after Alzheimer’s disease.

“We found that having epilepsy alone has decreased mortality, but having it in addition to other generative diseases of the central nervous system has a 200% increase in mortality,” Dr. del Pozo said.

Less than 2 minutes of transcranial magnetic stimulation (TMS) targeting specific areas of the brain can boost an individual’s ability to be hypnotized, in new findings that could increase the efficacy of therapeutic hypnosis and expand the pool of patients who can benefit from it.

“We were able to increase hypnotizability, a neuropsychological trait previously shown to be as stable as IQ in adulthood,” said co-senior author David Spiegel, MD, professor of psychiatry and behavioral sciences, Stanford University, Palo Alto, California.

“Our findings would allow us to combine neurostimulation with hypnosis to expand the number of people able to benefit from hypnosis and enhance their responsiveness to treatment,” Dr. Spiegel added.

The study was published online on January 4, 2024, in Nature Mental Health.

A Breakthrough for Hypnotherapy?

Hypnosis has long been used to treat and manage a host of psychiatric and neurologic symptoms. However, not all patients respond equally to this therapy type.

About two thirds of the general adult population are estimated to be at least somewhat hypnotizable, and 15% are highly hypnotizable.

Through brain imaging, the Stanford team found that high hypnotizability is associated with greater functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the dorsal anterior cingulate cortex.

In the double-blind study, they randomly assigned 80 patients (mean age, 48 years; 94% women) with fibromyalgia syndrome to active, or sham, continuous theta-burst stimulation over a personalized neuroimaging-derived left DLPFC target — a technique known as Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT). Individuals who were naturally highly hypnotizable were excluded.

“A novel aspect of this trial is that we used the person’s own brain networks, based on brain imaging, to target the right spot,” Co-senior author Nolan Williams, MD, with Stanford University, California, said in a news release.

The team chose patients with chronic pain because hypnosis has been shown to be a “highly effective analgesic that has a far better risk/benefit ratio than widely overutilized opioids that have serious fatal overdose potential,” Spiegel told this news organization.

The pre-to-post SHIFT change in hypnotic induction profile scores, a standardized measure of hypnotizability, was significantly greater in the active vs sham group after just 92 seconds of stimulation (P = .046).

Only the active SHIFT group showed a significant increase in hypnotizability following stimulation, an effect that lasted for about 1 hour.

“Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention,” the researchers wrote.

They note that because this was a “mechanistic study,” it did not explore the impact of increased hypnotizability on disease symptoms. They also note that further studies are needed to assess the dose-response relationships of SHIFT.

Transformative Research

“This line of research is fascinating,” Shaheen Lakhan, MD, PhD, neurologist, and researcher in Boston, told this news organization.

“We are nearing an era of personalized, noninvasive brain modulation. The ability to individually modulate the DLPFC opens new possibilities for brain health beyond hypnotizability for fibromyalgia,” said Dr. Lakhan, who wasn’t involved in the study.

“The DLPFC is involved in executive functions (and disorders) like attention (ADHD), emotional regulation (depression), motivation (schizophrenia), and impulse control (addiction),” he noted.

“Soon we may no longer need large expensive devices like transcranial magnetic stimulators as in this research study. Smartphones could deliver tailored digital therapeutics by engaging specific brain circuits,” Dr. Lakhan predicted.

“Imagine using an app to receive treatment customized to your unique brain and needs — all without anything implanted and delivered anywhere. The potential to precisely modulate the brain’s wiring to enhance cognition and mental health, without surgery or physical constraints, is incredibly promising. The possibilities are intriguing and could truly transform how we address brain diseases,” he added.

The study was supported by a grant from the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH). Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and holds equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Spiegel is a cofounder of Reveri Health, Inc., an interactive hypnosis app (not utilized in the current study).
 

A version of this article appeared on Medscape.com.

Less than 2 minutes of transcranial magnetic stimulation (TMS) targeting specific areas of the brain can boost an individual’s ability to be hypnotized, in new findings that could increase the efficacy of therapeutic hypnosis and expand the pool of patients who can benefit from it.

“We were able to increase hypnotizability, a neuropsychological trait previously shown to be as stable as IQ in adulthood,” said co-senior author David Spiegel, MD, professor of psychiatry and behavioral sciences, Stanford University, Palo Alto, California.

“Our findings would allow us to combine neurostimulation with hypnosis to expand the number of people able to benefit from hypnosis and enhance their responsiveness to treatment,” Dr. Spiegel added.

The study was published online on January 4, 2024, in Nature Mental Health.

A Breakthrough for Hypnotherapy?

Hypnosis has long been used to treat and manage a host of psychiatric and neurologic symptoms. However, not all patients respond equally to this therapy type.

About two thirds of the general adult population are estimated to be at least somewhat hypnotizable, and 15% are highly hypnotizable.

Through brain imaging, the Stanford team found that high hypnotizability is associated with greater functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the dorsal anterior cingulate cortex.

In the double-blind study, they randomly assigned 80 patients (mean age, 48 years; 94% women) with fibromyalgia syndrome to active, or sham, continuous theta-burst stimulation over a personalized neuroimaging-derived left DLPFC target — a technique known as Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT). Individuals who were naturally highly hypnotizable were excluded.

“A novel aspect of this trial is that we used the person’s own brain networks, based on brain imaging, to target the right spot,” Co-senior author Nolan Williams, MD, with Stanford University, California, said in a news release.

The team chose patients with chronic pain because hypnosis has been shown to be a “highly effective analgesic that has a far better risk/benefit ratio than widely overutilized opioids that have serious fatal overdose potential,” Spiegel told this news organization.

The pre-to-post SHIFT change in hypnotic induction profile scores, a standardized measure of hypnotizability, was significantly greater in the active vs sham group after just 92 seconds of stimulation (P = .046).

Only the active SHIFT group showed a significant increase in hypnotizability following stimulation, an effect that lasted for about 1 hour.

“Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention,” the researchers wrote.

They note that because this was a “mechanistic study,” it did not explore the impact of increased hypnotizability on disease symptoms. They also note that further studies are needed to assess the dose-response relationships of SHIFT.

Transformative Research

“This line of research is fascinating,” Shaheen Lakhan, MD, PhD, neurologist, and researcher in Boston, told this news organization.

“We are nearing an era of personalized, noninvasive brain modulation. The ability to individually modulate the DLPFC opens new possibilities for brain health beyond hypnotizability for fibromyalgia,” said Dr. Lakhan, who wasn’t involved in the study.

“The DLPFC is involved in executive functions (and disorders) like attention (ADHD), emotional regulation (depression), motivation (schizophrenia), and impulse control (addiction),” he noted.

“Soon we may no longer need large expensive devices like transcranial magnetic stimulators as in this research study. Smartphones could deliver tailored digital therapeutics by engaging specific brain circuits,” Dr. Lakhan predicted.

“Imagine using an app to receive treatment customized to your unique brain and needs — all without anything implanted and delivered anywhere. The potential to precisely modulate the brain’s wiring to enhance cognition and mental health, without surgery or physical constraints, is incredibly promising. The possibilities are intriguing and could truly transform how we address brain diseases,” he added.

The study was supported by a grant from the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH). Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and holds equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Spiegel is a cofounder of Reveri Health, Inc., an interactive hypnosis app (not utilized in the current study).
 

A version of this article appeared on Medscape.com.

Less than 2 minutes of transcranial magnetic stimulation (TMS) targeting specific areas of the brain can boost an individual’s ability to be hypnotized, in new findings that could increase the efficacy of therapeutic hypnosis and expand the pool of patients who can benefit from it.

“We were able to increase hypnotizability, a neuropsychological trait previously shown to be as stable as IQ in adulthood,” said co-senior author David Spiegel, MD, professor of psychiatry and behavioral sciences, Stanford University, Palo Alto, California.

“Our findings would allow us to combine neurostimulation with hypnosis to expand the number of people able to benefit from hypnosis and enhance their responsiveness to treatment,” Dr. Spiegel added.

The study was published online on January 4, 2024, in Nature Mental Health.

A Breakthrough for Hypnotherapy?

Hypnosis has long been used to treat and manage a host of psychiatric and neurologic symptoms. However, not all patients respond equally to this therapy type.

About two thirds of the general adult population are estimated to be at least somewhat hypnotizable, and 15% are highly hypnotizable.

Through brain imaging, the Stanford team found that high hypnotizability is associated with greater functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the dorsal anterior cingulate cortex.

In the double-blind study, they randomly assigned 80 patients (mean age, 48 years; 94% women) with fibromyalgia syndrome to active, or sham, continuous theta-burst stimulation over a personalized neuroimaging-derived left DLPFC target — a technique known as Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT). Individuals who were naturally highly hypnotizable were excluded.

“A novel aspect of this trial is that we used the person’s own brain networks, based on brain imaging, to target the right spot,” Co-senior author Nolan Williams, MD, with Stanford University, California, said in a news release.

The team chose patients with chronic pain because hypnosis has been shown to be a “highly effective analgesic that has a far better risk/benefit ratio than widely overutilized opioids that have serious fatal overdose potential,” Spiegel told this news organization.

The pre-to-post SHIFT change in hypnotic induction profile scores, a standardized measure of hypnotizability, was significantly greater in the active vs sham group after just 92 seconds of stimulation (P = .046).

Only the active SHIFT group showed a significant increase in hypnotizability following stimulation, an effect that lasted for about 1 hour.

“Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention,” the researchers wrote.

They note that because this was a “mechanistic study,” it did not explore the impact of increased hypnotizability on disease symptoms. They also note that further studies are needed to assess the dose-response relationships of SHIFT.

Transformative Research

“This line of research is fascinating,” Shaheen Lakhan, MD, PhD, neurologist, and researcher in Boston, told this news organization.

“We are nearing an era of personalized, noninvasive brain modulation. The ability to individually modulate the DLPFC opens new possibilities for brain health beyond hypnotizability for fibromyalgia,” said Dr. Lakhan, who wasn’t involved in the study.

“The DLPFC is involved in executive functions (and disorders) like attention (ADHD), emotional regulation (depression), motivation (schizophrenia), and impulse control (addiction),” he noted.

“Soon we may no longer need large expensive devices like transcranial magnetic stimulators as in this research study. Smartphones could deliver tailored digital therapeutics by engaging specific brain circuits,” Dr. Lakhan predicted.

“Imagine using an app to receive treatment customized to your unique brain and needs — all without anything implanted and delivered anywhere. The potential to precisely modulate the brain’s wiring to enhance cognition and mental health, without surgery or physical constraints, is incredibly promising. The possibilities are intriguing and could truly transform how we address brain diseases,” he added.

The study was supported by a grant from the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH). Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and holds equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Spiegel is a cofounder of Reveri Health, Inc., an interactive hypnosis app (not utilized in the current study).
 

A version of this article appeared on Medscape.com.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

The mechanisms underlying poststroke depression (PSD), a common and debilitating complication of stroke, are unclear. Is it neurobiological, psychosocial, or both?

Two studies offer new insight into this question. In the first, investigators systematically reviewed studies comparing stroke and non-stroke participants with depression and found the groups were similar in most dimensions of depressive symptoms. But surprisingly, anhedonia was less severe in patients with PSD compared with non-stroke controls, and those with PSD also showed greater emotional dysregulation.

“Our findings support previous recommendations that clinicians should adapt the provision of psychological support to the specific needs and difficulties of stroke survivors,” said lead author Joshua Blake, DClinPsy, lecturer in clinical psychology, University of East Anglia, Norwich, United Kingdom.

The study was published online in Neuropsychology Review

A second study used a machine learning algorithm to analyze blood samples from adults who had suffered a stroke, determining whether plasma protein data could predict mood and identifying potential proteins associated with mood in these patients.

“We can now look at a stroke survivor’s blood and predict their mood,” senior author Marion Buckwalter, MD, PhD, professor of neurology and neurosurgery at Stanford Medicine, California, said in a news release. “This means there is a genuine association between what’s happening in the blood and what’s happening with a person’s mood. It also means that, down the road, we may be able to develop new treatments for PSD.”

The study was published in November 2023 in Brain, Behavior, and Immunity.
 

‘Surprising’ Findings

“There has long been uncertainty over whether PSD might differ in its causes, phenomenology, and treatability, due to the presence of brain injury, related biological changes, and the psychosocial context unique to this population,” Dr. Blake said. “We felt that understanding symptomatologic similarities and differences would constructively contribute to this debate.”

The researchers reviewed 12 papers that sampled both stroke and non-stroke participants. “We compared profiles of depression symptoms, correlation strengths of individual depression symptoms with general depression, and latent item severity,” Dr. Blake reported.

They extracted 38 symptoms from five standardized depression tools and then organized the symptoms into nine dimensions.

They found mostly nonsignificant differences between patients with PSD and non-stroke controls in most dimensions, including negative affect, negative cognitions, somatic features, anxiety/worry, and suicidal ideation. Those with PSD more frequently had cognitive impairment, and “work inhibition” was more common in PSD.

But the most striking finding was greater severity/prevalence of emotional dysregulation in PSD vs non-stroke depression and also less anhedonia.

Dr. Blake acknowledged being “surprised.”

One possible explanation is that stroke recovery “appears to be a highly emotional journey, with extreme findings of both positive and negative emotions reported by survivors as they psychologically adjust,” which might be protective against anhedonia, he suggested.

Moreover, neurologically driven emotional dysregulation “may similarly reduce experiences of anhedonia.”

However, there was a “considerable risk of bias in many of the included studies, meaning it’s important that these findings are experimentally confirmed before stronger conclusions about phenomenological differences can be drawn,” he cautioned.
 

Common, Undertreated

Dr. Buckwalter said her team was motivated to conduct the research because PSD is among the top problems reported by chronic stroke patients, and for most, it is not adequately treated.

However, “despite the high prevalence of PSD, it is very poorly studied in the chronic time period.” In particular, PSD isn’t “well understood at a molecular level.”

She added that inflammation is a “promising candidate” as a mechanism, since neuroinflammation occurs in the stroke scar for decades, and chronic peripheral inflammation can produce neuroinflammation. Aberrant immune activation has also been implicated in major depression without stroke. But large studies with broad panels of plasma biomarkers are lacking in PSD.

To address this gap, the researchers used a proteomic approach. They recruited 85 chronic stroke patients (mean age, 65 years [interquartile range, 55-71], 41.2% female, 65.9% White, 17.6% Asian, and 0% Black) from the Stanford Stroke Recovery Program. Participants were between 5 months and 9 years after an ischemic stroke.

They analyzed a comprehensive panel of 1196 proteins in plasma samples, applying a machine learning algorithm to see whether the plasma protein levels “could be used to predict mood scores, using either the proteomics data alone or adding age and time since stroke.” The proteomics data were then incorporated into multivariable regression models, along with relevant clinical features, to ascertain the model’s predictive ability.

Mood was assessed using the Stroke Impact Scale mood questionnaire, with participants’ mood dichotomized into better mood (> 63) or worse mood (≤ 63).
 

‘Beautiful Mechanistic Model’

Machine learning verified a relationship between plasma proteomic data and mood, with the most accurate prediction occurring when the researchers added age and time since the stroke to the analysis.

Independent univariate analyses identified 202 proteins that were most highly correlated with mood in PSD. These were then organized into functional groups, including immune proteins, integrins, growth factors, synaptic function proteins, serotonin activity-related proteins, and cell death and stress-related functional groupings.

Although no single protein could predict depression, significant changes in levels of several proteins were found in PSD patients. A high proportion (45%) were proteins previously implicated in major depression, “likely providing a link to the underlying mechanisms of chronic PSD,” the authors stated.

Moreover, 80% of correlated immune proteins were higher in the plasma of people with worse mood, and several immune proteins known to have anti-inflammatory effects were reduced in those with worse mood.

And several pro-inflammatory cytokines were implicated. For example, interleukin 6, which has been extensively studied as a potential plasma marker of major depression in non-stroke cohorts, was significantly elevated in patients with worse mood after stroke (P = .0325), «implicating a broadly overactive immune system in PSD.»

“We demonstrated for the first time that we can use plasma protein measurements to predict mood in people with chronic stroke,” Dr. Buckwalter summarized. “This means there is a biological correlate of mood but [it] doesn’t tell us causality.”

To tease out causality, the researchers used their own data, as well as information from a literature review of previous studies, to assemble a model of how the immune response following a stroke could change both serotonin and brain plasticity.

“We used the most highly correlated proteins to construct a beautiful mechanistic model of how poststroke depression may work and how it may relate to mechanisms in major depression,” Dr. Buckwalter said.

The model “posits an increased inflammatory response that leads to decreased tryptophan, serotonin, and less synaptic function, all of which contribute to symptoms of depression.”

Currently, selective serotonin reuptake inhibitors represent the “best treatment” for people with PSD, but “unfortunately they don’t work for many patients,” Dr. Buckwalter noted. The findings “provide clues as to other molecular targets that are candidates novel therapies for poststroke depression.”

Dr. Blake commented that the proteomic study “complements the work by us and others interested in understanding PSD.”

Mood disorders “must be understood in terms of the dynamic relationships between structural neurological alterations, cellular and microbiological changes, psychological processes, and the person’s interactions with their social landscape,” Dr. Blake said.
 

New Treatments on the Horizon?

Gustavo C. Medeiros, MD, assistant professor, Department of Psychiatry, of the University of Maryland School of Medicine, Baltimore, said that knowing which individuals are more likely to develop PSD “allows treatment teams to implement earlier and more intensive interventions in those who are at higher risk.”

The findings [of the proteomic study] may also “help clarify the neurobiological correlates of PSD…[which] may help the development of new treatments that target these neurobiological changes,” said Dr. Medeiros, who wasn’t involved with either study.

However, he warned, “we should interpret their results with caution due to methodological reasons, including the relatively small sample size.”

Also commenting, Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, UCSF Weill Institute for Neurosciences, California, said the proteomic study has some “clear limitations,” including the lack of Black or African American patients in the cohort, which limits generalizability, “since we know that Black and African American people are disproportionately affected by stroke and have very high rates of PSD and very severe presentation.”

The study by Dr. Blake et al. “was interesting because the phenotype of depressive symptoms after stroke differs from what’s seen in the general population, and the authors figured out a way to better understand the nuances of such differences,” said Dr. Ovbiagele, who wasn’t involved with either study.

He said he was also surprised by the finding regarding anhedonia and suggested that the findings be replicated in a study directly comparing patients with PSD and patients with depression from the general population.

The study by Bidoki et al. was funded by AHA/Paul Allen Foundation, the Leducq Stroke-IMPaCT Transatlantic Network of Excellence (MSB), the Wu Tsai Neurosciences Institute (MSB), the Alfred E. Mann Foundation (NA), and an Alzheimer’s Association Research Fellowship to one of the authors. No source of funding was listed for the study by Dr. Blake et al. The authors of both studies, Dr. Medeiros and Dr. Ovbiagele, declare no relevant financial relationships.

A version of this article appeared on Medscape.com.

The mechanisms underlying poststroke depression (PSD), a common and debilitating complication of stroke, are unclear. Is it neurobiological, psychosocial, or both?

Two studies offer new insight into this question. In the first, investigators systematically reviewed studies comparing stroke and non-stroke participants with depression and found the groups were similar in most dimensions of depressive symptoms. But surprisingly, anhedonia was less severe in patients with PSD compared with non-stroke controls, and those with PSD also showed greater emotional dysregulation.

“Our findings support previous recommendations that clinicians should adapt the provision of psychological support to the specific needs and difficulties of stroke survivors,” said lead author Joshua Blake, DClinPsy, lecturer in clinical psychology, University of East Anglia, Norwich, United Kingdom.

The study was published online in Neuropsychology Review

A second study used a machine learning algorithm to analyze blood samples from adults who had suffered a stroke, determining whether plasma protein data could predict mood and identifying potential proteins associated with mood in these patients.

“We can now look at a stroke survivor’s blood and predict their mood,” senior author Marion Buckwalter, MD, PhD, professor of neurology and neurosurgery at Stanford Medicine, California, said in a news release. “This means there is a genuine association between what’s happening in the blood and what’s happening with a person’s mood. It also means that, down the road, we may be able to develop new treatments for PSD.”

The study was published in November 2023 in Brain, Behavior, and Immunity.
 

‘Surprising’ Findings

“There has long been uncertainty over whether PSD might differ in its causes, phenomenology, and treatability, due to the presence of brain injury, related biological changes, and the psychosocial context unique to this population,” Dr. Blake said. “We felt that understanding symptomatologic similarities and differences would constructively contribute to this debate.”

The researchers reviewed 12 papers that sampled both stroke and non-stroke participants. “We compared profiles of depression symptoms, correlation strengths of individual depression symptoms with general depression, and latent item severity,” Dr. Blake reported.

They extracted 38 symptoms from five standardized depression tools and then organized the symptoms into nine dimensions.

They found mostly nonsignificant differences between patients with PSD and non-stroke controls in most dimensions, including negative affect, negative cognitions, somatic features, anxiety/worry, and suicidal ideation. Those with PSD more frequently had cognitive impairment, and “work inhibition” was more common in PSD.

But the most striking finding was greater severity/prevalence of emotional dysregulation in PSD vs non-stroke depression and also less anhedonia.

Dr. Blake acknowledged being “surprised.”

One possible explanation is that stroke recovery “appears to be a highly emotional journey, with extreme findings of both positive and negative emotions reported by survivors as they psychologically adjust,” which might be protective against anhedonia, he suggested.

Moreover, neurologically driven emotional dysregulation “may similarly reduce experiences of anhedonia.”

However, there was a “considerable risk of bias in many of the included studies, meaning it’s important that these findings are experimentally confirmed before stronger conclusions about phenomenological differences can be drawn,” he cautioned.
 

Common, Undertreated

Dr. Buckwalter said her team was motivated to conduct the research because PSD is among the top problems reported by chronic stroke patients, and for most, it is not adequately treated.

However, “despite the high prevalence of PSD, it is very poorly studied in the chronic time period.” In particular, PSD isn’t “well understood at a molecular level.”

She added that inflammation is a “promising candidate” as a mechanism, since neuroinflammation occurs in the stroke scar for decades, and chronic peripheral inflammation can produce neuroinflammation. Aberrant immune activation has also been implicated in major depression without stroke. But large studies with broad panels of plasma biomarkers are lacking in PSD.

To address this gap, the researchers used a proteomic approach. They recruited 85 chronic stroke patients (mean age, 65 years [interquartile range, 55-71], 41.2% female, 65.9% White, 17.6% Asian, and 0% Black) from the Stanford Stroke Recovery Program. Participants were between 5 months and 9 years after an ischemic stroke.

They analyzed a comprehensive panel of 1196 proteins in plasma samples, applying a machine learning algorithm to see whether the plasma protein levels “could be used to predict mood scores, using either the proteomics data alone or adding age and time since stroke.” The proteomics data were then incorporated into multivariable regression models, along with relevant clinical features, to ascertain the model’s predictive ability.

Mood was assessed using the Stroke Impact Scale mood questionnaire, with participants’ mood dichotomized into better mood (> 63) or worse mood (≤ 63).
 

‘Beautiful Mechanistic Model’

Machine learning verified a relationship between plasma proteomic data and mood, with the most accurate prediction occurring when the researchers added age and time since the stroke to the analysis.

Independent univariate analyses identified 202 proteins that were most highly correlated with mood in PSD. These were then organized into functional groups, including immune proteins, integrins, growth factors, synaptic function proteins, serotonin activity-related proteins, and cell death and stress-related functional groupings.

Although no single protein could predict depression, significant changes in levels of several proteins were found in PSD patients. A high proportion (45%) were proteins previously implicated in major depression, “likely providing a link to the underlying mechanisms of chronic PSD,” the authors stated.

Moreover, 80% of correlated immune proteins were higher in the plasma of people with worse mood, and several immune proteins known to have anti-inflammatory effects were reduced in those with worse mood.

And several pro-inflammatory cytokines were implicated. For example, interleukin 6, which has been extensively studied as a potential plasma marker of major depression in non-stroke cohorts, was significantly elevated in patients with worse mood after stroke (P = .0325), «implicating a broadly overactive immune system in PSD.»

“We demonstrated for the first time that we can use plasma protein measurements to predict mood in people with chronic stroke,” Dr. Buckwalter summarized. “This means there is a biological correlate of mood but [it] doesn’t tell us causality.”

To tease out causality, the researchers used their own data, as well as information from a literature review of previous studies, to assemble a model of how the immune response following a stroke could change both serotonin and brain plasticity.

“We used the most highly correlated proteins to construct a beautiful mechanistic model of how poststroke depression may work and how it may relate to mechanisms in major depression,” Dr. Buckwalter said.

The model “posits an increased inflammatory response that leads to decreased tryptophan, serotonin, and less synaptic function, all of which contribute to symptoms of depression.”

Currently, selective serotonin reuptake inhibitors represent the “best treatment” for people with PSD, but “unfortunately they don’t work for many patients,” Dr. Buckwalter noted. The findings “provide clues as to other molecular targets that are candidates novel therapies for poststroke depression.”

Dr. Blake commented that the proteomic study “complements the work by us and others interested in understanding PSD.”

Mood disorders “must be understood in terms of the dynamic relationships between structural neurological alterations, cellular and microbiological changes, psychological processes, and the person’s interactions with their social landscape,” Dr. Blake said.
 

New Treatments on the Horizon?

Gustavo C. Medeiros, MD, assistant professor, Department of Psychiatry, of the University of Maryland School of Medicine, Baltimore, said that knowing which individuals are more likely to develop PSD “allows treatment teams to implement earlier and more intensive interventions in those who are at higher risk.”

The findings [of the proteomic study] may also “help clarify the neurobiological correlates of PSD…[which] may help the development of new treatments that target these neurobiological changes,” said Dr. Medeiros, who wasn’t involved with either study.

However, he warned, “we should interpret their results with caution due to methodological reasons, including the relatively small sample size.”

Also commenting, Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, UCSF Weill Institute for Neurosciences, California, said the proteomic study has some “clear limitations,” including the lack of Black or African American patients in the cohort, which limits generalizability, “since we know that Black and African American people are disproportionately affected by stroke and have very high rates of PSD and very severe presentation.”

The study by Dr. Blake et al. “was interesting because the phenotype of depressive symptoms after stroke differs from what’s seen in the general population, and the authors figured out a way to better understand the nuances of such differences,” said Dr. Ovbiagele, who wasn’t involved with either study.

He said he was also surprised by the finding regarding anhedonia and suggested that the findings be replicated in a study directly comparing patients with PSD and patients with depression from the general population.

The study by Bidoki et al. was funded by AHA/Paul Allen Foundation, the Leducq Stroke-IMPaCT Transatlantic Network of Excellence (MSB), the Wu Tsai Neurosciences Institute (MSB), the Alfred E. Mann Foundation (NA), and an Alzheimer’s Association Research Fellowship to one of the authors. No source of funding was listed for the study by Dr. Blake et al. The authors of both studies, Dr. Medeiros and Dr. Ovbiagele, declare no relevant financial relationships.

A version of this article appeared on Medscape.com.

The mechanisms underlying poststroke depression (PSD), a common and debilitating complication of stroke, are unclear. Is it neurobiological, psychosocial, or both?

Two studies offer new insight into this question. In the first, investigators systematically reviewed studies comparing stroke and non-stroke participants with depression and found the groups were similar in most dimensions of depressive symptoms. But surprisingly, anhedonia was less severe in patients with PSD compared with non-stroke controls, and those with PSD also showed greater emotional dysregulation.

“Our findings support previous recommendations that clinicians should adapt the provision of psychological support to the specific needs and difficulties of stroke survivors,” said lead author Joshua Blake, DClinPsy, lecturer in clinical psychology, University of East Anglia, Norwich, United Kingdom.

The study was published online in Neuropsychology Review

A second study used a machine learning algorithm to analyze blood samples from adults who had suffered a stroke, determining whether plasma protein data could predict mood and identifying potential proteins associated with mood in these patients.

“We can now look at a stroke survivor’s blood and predict their mood,” senior author Marion Buckwalter, MD, PhD, professor of neurology and neurosurgery at Stanford Medicine, California, said in a news release. “This means there is a genuine association between what’s happening in the blood and what’s happening with a person’s mood. It also means that, down the road, we may be able to develop new treatments for PSD.”

The study was published in November 2023 in Brain, Behavior, and Immunity.
 

‘Surprising’ Findings

“There has long been uncertainty over whether PSD might differ in its causes, phenomenology, and treatability, due to the presence of brain injury, related biological changes, and the psychosocial context unique to this population,” Dr. Blake said. “We felt that understanding symptomatologic similarities and differences would constructively contribute to this debate.”

The researchers reviewed 12 papers that sampled both stroke and non-stroke participants. “We compared profiles of depression symptoms, correlation strengths of individual depression symptoms with general depression, and latent item severity,” Dr. Blake reported.

They extracted 38 symptoms from five standardized depression tools and then organized the symptoms into nine dimensions.

They found mostly nonsignificant differences between patients with PSD and non-stroke controls in most dimensions, including negative affect, negative cognitions, somatic features, anxiety/worry, and suicidal ideation. Those with PSD more frequently had cognitive impairment, and “work inhibition” was more common in PSD.

But the most striking finding was greater severity/prevalence of emotional dysregulation in PSD vs non-stroke depression and also less anhedonia.

Dr. Blake acknowledged being “surprised.”

One possible explanation is that stroke recovery “appears to be a highly emotional journey, with extreme findings of both positive and negative emotions reported by survivors as they psychologically adjust,” which might be protective against anhedonia, he suggested.

Moreover, neurologically driven emotional dysregulation “may similarly reduce experiences of anhedonia.”

However, there was a “considerable risk of bias in many of the included studies, meaning it’s important that these findings are experimentally confirmed before stronger conclusions about phenomenological differences can be drawn,” he cautioned.
 

Common, Undertreated

Dr. Buckwalter said her team was motivated to conduct the research because PSD is among the top problems reported by chronic stroke patients, and for most, it is not adequately treated.

However, “despite the high prevalence of PSD, it is very poorly studied in the chronic time period.” In particular, PSD isn’t “well understood at a molecular level.”

She added that inflammation is a “promising candidate” as a mechanism, since neuroinflammation occurs in the stroke scar for decades, and chronic peripheral inflammation can produce neuroinflammation. Aberrant immune activation has also been implicated in major depression without stroke. But large studies with broad panels of plasma biomarkers are lacking in PSD.

To address this gap, the researchers used a proteomic approach. They recruited 85 chronic stroke patients (mean age, 65 years [interquartile range, 55-71], 41.2% female, 65.9% White, 17.6% Asian, and 0% Black) from the Stanford Stroke Recovery Program. Participants were between 5 months and 9 years after an ischemic stroke.

They analyzed a comprehensive panel of 1196 proteins in plasma samples, applying a machine learning algorithm to see whether the plasma protein levels “could be used to predict mood scores, using either the proteomics data alone or adding age and time since stroke.” The proteomics data were then incorporated into multivariable regression models, along with relevant clinical features, to ascertain the model’s predictive ability.

Mood was assessed using the Stroke Impact Scale mood questionnaire, with participants’ mood dichotomized into better mood (> 63) or worse mood (≤ 63).
 

‘Beautiful Mechanistic Model’

Machine learning verified a relationship between plasma proteomic data and mood, with the most accurate prediction occurring when the researchers added age and time since the stroke to the analysis.

Independent univariate analyses identified 202 proteins that were most highly correlated with mood in PSD. These were then organized into functional groups, including immune proteins, integrins, growth factors, synaptic function proteins, serotonin activity-related proteins, and cell death and stress-related functional groupings.

Although no single protein could predict depression, significant changes in levels of several proteins were found in PSD patients. A high proportion (45%) were proteins previously implicated in major depression, “likely providing a link to the underlying mechanisms of chronic PSD,” the authors stated.

Moreover, 80% of correlated immune proteins were higher in the plasma of people with worse mood, and several immune proteins known to have anti-inflammatory effects were reduced in those with worse mood.

And several pro-inflammatory cytokines were implicated. For example, interleukin 6, which has been extensively studied as a potential plasma marker of major depression in non-stroke cohorts, was significantly elevated in patients with worse mood after stroke (P = .0325), «implicating a broadly overactive immune system in PSD.»

“We demonstrated for the first time that we can use plasma protein measurements to predict mood in people with chronic stroke,” Dr. Buckwalter summarized. “This means there is a biological correlate of mood but [it] doesn’t tell us causality.”

To tease out causality, the researchers used their own data, as well as information from a literature review of previous studies, to assemble a model of how the immune response following a stroke could change both serotonin and brain plasticity.

“We used the most highly correlated proteins to construct a beautiful mechanistic model of how poststroke depression may work and how it may relate to mechanisms in major depression,” Dr. Buckwalter said.

The model “posits an increased inflammatory response that leads to decreased tryptophan, serotonin, and less synaptic function, all of which contribute to symptoms of depression.”

Currently, selective serotonin reuptake inhibitors represent the “best treatment” for people with PSD, but “unfortunately they don’t work for many patients,” Dr. Buckwalter noted. The findings “provide clues as to other molecular targets that are candidates novel therapies for poststroke depression.”

Dr. Blake commented that the proteomic study “complements the work by us and others interested in understanding PSD.”

Mood disorders “must be understood in terms of the dynamic relationships between structural neurological alterations, cellular and microbiological changes, psychological processes, and the person’s interactions with their social landscape,” Dr. Blake said.
 

New Treatments on the Horizon?

Gustavo C. Medeiros, MD, assistant professor, Department of Psychiatry, of the University of Maryland School of Medicine, Baltimore, said that knowing which individuals are more likely to develop PSD “allows treatment teams to implement earlier and more intensive interventions in those who are at higher risk.”

The findings [of the proteomic study] may also “help clarify the neurobiological correlates of PSD…[which] may help the development of new treatments that target these neurobiological changes,” said Dr. Medeiros, who wasn’t involved with either study.

However, he warned, “we should interpret their results with caution due to methodological reasons, including the relatively small sample size.”

Also commenting, Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, UCSF Weill Institute for Neurosciences, California, said the proteomic study has some “clear limitations,” including the lack of Black or African American patients in the cohort, which limits generalizability, “since we know that Black and African American people are disproportionately affected by stroke and have very high rates of PSD and very severe presentation.”

The study by Dr. Blake et al. “was interesting because the phenotype of depressive symptoms after stroke differs from what’s seen in the general population, and the authors figured out a way to better understand the nuances of such differences,” said Dr. Ovbiagele, who wasn’t involved with either study.

He said he was also surprised by the finding regarding anhedonia and suggested that the findings be replicated in a study directly comparing patients with PSD and patients with depression from the general population.

The study by Bidoki et al. was funded by AHA/Paul Allen Foundation, the Leducq Stroke-IMPaCT Transatlantic Network of Excellence (MSB), the Wu Tsai Neurosciences Institute (MSB), the Alfred E. Mann Foundation (NA), and an Alzheimer’s Association Research Fellowship to one of the authors. No source of funding was listed for the study by Dr. Blake et al. The authors of both studies, Dr. Medeiros and Dr. Ovbiagele, declare no relevant financial relationships.

A version of this article appeared on Medscape.com.

Ten years ago, Clare Gerada, FRCGP, an advocate for physician well-being and today president of the UK’s Royal College of General Practitioners, made a prediction to the audience at the International Conference on Physician Health.

“We have seen a massive increase in eating disorders [among doctors],” she said. “I’m not sure anybody is quite aware of the tsunami of eating disorders,” she believed would soon strike predominantly female physicians.

That was 2014. Did the tsunami hit?

Quite possibly. Data are limited on the prevalence of eating disorders (EDs) among healthcare workers, but studies do exist. A 2019 global review and meta-analysis determined “the summary prevalence of eating disorder (ED) risk among medical students was 10.4%.”

A 2022 update of that review boosted the estimate to 17.35%.

Tsunami or not, that’s nearly double the 9% rate within the US general public (from a 2020 report from STRIPED and the Academy of Eating Disorders). And while the following stat isn’t an indicator of EDs per se, 19% of doctors admit to unhealthy eating habits, according to a recent Medscape Medical News physician survey.

To her credit, Dr. Gerada, awarded a damehood in 2020, was in a position to know what was coming. Her statement was informed by research showing an increasing number of young doctors seeking treatment for mental health issues, including EDs, through the NHS Practitioner Health program, a mental health service she established in 2008.

So ... what puts doctors at such a high risk for EDs?

Be Careful of ‘Overlap Traits’

As with many mental health issues, EDs have no single cause. Researchers believe they stem from a complex interaction of genetic, biological, behavioral, psychological, and social factors. But the medical field should take note: Some personality traits commonly associated with EDs are often shared by successful physicians.

“I think some of the overlap traits would be being highly driven, goal-oriented and self-critical,” said Lesley Williams, MD, a family medicine physician at the Mayo Clinic in Phoenix, Arizona. “A lot of those traits can make you a very successful physician and physician-in-training but could also potentially spill over into body image and rigidity around food.”

Of course, we want physicians to strive for excellence, and the majority of diligent, driven doctors will not develop an ED.

But when pushed too far, those admirable qualities can easily become perfectionism — which has long been recognized as a risk factor for EDs, an association supported by decades of research.

Medical School: Where EDs Begin and Little Education About Them Happens

“I think medicine in general attracts people that often share similar characteristics to those who struggle with EDs — high-achieving, hardworking perfectionists who put a lot of pressure on themselves,” said Elizabeth McNaught, MD, a general practitioner and medical director at Family Mental Wealth.

Diagnosed with an ED at 14, Dr. McNaught has experienced this firsthand and shared her story in a 2020 memoir, Life Hurts: A Doctor’s Personal Journey Through Anorexia.

Competitive, high-stress environments can also be a trigger, Dr. McNaught explained. “The pressure of medical school,” for example, “can perpetuate an eating disorder if that’s something that you’re struggling with,” she said.

Pressure to perform may not be the only problem. Medical students are taught to view weight as a key indicator of health. Multiple studies suggested that not only does weight stigma exist in healthcare but also it has increased over time and negatively affects patients’ psychological well-being and physical health.

There is far less public discourse about how weight stigma can be harmful to medical students and physicians themselves. Dr. Williams believed the weight-centric paradigm was key.

“For so long, we believed that health presents itself within these confines on a BMI chart and anything outside of that is unhealthy and must be fixed,” she said. “I can say from having gone through medical education, having that continual messaging does make someone feel that if I myself am not within those confines, then I need to do something to fix that immediately if I’m going to continue to care for patients.”

In general, Dr. Williams, and Dr. McNaught agreed that medical training around EDs is lacking, producing doctors who are ill-equipped to diagnose, treat, or even discuss them with patients. Dr. Williams recalled only one lecture on the topic in med school.

“And yet, anorexia carries the second highest death rate of all mental illnesses after opioid-use disorders,” she said, “so it’s astonishing that that just wasn’t included.”

MDs Hiding Mental Health Issues

Claire Anderson, MD (a pseudonym), emphatically stated she would never tell anyone at the hospital where she works in the emergency department that she has an ED.

“There is still a lot of misunderstanding about mental health, and I never want people to doubt my ability to care for people,” Dr. Anderson said. “There’s so much stigma around eating disorders, and I also feel like once it’s out there, I can’t take it back, and I don’t want to feel like people are watching me.”

Melissa Klein, PhD, a clinical psychologist specializing in EDs, has more than 25 years of experience working the inpatient ED unit at New York Presbyterian. Having treated medical professionals, Dr. Klein said they have legitimate concerns about revealing their struggles.

“Sometimes, they do get reported to higher ups — the boards,” Dr. Klein said, “and they’re told that they have to get help in order for them to continue to work in their profession. I think people might be scared to ask for help because of that reason.”

Doctors Often Ignore EDs or Teach ‘Bad Habits’

Dr. Anderson firmly believed that if her early treatment from doctors had been better, she might not be struggling so much today.

The first time Dr. Anderson’s mother brought up her daughter’s sudden weight loss at 14, their family doctor conferred with a chart and said there was no reason to worry; Dr. Anderson’s weight was “normal.” “I was eating like 500 calories a day and swimming for 3 hours, and [by saying that], they assured me I was fine,” she recalls.

At 15, when Dr. Anderson went in for an initial assessment for an ED, she thought she’d be connected with a nutritionist and sent home. “I didn’t have a lot of classic thoughts of wanting to be thin or wanting to lose weight,” she said.

Instead, Dr. Anderson was sent to inpatient care, which she credits with escalating her ED. “I picked up on a lot of really bad habits when I went there — I sort of learned how to have an eating disorder,” she said. “When I left, it was very different than when I went in, which is kind of sad.”

Throughout high school, Dr. Anderson went in and out of so many hospitals and treatment programs that she’s lost track of them. Then, in 2008, she left formal treatment altogether. “I had been really angry with the treatment programs for trying to fit me into their box with a rigid schedule of inpatient and outpatient care,” she recalled. “I didn’t want to live in that world anymore.”

After working with a new psychiatrist, Dr. Anderson’s situation improved until a particularly stressful second year of residency. “That’s when I just tanked,” she said. “Residency, and especially being on my own and with COVID, things have not been great for me.”

Dr. Anderson now sees an eating disorder specialist, but she pays for this out-of-pocket. “I have terrible insurance,” she said with a laugh, aware of that irony.

If You Are Struggling, Don’t Be Ashamed

Some physicians who’ve experienced EDs firsthand are working to improve training on diagnosing and treating the conditions. Dr. McNaught has developed and launched a new eLearning program for healthcare workers on how to recognize the early signs and symptoms of an ED and provide support.

“It’s not only so they can recognize it in their patients but also if colleagues and family and friends are struggling,” she said.

In 2021, the American Psychiatric Association (APA) approved the APA Practice Guideline for the Treatment of Patients With Eating Disorders, which aims to improve patient care and treatment outcomes.

But Dr. Klein is concerned that increased stress since the COVID-19 pandemic may be putting healthcare workers at even greater risk.

“When people are under stress or when they feel like there are things in their life that maybe they can’t control, sometimes turning to an eating disorder is a way to cope,” she said, “In that sense, the stress on medical professionals is something that could lead to eating disorder behaviors.”

Dr. Klein’s message to healthcare workers: Don’t be ashamed. She described an ED as “a monster that takes over your brain. Once it starts, it’s very hard to turn it around on your own. So, I hope anyone who is suffering, in whatever field they’re in, that they are able to ask for help.”

A version of this article appeared on Medscape.com.

Ten years ago, Clare Gerada, FRCGP, an advocate for physician well-being and today president of the UK’s Royal College of General Practitioners, made a prediction to the audience at the International Conference on Physician Health.

“We have seen a massive increase in eating disorders [among doctors],” she said. “I’m not sure anybody is quite aware of the tsunami of eating disorders,” she believed would soon strike predominantly female physicians.

That was 2014. Did the tsunami hit?

Quite possibly. Data are limited on the prevalence of eating disorders (EDs) among healthcare workers, but studies do exist. A 2019 global review and meta-analysis determined “the summary prevalence of eating disorder (ED) risk among medical students was 10.4%.”

A 2022 update of that review boosted the estimate to 17.35%.

Tsunami or not, that’s nearly double the 9% rate within the US general public (from a 2020 report from STRIPED and the Academy of Eating Disorders). And while the following stat isn’t an indicator of EDs per se, 19% of doctors admit to unhealthy eating habits, according to a recent Medscape Medical News physician survey.

To her credit, Dr. Gerada, awarded a damehood in 2020, was in a position to know what was coming. Her statement was informed by research showing an increasing number of young doctors seeking treatment for mental health issues, including EDs, through the NHS Practitioner Health program, a mental health service she established in 2008.

So ... what puts doctors at such a high risk for EDs?

Be Careful of ‘Overlap Traits’

As with many mental health issues, EDs have no single cause. Researchers believe they stem from a complex interaction of genetic, biological, behavioral, psychological, and social factors. But the medical field should take note: Some personality traits commonly associated with EDs are often shared by successful physicians.

“I think some of the overlap traits would be being highly driven, goal-oriented and self-critical,” said Lesley Williams, MD, a family medicine physician at the Mayo Clinic in Phoenix, Arizona. “A lot of those traits can make you a very successful physician and physician-in-training but could also potentially spill over into body image and rigidity around food.”

Of course, we want physicians to strive for excellence, and the majority of diligent, driven doctors will not develop an ED.

But when pushed too far, those admirable qualities can easily become perfectionism — which has long been recognized as a risk factor for EDs, an association supported by decades of research.

Medical School: Where EDs Begin and Little Education About Them Happens

“I think medicine in general attracts people that often share similar characteristics to those who struggle with EDs — high-achieving, hardworking perfectionists who put a lot of pressure on themselves,” said Elizabeth McNaught, MD, a general practitioner and medical director at Family Mental Wealth.

Diagnosed with an ED at 14, Dr. McNaught has experienced this firsthand and shared her story in a 2020 memoir, Life Hurts: A Doctor’s Personal Journey Through Anorexia.

Competitive, high-stress environments can also be a trigger, Dr. McNaught explained. “The pressure of medical school,” for example, “can perpetuate an eating disorder if that’s something that you’re struggling with,” she said.

Pressure to perform may not be the only problem. Medical students are taught to view weight as a key indicator of health. Multiple studies suggested that not only does weight stigma exist in healthcare but also it has increased over time and negatively affects patients’ psychological well-being and physical health.

There is far less public discourse about how weight stigma can be harmful to medical students and physicians themselves. Dr. Williams believed the weight-centric paradigm was key.

“For so long, we believed that health presents itself within these confines on a BMI chart and anything outside of that is unhealthy and must be fixed,” she said. “I can say from having gone through medical education, having that continual messaging does make someone feel that if I myself am not within those confines, then I need to do something to fix that immediately if I’m going to continue to care for patients.”

In general, Dr. Williams, and Dr. McNaught agreed that medical training around EDs is lacking, producing doctors who are ill-equipped to diagnose, treat, or even discuss them with patients. Dr. Williams recalled only one lecture on the topic in med school.

“And yet, anorexia carries the second highest death rate of all mental illnesses after opioid-use disorders,” she said, “so it’s astonishing that that just wasn’t included.”

MDs Hiding Mental Health Issues

Claire Anderson, MD (a pseudonym), emphatically stated she would never tell anyone at the hospital where she works in the emergency department that she has an ED.

“There is still a lot of misunderstanding about mental health, and I never want people to doubt my ability to care for people,” Dr. Anderson said. “There’s so much stigma around eating disorders, and I also feel like once it’s out there, I can’t take it back, and I don’t want to feel like people are watching me.”

Melissa Klein, PhD, a clinical psychologist specializing in EDs, has more than 25 years of experience working the inpatient ED unit at New York Presbyterian. Having treated medical professionals, Dr. Klein said they have legitimate concerns about revealing their struggles.

“Sometimes, they do get reported to higher ups — the boards,” Dr. Klein said, “and they’re told that they have to get help in order for them to continue to work in their profession. I think people might be scared to ask for help because of that reason.”

Doctors Often Ignore EDs or Teach ‘Bad Habits’

Dr. Anderson firmly believed that if her early treatment from doctors had been better, she might not be struggling so much today.

The first time Dr. Anderson’s mother brought up her daughter’s sudden weight loss at 14, their family doctor conferred with a chart and said there was no reason to worry; Dr. Anderson’s weight was “normal.” “I was eating like 500 calories a day and swimming for 3 hours, and [by saying that], they assured me I was fine,” she recalls.

At 15, when Dr. Anderson went in for an initial assessment for an ED, she thought she’d be connected with a nutritionist and sent home. “I didn’t have a lot of classic thoughts of wanting to be thin or wanting to lose weight,” she said.

Instead, Dr. Anderson was sent to inpatient care, which she credits with escalating her ED. “I picked up on a lot of really bad habits when I went there — I sort of learned how to have an eating disorder,” she said. “When I left, it was very different than when I went in, which is kind of sad.”

Throughout high school, Dr. Anderson went in and out of so many hospitals and treatment programs that she’s lost track of them. Then, in 2008, she left formal treatment altogether. “I had been really angry with the treatment programs for trying to fit me into their box with a rigid schedule of inpatient and outpatient care,” she recalled. “I didn’t want to live in that world anymore.”

After working with a new psychiatrist, Dr. Anderson’s situation improved until a particularly stressful second year of residency. “That’s when I just tanked,” she said. “Residency, and especially being on my own and with COVID, things have not been great for me.”

Dr. Anderson now sees an eating disorder specialist, but she pays for this out-of-pocket. “I have terrible insurance,” she said with a laugh, aware of that irony.

If You Are Struggling, Don’t Be Ashamed

Some physicians who’ve experienced EDs firsthand are working to improve training on diagnosing and treating the conditions. Dr. McNaught has developed and launched a new eLearning program for healthcare workers on how to recognize the early signs and symptoms of an ED and provide support.

“It’s not only so they can recognize it in their patients but also if colleagues and family and friends are struggling,” she said.

In 2021, the American Psychiatric Association (APA) approved the APA Practice Guideline for the Treatment of Patients With Eating Disorders, which aims to improve patient care and treatment outcomes.

But Dr. Klein is concerned that increased stress since the COVID-19 pandemic may be putting healthcare workers at even greater risk.

“When people are under stress or when they feel like there are things in their life that maybe they can’t control, sometimes turning to an eating disorder is a way to cope,” she said, “In that sense, the stress on medical professionals is something that could lead to eating disorder behaviors.”

Dr. Klein’s message to healthcare workers: Don’t be ashamed. She described an ED as “a monster that takes over your brain. Once it starts, it’s very hard to turn it around on your own. So, I hope anyone who is suffering, in whatever field they’re in, that they are able to ask for help.”

A version of this article appeared on Medscape.com.

Ten years ago, Clare Gerada, FRCGP, an advocate for physician well-being and today president of the UK’s Royal College of General Practitioners, made a prediction to the audience at the International Conference on Physician Health.

“We have seen a massive increase in eating disorders [among doctors],” she said. “I’m not sure anybody is quite aware of the tsunami of eating disorders,” she believed would soon strike predominantly female physicians.

That was 2014. Did the tsunami hit?

Quite possibly. Data are limited on the prevalence of eating disorders (EDs) among healthcare workers, but studies do exist. A 2019 global review and meta-analysis determined “the summary prevalence of eating disorder (ED) risk among medical students was 10.4%.”

A 2022 update of that review boosted the estimate to 17.35%.

Tsunami or not, that’s nearly double the 9% rate within the US general public (from a 2020 report from STRIPED and the Academy of Eating Disorders). And while the following stat isn’t an indicator of EDs per se, 19% of doctors admit to unhealthy eating habits, according to a recent Medscape Medical News physician survey.

To her credit, Dr. Gerada, awarded a damehood in 2020, was in a position to know what was coming. Her statement was informed by research showing an increasing number of young doctors seeking treatment for mental health issues, including EDs, through the NHS Practitioner Health program, a mental health service she established in 2008.

So ... what puts doctors at such a high risk for EDs?

Be Careful of ‘Overlap Traits’

As with many mental health issues, EDs have no single cause. Researchers believe they stem from a complex interaction of genetic, biological, behavioral, psychological, and social factors. But the medical field should take note: Some personality traits commonly associated with EDs are often shared by successful physicians.

“I think some of the overlap traits would be being highly driven, goal-oriented and self-critical,” said Lesley Williams, MD, a family medicine physician at the Mayo Clinic in Phoenix, Arizona. “A lot of those traits can make you a very successful physician and physician-in-training but could also potentially spill over into body image and rigidity around food.”

Of course, we want physicians to strive for excellence, and the majority of diligent, driven doctors will not develop an ED.

But when pushed too far, those admirable qualities can easily become perfectionism — which has long been recognized as a risk factor for EDs, an association supported by decades of research.

Medical School: Where EDs Begin and Little Education About Them Happens

“I think medicine in general attracts people that often share similar characteristics to those who struggle with EDs — high-achieving, hardworking perfectionists who put a lot of pressure on themselves,” said Elizabeth McNaught, MD, a general practitioner and medical director at Family Mental Wealth.

Diagnosed with an ED at 14, Dr. McNaught has experienced this firsthand and shared her story in a 2020 memoir, Life Hurts: A Doctor’s Personal Journey Through Anorexia.

Competitive, high-stress environments can also be a trigger, Dr. McNaught explained. “The pressure of medical school,” for example, “can perpetuate an eating disorder if that’s something that you’re struggling with,” she said.

Pressure to perform may not be the only problem. Medical students are taught to view weight as a key indicator of health. Multiple studies suggested that not only does weight stigma exist in healthcare but also it has increased over time and negatively affects patients’ psychological well-being and physical health.

There is far less public discourse about how weight stigma can be harmful to medical students and physicians themselves. Dr. Williams believed the weight-centric paradigm was key.

“For so long, we believed that health presents itself within these confines on a BMI chart and anything outside of that is unhealthy and must be fixed,” she said. “I can say from having gone through medical education, having that continual messaging does make someone feel that if I myself am not within those confines, then I need to do something to fix that immediately if I’m going to continue to care for patients.”

In general, Dr. Williams, and Dr. McNaught agreed that medical training around EDs is lacking, producing doctors who are ill-equipped to diagnose, treat, or even discuss them with patients. Dr. Williams recalled only one lecture on the topic in med school.

“And yet, anorexia carries the second highest death rate of all mental illnesses after opioid-use disorders,” she said, “so it’s astonishing that that just wasn’t included.”

MDs Hiding Mental Health Issues

Claire Anderson, MD (a pseudonym), emphatically stated she would never tell anyone at the hospital where she works in the emergency department that she has an ED.

“There is still a lot of misunderstanding about mental health, and I never want people to doubt my ability to care for people,” Dr. Anderson said. “There’s so much stigma around eating disorders, and I also feel like once it’s out there, I can’t take it back, and I don’t want to feel like people are watching me.”

Melissa Klein, PhD, a clinical psychologist specializing in EDs, has more than 25 years of experience working the inpatient ED unit at New York Presbyterian. Having treated medical professionals, Dr. Klein said they have legitimate concerns about revealing their struggles.

“Sometimes, they do get reported to higher ups — the boards,” Dr. Klein said, “and they’re told that they have to get help in order for them to continue to work in their profession. I think people might be scared to ask for help because of that reason.”

Doctors Often Ignore EDs or Teach ‘Bad Habits’

Dr. Anderson firmly believed that if her early treatment from doctors had been better, she might not be struggling so much today.

The first time Dr. Anderson’s mother brought up her daughter’s sudden weight loss at 14, their family doctor conferred with a chart and said there was no reason to worry; Dr. Anderson’s weight was “normal.” “I was eating like 500 calories a day and swimming for 3 hours, and [by saying that], they assured me I was fine,” she recalls.

At 15, when Dr. Anderson went in for an initial assessment for an ED, she thought she’d be connected with a nutritionist and sent home. “I didn’t have a lot of classic thoughts of wanting to be thin or wanting to lose weight,” she said.

Instead, Dr. Anderson was sent to inpatient care, which she credits with escalating her ED. “I picked up on a lot of really bad habits when I went there — I sort of learned how to have an eating disorder,” she said. “When I left, it was very different than when I went in, which is kind of sad.”

Throughout high school, Dr. Anderson went in and out of so many hospitals and treatment programs that she’s lost track of them. Then, in 2008, she left formal treatment altogether. “I had been really angry with the treatment programs for trying to fit me into their box with a rigid schedule of inpatient and outpatient care,” she recalled. “I didn’t want to live in that world anymore.”

After working with a new psychiatrist, Dr. Anderson’s situation improved until a particularly stressful second year of residency. “That’s when I just tanked,” she said. “Residency, and especially being on my own and with COVID, things have not been great for me.”

Dr. Anderson now sees an eating disorder specialist, but she pays for this out-of-pocket. “I have terrible insurance,” she said with a laugh, aware of that irony.

If You Are Struggling, Don’t Be Ashamed

Some physicians who’ve experienced EDs firsthand are working to improve training on diagnosing and treating the conditions. Dr. McNaught has developed and launched a new eLearning program for healthcare workers on how to recognize the early signs and symptoms of an ED and provide support.

“It’s not only so they can recognize it in their patients but also if colleagues and family and friends are struggling,” she said.

In 2021, the American Psychiatric Association (APA) approved the APA Practice Guideline for the Treatment of Patients With Eating Disorders, which aims to improve patient care and treatment outcomes.

But Dr. Klein is concerned that increased stress since the COVID-19 pandemic may be putting healthcare workers at even greater risk.

“When people are under stress or when they feel like there are things in their life that maybe they can’t control, sometimes turning to an eating disorder is a way to cope,” she said, “In that sense, the stress on medical professionals is something that could lead to eating disorder behaviors.”

Dr. Klein’s message to healthcare workers: Don’t be ashamed. She described an ED as “a monster that takes over your brain. Once it starts, it’s very hard to turn it around on your own. So, I hope anyone who is suffering, in whatever field they’re in, that they are able to ask for help.”

A version of this article appeared on Medscape.com.