Mental Health

My 50th medical school reunion has come and gone. This milestone offered me another opportunity to look back over the last 5 decades of pediatrics that I have watched pass under the bridge. Triggered by the discovery of two recently published studies, this particular view back over my shoulder induced a wave of sadness, anger, and frustration that I have had trouble shaking.

The first study demonstrated a strong positive effect of exercise on academic achievement, the other found that children who were more physically active have weathered the pandemic with fewer mental health problems.

These studies are just two pieces of a growing body of evidence that our sedentary lifestyles are shortening our lives and launching our children into adulthood burdened with a raft of health risks they could possibly have avoided by being more physically active. Encountering these two papers just as the alumni office was inviting me to engage in an orgy of retrospection and introspection made me consider how little I and others in my profession have done to substantially address this scourge on our young people.

Yes, I have tried to encourage my patients to be less sedentary and more active. Yes, I have tried to set a very visible example by bicycling and walking around town. Yes, I have coached youth sports teams. All of my children and grandchildren are leading active lives and appear to be reaping the benefits. But in the grander scheme of things I feel that neither I nor the American Academy of Pediatrics has made a difference.

In March of 2020 the AAP published a clinical report that lists the numerous positive associations between activity and health that includes a comprehensive collection of suggestions for providers on how we might assess the problem of inactivity and then play a role in addressing it with our patients and our communities. Unfortunately, the message’s importance was lost in the glut of pandemic news.

While the AAP’s report should have been published many decades ago, I doubt the delay lessened its impact significantly because the report is primarily a compendium of recommendations that in the long run will be seen as just another example of us believers preaching to the choir.

Making lifestyle changes on the order of magnitude necessary to convert an increasingly sedentary population into one that unconsciously becomes physically active requires more than recommendations. It is only natural that folks have trouble saying “No.”

No to the entertainment of electronic devices. No to the comforts of all-weather enclosed transportation. No to hours on the couch. Overcoming the inertia built into our society is going to require more than encouragement, recommendations, and professional sports–sponsored presidential initiatives.

Mandate has become a politically charged dirty word. But our current experience with the COVID-19 vaccines should help us realize that there is a significant segment of the population that doesn’t like being told what to do even if the outcome is in their best interest. Education and rewards have fallen short, but the evidence is mounting that mandates can work.

There was a time when physical activity was built into every child’s school day. For a variety of bad reasons, vigorous physical education classes and once- or twice-daily outdoor recesses have disappeared from the educational landscape. It is time to return to them in a robust form. Unfortunately, because activity isn’t happening at home it will take a government mandate.

There will be pushback. Even from some educators whose observations should have shown them the critical role of physical activity in health and academic success. We must move the distraction of the phenomenon once known simply as hyperactivity to the back burner and tackle the real epidemic of hypoactivity that is destroying our children.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

My 50th medical school reunion has come and gone. This milestone offered me another opportunity to look back over the last 5 decades of pediatrics that I have watched pass under the bridge. Triggered by the discovery of two recently published studies, this particular view back over my shoulder induced a wave of sadness, anger, and frustration that I have had trouble shaking.

The first study demonstrated a strong positive effect of exercise on academic achievement, the other found that children who were more physically active have weathered the pandemic with fewer mental health problems.

These studies are just two pieces of a growing body of evidence that our sedentary lifestyles are shortening our lives and launching our children into adulthood burdened with a raft of health risks they could possibly have avoided by being more physically active. Encountering these two papers just as the alumni office was inviting me to engage in an orgy of retrospection and introspection made me consider how little I and others in my profession have done to substantially address this scourge on our young people.

Yes, I have tried to encourage my patients to be less sedentary and more active. Yes, I have tried to set a very visible example by bicycling and walking around town. Yes, I have coached youth sports teams. All of my children and grandchildren are leading active lives and appear to be reaping the benefits. But in the grander scheme of things I feel that neither I nor the American Academy of Pediatrics has made a difference.

In March of 2020 the AAP published a clinical report that lists the numerous positive associations between activity and health that includes a comprehensive collection of suggestions for providers on how we might assess the problem of inactivity and then play a role in addressing it with our patients and our communities. Unfortunately, the message’s importance was lost in the glut of pandemic news.

While the AAP’s report should have been published many decades ago, I doubt the delay lessened its impact significantly because the report is primarily a compendium of recommendations that in the long run will be seen as just another example of us believers preaching to the choir.

Making lifestyle changes on the order of magnitude necessary to convert an increasingly sedentary population into one that unconsciously becomes physically active requires more than recommendations. It is only natural that folks have trouble saying “No.”

No to the entertainment of electronic devices. No to the comforts of all-weather enclosed transportation. No to hours on the couch. Overcoming the inertia built into our society is going to require more than encouragement, recommendations, and professional sports–sponsored presidential initiatives.

Mandate has become a politically charged dirty word. But our current experience with the COVID-19 vaccines should help us realize that there is a significant segment of the population that doesn’t like being told what to do even if the outcome is in their best interest. Education and rewards have fallen short, but the evidence is mounting that mandates can work.

There was a time when physical activity was built into every child’s school day. For a variety of bad reasons, vigorous physical education classes and once- or twice-daily outdoor recesses have disappeared from the educational landscape. It is time to return to them in a robust form. Unfortunately, because activity isn’t happening at home it will take a government mandate.

There will be pushback. Even from some educators whose observations should have shown them the critical role of physical activity in health and academic success. We must move the distraction of the phenomenon once known simply as hyperactivity to the back burner and tackle the real epidemic of hypoactivity that is destroying our children.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

My 50th medical school reunion has come and gone. This milestone offered me another opportunity to look back over the last 5 decades of pediatrics that I have watched pass under the bridge. Triggered by the discovery of two recently published studies, this particular view back over my shoulder induced a wave of sadness, anger, and frustration that I have had trouble shaking.

The first study demonstrated a strong positive effect of exercise on academic achievement, the other found that children who were more physically active have weathered the pandemic with fewer mental health problems.

These studies are just two pieces of a growing body of evidence that our sedentary lifestyles are shortening our lives and launching our children into adulthood burdened with a raft of health risks they could possibly have avoided by being more physically active. Encountering these two papers just as the alumni office was inviting me to engage in an orgy of retrospection and introspection made me consider how little I and others in my profession have done to substantially address this scourge on our young people.

Yes, I have tried to encourage my patients to be less sedentary and more active. Yes, I have tried to set a very visible example by bicycling and walking around town. Yes, I have coached youth sports teams. All of my children and grandchildren are leading active lives and appear to be reaping the benefits. But in the grander scheme of things I feel that neither I nor the American Academy of Pediatrics has made a difference.

In March of 2020 the AAP published a clinical report that lists the numerous positive associations between activity and health that includes a comprehensive collection of suggestions for providers on how we might assess the problem of inactivity and then play a role in addressing it with our patients and our communities. Unfortunately, the message’s importance was lost in the glut of pandemic news.

While the AAP’s report should have been published many decades ago, I doubt the delay lessened its impact significantly because the report is primarily a compendium of recommendations that in the long run will be seen as just another example of us believers preaching to the choir.

Making lifestyle changes on the order of magnitude necessary to convert an increasingly sedentary population into one that unconsciously becomes physically active requires more than recommendations. It is only natural that folks have trouble saying “No.”

No to the entertainment of electronic devices. No to the comforts of all-weather enclosed transportation. No to hours on the couch. Overcoming the inertia built into our society is going to require more than encouragement, recommendations, and professional sports–sponsored presidential initiatives.

Mandate has become a politically charged dirty word. But our current experience with the COVID-19 vaccines should help us realize that there is a significant segment of the population that doesn’t like being told what to do even if the outcome is in their best interest. Education and rewards have fallen short, but the evidence is mounting that mandates can work.

There was a time when physical activity was built into every child’s school day. For a variety of bad reasons, vigorous physical education classes and once- or twice-daily outdoor recesses have disappeared from the educational landscape. It is time to return to them in a robust form. Unfortunately, because activity isn’t happening at home it will take a government mandate.

There will be pushback. Even from some educators whose observations should have shown them the critical role of physical activity in health and academic success. We must move the distraction of the phenomenon once known simply as hyperactivity to the back burner and tackle the real epidemic of hypoactivity that is destroying our children.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Many years ago, drug development in psychiatry turned to control of specific symptoms across disorders rather than within disorders, but regulatory agencies are still not yet on board, according to an expert psychopharmacologist outlining the ongoing evolution at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sponsored by Medscape Live.

If this reorientation is going to lead to the broad indications the newer drugs likely deserve, which is control of specific types of symptoms regardless of the diagnosis, “we have to move the [Food and Drug Administration] along,” said Stephen M. Stahl, MD, PhD, chairman of the Neuroscience Institute and an adjunct professor of psychiatry at the University of California, San Diego.

On the side of drug development and clinical practice, the reorientation has already taken place. Dr. Stahl described numerous brain circuits known to produce symptoms when function is altered that are now treatment targets. This includes the ventral medial prefrontal cortex where deficient information processing leads to depression and the orbital frontal cortex where altered function leads to impulsivity.

“It is not like each part of the brain does a little bit of everything. Rather, each part of the brain has an assignment and duty and function,” Dr. Stahl explained. By addressing the disturbed signaling in brain circuits that lead to depression, impulsivity, agitation, or other symptoms, there is an opportunity for control, regardless of the psychiatric diagnosis with which the symptom is associated.

For example, Dr. Stahl predicted that pimavanserin, a highly selective 5-HT_2A inverse agonist that is already approved for psychosis in Parkinson’s disease, is now likely to be approved for psychosis associated with other conditions on the basis of recent positive clinical studies in these other disorders.

Brexpiprazole, a serotonin-dopamine activity modulator already known to be useful for control of the agitation characteristic of schizophrenia, is now showing the same type of activity against agitation when it is associated with Alzheimer’s disease. Again, Dr. Stahl thinks this drug is on course for an indication across diseases once studies are conducted in each disease individually.

Another drug being evaluated for agitation, the N-methyl-D-aspartate receptor antagonist dextromethorphan bupropion, is also being tested for treatment of symptoms across multiple disorders, he reported.

However, the FDA has so far taken the position that each drug must be tested separately for a given symptom in each disorder for which it is being considered despite the underlying premise that it is the symptom, not the disease, that is important.

“Psychiatric disorders are syndromes, categorized by a collection of symptoms defined descriptively but not neurobiologically,” Dr. Stahl said. Unlike physiological diseases where symptoms, like a fever or abdominal cramps, are the product of a disease, psychiatric symptoms are the disease and a fundamental target – regardless of the DSM-based diagnosis.

To some degree, the symptoms of psychiatric disorders have always been the focus of treatment, but a pivot toward developing therapies that will control a symptom regardless of the underlying diagnosis is an important conceptual change. It is being made possible by advances in the detail with which the neuropathology of these symptoms is understood .

“By my count, 79 symptoms are described in DSM-5, but they are spread across hundreds of syndromes because they are grouped together in different ways,” Dr. Stahl observed.

He noted that clinicians make a diagnosis on the basis symptom groupings, but their interventions are selected to address the manifestations of the disease, not the disease itself.

“If you are a real psychopharmacologist treating real patients, you are treating the specific symptoms of the specific patient,” according to Dr. Stahl.

So far, the FDA has not made this leap, insisting on trials in these categorical disorders rather than permitting trial designs that allow benefit to be demonstrated against a symptom regardless of the syndrome with which it is associated.

Of egregious examples, Dr. Stahl recounted a recent trial of a 5-HT₂ antagonist that looked so promising against psychosis in Alzheimer’s disease that the trialists enrolled patients with psychosis regardless of type of dementia, such as vascular dementia and Lewy body disease. The efficacy was impressive.

“It worked so well that they stopped the trial, but the FDA declined to approve it,” Dr. Stahl recounted. Despite clear evidence of benefit, the regulators insisted that the investigators needed to show a significant benefit in each condition individually.

While the trial investigators acknowledged that there was not enough power in the trial to show a statistically significant benefit in each category, they argued that the overall benefit and the consistent response across categories required them to stop the trial for ethical reasons.

“That’s your problem, the FDA said to the investigators,” according to Dr. Stahl.

The failure of the FDA to recognize the efficacy of psychopharmacologic therapies across symptoms regardless of the associated disease is a failure to stay current with an important evolution in medicine, Dr. Stahl indicated.

“What we have come to understand is the neurobiology of any given symptom is likely to be the same across disorders,” he said.
 

Agency’s arbitrary decisions cited

“I completely agree with Dr. Stahl,” said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience, University of Cincinnati.

In addition to the fact that symptoms are present across multiple categories, many patients manifest multiple symptoms at one time, Dr. Nasrallah pointed out. For neurodegenerative disorders associated with psychosis, depression, anxiety, aggression, and other symptoms, it is already well known that the heterogeneous symptoms “cannot be treated with a single drug,” he said. Rather different drugs targeting each symptom individually is essential for effective management.

Dr. Nasrallah, who chaired the Psychopharmacology Update meeting, has made this point many times in the past, including in his role as the editor of Current Psychiatry. In one editorial 10 years ago, he wrote that “it makes little sense for the FDA to mandate that a drug must work for a DSM diagnosis instead of specific symptoms.”

“The FDA must update its old policy, which has led to the widespread off-label use of psychiatric drugs, an artificial concept, simply because the FDA arbitrarily decided a long time ago that new drugs must be approved for a specific DSM diagnosis,” Dr. Nasrallah said.

Dr. Stahl reported financial relationships with more than 20 pharmaceutical companies, including those that are involved in the development of drugs included in his talk. Medscape Live and this news organization are owned by the same parent company.

Many years ago, drug development in psychiatry turned to control of specific symptoms across disorders rather than within disorders, but regulatory agencies are still not yet on board, according to an expert psychopharmacologist outlining the ongoing evolution at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sponsored by Medscape Live.

If this reorientation is going to lead to the broad indications the newer drugs likely deserve, which is control of specific types of symptoms regardless of the diagnosis, “we have to move the [Food and Drug Administration] along,” said Stephen M. Stahl, MD, PhD, chairman of the Neuroscience Institute and an adjunct professor of psychiatry at the University of California, San Diego.

On the side of drug development and clinical practice, the reorientation has already taken place. Dr. Stahl described numerous brain circuits known to produce symptoms when function is altered that are now treatment targets. This includes the ventral medial prefrontal cortex where deficient information processing leads to depression and the orbital frontal cortex where altered function leads to impulsivity.

“It is not like each part of the brain does a little bit of everything. Rather, each part of the brain has an assignment and duty and function,” Dr. Stahl explained. By addressing the disturbed signaling in brain circuits that lead to depression, impulsivity, agitation, or other symptoms, there is an opportunity for control, regardless of the psychiatric diagnosis with which the symptom is associated.

For example, Dr. Stahl predicted that pimavanserin, a highly selective 5-HT_2A inverse agonist that is already approved for psychosis in Parkinson’s disease, is now likely to be approved for psychosis associated with other conditions on the basis of recent positive clinical studies in these other disorders.

Brexpiprazole, a serotonin-dopamine activity modulator already known to be useful for control of the agitation characteristic of schizophrenia, is now showing the same type of activity against agitation when it is associated with Alzheimer’s disease. Again, Dr. Stahl thinks this drug is on course for an indication across diseases once studies are conducted in each disease individually.

Another drug being evaluated for agitation, the N-methyl-D-aspartate receptor antagonist dextromethorphan bupropion, is also being tested for treatment of symptoms across multiple disorders, he reported.

However, the FDA has so far taken the position that each drug must be tested separately for a given symptom in each disorder for which it is being considered despite the underlying premise that it is the symptom, not the disease, that is important.

“Psychiatric disorders are syndromes, categorized by a collection of symptoms defined descriptively but not neurobiologically,” Dr. Stahl said. Unlike physiological diseases where symptoms, like a fever or abdominal cramps, are the product of a disease, psychiatric symptoms are the disease and a fundamental target – regardless of the DSM-based diagnosis.

To some degree, the symptoms of psychiatric disorders have always been the focus of treatment, but a pivot toward developing therapies that will control a symptom regardless of the underlying diagnosis is an important conceptual change. It is being made possible by advances in the detail with which the neuropathology of these symptoms is understood .

“By my count, 79 symptoms are described in DSM-5, but they are spread across hundreds of syndromes because they are grouped together in different ways,” Dr. Stahl observed.

He noted that clinicians make a diagnosis on the basis symptom groupings, but their interventions are selected to address the manifestations of the disease, not the disease itself.

“If you are a real psychopharmacologist treating real patients, you are treating the specific symptoms of the specific patient,” according to Dr. Stahl.

So far, the FDA has not made this leap, insisting on trials in these categorical disorders rather than permitting trial designs that allow benefit to be demonstrated against a symptom regardless of the syndrome with which it is associated.

Of egregious examples, Dr. Stahl recounted a recent trial of a 5-HT₂ antagonist that looked so promising against psychosis in Alzheimer’s disease that the trialists enrolled patients with psychosis regardless of type of dementia, such as vascular dementia and Lewy body disease. The efficacy was impressive.

“It worked so well that they stopped the trial, but the FDA declined to approve it,” Dr. Stahl recounted. Despite clear evidence of benefit, the regulators insisted that the investigators needed to show a significant benefit in each condition individually.

While the trial investigators acknowledged that there was not enough power in the trial to show a statistically significant benefit in each category, they argued that the overall benefit and the consistent response across categories required them to stop the trial for ethical reasons.

“That’s your problem, the FDA said to the investigators,” according to Dr. Stahl.

The failure of the FDA to recognize the efficacy of psychopharmacologic therapies across symptoms regardless of the associated disease is a failure to stay current with an important evolution in medicine, Dr. Stahl indicated.

“What we have come to understand is the neurobiology of any given symptom is likely to be the same across disorders,” he said.
 

Agency’s arbitrary decisions cited

“I completely agree with Dr. Stahl,” said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience, University of Cincinnati.

In addition to the fact that symptoms are present across multiple categories, many patients manifest multiple symptoms at one time, Dr. Nasrallah pointed out. For neurodegenerative disorders associated with psychosis, depression, anxiety, aggression, and other symptoms, it is already well known that the heterogeneous symptoms “cannot be treated with a single drug,” he said. Rather different drugs targeting each symptom individually is essential for effective management.

Dr. Nasrallah, who chaired the Psychopharmacology Update meeting, has made this point many times in the past, including in his role as the editor of Current Psychiatry. In one editorial 10 years ago, he wrote that “it makes little sense for the FDA to mandate that a drug must work for a DSM diagnosis instead of specific symptoms.”

“The FDA must update its old policy, which has led to the widespread off-label use of psychiatric drugs, an artificial concept, simply because the FDA arbitrarily decided a long time ago that new drugs must be approved for a specific DSM diagnosis,” Dr. Nasrallah said.

Dr. Stahl reported financial relationships with more than 20 pharmaceutical companies, including those that are involved in the development of drugs included in his talk. Medscape Live and this news organization are owned by the same parent company.

Many years ago, drug development in psychiatry turned to control of specific symptoms across disorders rather than within disorders, but regulatory agencies are still not yet on board, according to an expert psychopharmacologist outlining the ongoing evolution at the virtual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists, sponsored by Medscape Live.

If this reorientation is going to lead to the broad indications the newer drugs likely deserve, which is control of specific types of symptoms regardless of the diagnosis, “we have to move the [Food and Drug Administration] along,” said Stephen M. Stahl, MD, PhD, chairman of the Neuroscience Institute and an adjunct professor of psychiatry at the University of California, San Diego.

On the side of drug development and clinical practice, the reorientation has already taken place. Dr. Stahl described numerous brain circuits known to produce symptoms when function is altered that are now treatment targets. This includes the ventral medial prefrontal cortex where deficient information processing leads to depression and the orbital frontal cortex where altered function leads to impulsivity.

“It is not like each part of the brain does a little bit of everything. Rather, each part of the brain has an assignment and duty and function,” Dr. Stahl explained. By addressing the disturbed signaling in brain circuits that lead to depression, impulsivity, agitation, or other symptoms, there is an opportunity for control, regardless of the psychiatric diagnosis with which the symptom is associated.

For example, Dr. Stahl predicted that pimavanserin, a highly selective 5-HT_2A inverse agonist that is already approved for psychosis in Parkinson’s disease, is now likely to be approved for psychosis associated with other conditions on the basis of recent positive clinical studies in these other disorders.

Brexpiprazole, a serotonin-dopamine activity modulator already known to be useful for control of the agitation characteristic of schizophrenia, is now showing the same type of activity against agitation when it is associated with Alzheimer’s disease. Again, Dr. Stahl thinks this drug is on course for an indication across diseases once studies are conducted in each disease individually.

Another drug being evaluated for agitation, the N-methyl-D-aspartate receptor antagonist dextromethorphan bupropion, is also being tested for treatment of symptoms across multiple disorders, he reported.

However, the FDA has so far taken the position that each drug must be tested separately for a given symptom in each disorder for which it is being considered despite the underlying premise that it is the symptom, not the disease, that is important.

“Psychiatric disorders are syndromes, categorized by a collection of symptoms defined descriptively but not neurobiologically,” Dr. Stahl said. Unlike physiological diseases where symptoms, like a fever or abdominal cramps, are the product of a disease, psychiatric symptoms are the disease and a fundamental target – regardless of the DSM-based diagnosis.

To some degree, the symptoms of psychiatric disorders have always been the focus of treatment, but a pivot toward developing therapies that will control a symptom regardless of the underlying diagnosis is an important conceptual change. It is being made possible by advances in the detail with which the neuropathology of these symptoms is understood .

“By my count, 79 symptoms are described in DSM-5, but they are spread across hundreds of syndromes because they are grouped together in different ways,” Dr. Stahl observed.

He noted that clinicians make a diagnosis on the basis symptom groupings, but their interventions are selected to address the manifestations of the disease, not the disease itself.

“If you are a real psychopharmacologist treating real patients, you are treating the specific symptoms of the specific patient,” according to Dr. Stahl.

So far, the FDA has not made this leap, insisting on trials in these categorical disorders rather than permitting trial designs that allow benefit to be demonstrated against a symptom regardless of the syndrome with which it is associated.

Of egregious examples, Dr. Stahl recounted a recent trial of a 5-HT₂ antagonist that looked so promising against psychosis in Alzheimer’s disease that the trialists enrolled patients with psychosis regardless of type of dementia, such as vascular dementia and Lewy body disease. The efficacy was impressive.

“It worked so well that they stopped the trial, but the FDA declined to approve it,” Dr. Stahl recounted. Despite clear evidence of benefit, the regulators insisted that the investigators needed to show a significant benefit in each condition individually.

While the trial investigators acknowledged that there was not enough power in the trial to show a statistically significant benefit in each category, they argued that the overall benefit and the consistent response across categories required them to stop the trial for ethical reasons.

“That’s your problem, the FDA said to the investigators,” according to Dr. Stahl.

The failure of the FDA to recognize the efficacy of psychopharmacologic therapies across symptoms regardless of the associated disease is a failure to stay current with an important evolution in medicine, Dr. Stahl indicated.

“What we have come to understand is the neurobiology of any given symptom is likely to be the same across disorders,” he said.
 

Agency’s arbitrary decisions cited

“I completely agree with Dr. Stahl,” said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience, University of Cincinnati.

In addition to the fact that symptoms are present across multiple categories, many patients manifest multiple symptoms at one time, Dr. Nasrallah pointed out. For neurodegenerative disorders associated with psychosis, depression, anxiety, aggression, and other symptoms, it is already well known that the heterogeneous symptoms “cannot be treated with a single drug,” he said. Rather different drugs targeting each symptom individually is essential for effective management.

Dr. Nasrallah, who chaired the Psychopharmacology Update meeting, has made this point many times in the past, including in his role as the editor of Current Psychiatry. In one editorial 10 years ago, he wrote that “it makes little sense for the FDA to mandate that a drug must work for a DSM diagnosis instead of specific symptoms.”

“The FDA must update its old policy, which has led to the widespread off-label use of psychiatric drugs, an artificial concept, simply because the FDA arbitrarily decided a long time ago that new drugs must be approved for a specific DSM diagnosis,” Dr. Nasrallah said.

Dr. Stahl reported financial relationships with more than 20 pharmaceutical companies, including those that are involved in the development of drugs included in his talk. Medscape Live and this news organization are owned by the same parent company.

A combination of droperidol and midazolam was more effective than haloperidol plus lorazepam for achieving sedation in agitated patients in an emergency department setting in a study involving 86 adult patients at a single tertiary medical care center.

Patients with acute agitation present significant safety concerns in the emergency department, according to Jessica Javed, MD, of the University of Louisville (Ky.) and colleagues.

A combination of haloperidol and lorazepam has been widely used to curb agitation in these patients, but droperidol and midazolam could be more effective, owing to faster onset of action, Dr. Javed noted in a presentation at the annual meeting of the American College of Emergency Physicians.

Dr. Javed and colleagues conducted a prospective study to compare time to adequate sedation in agitated patients in the ED. In the trial, 43 patients received droperidol 5 mg plus midazolam 5 mg, and 43 patients received haloperidol plus lorazepam 2 mg. The average age of the patients in the droperidol/midazolam group was 34 years; the average age of the patients in the haloperidol/lorazepam group was 38 years. Baseline demographics, including height, weight, body mass index, and baseline Sedation Assessment Tool (SAT) scores, were similar between the groups.

The SAT score scale ranges from +3 (combative, violent, or out of control) to –3 (no response to stimulation); zero indicates being awake and calm/cooperative. The median baseline SAT score was 3 for both treatment groups.

The primary outcome was the proportion of patients with adequate sedation (defined as SAT scores of ≤0) 10 min after treatment.

Significantly more patients in the droperidol/midazolam group met this outcome, compared with the patients in the haloperidol/lorazepam group (51.2% vs. 7%). Also, significantly more patients in the droperidol/midazolam group achieved adequate sedation at 5, 10, 15, and 30 min than in the haloperidol/lorazepam group.

Fewer patients in the haloperidol/lorazepam group required supplemental oxygen, compared with the droperidol/midazolam group (9.3% vs. 25.6%). However, none of the droperidol/midazolam patients required rescue sedation, compared with 16.3% of the haloperidol/lorazepam patients, Dr. Javed noted. None of the patients required endotracheal intubation or experienced extrapyramidal symptoms, she said.

The study was limited by the small sample size and inclusion of data from only a single center.

The results suggest that droperidol/midazolam is superior to intramuscular haloperidol/lorazepam for producing adequate sedation after 10 min in agitated patients, Dr. Javed concluded.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.
 

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

A combination of droperidol and midazolam was more effective than haloperidol plus lorazepam for achieving sedation in agitated patients in an emergency department setting in a study involving 86 adult patients at a single tertiary medical care center.

Patients with acute agitation present significant safety concerns in the emergency department, according to Jessica Javed, MD, of the University of Louisville (Ky.) and colleagues.

A combination of haloperidol and lorazepam has been widely used to curb agitation in these patients, but droperidol and midazolam could be more effective, owing to faster onset of action, Dr. Javed noted in a presentation at the annual meeting of the American College of Emergency Physicians.

Dr. Javed and colleagues conducted a prospective study to compare time to adequate sedation in agitated patients in the ED. In the trial, 43 patients received droperidol 5 mg plus midazolam 5 mg, and 43 patients received haloperidol plus lorazepam 2 mg. The average age of the patients in the droperidol/midazolam group was 34 years; the average age of the patients in the haloperidol/lorazepam group was 38 years. Baseline demographics, including height, weight, body mass index, and baseline Sedation Assessment Tool (SAT) scores, were similar between the groups.

The SAT score scale ranges from +3 (combative, violent, or out of control) to –3 (no response to stimulation); zero indicates being awake and calm/cooperative. The median baseline SAT score was 3 for both treatment groups.

The primary outcome was the proportion of patients with adequate sedation (defined as SAT scores of ≤0) 10 min after treatment.

Significantly more patients in the droperidol/midazolam group met this outcome, compared with the patients in the haloperidol/lorazepam group (51.2% vs. 7%). Also, significantly more patients in the droperidol/midazolam group achieved adequate sedation at 5, 10, 15, and 30 min than in the haloperidol/lorazepam group.

Fewer patients in the haloperidol/lorazepam group required supplemental oxygen, compared with the droperidol/midazolam group (9.3% vs. 25.6%). However, none of the droperidol/midazolam patients required rescue sedation, compared with 16.3% of the haloperidol/lorazepam patients, Dr. Javed noted. None of the patients required endotracheal intubation or experienced extrapyramidal symptoms, she said.

The study was limited by the small sample size and inclusion of data from only a single center.

The results suggest that droperidol/midazolam is superior to intramuscular haloperidol/lorazepam for producing adequate sedation after 10 min in agitated patients, Dr. Javed concluded.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.
 

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

A combination of droperidol and midazolam was more effective than haloperidol plus lorazepam for achieving sedation in agitated patients in an emergency department setting in a study involving 86 adult patients at a single tertiary medical care center.

Patients with acute agitation present significant safety concerns in the emergency department, according to Jessica Javed, MD, of the University of Louisville (Ky.) and colleagues.

A combination of haloperidol and lorazepam has been widely used to curb agitation in these patients, but droperidol and midazolam could be more effective, owing to faster onset of action, Dr. Javed noted in a presentation at the annual meeting of the American College of Emergency Physicians.

Dr. Javed and colleagues conducted a prospective study to compare time to adequate sedation in agitated patients in the ED. In the trial, 43 patients received droperidol 5 mg plus midazolam 5 mg, and 43 patients received haloperidol plus lorazepam 2 mg. The average age of the patients in the droperidol/midazolam group was 34 years; the average age of the patients in the haloperidol/lorazepam group was 38 years. Baseline demographics, including height, weight, body mass index, and baseline Sedation Assessment Tool (SAT) scores, were similar between the groups.

The SAT score scale ranges from +3 (combative, violent, or out of control) to –3 (no response to stimulation); zero indicates being awake and calm/cooperative. The median baseline SAT score was 3 for both treatment groups.

The primary outcome was the proportion of patients with adequate sedation (defined as SAT scores of ≤0) 10 min after treatment.

Significantly more patients in the droperidol/midazolam group met this outcome, compared with the patients in the haloperidol/lorazepam group (51.2% vs. 7%). Also, significantly more patients in the droperidol/midazolam group achieved adequate sedation at 5, 10, 15, and 30 min than in the haloperidol/lorazepam group.

Fewer patients in the haloperidol/lorazepam group required supplemental oxygen, compared with the droperidol/midazolam group (9.3% vs. 25.6%). However, none of the droperidol/midazolam patients required rescue sedation, compared with 16.3% of the haloperidol/lorazepam patients, Dr. Javed noted. None of the patients required endotracheal intubation or experienced extrapyramidal symptoms, she said.

The study was limited by the small sample size and inclusion of data from only a single center.

The results suggest that droperidol/midazolam is superior to intramuscular haloperidol/lorazepam for producing adequate sedation after 10 min in agitated patients, Dr. Javed concluded.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.
 

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

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

HconQ/ThinkStock

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.

The findings were published online Oct. 27 in The Lancet Global Health.
 

Alternative mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.

Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
 

Additional analysis requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Dr. Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.

To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
 

‘A $10 medicine’

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”

By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.

Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered safety, efficacy questions

In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.

The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.

“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.

In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.

“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.

Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

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

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

HconQ/ThinkStock

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.

The findings were published online Oct. 27 in The Lancet Global Health.
 

Alternative mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.

Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
 

Additional analysis requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Dr. Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.

To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
 

‘A $10 medicine’

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”

By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.

Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered safety, efficacy questions

In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.

The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.

“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.

In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.

“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.

Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

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

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

HconQ/ThinkStock

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.

The findings were published online Oct. 27 in The Lancet Global Health.
 

Alternative mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.

Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
 

Additional analysis requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Dr. Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.

To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
 

‘A $10 medicine’

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”

By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.

Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered safety, efficacy questions

In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.

The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.

“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.

In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.

“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.

Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

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

The majority of families of preschool children with a diagnosis of attention-deficit/hyperactivity disorder were not offered behavior therapy as a first-line treatment, according to data from nearly 200 children.

The American Academy of Pediatrics’ current clinical practice guidelines recommend parent training in behavior management (PTBM) as a first-line treatment for children aged 4-5 years diagnosed with attention-deficit/hyperactivity disorder (ADHD) or symptoms of ADHD such as hyperactivity or impulsivity, but data on how well primary care providers follow this recommendation in practice are lacking, wrote Yair Bannett, MD, of Stanford (Calif.) University, and colleagues.

To investigate the rates of PTBM recommendations, the researchers reviewed electronic health records for 22,714 children aged 48-71 months who had at least two visits to any 1 of 10 primary care practices in a California pediatric health network between Oct. 1, 2015, and Dec. 31, 2019. Children with an autism diagnosis were excluded; ADHD-related visits were identified via ADHD diagnosis codes or symptom-level diagnosis codes.

In the study, published in JAMA Pediatrics, 192 children (1%) had either an ADHD diagnosis or ADHD symptoms; of these, 21 (11%) received referrals for PTBM during ADHD-related primary care visits. Records showed an additional 55 patients (29%) had a mention of counseling on PTBM by a primary care provider, including handouts.

PCPs prescribed ADHD medications for 32 children; 9 of these had documented PTBM recommendations, and in 4 cases, the PCPs recommended PTBM before prescribing a first medication.

A majority (73%) of the children were male, 64% were privately insured, 56% had subspecialists involved in their care, and 17% were prescribed ADHD medications (88% of which were stimulants).

In a multivariate analysis, children with public insurance were significantly less likely to receive a PTBM recommendation than were those with private insurance (adjusted relative risk 0.87).

The most common recommendation overall was routine/habit modifications (for 79 children), such as reducing sugar or adding supplements to the diet; improving sleep hygiene; and limiting screen time.

The low rates of PTBM among publicly insured patients in particular highlight the need to identify factors behind disparities in recommended treatments, the researchers noted.

The study findings were limited by several factors including the reliance on primary care provider documentation during the study period and the inclusion only of medical record reviews with diagnostic codes for ADHD, the researchers noted. Further studies beyond a single health care system are needed to assess generalizability, they added.

However, the results present an opportunity for primary care providers to improve adherence to clinical practice guidelines and establish behavioral treatment at an early age to mitigate long-term morbidity, they concluded.
 

Low rates highlight barriers and opportunities

“We were surprised to find very low rates of documented recommendations for behavioral treatment mentioned by PCPs,” Dr. Bannett said in an interview. The researchers were surprised that recommendations for changes in daily routines and habits, such as reduced sugar intake, regular exercise, better sleep, and reduced screen time, were the most common recommendations for families of children presenting with symptoms of ADHD. “Though these are good recommendations that can support the general health of any young child, there is no evidence to support their benefit in alleviating symptoms of ADHD,” he said.

Dr. Bannett acknowledged the challenge for pediatricians to stay current on where and how families can access this type of behavioral treatment, but the evidence supports behavior therapy over medication in preschool children, he said.

“I think that it is important for primary care clinicians to know that there are options for parent training in behavioral management for both privately and publicly insured patients,” said Dr. Bannett. “In California, for example, parent training programs are offered through county mental health services. In some counties, there are other organizations that offer parent training for underserved populations and those with public insurance,” he said.

Dr. Bannett noted that online treatments, including behavioral treatments, may be possible for some families.

He cited Triple P, an evidence-based curriculum for parent training in behavior management, which offers an online course for parents at triplep-parenting.com, and an online parent training course offered through the CHADD website (chadd.org/parent-to-parent/).

Dr. Bannett noted that the researchers are planning a follow-up study to investigate the reasons behind the low referral rates for PTBM. “A known barrier is the limited availability of therapists who can provide this type of therapy,” Dr. Bannett said. “Research is needed on the effectiveness of online versions of parent training, which can overcome some of the access barriers many families experience,” he added.

“Additionally, since behavioral treatment requires a significant effort on the part of the parents and caregivers, who often are not able to complete the therapy, there is a need for research on ways to enhance parent and family engagement and participation in these important evidence-based treatments,” as well as a need to research ways to increase adherence to evidence-based practices, said Dr. Bannett. “We are currently planning intervention studies that will enhance primary care clinicians’ knowledge and clinical practice; for example, decision support tools in the electronic health record, and up-to-date information about available resources and behavioral therapists in their community that they can share with families,” he said. 
 

Barriers make it difficult to adhere to guidelines

The study authors missed a significant element of the AAP guidelines by failing to acknowledge the extensive accompanying section on barriers to adoption, which details why most pediatricians in clinical practice do not prescribe PTBM, Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., said in an interview.

“Academically, it is a wonderful article,” said Dr. Lessin, who was a member of the authoring committee of the AAP guidelines and a major contributor to the section on barriers. The AAP guidelines recommend PTBM because it is evidence based, but the barrier section is essential to understanding that this evidence-based recommendation is nearly impossible to follow in real-world clinical practice, he emphasized. 

The American Academy of Pediatrics’ “Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents,” published in October of 2019 in Pediatrics, included a full subsection on barriers as to why the guidelines might not be followed in many cases in a real-world setting, and the study authors failed to acknowledge this section and its implications, said Dr. Lessin. Notably, the barriers section was originally published in Pediatrics under a Supplemental Data tab that might easily be overlooked by someone reviewing the main practice guideline recommendations, he said.

In most areas of the country, PTBM is simply unavailable, Dr. Lessin said. 

There is a dearth of mental health providers in the United States in general, and “a monstrous shortage of mental health practitioners for young children,” he said. Children in underserved areas barely have access to a medical home, let alone mental health subspecialists, he added.

Even in areas where specialized behavior therapy may be available, it can be prohibitively expensive for all but the wealthiest patients, Dr. Lessin noted. Insurance does not cover this type of behavior therapy, and most mental health professionals don’t accept Medicaid, nor commercial insurance, he said. 

“I don’t even bother with those referrals, because they are not available,” said Dr. Lessin. The take-home message is that most community-based pediatricians are not following the guidelines because the barriers are so enormous, he said.

The study was supported by a research grant from the Society of Developmental and Behavioral Pediatrics and salary support through the Instructor Support Program at the department of pediatrics, Lucile Packard Children’s Hospital Stanford, to Dr. Bannett. The researchers had no other financial conflicts to disclose. Dr. Lessin had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

The majority of families of preschool children with a diagnosis of attention-deficit/hyperactivity disorder were not offered behavior therapy as a first-line treatment, according to data from nearly 200 children.

The American Academy of Pediatrics’ current clinical practice guidelines recommend parent training in behavior management (PTBM) as a first-line treatment for children aged 4-5 years diagnosed with attention-deficit/hyperactivity disorder (ADHD) or symptoms of ADHD such as hyperactivity or impulsivity, but data on how well primary care providers follow this recommendation in practice are lacking, wrote Yair Bannett, MD, of Stanford (Calif.) University, and colleagues.

To investigate the rates of PTBM recommendations, the researchers reviewed electronic health records for 22,714 children aged 48-71 months who had at least two visits to any 1 of 10 primary care practices in a California pediatric health network between Oct. 1, 2015, and Dec. 31, 2019. Children with an autism diagnosis were excluded; ADHD-related visits were identified via ADHD diagnosis codes or symptom-level diagnosis codes.

In the study, published in JAMA Pediatrics, 192 children (1%) had either an ADHD diagnosis or ADHD symptoms; of these, 21 (11%) received referrals for PTBM during ADHD-related primary care visits. Records showed an additional 55 patients (29%) had a mention of counseling on PTBM by a primary care provider, including handouts.

PCPs prescribed ADHD medications for 32 children; 9 of these had documented PTBM recommendations, and in 4 cases, the PCPs recommended PTBM before prescribing a first medication.

A majority (73%) of the children were male, 64% were privately insured, 56% had subspecialists involved in their care, and 17% were prescribed ADHD medications (88% of which were stimulants).

In a multivariate analysis, children with public insurance were significantly less likely to receive a PTBM recommendation than were those with private insurance (adjusted relative risk 0.87).

The most common recommendation overall was routine/habit modifications (for 79 children), such as reducing sugar or adding supplements to the diet; improving sleep hygiene; and limiting screen time.

The low rates of PTBM among publicly insured patients in particular highlight the need to identify factors behind disparities in recommended treatments, the researchers noted.

The study findings were limited by several factors including the reliance on primary care provider documentation during the study period and the inclusion only of medical record reviews with diagnostic codes for ADHD, the researchers noted. Further studies beyond a single health care system are needed to assess generalizability, they added.

However, the results present an opportunity for primary care providers to improve adherence to clinical practice guidelines and establish behavioral treatment at an early age to mitigate long-term morbidity, they concluded.
 

Low rates highlight barriers and opportunities

“We were surprised to find very low rates of documented recommendations for behavioral treatment mentioned by PCPs,” Dr. Bannett said in an interview. The researchers were surprised that recommendations for changes in daily routines and habits, such as reduced sugar intake, regular exercise, better sleep, and reduced screen time, were the most common recommendations for families of children presenting with symptoms of ADHD. “Though these are good recommendations that can support the general health of any young child, there is no evidence to support their benefit in alleviating symptoms of ADHD,” he said.

Dr. Bannett acknowledged the challenge for pediatricians to stay current on where and how families can access this type of behavioral treatment, but the evidence supports behavior therapy over medication in preschool children, he said.

“I think that it is important for primary care clinicians to know that there are options for parent training in behavioral management for both privately and publicly insured patients,” said Dr. Bannett. “In California, for example, parent training programs are offered through county mental health services. In some counties, there are other organizations that offer parent training for underserved populations and those with public insurance,” he said.

Dr. Bannett noted that online treatments, including behavioral treatments, may be possible for some families.

He cited Triple P, an evidence-based curriculum for parent training in behavior management, which offers an online course for parents at triplep-parenting.com, and an online parent training course offered through the CHADD website (chadd.org/parent-to-parent/).

Dr. Bannett noted that the researchers are planning a follow-up study to investigate the reasons behind the low referral rates for PTBM. “A known barrier is the limited availability of therapists who can provide this type of therapy,” Dr. Bannett said. “Research is needed on the effectiveness of online versions of parent training, which can overcome some of the access barriers many families experience,” he added.

“Additionally, since behavioral treatment requires a significant effort on the part of the parents and caregivers, who often are not able to complete the therapy, there is a need for research on ways to enhance parent and family engagement and participation in these important evidence-based treatments,” as well as a need to research ways to increase adherence to evidence-based practices, said Dr. Bannett. “We are currently planning intervention studies that will enhance primary care clinicians’ knowledge and clinical practice; for example, decision support tools in the electronic health record, and up-to-date information about available resources and behavioral therapists in their community that they can share with families,” he said. 
 

Barriers make it difficult to adhere to guidelines

The study authors missed a significant element of the AAP guidelines by failing to acknowledge the extensive accompanying section on barriers to adoption, which details why most pediatricians in clinical practice do not prescribe PTBM, Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., said in an interview.

“Academically, it is a wonderful article,” said Dr. Lessin, who was a member of the authoring committee of the AAP guidelines and a major contributor to the section on barriers. The AAP guidelines recommend PTBM because it is evidence based, but the barrier section is essential to understanding that this evidence-based recommendation is nearly impossible to follow in real-world clinical practice, he emphasized. 

The American Academy of Pediatrics’ “Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents,” published in October of 2019 in Pediatrics, included a full subsection on barriers as to why the guidelines might not be followed in many cases in a real-world setting, and the study authors failed to acknowledge this section and its implications, said Dr. Lessin. Notably, the barriers section was originally published in Pediatrics under a Supplemental Data tab that might easily be overlooked by someone reviewing the main practice guideline recommendations, he said.

In most areas of the country, PTBM is simply unavailable, Dr. Lessin said. 

There is a dearth of mental health providers in the United States in general, and “a monstrous shortage of mental health practitioners for young children,” he said. Children in underserved areas barely have access to a medical home, let alone mental health subspecialists, he added.

Even in areas where specialized behavior therapy may be available, it can be prohibitively expensive for all but the wealthiest patients, Dr. Lessin noted. Insurance does not cover this type of behavior therapy, and most mental health professionals don’t accept Medicaid, nor commercial insurance, he said. 

“I don’t even bother with those referrals, because they are not available,” said Dr. Lessin. The take-home message is that most community-based pediatricians are not following the guidelines because the barriers are so enormous, he said.

The study was supported by a research grant from the Society of Developmental and Behavioral Pediatrics and salary support through the Instructor Support Program at the department of pediatrics, Lucile Packard Children’s Hospital Stanford, to Dr. Bannett. The researchers had no other financial conflicts to disclose. Dr. Lessin had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

The majority of families of preschool children with a diagnosis of attention-deficit/hyperactivity disorder were not offered behavior therapy as a first-line treatment, according to data from nearly 200 children.

The American Academy of Pediatrics’ current clinical practice guidelines recommend parent training in behavior management (PTBM) as a first-line treatment for children aged 4-5 years diagnosed with attention-deficit/hyperactivity disorder (ADHD) or symptoms of ADHD such as hyperactivity or impulsivity, but data on how well primary care providers follow this recommendation in practice are lacking, wrote Yair Bannett, MD, of Stanford (Calif.) University, and colleagues.

To investigate the rates of PTBM recommendations, the researchers reviewed electronic health records for 22,714 children aged 48-71 months who had at least two visits to any 1 of 10 primary care practices in a California pediatric health network between Oct. 1, 2015, and Dec. 31, 2019. Children with an autism diagnosis were excluded; ADHD-related visits were identified via ADHD diagnosis codes or symptom-level diagnosis codes.

In the study, published in JAMA Pediatrics, 192 children (1%) had either an ADHD diagnosis or ADHD symptoms; of these, 21 (11%) received referrals for PTBM during ADHD-related primary care visits. Records showed an additional 55 patients (29%) had a mention of counseling on PTBM by a primary care provider, including handouts.

PCPs prescribed ADHD medications for 32 children; 9 of these had documented PTBM recommendations, and in 4 cases, the PCPs recommended PTBM before prescribing a first medication.

A majority (73%) of the children were male, 64% were privately insured, 56% had subspecialists involved in their care, and 17% were prescribed ADHD medications (88% of which were stimulants).

In a multivariate analysis, children with public insurance were significantly less likely to receive a PTBM recommendation than were those with private insurance (adjusted relative risk 0.87).

The most common recommendation overall was routine/habit modifications (for 79 children), such as reducing sugar or adding supplements to the diet; improving sleep hygiene; and limiting screen time.

The low rates of PTBM among publicly insured patients in particular highlight the need to identify factors behind disparities in recommended treatments, the researchers noted.

The study findings were limited by several factors including the reliance on primary care provider documentation during the study period and the inclusion only of medical record reviews with diagnostic codes for ADHD, the researchers noted. Further studies beyond a single health care system are needed to assess generalizability, they added.

However, the results present an opportunity for primary care providers to improve adherence to clinical practice guidelines and establish behavioral treatment at an early age to mitigate long-term morbidity, they concluded.
 

Low rates highlight barriers and opportunities

“We were surprised to find very low rates of documented recommendations for behavioral treatment mentioned by PCPs,” Dr. Bannett said in an interview. The researchers were surprised that recommendations for changes in daily routines and habits, such as reduced sugar intake, regular exercise, better sleep, and reduced screen time, were the most common recommendations for families of children presenting with symptoms of ADHD. “Though these are good recommendations that can support the general health of any young child, there is no evidence to support their benefit in alleviating symptoms of ADHD,” he said.

Dr. Bannett acknowledged the challenge for pediatricians to stay current on where and how families can access this type of behavioral treatment, but the evidence supports behavior therapy over medication in preschool children, he said.

“I think that it is important for primary care clinicians to know that there are options for parent training in behavioral management for both privately and publicly insured patients,” said Dr. Bannett. “In California, for example, parent training programs are offered through county mental health services. In some counties, there are other organizations that offer parent training for underserved populations and those with public insurance,” he said.

Dr. Bannett noted that online treatments, including behavioral treatments, may be possible for some families.

He cited Triple P, an evidence-based curriculum for parent training in behavior management, which offers an online course for parents at triplep-parenting.com, and an online parent training course offered through the CHADD website (chadd.org/parent-to-parent/).

Dr. Bannett noted that the researchers are planning a follow-up study to investigate the reasons behind the low referral rates for PTBM. “A known barrier is the limited availability of therapists who can provide this type of therapy,” Dr. Bannett said. “Research is needed on the effectiveness of online versions of parent training, which can overcome some of the access barriers many families experience,” he added.

“Additionally, since behavioral treatment requires a significant effort on the part of the parents and caregivers, who often are not able to complete the therapy, there is a need for research on ways to enhance parent and family engagement and participation in these important evidence-based treatments,” as well as a need to research ways to increase adherence to evidence-based practices, said Dr. Bannett. “We are currently planning intervention studies that will enhance primary care clinicians’ knowledge and clinical practice; for example, decision support tools in the electronic health record, and up-to-date information about available resources and behavioral therapists in their community that they can share with families,” he said. 
 

Barriers make it difficult to adhere to guidelines

The study authors missed a significant element of the AAP guidelines by failing to acknowledge the extensive accompanying section on barriers to adoption, which details why most pediatricians in clinical practice do not prescribe PTBM, Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., said in an interview.

“Academically, it is a wonderful article,” said Dr. Lessin, who was a member of the authoring committee of the AAP guidelines and a major contributor to the section on barriers. The AAP guidelines recommend PTBM because it is evidence based, but the barrier section is essential to understanding that this evidence-based recommendation is nearly impossible to follow in real-world clinical practice, he emphasized. 

The American Academy of Pediatrics’ “Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents,” published in October of 2019 in Pediatrics, included a full subsection on barriers as to why the guidelines might not be followed in many cases in a real-world setting, and the study authors failed to acknowledge this section and its implications, said Dr. Lessin. Notably, the barriers section was originally published in Pediatrics under a Supplemental Data tab that might easily be overlooked by someone reviewing the main practice guideline recommendations, he said.

In most areas of the country, PTBM is simply unavailable, Dr. Lessin said. 

There is a dearth of mental health providers in the United States in general, and “a monstrous shortage of mental health practitioners for young children,” he said. Children in underserved areas barely have access to a medical home, let alone mental health subspecialists, he added.

Even in areas where specialized behavior therapy may be available, it can be prohibitively expensive for all but the wealthiest patients, Dr. Lessin noted. Insurance does not cover this type of behavior therapy, and most mental health professionals don’t accept Medicaid, nor commercial insurance, he said. 

“I don’t even bother with those referrals, because they are not available,” said Dr. Lessin. The take-home message is that most community-based pediatricians are not following the guidelines because the barriers are so enormous, he said.

The study was supported by a research grant from the Society of Developmental and Behavioral Pediatrics and salary support through the Instructor Support Program at the department of pediatrics, Lucile Packard Children’s Hospital Stanford, to Dr. Bannett. The researchers had no other financial conflicts to disclose. Dr. Lessin had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

In patients with advanced cancer who are prescribed immune checkpoint inhibitors, comedications must be carefully assessed before patients start ICI therapy, most notably proton pump inhibitors, glucocorticoids, antibiotics, and psychotropic drugs.

“Our results confirm the detrimental impact on oncological outcomes of antibiotics and glucocorticoids at a dosage ≥10 mg/day when given within 1 month before or after ICI onset,” Marie Kostine, MD, of Bordeaux (France) University Hospital, and colleagues wrote in the European Journal of Cancer. “Moreover, we show that other comedications may significantly alter the antitumoral response of ICI, such as proton pump inhibitors, psychotropic drugs, morphine, aspirin, and insulin, whereas others seem to have no impact.”

While immune checkpoint inhibitors are transforming the treatment of advanced cancers, gut microbiota composition is an important determinant of response to ICIs. Antibiotic treatments are known to alter the gut microbiota. Other drugs, such as proton pump inhibitors, antidiabetic agents, aspirin, NSAIDs, glucocorticoids, immunomodulators, psychotropic drugs, and analgesics, have been associated with changes in microbiome composition. Since many patients with advanced cancer are exposed to such drugs, this study looked at the possible influence of these comedications on the antitumor effect and safety of ICIs.

The observational study included 635 patients with advanced cancer treated with ICIs between May 2015 and September 2017. Comedications given within 1 month before or 1 month after the first administration of an ICI were reviewed from medical records. Psychotropic drugs, proton pump inhibitors, ACE inhibitors and/or angiotensin II receptor blockers (ARBs), glucocorticoids, antibiotics, statins, and morphine were the most prescribed comedications.

Baseline use of antibiotics, glucocorticoids greater than 10 mg/day, proton pump inhibitors, psychotropic drugs, morphine, and insulin was associated with decreased overall survival and tumor response. However, the coadministration of statins, ACE inhibitors and/or ARBs, NSAIDs, aspirin, and oral diabetes drugs did not impact patient outcomes. Additionally, treatments that altered the response to ICIs were associated with a decreased incidence of immune-related adverse events.

“These results suggest some practical advice in a patient candidate to ICIs,” the authors wrote. “First, antibiotic treatment should be limited to documented infections,” and “withdrawal of proton pump inhibitors and psychotropic drugs should be considered.

“Regarding baseline glucocorticoids use, the cutoff of 10 mg/day should be respected, considering the deleterious effect of higher dosage. Moreover, because of the lack of impact of inhaled or topical glucocorticoids, local routes should be preferred,” the authors wrote. “Conversely, our study brings reassuring data regarding the use of glucocorticoids for the management of immune-related adverse events, which did not alter ICI efficacy, confirming previous reports.”

The authors noted that the observational nature of the study does not allow any causal conclusion, adding that it remains unknown whether the effect of comedications “on cancer outcomes is thoroughly mediated by changes in microbiota or other immunomodulatory properties.”

Along with the retrospective design, study limitations included reporting bias and missing data on baseline comedications, specific prognostic factors and cancer outcomes.

The authors noted no conflicts of interest.

In patients with advanced cancer who are prescribed immune checkpoint inhibitors, comedications must be carefully assessed before patients start ICI therapy, most notably proton pump inhibitors, glucocorticoids, antibiotics, and psychotropic drugs.

“Our results confirm the detrimental impact on oncological outcomes of antibiotics and glucocorticoids at a dosage ≥10 mg/day when given within 1 month before or after ICI onset,” Marie Kostine, MD, of Bordeaux (France) University Hospital, and colleagues wrote in the European Journal of Cancer. “Moreover, we show that other comedications may significantly alter the antitumoral response of ICI, such as proton pump inhibitors, psychotropic drugs, morphine, aspirin, and insulin, whereas others seem to have no impact.”

While immune checkpoint inhibitors are transforming the treatment of advanced cancers, gut microbiota composition is an important determinant of response to ICIs. Antibiotic treatments are known to alter the gut microbiota. Other drugs, such as proton pump inhibitors, antidiabetic agents, aspirin, NSAIDs, glucocorticoids, immunomodulators, psychotropic drugs, and analgesics, have been associated with changes in microbiome composition. Since many patients with advanced cancer are exposed to such drugs, this study looked at the possible influence of these comedications on the antitumor effect and safety of ICIs.

The observational study included 635 patients with advanced cancer treated with ICIs between May 2015 and September 2017. Comedications given within 1 month before or 1 month after the first administration of an ICI were reviewed from medical records. Psychotropic drugs, proton pump inhibitors, ACE inhibitors and/or angiotensin II receptor blockers (ARBs), glucocorticoids, antibiotics, statins, and morphine were the most prescribed comedications.

Baseline use of antibiotics, glucocorticoids greater than 10 mg/day, proton pump inhibitors, psychotropic drugs, morphine, and insulin was associated with decreased overall survival and tumor response. However, the coadministration of statins, ACE inhibitors and/or ARBs, NSAIDs, aspirin, and oral diabetes drugs did not impact patient outcomes. Additionally, treatments that altered the response to ICIs were associated with a decreased incidence of immune-related adverse events.

“These results suggest some practical advice in a patient candidate to ICIs,” the authors wrote. “First, antibiotic treatment should be limited to documented infections,” and “withdrawal of proton pump inhibitors and psychotropic drugs should be considered.

“Regarding baseline glucocorticoids use, the cutoff of 10 mg/day should be respected, considering the deleterious effect of higher dosage. Moreover, because of the lack of impact of inhaled or topical glucocorticoids, local routes should be preferred,” the authors wrote. “Conversely, our study brings reassuring data regarding the use of glucocorticoids for the management of immune-related adverse events, which did not alter ICI efficacy, confirming previous reports.”

The authors noted that the observational nature of the study does not allow any causal conclusion, adding that it remains unknown whether the effect of comedications “on cancer outcomes is thoroughly mediated by changes in microbiota or other immunomodulatory properties.”

Along with the retrospective design, study limitations included reporting bias and missing data on baseline comedications, specific prognostic factors and cancer outcomes.

The authors noted no conflicts of interest.

In patients with advanced cancer who are prescribed immune checkpoint inhibitors, comedications must be carefully assessed before patients start ICI therapy, most notably proton pump inhibitors, glucocorticoids, antibiotics, and psychotropic drugs.

“Our results confirm the detrimental impact on oncological outcomes of antibiotics and glucocorticoids at a dosage ≥10 mg/day when given within 1 month before or after ICI onset,” Marie Kostine, MD, of Bordeaux (France) University Hospital, and colleagues wrote in the European Journal of Cancer. “Moreover, we show that other comedications may significantly alter the antitumoral response of ICI, such as proton pump inhibitors, psychotropic drugs, morphine, aspirin, and insulin, whereas others seem to have no impact.”

While immune checkpoint inhibitors are transforming the treatment of advanced cancers, gut microbiota composition is an important determinant of response to ICIs. Antibiotic treatments are known to alter the gut microbiota. Other drugs, such as proton pump inhibitors, antidiabetic agents, aspirin, NSAIDs, glucocorticoids, immunomodulators, psychotropic drugs, and analgesics, have been associated with changes in microbiome composition. Since many patients with advanced cancer are exposed to such drugs, this study looked at the possible influence of these comedications on the antitumor effect and safety of ICIs.

The observational study included 635 patients with advanced cancer treated with ICIs between May 2015 and September 2017. Comedications given within 1 month before or 1 month after the first administration of an ICI were reviewed from medical records. Psychotropic drugs, proton pump inhibitors, ACE inhibitors and/or angiotensin II receptor blockers (ARBs), glucocorticoids, antibiotics, statins, and morphine were the most prescribed comedications.

Baseline use of antibiotics, glucocorticoids greater than 10 mg/day, proton pump inhibitors, psychotropic drugs, morphine, and insulin was associated with decreased overall survival and tumor response. However, the coadministration of statins, ACE inhibitors and/or ARBs, NSAIDs, aspirin, and oral diabetes drugs did not impact patient outcomes. Additionally, treatments that altered the response to ICIs were associated with a decreased incidence of immune-related adverse events.

“These results suggest some practical advice in a patient candidate to ICIs,” the authors wrote. “First, antibiotic treatment should be limited to documented infections,” and “withdrawal of proton pump inhibitors and psychotropic drugs should be considered.

“Regarding baseline glucocorticoids use, the cutoff of 10 mg/day should be respected, considering the deleterious effect of higher dosage. Moreover, because of the lack of impact of inhaled or topical glucocorticoids, local routes should be preferred,” the authors wrote. “Conversely, our study brings reassuring data regarding the use of glucocorticoids for the management of immune-related adverse events, which did not alter ICI efficacy, confirming previous reports.”

The authors noted that the observational nature of the study does not allow any causal conclusion, adding that it remains unknown whether the effect of comedications “on cancer outcomes is thoroughly mediated by changes in microbiota or other immunomodulatory properties.”

Along with the retrospective design, study limitations included reporting bias and missing data on baseline comedications, specific prognostic factors and cancer outcomes.

The authors noted no conflicts of interest.

New evidence points to the importance of helping mothers with their mental health during pregnancy.

Researchers from the National Institutes of Health in Bethesda, Md., have found that feelings of stress or depression while pregnant are linked to changes in the placenta where the child is growing. The findings, published in Epigenomics, show these changes could alter gene activity.

Stress and depression are not uncommon among expectant women, with depression affecting an estimated 1 in 10 pregnancies, according to the American College of Obstetricians and Gynecologists.

And current evidence already suggests that depression during pregnancy can negatively affect a child later in life. For instance, one study found that depression during pregnancy was linked to behavioral and emotional disorders during childhood, and another found that it raised the risk of depression at age 18.

To investigate stress and depression during pregnancy, the NIH investigators evaluated 301 pregnant women from 12 clinics in the United States who had taken part in an earlier clinical study. The group was ethnically diverse, with 34% identifying as Hispanic, 26% as non-Hispanic White, 24% as non-Hispanic Black, and 17% as Asian or Pacific Islander.

At the start of the study, the women were asked to complete questionnaires routinely used to screen for stress and depression. They completed the questionnaire five more times during their pregnancies. Shortly after each woman gave birth, researchers took tissue samples from the placenta and analyzed the genetics.

The purpose of studying the placenta, according to lead researcher Markos Tesfaye, MD, a postdoctoral fellow at the NIH, is that chemical changes can regulate whether a nearby gene can be activated.

There is evidence that chemical modifications in the placenta can lead to changes in fetal tissues, such as the brain, he said. And the placenta is known for making neurotransmitters, which are needed for fetal brain development.

The team found 16 areas where changes to the exterior of placental DNA were linked to depression in the second or third trimester. They also found two areas where these changes were associated with stress in the third trimester.

“Maternal depression leaves signals in the placenta at genes critical for fetal brain programming,” said study author Fasil Tekola-Ayele, PhD, from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Two of the chemical changes linked to depression were near genes that are known to be involved with fetal brain development and neurologic and psychiatric illnesses.

“The findings illustrate that the developing fetus is sensitive to the mother›s condition during pregnancy, including maternal symptoms of low mood and perceived stress,” said Thalia K. Robakis, MD, from the women’s mental health program at Icahn School of Medicine at Mount Sinai, New York, who was not involved in the study.

But Dr. Robakis cautioned that no clinical outcomes were measured among the babies born, meaning that the study could not document any effects of maternal depression and stress on fetal development. Rather, the work contributes to figuring out what mechanisms are involved.

“Pregnant women should continue to focus on optimizing their own physical and mental health,” Dr. Robakis said. “And they should know that a happy, healthy mother is the most important factor supporting the development of a happy, healthy baby.”

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

New evidence points to the importance of helping mothers with their mental health during pregnancy.

Researchers from the National Institutes of Health in Bethesda, Md., have found that feelings of stress or depression while pregnant are linked to changes in the placenta where the child is growing. The findings, published in Epigenomics, show these changes could alter gene activity.

Stress and depression are not uncommon among expectant women, with depression affecting an estimated 1 in 10 pregnancies, according to the American College of Obstetricians and Gynecologists.

And current evidence already suggests that depression during pregnancy can negatively affect a child later in life. For instance, one study found that depression during pregnancy was linked to behavioral and emotional disorders during childhood, and another found that it raised the risk of depression at age 18.

To investigate stress and depression during pregnancy, the NIH investigators evaluated 301 pregnant women from 12 clinics in the United States who had taken part in an earlier clinical study. The group was ethnically diverse, with 34% identifying as Hispanic, 26% as non-Hispanic White, 24% as non-Hispanic Black, and 17% as Asian or Pacific Islander.

At the start of the study, the women were asked to complete questionnaires routinely used to screen for stress and depression. They completed the questionnaire five more times during their pregnancies. Shortly after each woman gave birth, researchers took tissue samples from the placenta and analyzed the genetics.

The purpose of studying the placenta, according to lead researcher Markos Tesfaye, MD, a postdoctoral fellow at the NIH, is that chemical changes can regulate whether a nearby gene can be activated.

There is evidence that chemical modifications in the placenta can lead to changes in fetal tissues, such as the brain, he said. And the placenta is known for making neurotransmitters, which are needed for fetal brain development.

The team found 16 areas where changes to the exterior of placental DNA were linked to depression in the second or third trimester. They also found two areas where these changes were associated with stress in the third trimester.

“Maternal depression leaves signals in the placenta at genes critical for fetal brain programming,” said study author Fasil Tekola-Ayele, PhD, from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Two of the chemical changes linked to depression were near genes that are known to be involved with fetal brain development and neurologic and psychiatric illnesses.

“The findings illustrate that the developing fetus is sensitive to the mother›s condition during pregnancy, including maternal symptoms of low mood and perceived stress,” said Thalia K. Robakis, MD, from the women’s mental health program at Icahn School of Medicine at Mount Sinai, New York, who was not involved in the study.

But Dr. Robakis cautioned that no clinical outcomes were measured among the babies born, meaning that the study could not document any effects of maternal depression and stress on fetal development. Rather, the work contributes to figuring out what mechanisms are involved.

“Pregnant women should continue to focus on optimizing their own physical and mental health,” Dr. Robakis said. “And they should know that a happy, healthy mother is the most important factor supporting the development of a happy, healthy baby.”

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

New evidence points to the importance of helping mothers with their mental health during pregnancy.

Researchers from the National Institutes of Health in Bethesda, Md., have found that feelings of stress or depression while pregnant are linked to changes in the placenta where the child is growing. The findings, published in Epigenomics, show these changes could alter gene activity.

Stress and depression are not uncommon among expectant women, with depression affecting an estimated 1 in 10 pregnancies, according to the American College of Obstetricians and Gynecologists.

And current evidence already suggests that depression during pregnancy can negatively affect a child later in life. For instance, one study found that depression during pregnancy was linked to behavioral and emotional disorders during childhood, and another found that it raised the risk of depression at age 18.

To investigate stress and depression during pregnancy, the NIH investigators evaluated 301 pregnant women from 12 clinics in the United States who had taken part in an earlier clinical study. The group was ethnically diverse, with 34% identifying as Hispanic, 26% as non-Hispanic White, 24% as non-Hispanic Black, and 17% as Asian or Pacific Islander.

At the start of the study, the women were asked to complete questionnaires routinely used to screen for stress and depression. They completed the questionnaire five more times during their pregnancies. Shortly after each woman gave birth, researchers took tissue samples from the placenta and analyzed the genetics.

The purpose of studying the placenta, according to lead researcher Markos Tesfaye, MD, a postdoctoral fellow at the NIH, is that chemical changes can regulate whether a nearby gene can be activated.

There is evidence that chemical modifications in the placenta can lead to changes in fetal tissues, such as the brain, he said. And the placenta is known for making neurotransmitters, which are needed for fetal brain development.

The team found 16 areas where changes to the exterior of placental DNA were linked to depression in the second or third trimester. They also found two areas where these changes were associated with stress in the third trimester.

“Maternal depression leaves signals in the placenta at genes critical for fetal brain programming,” said study author Fasil Tekola-Ayele, PhD, from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Two of the chemical changes linked to depression were near genes that are known to be involved with fetal brain development and neurologic and psychiatric illnesses.

“The findings illustrate that the developing fetus is sensitive to the mother›s condition during pregnancy, including maternal symptoms of low mood and perceived stress,” said Thalia K. Robakis, MD, from the women’s mental health program at Icahn School of Medicine at Mount Sinai, New York, who was not involved in the study.

But Dr. Robakis cautioned that no clinical outcomes were measured among the babies born, meaning that the study could not document any effects of maternal depression and stress on fetal development. Rather, the work contributes to figuring out what mechanisms are involved.

“Pregnant women should continue to focus on optimizing their own physical and mental health,” Dr. Robakis said. “And they should know that a happy, healthy mother is the most important factor supporting the development of a happy, healthy baby.”

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

In this modern age of health care where telemedicine rules, conversational agents (CAs) that use text messaging systems are becoming a major mode of communication.

Many people are familiar with voice-enabled agents, such as Apple’s Siri, Google Now, and Microsoft’s Cortana. However, CAs come in different forms of complexity, ranging from a short message service–based texting platform to an embodied conversational agent (ECA).

ECAs allow participants to interact with a physical or graphical figure that simulates a person in appearance, behavior, and dialect. These are essentially virtual humans, or avatars, who talk with participants. By taking greater advantage of these automated agents, some have projected there may be $11 billion in combined cost savings across a variety of business sectors by 2023.¹ The health care field is one sector in which CAs can play an important role. Because of their accessibility, CAs have the potential to improve mental health by combating health care inequities and stigma, encouraging disclosure from participants, and serving as companions during the COVID-19 pandemic.

CAs provide accessible health care for rural, low socioeconomic status (SES), and minority communities in a variety of advantageous ways. For example, one study found that long-term use of a text-based agent that combines motivational interviewing and cognitive-behavioral therapy (CBT) can support smoking cessation in adolescents of low SES.²

CAs can help vulnerable participants advocate for themselves and proactively maintain their mental health through access to health care resources. In specific cases, these agents equalize health care treatment for different populations. Even though some participants live in secluded areas or are blocked by barriers, these text-based agents can still provide self-help intervention for them at any time on an individual basis, regardless of their location or socioeconomic status. Furthermore, they serve as highly cost-effective mental health promotion tools for large populations, some of which might not otherwise be reached by mental health care.

In combating mental illnesses such as depression and anxiety, studies have found that CAs are great treatment tools. For example, participants in an experimental group who received a self-help program based on CBT from a text-based CA named Woebot experienced significantly reduced depression symptoms when compared to the control group of participants, who received only information from a self-help electronic book.³ As a result, CAs might prove successful in treating younger populations who find online tools more feasible and accessible. Often, this population self-identifies depressive and anxiety symptoms without consulting a health care professional. Thus, this tool would prove useful to those who are bothered by the stigma of seeing a mental health professional.

Virtual human–based CAs also encourage participants to disclose more information in a nonjudgmental manner, especially among people with diseases with stigma. CAs use neutral languages, which may be helpful when dealing with stigmatized issues such as HIV, family planning, and abortion care because this heightens confidentiality and privacy. When participants believe that the agent does not “judge” or evaluate their capabilities, this elicits more sensitive information from them. For example, one study found that military service members who believed that they were interacting with a computer rather than a human operator reported lower fear of self-disclosure, displayed more sadness, and were rated by observers as more willing to disclose posttraumatic stress disorder symptoms.⁴ Additional findings show that participants prefer CAs when topics are highly sensitive and more likely to evoke negative self-admissions.

In what we hope will soon be a post–COVID-19 landscape of medicine, CAs are fast being used on the front lines of health care technology. Empathetic CAs can combat adverse effects of social exclusion during these pressing times. Etsuko Ishii, a researcher affiliated with the Hong Kong University of Science and Technology, and associates demonstrated that a virtual CA was as effective as a COVID-19 companion because it uses natural language processing (NLP) and nonverbal facial expressions to give users the feeling that they are being treated with empathy.⁵ While minimizing the number of in-person interactions that could potentially spread COVID-19, these agents promote virtual companionship that mirrors natural conversations and provide emotional support with psychological safety as participants express their pent-up thoughts. Not only do these agents help recover mood quickly, but they also have the power to overcome geographic barriers, be constantly available, and alleviate the high demand for mental health care. As a result, CAs have the potential to facilitate better communication and sustain social interactions within the isolated environment the pandemic has created.

CAs can predict, detect, and determine treatment solutions for mental health conditions based on behavioral insights. These agents’ natural language processing also allows them to be powerful therapeutic agents that can serve different communities, particularly for populations with limited access to medical resources. As the use of CAs becomes more integrated into telemedicine, their utility will continue to grow as their proven versatility in many situations expands the boundaries of health care technology.
 

Ms. Wong, a medical student at New York Institute of Technology College of Osteopathic Medicine in Old Westbury, conducts research related to mental health care services. She disclosed writing a telemental health software platform called Orchid. Dr. Vo, a board-certified psychiatrist, is the medical director of telehealth for the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia. She is a faculty member of the University of Pennsylvania, also in Philadelphia. Dr. Vo conducts digital health research focused on using automation and artificial intelligence for suicide risk screening and connecting patients to mental health care services. She disclosed serving as cofounder of Orchid.

References

1. Chatbots: Vendor opportunities & market forecasts 2020-2024. Juniper Research, 2020.

2. Simon P et al. On using chatbots to promote smoking cessation among adolescents of low socioeconomic status, Artificial Intelligence and Work: Association for the Advancement of Artificial Intelligence (AAAI) 2019 Fall Symposium, 2019.

3. Fitzpatrick KK et al. JMIR Mental Health. 2017;4(2):e19.

4. Lucas GM et al. Front Robot AI. 2017 Oct 12. doi: 10.3389/frobt.2017.00051.

5. Ishii E et al. ERICA: An empathetic android companion for COVID-19 quarantine. arXiv preprint arXiv:2106.02325.

In this modern age of health care where telemedicine rules, conversational agents (CAs) that use text messaging systems are becoming a major mode of communication.

Many people are familiar with voice-enabled agents, such as Apple’s Siri, Google Now, and Microsoft’s Cortana. However, CAs come in different forms of complexity, ranging from a short message service–based texting platform to an embodied conversational agent (ECA).

ECAs allow participants to interact with a physical or graphical figure that simulates a person in appearance, behavior, and dialect. These are essentially virtual humans, or avatars, who talk with participants. By taking greater advantage of these automated agents, some have projected there may be $11 billion in combined cost savings across a variety of business sectors by 2023.¹ The health care field is one sector in which CAs can play an important role. Because of their accessibility, CAs have the potential to improve mental health by combating health care inequities and stigma, encouraging disclosure from participants, and serving as companions during the COVID-19 pandemic.

CAs provide accessible health care for rural, low socioeconomic status (SES), and minority communities in a variety of advantageous ways. For example, one study found that long-term use of a text-based agent that combines motivational interviewing and cognitive-behavioral therapy (CBT) can support smoking cessation in adolescents of low SES.²

CAs can help vulnerable participants advocate for themselves and proactively maintain their mental health through access to health care resources. In specific cases, these agents equalize health care treatment for different populations. Even though some participants live in secluded areas or are blocked by barriers, these text-based agents can still provide self-help intervention for them at any time on an individual basis, regardless of their location or socioeconomic status. Furthermore, they serve as highly cost-effective mental health promotion tools for large populations, some of which might not otherwise be reached by mental health care.

In combating mental illnesses such as depression and anxiety, studies have found that CAs are great treatment tools. For example, participants in an experimental group who received a self-help program based on CBT from a text-based CA named Woebot experienced significantly reduced depression symptoms when compared to the control group of participants, who received only information from a self-help electronic book.³ As a result, CAs might prove successful in treating younger populations who find online tools more feasible and accessible. Often, this population self-identifies depressive and anxiety symptoms without consulting a health care professional. Thus, this tool would prove useful to those who are bothered by the stigma of seeing a mental health professional.

Virtual human–based CAs also encourage participants to disclose more information in a nonjudgmental manner, especially among people with diseases with stigma. CAs use neutral languages, which may be helpful when dealing with stigmatized issues such as HIV, family planning, and abortion care because this heightens confidentiality and privacy. When participants believe that the agent does not “judge” or evaluate their capabilities, this elicits more sensitive information from them. For example, one study found that military service members who believed that they were interacting with a computer rather than a human operator reported lower fear of self-disclosure, displayed more sadness, and were rated by observers as more willing to disclose posttraumatic stress disorder symptoms.⁴ Additional findings show that participants prefer CAs when topics are highly sensitive and more likely to evoke negative self-admissions.

In what we hope will soon be a post–COVID-19 landscape of medicine, CAs are fast being used on the front lines of health care technology. Empathetic CAs can combat adverse effects of social exclusion during these pressing times. Etsuko Ishii, a researcher affiliated with the Hong Kong University of Science and Technology, and associates demonstrated that a virtual CA was as effective as a COVID-19 companion because it uses natural language processing (NLP) and nonverbal facial expressions to give users the feeling that they are being treated with empathy.⁵ While minimizing the number of in-person interactions that could potentially spread COVID-19, these agents promote virtual companionship that mirrors natural conversations and provide emotional support with psychological safety as participants express their pent-up thoughts. Not only do these agents help recover mood quickly, but they also have the power to overcome geographic barriers, be constantly available, and alleviate the high demand for mental health care. As a result, CAs have the potential to facilitate better communication and sustain social interactions within the isolated environment the pandemic has created.

CAs can predict, detect, and determine treatment solutions for mental health conditions based on behavioral insights. These agents’ natural language processing also allows them to be powerful therapeutic agents that can serve different communities, particularly for populations with limited access to medical resources. As the use of CAs becomes more integrated into telemedicine, their utility will continue to grow as their proven versatility in many situations expands the boundaries of health care technology.
 

Ms. Wong, a medical student at New York Institute of Technology College of Osteopathic Medicine in Old Westbury, conducts research related to mental health care services. She disclosed writing a telemental health software platform called Orchid. Dr. Vo, a board-certified psychiatrist, is the medical director of telehealth for the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia. She is a faculty member of the University of Pennsylvania, also in Philadelphia. Dr. Vo conducts digital health research focused on using automation and artificial intelligence for suicide risk screening and connecting patients to mental health care services. She disclosed serving as cofounder of Orchid.

References

1. Chatbots: Vendor opportunities & market forecasts 2020-2024. Juniper Research, 2020.

2. Simon P et al. On using chatbots to promote smoking cessation among adolescents of low socioeconomic status, Artificial Intelligence and Work: Association for the Advancement of Artificial Intelligence (AAAI) 2019 Fall Symposium, 2019.

3. Fitzpatrick KK et al. JMIR Mental Health. 2017;4(2):e19.

4. Lucas GM et al. Front Robot AI. 2017 Oct 12. doi: 10.3389/frobt.2017.00051.

5. Ishii E et al. ERICA: An empathetic android companion for COVID-19 quarantine. arXiv preprint arXiv:2106.02325.

In this modern age of health care where telemedicine rules, conversational agents (CAs) that use text messaging systems are becoming a major mode of communication.

Many people are familiar with voice-enabled agents, such as Apple’s Siri, Google Now, and Microsoft’s Cortana. However, CAs come in different forms of complexity, ranging from a short message service–based texting platform to an embodied conversational agent (ECA).

ECAs allow participants to interact with a physical or graphical figure that simulates a person in appearance, behavior, and dialect. These are essentially virtual humans, or avatars, who talk with participants. By taking greater advantage of these automated agents, some have projected there may be $11 billion in combined cost savings across a variety of business sectors by 2023.¹ The health care field is one sector in which CAs can play an important role. Because of their accessibility, CAs have the potential to improve mental health by combating health care inequities and stigma, encouraging disclosure from participants, and serving as companions during the COVID-19 pandemic.

CAs provide accessible health care for rural, low socioeconomic status (SES), and minority communities in a variety of advantageous ways. For example, one study found that long-term use of a text-based agent that combines motivational interviewing and cognitive-behavioral therapy (CBT) can support smoking cessation in adolescents of low SES.²

CAs can help vulnerable participants advocate for themselves and proactively maintain their mental health through access to health care resources. In specific cases, these agents equalize health care treatment for different populations. Even though some participants live in secluded areas or are blocked by barriers, these text-based agents can still provide self-help intervention for them at any time on an individual basis, regardless of their location or socioeconomic status. Furthermore, they serve as highly cost-effective mental health promotion tools for large populations, some of which might not otherwise be reached by mental health care.

In combating mental illnesses such as depression and anxiety, studies have found that CAs are great treatment tools. For example, participants in an experimental group who received a self-help program based on CBT from a text-based CA named Woebot experienced significantly reduced depression symptoms when compared to the control group of participants, who received only information from a self-help electronic book.³ As a result, CAs might prove successful in treating younger populations who find online tools more feasible and accessible. Often, this population self-identifies depressive and anxiety symptoms without consulting a health care professional. Thus, this tool would prove useful to those who are bothered by the stigma of seeing a mental health professional.

Virtual human–based CAs also encourage participants to disclose more information in a nonjudgmental manner, especially among people with diseases with stigma. CAs use neutral languages, which may be helpful when dealing with stigmatized issues such as HIV, family planning, and abortion care because this heightens confidentiality and privacy. When participants believe that the agent does not “judge” or evaluate their capabilities, this elicits more sensitive information from them. For example, one study found that military service members who believed that they were interacting with a computer rather than a human operator reported lower fear of self-disclosure, displayed more sadness, and were rated by observers as more willing to disclose posttraumatic stress disorder symptoms.⁴ Additional findings show that participants prefer CAs when topics are highly sensitive and more likely to evoke negative self-admissions.

In what we hope will soon be a post–COVID-19 landscape of medicine, CAs are fast being used on the front lines of health care technology. Empathetic CAs can combat adverse effects of social exclusion during these pressing times. Etsuko Ishii, a researcher affiliated with the Hong Kong University of Science and Technology, and associates demonstrated that a virtual CA was as effective as a COVID-19 companion because it uses natural language processing (NLP) and nonverbal facial expressions to give users the feeling that they are being treated with empathy.⁵ While minimizing the number of in-person interactions that could potentially spread COVID-19, these agents promote virtual companionship that mirrors natural conversations and provide emotional support with psychological safety as participants express their pent-up thoughts. Not only do these agents help recover mood quickly, but they also have the power to overcome geographic barriers, be constantly available, and alleviate the high demand for mental health care. As a result, CAs have the potential to facilitate better communication and sustain social interactions within the isolated environment the pandemic has created.

CAs can predict, detect, and determine treatment solutions for mental health conditions based on behavioral insights. These agents’ natural language processing also allows them to be powerful therapeutic agents that can serve different communities, particularly for populations with limited access to medical resources. As the use of CAs becomes more integrated into telemedicine, their utility will continue to grow as their proven versatility in many situations expands the boundaries of health care technology.
 

Ms. Wong, a medical student at New York Institute of Technology College of Osteopathic Medicine in Old Westbury, conducts research related to mental health care services. She disclosed writing a telemental health software platform called Orchid. Dr. Vo, a board-certified psychiatrist, is the medical director of telehealth for the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia. She is a faculty member of the University of Pennsylvania, also in Philadelphia. Dr. Vo conducts digital health research focused on using automation and artificial intelligence for suicide risk screening and connecting patients to mental health care services. She disclosed serving as cofounder of Orchid.

References

1. Chatbots: Vendor opportunities & market forecasts 2020-2024. Juniper Research, 2020.

2. Simon P et al. On using chatbots to promote smoking cessation among adolescents of low socioeconomic status, Artificial Intelligence and Work: Association for the Advancement of Artificial Intelligence (AAAI) 2019 Fall Symposium, 2019.

3. Fitzpatrick KK et al. JMIR Mental Health. 2017;4(2):e19.

4. Lucas GM et al. Front Robot AI. 2017 Oct 12. doi: 10.3389/frobt.2017.00051.

5. Ishii E et al. ERICA: An empathetic android companion for COVID-19 quarantine. arXiv preprint arXiv:2106.02325.

At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.

This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
 

Augmenting exposure therapy

How did you begin using artificial intelligence as a way of delivering exposure therapy?

Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.

Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.

Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.

Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
 

When did you begin researching augmented reality as a clinical tool?

I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.

I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.

We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.

Initially, we had a company create the software for us, but we’ve since brought all the programming inside.

The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
 

Virtual phobias, real fear

A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.

Like a lie detector test?

Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.

We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.

With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.

Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.

When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.

In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.

Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.

Everybody who got the treatment was able to touch the tank containing the tarantula. It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
 

That’s pretty effective.

It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.

Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.

After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
 

Treating PTSD in first responders

Did you start with spiders and dogs because those are common fears?

We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.

I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.

After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.

We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.

We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.

They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.

There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.

Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.

Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
 

What else is next for you and your group?

The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.

We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.

There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.

Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
 

Last question: Do you actually interact with Tony, the tarantula?

Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.

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

At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.

This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
 

Augmenting exposure therapy

How did you begin using artificial intelligence as a way of delivering exposure therapy?

Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.

Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.

Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.

Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
 

When did you begin researching augmented reality as a clinical tool?

I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.

I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.

We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.

Initially, we had a company create the software for us, but we’ve since brought all the programming inside.

The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
 

Virtual phobias, real fear

A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.

Like a lie detector test?

Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.

We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.

With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.

Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.

When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.

In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.

Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.

Everybody who got the treatment was able to touch the tank containing the tarantula. It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
 

That’s pretty effective.

It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.

Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.

After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
 

Treating PTSD in first responders

Did you start with spiders and dogs because those are common fears?

We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.

I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.

After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.

We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.

We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.

They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.

There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.

Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.

Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
 

What else is next for you and your group?

The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.

We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.

There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.

Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
 

Last question: Do you actually interact with Tony, the tarantula?

Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.

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

At Wayne State University’s Stress, Trauma, and Anxiety Research Clinic (STARC) in Michigan, researchers are developing novel interventions for treating some very ancient phobias hardwired into the human brain. By using augmented reality as means of conducting exposure therapy, STARC researchers – including Shantanu Madaboosi, Rakesh Ramaswamy, and Lana Grasser – and STARC director Arash Javanbakht, MD, have produced compelling evidence that they can free patients of their often debilitating fears of spiders, dogs, and snakes. Yet their work doesn’t stop there, and research into treating anxiety and posttraumatic stress disorder among first responders and others with high-stress occupations is ongoing.

This news organization spoke with Dr. Javanbakht, a psychiatrist, about the technological advances that have made this work possible; the future of remote-based psychiatry; and his tarantula colleague, Tony.
 

Augmenting exposure therapy

How did you begin using artificial intelligence as a way of delivering exposure therapy?

Exposure therapy is a very effective treatment for phobias, obsessive-compulsive disorder, and PTSD. But the problem we had is that, if someone comes to me and says they’re afraid of dogs, snakes, or spiders, I don’t have those in my office. Or, if its social phobia, I can’t create those scenarios. So, despite being such an effective treatment, it’s not utilized as much as it should be.

Several years ago, I saw a TED talk by the CEO of an augmented reality company who happened to be a neuroscientist. I thought the concept was amazing, because it offered a way to overcome those limitations.

Mixed augmented reality allows us to bring all those feared objects to the clinic. I can bring my Labrador to the office for someone who’s afraid of dogs, and they can get the exposure to that one dog. But we know good exposure therapy needs to be generalizable, with as many different breeds of dogs as possible, and is context dependent. If the patient sees a dog in their neighborhood, their fear response may come back. Doing it in a real-life context, and offering as many contexts as possible, makes it more effective.

Augmented reality allows all of these options because you can have as many different types of virtual objects as you want, and the difference between augmented reality and virtual reality is that augmented reality happens in a real-life context. You wear the goggles and you can walk around the environment and track the object, so the context is more realistic.
 

When did you begin researching augmented reality as a clinical tool?

I became a faculty member here in 2015, right out of my residency training, and I think it was around 2016 or 2017 that we began this work.

I’m very much involved in exposure therapy, utilize it myself, train others, and research how it works and changes the brain. I knew the ins and outs and what would make a better exposure therapy, based on my knowledge of neuroscience.

We spend time thinking about how we can apply these neuroscientific principles in software that can also be easily used by a not very technologically savvy therapist. Because that has been a big barrier when it comes to technology and human use in medicine.

Initially, we had a company create the software for us, but we’ve since brought all the programming inside.

The cool thing about these augmented reality devices is that they have excellent surface mapping. As soon as the person wears the goggles, it automatically maps the surfaces and provides a 3D view of the patient’s environment on the therapist’s computer. Say you’re treating a patient with a fear of spiders. Through drop-down menus, the therapist can choose what type of spider, its color and size, where it should be placed, and the motion. I can choose to move the spider from 6 feet away on the floor to the walls to the ceiling.
 

Virtual phobias, real fear

A big question for a lot of people was if the spiders are virtual, will they be scary, because it has to be realistic enough to create a fear response for the therapy to work. We use a couple of wires that you can put on a person’s finger and hook them up to a tablet or a cell phone. This provides an online measure of a person’s autonomic sympathetic response.

Like a lie detector test?

Exactly. We put that on their fingers and exposed them to a real-life tarantula and to our virtual tarantulas, and the fear response was no different. That means these do create an objective fear reaction in the body.

We also had people who said, “I know this is not real. I won’t be scared.” And when we started the therapy, it was with a tiny spider 5 meters away from them, and they’d lift their legs off the floor.

With the treatment, we’d come to one room and start with a very little spider, far from them. Then gradually we move them up to bigger, more diverse types of spiders, which are moving around. The patient comes near and tries to touch them.

Then at some point, I’d put a spiderweb on the door, put a few spiders on that, open the door, and have the patient walk through it. They kept walking through this spiderweb.

When they were desensitized to these spiders in this context – and as I said, context is important – we’d go to another room. This was darker, more like a basement, and we’d continue the same thing. That would actually take much less time because they already had desensitized a lot.

In our field, sense of control is very important, especially for when a patient goes home. So at the end, I’d leave the room and talk to the patient via a baby monitor. The patient was surrounded by 20 tarantulas, without the prompt moving around the environment.

Now that they’re desensitized to my virtual spiders, the question is, how would that apply to a real spider? So, we had a real live tarantula, whose name was Tony Stark, because we’re the STARC lab. We’d put Tony at the end of a long hallway before the treatment and see how close the patients could get to him.

Everybody who got the treatment was able to touch the tank containing the tarantula. It was only one treatment session; nobody’s was longer than 1 hour, and the average treatment time was 38 minutes.
 

That’s pretty effective.

It’s pretty good, compared with other studies. And I believe this is because of all the components I mentioned: being able to use your real environment; combining it with the real tarantula; the variety of the types of the feared objects; and, of course, giving the patient a sense of autonomy at the end.

Then we had to see how prolonged the effects are. We had them come in 1 week and 1 month after the treatment. I’d remind them of the principles of good exposure therapy and ask them to keep practicing at home between the sessions, looking at pictures and videos. But we never tested who did or did not do it.

After 1 week and 1 month, the effects were either the same or better. A larger number of people at 1 month were able to touch the tarantula than right after treatment.
 

Treating PTSD in first responders

Did you start with spiders and dogs because those are common fears?

We started with spiders because that worked with the initial goal of creating a prototype. Spiders’ behavior is simple enough for the programming, which takes a lot of time. Another reason for choosing spiders was that we had a lot of other studies of real and virtual reality exposure therapy to compare against.

I think another reason for our success is that, when you do real exposure therapy, you have just one scared tarantula in the corner of their tank, and they don’t listen to you. But my spiders listen to me and do exactly what I tell them.

After our initial success, we obtained more funds to expand it to other phobias. The cool thing is that we don’t need separate software for different phobias. You can choose dogs or snakes, add it to the person’s environment, and decide their behaviors.

We just started a clinical trial using dogs, and another group in Turkey is running a clinical trial with dogs. Eastern Michigan University is working with spiders. And a clinic at the University of Nebraska Medical Center is going to start using them in real-world clinics, not for research.

We have another project whose goal is helping reduce the impact of trauma and also treating PTSD in first responders, who are exposed to a lot of horrible things. Rates of PTSD are around 20%-30% among cops, firefighters, and EMS personnel.

They commonly find it very painful being in crowds because the fight-or-flight instinct in the brain is constantly screening for any sign of threat in their environment. We’re working on them walking into an empty room wearing the goggles, and then their therapist can scale the stimulus up and down.

There’ll be two people in front of you talking to each other, and then another group comes in, and people get louder. People can look at you and talk to you. There’s kids running, Fourth of July fireworks, and other things that might bother someone who’s been involved in gun- or explosion-related traumas. You gradually scale up when the person is next to their therapist.

Another thing we’re doing is related to cardiopulmonary resuscitation. If a young person dies in a CPR situation, that is really painful and traumatic. So, for exposure therapy to that, we’re creating a difficult CPR scenario when that person may die. The responder wears the goggles and basically watches a group of people doing CPR while standing next to a therapist who can help them navigate it and then scale it off.

Another goal is combining this with telemedicine, where the person can do it in their real-life environment. Imagine a person with military trauma. You can put them back in the barracks, connected with their psychiatrists via telemedicine. Then we would put humans in military fatigues near them and have them interact with them to feel comfortable with that situation.
 

What else is next for you and your group?

The next biggest challenge that we’re tackling is PTSD, because of course creating human-encounter scenarios is much more complicated than spiders and dogs. We’re in the midst of developing this so we can basically bring it to people’s homes.

We’ve been working with some military personnel to see if we can basically give a device to a veteran with PTSD, so they can go home and practice on their own.

There’s another possibility for training. Let’s take the example of a police force, which can have a lot of difficulties and mistakes because of lack of exposure and training. They can wear these goggles, get fully geared up, and be placed in encounters with people of different backgrounds, of different severity, with people who could be severely mentally ill or present different challenges for the officers.

Those situations can teach them a lot. I’m the creator of this thing, but even I’m often surprised by how realistic this technology can be. I find myself interacting with avatars the same way I would if they were real humans. I actually had one of my colleagues, when we started launching the programming with the dogs, immediately jump back. It’s just like the animal brain reacts to them.
 

Last question: Do you actually interact with Tony, the tarantula?

Oh, Tony is my friend. Unfortunately, he’s not with our lab at this moment. He’s on a sabbatical at Eastern Michigan University for their clinical trials. But yes, I’ve held him. He’s very friendly.

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

Misuse of buprenorphine in the United States by patients with opioid use disorder (OUD) dropped sharply between 2015 and 2019, new research shows.

Analyses of data from the National Survey on Drug Use and Health also showed that about 50% of the patients with OUD were not receiving substance use treatment – and that some may be misusing buprenorphine in an effort to self-treat their addiction.

Interestingly, there was no association between buprenorphine misuse and income among those with OUD or with race, ethnicity, or insurance status regardless of OUD status, which bucks commonly held perceptions of those with the disorder.

Overall, the findings “underscore the need to pursue actions that expand access to buprenorphine-based OUD treatment, to develop strategies to monitor and reduce buprenorphine misuse, and to address associated conditions,” the investigators, led by Beth Han, MD, PhD, National Institute on Drug Abuse (NIDA), write.

The study was published online October 15 in JAMA Network Open.
 

Opioid deaths

Centers for Disease Control and Prevention data show more than 93,000 individuals in the United States died from a drug overdose in 2020, a 29.4% increase from the previous year. Of those deaths, 69,710 involved opioids.

Buprenorphine, a medication approved by the U.S. Food and Drug Administration to treat OUD, has been shown to reduce opioid cravings and withdrawal symptoms and lower overdose risk.

The new survey included responses from 214,505 adults. Of these, 51.7% were women, 45.5% were age 50 years or older, and 63.9% were non-Hispanic White.

Responses were collected between 2015-2019 as part of an annual survey administered annually by the Substance Abuse and Mental Health Services Administration.

Misuse was defined as any use outside the prescribed amount, frequency, duration, or indication.

In 2019, hydrocodone, oxycodone, codeine, and tramadol were the most misused prescription opioid products. An estimated 2.4 million adults used buprenorphine, with 1.7 million reporting no misuse in the past 12 months.

While buprenorphine misuse was stable between 2015 and 2019 among individuals without OUD, misuse declined significantly among those with OUD – from 20.5% in 2015 to 15.9% in 2019 (P = .04).
 

A different picture of misuse

The demographic data reveals a picture of buprenorphine misuse that researchers note is quite different from common perceptions about people with substance use.

Those with OUD who misused buprenorphine were more likely to be non-Hispanic White (82.9% vs. 73.6%, respectively) and less likely to live in large metropolitan areas (47.7% vs. 58.1%).

Among participants with OUD, buprenorphine misuse was significantly associated with age, especially in those between 24 and 34 years (adjusted odds ratio [aOR], 2.9; 95% confidence interval, 1.4-5.8) and between 35 and 49 years (aOR, 2.3; 95% CI, 1.2-4.5).

It was also significantly associated with living in nonmetropolitan areas (aOR, 1.8; 95% CI, 1.0-3.0) and having past-year polysubstance use and use disorders (aOR, 3.9; 95% CI, 1.3-11.2); but negatively associated with past-year treatment for illicit drug use–only treatment (aOR, 0.4; 95% CI, 0.3-0.7).

There was no significant association between buprenorphine misuse and income in participants with OUD or with race, ethnicity, or insurance status, regardless of OUD status.

“Perceptions that persons of racial and ethnic minority groups and people living in poverty are more likely to misuse their medication are incorrect,” the researchers write.

“Nevertheless, these factors have been found to be important factors associated with opioid harms and receipt of buprenorphine treatment,” they add.

Between 2015 and 2017, the largest increase in opioid-related drug overdose deaths was among Black people aged 25 to 34, and the largest increase involving synthetic opioids was among Hispanic individuals aged 45 to 54. At the same time, White people were more likely to receive buprenorphine treatment for OUD.
 

‘Don’t exaggerate concerns’

Among survey participants with OUD, 57% of those who had misused buprenorphine in the past year had received no substance use treatment. Among those with OUD who had not misused the drug in the past year, 49% had received no treatment for their addiction.

The most common reason for buprenorphine misuse cited by those with OUD was “because I am hooked” (27.3%), which researchers said suggests people may be taking buprenorphine without a prescription to self-treat their OUD.

The investigators note that although buprenorphine is inexpensive and effective, clinicians currently must receive a federal waiver to prescribe it to more than 30 patients at a time.

Concern over potential misuse may be one reason some clinicians have been reluctant to complete the training process. However, the study results showed misuse rates of other opioids, including oxycodone and hydrocodone, were higher than those reported for buprenorphine.

“Many other prescription opioids are misused at much higher rates,” co-investigator Wilson Compton, MD, MPE, deputy director of NIDA, told this news organization.

“While there are concerns about all of them, we want to make sure that people don’t exaggerate the concerns – and understanding that oxycodone and hydrocodone are so much more frequently misused is important,” added Dr. Compton.
 

Symptom of inadequate access?

Commenting on the research, Bobby Mukkamala, MD, chair of the American Medical Association Board of Trustees, said individuals who misuse buprenorphine “commonly do so to alleviate uncontrolled pain or symptoms of withdrawal.”

“So-called misuse of buprenorphine is a symptom of inadequate access to physicians to treat opioid use disorder,” said Dr. Mukkamala, who also chairs the AMA Substance Use and Pain Care Task Force.

A 2020 study from the U.S. Department of Health & Human Services showed 40% of U.S. counties have no clinicians with a federal waiver permitting them to prescribe buprenorphine in an office setting.

In April, the HHS released new practice guidelines that allow certain practitioners licensed under state law who have a valid Drug Enforcement Administration registration to treat up to 30 patients with buprenorphine without having to complete requirements related to training, counseling, and other ancillary services known as an “X-waiver.”

The move was welcomed by many in the field, but Dr. Mukkamala said the agency did not go far enough.

“The AMA supports removing the federal X-waiver requirement to help destigmatize the provision of buprenorphine as well as remove the many administrative barriers that come with the federal requirement,” he said.

The study was funded by the National Institute on Drug Abuse. The study authors have disclosed no relevant financial relationships.

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

Misuse of buprenorphine in the United States by patients with opioid use disorder (OUD) dropped sharply between 2015 and 2019, new research shows.

Analyses of data from the National Survey on Drug Use and Health also showed that about 50% of the patients with OUD were not receiving substance use treatment – and that some may be misusing buprenorphine in an effort to self-treat their addiction.

Interestingly, there was no association between buprenorphine misuse and income among those with OUD or with race, ethnicity, or insurance status regardless of OUD status, which bucks commonly held perceptions of those with the disorder.

Overall, the findings “underscore the need to pursue actions that expand access to buprenorphine-based OUD treatment, to develop strategies to monitor and reduce buprenorphine misuse, and to address associated conditions,” the investigators, led by Beth Han, MD, PhD, National Institute on Drug Abuse (NIDA), write.

The study was published online October 15 in JAMA Network Open.
 

Opioid deaths

Centers for Disease Control and Prevention data show more than 93,000 individuals in the United States died from a drug overdose in 2020, a 29.4% increase from the previous year. Of those deaths, 69,710 involved opioids.

Buprenorphine, a medication approved by the U.S. Food and Drug Administration to treat OUD, has been shown to reduce opioid cravings and withdrawal symptoms and lower overdose risk.

The new survey included responses from 214,505 adults. Of these, 51.7% were women, 45.5% were age 50 years or older, and 63.9% were non-Hispanic White.

Responses were collected between 2015-2019 as part of an annual survey administered annually by the Substance Abuse and Mental Health Services Administration.

Misuse was defined as any use outside the prescribed amount, frequency, duration, or indication.

In 2019, hydrocodone, oxycodone, codeine, and tramadol were the most misused prescription opioid products. An estimated 2.4 million adults used buprenorphine, with 1.7 million reporting no misuse in the past 12 months.

While buprenorphine misuse was stable between 2015 and 2019 among individuals without OUD, misuse declined significantly among those with OUD – from 20.5% in 2015 to 15.9% in 2019 (P = .04).
 

A different picture of misuse

The demographic data reveals a picture of buprenorphine misuse that researchers note is quite different from common perceptions about people with substance use.

Those with OUD who misused buprenorphine were more likely to be non-Hispanic White (82.9% vs. 73.6%, respectively) and less likely to live in large metropolitan areas (47.7% vs. 58.1%).

Among participants with OUD, buprenorphine misuse was significantly associated with age, especially in those between 24 and 34 years (adjusted odds ratio [aOR], 2.9; 95% confidence interval, 1.4-5.8) and between 35 and 49 years (aOR, 2.3; 95% CI, 1.2-4.5).

It was also significantly associated with living in nonmetropolitan areas (aOR, 1.8; 95% CI, 1.0-3.0) and having past-year polysubstance use and use disorders (aOR, 3.9; 95% CI, 1.3-11.2); but negatively associated with past-year treatment for illicit drug use–only treatment (aOR, 0.4; 95% CI, 0.3-0.7).

There was no significant association between buprenorphine misuse and income in participants with OUD or with race, ethnicity, or insurance status, regardless of OUD status.

“Perceptions that persons of racial and ethnic minority groups and people living in poverty are more likely to misuse their medication are incorrect,” the researchers write.

“Nevertheless, these factors have been found to be important factors associated with opioid harms and receipt of buprenorphine treatment,” they add.

Between 2015 and 2017, the largest increase in opioid-related drug overdose deaths was among Black people aged 25 to 34, and the largest increase involving synthetic opioids was among Hispanic individuals aged 45 to 54. At the same time, White people were more likely to receive buprenorphine treatment for OUD.
 

‘Don’t exaggerate concerns’

Among survey participants with OUD, 57% of those who had misused buprenorphine in the past year had received no substance use treatment. Among those with OUD who had not misused the drug in the past year, 49% had received no treatment for their addiction.

The most common reason for buprenorphine misuse cited by those with OUD was “because I am hooked” (27.3%), which researchers said suggests people may be taking buprenorphine without a prescription to self-treat their OUD.

The investigators note that although buprenorphine is inexpensive and effective, clinicians currently must receive a federal waiver to prescribe it to more than 30 patients at a time.

Concern over potential misuse may be one reason some clinicians have been reluctant to complete the training process. However, the study results showed misuse rates of other opioids, including oxycodone and hydrocodone, were higher than those reported for buprenorphine.

“Many other prescription opioids are misused at much higher rates,” co-investigator Wilson Compton, MD, MPE, deputy director of NIDA, told this news organization.

“While there are concerns about all of them, we want to make sure that people don’t exaggerate the concerns – and understanding that oxycodone and hydrocodone are so much more frequently misused is important,” added Dr. Compton.
 

Symptom of inadequate access?

Commenting on the research, Bobby Mukkamala, MD, chair of the American Medical Association Board of Trustees, said individuals who misuse buprenorphine “commonly do so to alleviate uncontrolled pain or symptoms of withdrawal.”

“So-called misuse of buprenorphine is a symptom of inadequate access to physicians to treat opioid use disorder,” said Dr. Mukkamala, who also chairs the AMA Substance Use and Pain Care Task Force.

A 2020 study from the U.S. Department of Health & Human Services showed 40% of U.S. counties have no clinicians with a federal waiver permitting them to prescribe buprenorphine in an office setting.

In April, the HHS released new practice guidelines that allow certain practitioners licensed under state law who have a valid Drug Enforcement Administration registration to treat up to 30 patients with buprenorphine without having to complete requirements related to training, counseling, and other ancillary services known as an “X-waiver.”

The move was welcomed by many in the field, but Dr. Mukkamala said the agency did not go far enough.

“The AMA supports removing the federal X-waiver requirement to help destigmatize the provision of buprenorphine as well as remove the many administrative barriers that come with the federal requirement,” he said.

The study was funded by the National Institute on Drug Abuse. The study authors have disclosed no relevant financial relationships.

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

Misuse of buprenorphine in the United States by patients with opioid use disorder (OUD) dropped sharply between 2015 and 2019, new research shows.

Analyses of data from the National Survey on Drug Use and Health also showed that about 50% of the patients with OUD were not receiving substance use treatment – and that some may be misusing buprenorphine in an effort to self-treat their addiction.

Interestingly, there was no association between buprenorphine misuse and income among those with OUD or with race, ethnicity, or insurance status regardless of OUD status, which bucks commonly held perceptions of those with the disorder.

Overall, the findings “underscore the need to pursue actions that expand access to buprenorphine-based OUD treatment, to develop strategies to monitor and reduce buprenorphine misuse, and to address associated conditions,” the investigators, led by Beth Han, MD, PhD, National Institute on Drug Abuse (NIDA), write.

The study was published online October 15 in JAMA Network Open.
 

Opioid deaths

Centers for Disease Control and Prevention data show more than 93,000 individuals in the United States died from a drug overdose in 2020, a 29.4% increase from the previous year. Of those deaths, 69,710 involved opioids.

Buprenorphine, a medication approved by the U.S. Food and Drug Administration to treat OUD, has been shown to reduce opioid cravings and withdrawal symptoms and lower overdose risk.

The new survey included responses from 214,505 adults. Of these, 51.7% were women, 45.5% were age 50 years or older, and 63.9% were non-Hispanic White.

Responses were collected between 2015-2019 as part of an annual survey administered annually by the Substance Abuse and Mental Health Services Administration.

Misuse was defined as any use outside the prescribed amount, frequency, duration, or indication.

In 2019, hydrocodone, oxycodone, codeine, and tramadol were the most misused prescription opioid products. An estimated 2.4 million adults used buprenorphine, with 1.7 million reporting no misuse in the past 12 months.

While buprenorphine misuse was stable between 2015 and 2019 among individuals without OUD, misuse declined significantly among those with OUD – from 20.5% in 2015 to 15.9% in 2019 (P = .04).
 

A different picture of misuse

The demographic data reveals a picture of buprenorphine misuse that researchers note is quite different from common perceptions about people with substance use.

Those with OUD who misused buprenorphine were more likely to be non-Hispanic White (82.9% vs. 73.6%, respectively) and less likely to live in large metropolitan areas (47.7% vs. 58.1%).

Among participants with OUD, buprenorphine misuse was significantly associated with age, especially in those between 24 and 34 years (adjusted odds ratio [aOR], 2.9; 95% confidence interval, 1.4-5.8) and between 35 and 49 years (aOR, 2.3; 95% CI, 1.2-4.5).

It was also significantly associated with living in nonmetropolitan areas (aOR, 1.8; 95% CI, 1.0-3.0) and having past-year polysubstance use and use disorders (aOR, 3.9; 95% CI, 1.3-11.2); but negatively associated with past-year treatment for illicit drug use–only treatment (aOR, 0.4; 95% CI, 0.3-0.7).

There was no significant association between buprenorphine misuse and income in participants with OUD or with race, ethnicity, or insurance status, regardless of OUD status.

“Perceptions that persons of racial and ethnic minority groups and people living in poverty are more likely to misuse their medication are incorrect,” the researchers write.

“Nevertheless, these factors have been found to be important factors associated with opioid harms and receipt of buprenorphine treatment,” they add.

Between 2015 and 2017, the largest increase in opioid-related drug overdose deaths was among Black people aged 25 to 34, and the largest increase involving synthetic opioids was among Hispanic individuals aged 45 to 54. At the same time, White people were more likely to receive buprenorphine treatment for OUD.
 

‘Don’t exaggerate concerns’

Among survey participants with OUD, 57% of those who had misused buprenorphine in the past year had received no substance use treatment. Among those with OUD who had not misused the drug in the past year, 49% had received no treatment for their addiction.

The most common reason for buprenorphine misuse cited by those with OUD was “because I am hooked” (27.3%), which researchers said suggests people may be taking buprenorphine without a prescription to self-treat their OUD.

The investigators note that although buprenorphine is inexpensive and effective, clinicians currently must receive a federal waiver to prescribe it to more than 30 patients at a time.

Concern over potential misuse may be one reason some clinicians have been reluctant to complete the training process. However, the study results showed misuse rates of other opioids, including oxycodone and hydrocodone, were higher than those reported for buprenorphine.

“Many other prescription opioids are misused at much higher rates,” co-investigator Wilson Compton, MD, MPE, deputy director of NIDA, told this news organization.

“While there are concerns about all of them, we want to make sure that people don’t exaggerate the concerns – and understanding that oxycodone and hydrocodone are so much more frequently misused is important,” added Dr. Compton.
 

Symptom of inadequate access?

Commenting on the research, Bobby Mukkamala, MD, chair of the American Medical Association Board of Trustees, said individuals who misuse buprenorphine “commonly do so to alleviate uncontrolled pain or symptoms of withdrawal.”

“So-called misuse of buprenorphine is a symptom of inadequate access to physicians to treat opioid use disorder,” said Dr. Mukkamala, who also chairs the AMA Substance Use and Pain Care Task Force.

A 2020 study from the U.S. Department of Health & Human Services showed 40% of U.S. counties have no clinicians with a federal waiver permitting them to prescribe buprenorphine in an office setting.

In April, the HHS released new practice guidelines that allow certain practitioners licensed under state law who have a valid Drug Enforcement Administration registration to treat up to 30 patients with buprenorphine without having to complete requirements related to training, counseling, and other ancillary services known as an “X-waiver.”

The move was welcomed by many in the field, but Dr. Mukkamala said the agency did not go far enough.

“The AMA supports removing the federal X-waiver requirement to help destigmatize the provision of buprenorphine as well as remove the many administrative barriers that come with the federal requirement,” he said.

The study was funded by the National Institute on Drug Abuse. The study authors have disclosed no relevant financial relationships.

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