MDedge Pediatrics

A new position statement from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) stresses the importance of a mental health evaluation for people with gender dysphoria – in particular for children and adolescents – before any firm decisions are made on whether to prescribe hormonal treatments to transition, or perform surgeries, often referred to as “gender-affirming care.”

“There is a paucity of quality evidence on the outcomes of those presenting with gender dysphoria. In particular, there is a need for better evidence in relation to outcomes for children and young people,” the guidance states.

Because gender dysphoria “is associated with significant distress ... each case should be assessed by a mental health professional, which will frequently be a psychiatrist, with the person at the center of care. It is important the psychological state and context in which gender dysphoria has arisen is explored to assess the most appropriate treatment,” it adds.

The move by the psychiatry body represents a big shift in the landscape regarding recommendations for the treatment of gender dysphoria in Australia and New Zealand.

Asked to explain the new RANZCP position, Philip Morris, MBBS, FRANZCP, said: “The College acknowledged the complexity of the issues and the legitimacy of different approaches.”

Exploration of a patient’s reasons for identifying as transgender is essential, he said in an interview, especially when it comes to young people.

“There may be other reasons for doing it, and we need to look for those, identify them and treat them. This needs to be done before initiating hormones and changing the whole physical nature of the child,” he said.

“A cautious psychotherapy-first approach makes sense. If we can do that with adolescents, then we will take a big step in the right direction,” stressed Dr. Morris, who is president of the National Association of Practising Psychiatrists in Australia.
 

Keira Bell case and Scandinavian stance lead to more open discussion

The rapid rise in gender dysphoria among adolescents in the Western world, referred to as “rapid-onset” or “late-onset” gender dysphoria, has seen a huge increase in the number of natal girls presenting and created frenzied debate that has intensified worldwide in the last 12 months about how to best treat youth with gender dysphoria.

Concerns have arisen that some transgender identification is due to social contagion, and there is a growing number of “detransitioners” – people who identified as transgender, transitioned to the opposite gender, but then regretted their decision, changed their minds, and “detransitioned” back to their birth sex. If they have had hormone therapy, and in some cases surgery, they are left with irreversible changes to their bodies.

As a result, Scandinavian countries, most notably Finland, once eager advocates of the gender-affirmative approach, have pulled back and issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.

This, along with a landmark High Court decision in the U.K. regarding the use of puberty-blocking drugs for children with gender dysphoria, brought by detransitioner Keira Bell, which was recently overturned by the Appeal Court, but which Ms. Bell now says she will take to the Supreme Court, has led to a considerable shift in the conversation around treating transgender adolescents with hormonal therapy, says Dr. Morris.

“This [has moved from] ... a topic that could previously not be talked about freely to one that we can discuss more openly now. This is a big improvement. Previously, everyone thought it was all settled, but it’s not, certainly not from a medical angle,” he states.
 

At odds with prior Australian recommendations

The RANZCP had previously endorsed the standard guidelines of the Royal Children’s Hospital (RCH) Melbourne, followed by most gender-identity services in Australia and similar guidance from New Zealand, which both recommend gender-affirming care.

“Increasing evidence demonstrates that with supportive, gender-affirming care during childhood and adolescence, harms can be ameliorated and mental health and well-being outcomes can be significantly improved,” state the RCH guidelines.

But in 2019, RANZCP removed its endorsement of the RCH guidelines and started a consultation, which resulted in the new position statement.

However, Ken Pang, MD, of the Murdoch Children’s Research Institute in Melbourne and an author of the RCH guidelines, says the key recommendations of the new RANZCP position statement are consistent with their own guidelines.

The former note “the need for a skilled mental health clinician in providing comprehensive exploration of a child or adolescent’s biopsychosocial context,” Dr. Pang says.

However, it’s difficult not to see the contrast in stance when the new RANZCP statement maintains: “Research on gender dysphoria is still emerging. There are polarized views and mixed evidence regarding treatment options for people presenting with gender identity concerns, especially children and young people.”

Dr. Pang says the RCH guidelines do, however, recognize the need for further research in the field.

“I look forward to being able to incorporate such research, including from our own Trans20 study, into future revisions of our guidelines,” he told this news organization.
 

Watch your backs with affirmative therapy: Will there be a compromise?

Dr. Morris says there will obviously be cases where “the child might transition with a medical intervention, but that wouldn’t be the first step.”

And yet, he adds, “There are those who push the pro-trans view that everyone should be allowed to transition, and the doctors are only technicians that provide hormones with no questions asked.” 

But from a doctor’s perspective, clinicians will still be held responsible in medical and legal terms for the treatments given, he stressed.

“I don’t think they will ever not be accountable for that. They will always need to determine in their own mind whether their actions have positive value that outweigh any disadvantages,” Dr. Morris continues.

The RANZCP statement does, in fact, stress just this.

All health care professionals need to “be aware of ethical and medicolegal dilemmas” pertaining to affirmative therapy, it indicates. “Psychiatrists should practice within the relevant laws and accepted professional standards in relation to assessing capacity and obtaining consent...”

Dr. Morris hopes there will ultimately be many more checks and balances in place and that courts and clinicians will need to step back and not assume every child who seeks to transition is doing it as a result of pure gender dysphoria.

He predicts that things will end in a compromise. 

“In my view, this compromise will treat children with respect and approach them like any other patient that presents with a condition that requires proper assessment and treatment.”

“In the end, some cases will be transitioned, but there will be fewer than [are] transitioned at the moment,” he predicts.

Dr. Morris has reported no relevant financial relationships. Dr. Pang is a member of the Australian Professional Association for Trans Health and its research committee.

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

A new position statement from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) stresses the importance of a mental health evaluation for people with gender dysphoria – in particular for children and adolescents – before any firm decisions are made on whether to prescribe hormonal treatments to transition, or perform surgeries, often referred to as “gender-affirming care.”

“There is a paucity of quality evidence on the outcomes of those presenting with gender dysphoria. In particular, there is a need for better evidence in relation to outcomes for children and young people,” the guidance states.

Because gender dysphoria “is associated with significant distress ... each case should be assessed by a mental health professional, which will frequently be a psychiatrist, with the person at the center of care. It is important the psychological state and context in which gender dysphoria has arisen is explored to assess the most appropriate treatment,” it adds.

The move by the psychiatry body represents a big shift in the landscape regarding recommendations for the treatment of gender dysphoria in Australia and New Zealand.

Asked to explain the new RANZCP position, Philip Morris, MBBS, FRANZCP, said: “The College acknowledged the complexity of the issues and the legitimacy of different approaches.”

Exploration of a patient’s reasons for identifying as transgender is essential, he said in an interview, especially when it comes to young people.

“There may be other reasons for doing it, and we need to look for those, identify them and treat them. This needs to be done before initiating hormones and changing the whole physical nature of the child,” he said.

“A cautious psychotherapy-first approach makes sense. If we can do that with adolescents, then we will take a big step in the right direction,” stressed Dr. Morris, who is president of the National Association of Practising Psychiatrists in Australia.
 

Keira Bell case and Scandinavian stance lead to more open discussion

The rapid rise in gender dysphoria among adolescents in the Western world, referred to as “rapid-onset” or “late-onset” gender dysphoria, has seen a huge increase in the number of natal girls presenting and created frenzied debate that has intensified worldwide in the last 12 months about how to best treat youth with gender dysphoria.

Concerns have arisen that some transgender identification is due to social contagion, and there is a growing number of “detransitioners” – people who identified as transgender, transitioned to the opposite gender, but then regretted their decision, changed their minds, and “detransitioned” back to their birth sex. If they have had hormone therapy, and in some cases surgery, they are left with irreversible changes to their bodies.

As a result, Scandinavian countries, most notably Finland, once eager advocates of the gender-affirmative approach, have pulled back and issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.

This, along with a landmark High Court decision in the U.K. regarding the use of puberty-blocking drugs for children with gender dysphoria, brought by detransitioner Keira Bell, which was recently overturned by the Appeal Court, but which Ms. Bell now says she will take to the Supreme Court, has led to a considerable shift in the conversation around treating transgender adolescents with hormonal therapy, says Dr. Morris.

“This [has moved from] ... a topic that could previously not be talked about freely to one that we can discuss more openly now. This is a big improvement. Previously, everyone thought it was all settled, but it’s not, certainly not from a medical angle,” he states.
 

At odds with prior Australian recommendations

The RANZCP had previously endorsed the standard guidelines of the Royal Children’s Hospital (RCH) Melbourne, followed by most gender-identity services in Australia and similar guidance from New Zealand, which both recommend gender-affirming care.

“Increasing evidence demonstrates that with supportive, gender-affirming care during childhood and adolescence, harms can be ameliorated and mental health and well-being outcomes can be significantly improved,” state the RCH guidelines.

But in 2019, RANZCP removed its endorsement of the RCH guidelines and started a consultation, which resulted in the new position statement.

However, Ken Pang, MD, of the Murdoch Children’s Research Institute in Melbourne and an author of the RCH guidelines, says the key recommendations of the new RANZCP position statement are consistent with their own guidelines.

The former note “the need for a skilled mental health clinician in providing comprehensive exploration of a child or adolescent’s biopsychosocial context,” Dr. Pang says.

However, it’s difficult not to see the contrast in stance when the new RANZCP statement maintains: “Research on gender dysphoria is still emerging. There are polarized views and mixed evidence regarding treatment options for people presenting with gender identity concerns, especially children and young people.”

Dr. Pang says the RCH guidelines do, however, recognize the need for further research in the field.

“I look forward to being able to incorporate such research, including from our own Trans20 study, into future revisions of our guidelines,” he told this news organization.
 

Watch your backs with affirmative therapy: Will there be a compromise?

Dr. Morris says there will obviously be cases where “the child might transition with a medical intervention, but that wouldn’t be the first step.”

And yet, he adds, “There are those who push the pro-trans view that everyone should be allowed to transition, and the doctors are only technicians that provide hormones with no questions asked.” 

But from a doctor’s perspective, clinicians will still be held responsible in medical and legal terms for the treatments given, he stressed.

“I don’t think they will ever not be accountable for that. They will always need to determine in their own mind whether their actions have positive value that outweigh any disadvantages,” Dr. Morris continues.

The RANZCP statement does, in fact, stress just this.

All health care professionals need to “be aware of ethical and medicolegal dilemmas” pertaining to affirmative therapy, it indicates. “Psychiatrists should practice within the relevant laws and accepted professional standards in relation to assessing capacity and obtaining consent...”

Dr. Morris hopes there will ultimately be many more checks and balances in place and that courts and clinicians will need to step back and not assume every child who seeks to transition is doing it as a result of pure gender dysphoria.

He predicts that things will end in a compromise. 

“In my view, this compromise will treat children with respect and approach them like any other patient that presents with a condition that requires proper assessment and treatment.”

“In the end, some cases will be transitioned, but there will be fewer than [are] transitioned at the moment,” he predicts.

Dr. Morris has reported no relevant financial relationships. Dr. Pang is a member of the Australian Professional Association for Trans Health and its research committee.

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

A new position statement from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) stresses the importance of a mental health evaluation for people with gender dysphoria – in particular for children and adolescents – before any firm decisions are made on whether to prescribe hormonal treatments to transition, or perform surgeries, often referred to as “gender-affirming care.”

“There is a paucity of quality evidence on the outcomes of those presenting with gender dysphoria. In particular, there is a need for better evidence in relation to outcomes for children and young people,” the guidance states.

Because gender dysphoria “is associated with significant distress ... each case should be assessed by a mental health professional, which will frequently be a psychiatrist, with the person at the center of care. It is important the psychological state and context in which gender dysphoria has arisen is explored to assess the most appropriate treatment,” it adds.

The move by the psychiatry body represents a big shift in the landscape regarding recommendations for the treatment of gender dysphoria in Australia and New Zealand.

Asked to explain the new RANZCP position, Philip Morris, MBBS, FRANZCP, said: “The College acknowledged the complexity of the issues and the legitimacy of different approaches.”

Exploration of a patient’s reasons for identifying as transgender is essential, he said in an interview, especially when it comes to young people.

“There may be other reasons for doing it, and we need to look for those, identify them and treat them. This needs to be done before initiating hormones and changing the whole physical nature of the child,” he said.

“A cautious psychotherapy-first approach makes sense. If we can do that with adolescents, then we will take a big step in the right direction,” stressed Dr. Morris, who is president of the National Association of Practising Psychiatrists in Australia.
 

Keira Bell case and Scandinavian stance lead to more open discussion

The rapid rise in gender dysphoria among adolescents in the Western world, referred to as “rapid-onset” or “late-onset” gender dysphoria, has seen a huge increase in the number of natal girls presenting and created frenzied debate that has intensified worldwide in the last 12 months about how to best treat youth with gender dysphoria.

Concerns have arisen that some transgender identification is due to social contagion, and there is a growing number of “detransitioners” – people who identified as transgender, transitioned to the opposite gender, but then regretted their decision, changed their minds, and “detransitioned” back to their birth sex. If they have had hormone therapy, and in some cases surgery, they are left with irreversible changes to their bodies.

As a result, Scandinavian countries, most notably Finland, once eager advocates of the gender-affirmative approach, have pulled back and issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.

This, along with a landmark High Court decision in the U.K. regarding the use of puberty-blocking drugs for children with gender dysphoria, brought by detransitioner Keira Bell, which was recently overturned by the Appeal Court, but which Ms. Bell now says she will take to the Supreme Court, has led to a considerable shift in the conversation around treating transgender adolescents with hormonal therapy, says Dr. Morris.

“This [has moved from] ... a topic that could previously not be talked about freely to one that we can discuss more openly now. This is a big improvement. Previously, everyone thought it was all settled, but it’s not, certainly not from a medical angle,” he states.
 

At odds with prior Australian recommendations

The RANZCP had previously endorsed the standard guidelines of the Royal Children’s Hospital (RCH) Melbourne, followed by most gender-identity services in Australia and similar guidance from New Zealand, which both recommend gender-affirming care.

“Increasing evidence demonstrates that with supportive, gender-affirming care during childhood and adolescence, harms can be ameliorated and mental health and well-being outcomes can be significantly improved,” state the RCH guidelines.

But in 2019, RANZCP removed its endorsement of the RCH guidelines and started a consultation, which resulted in the new position statement.

However, Ken Pang, MD, of the Murdoch Children’s Research Institute in Melbourne and an author of the RCH guidelines, says the key recommendations of the new RANZCP position statement are consistent with their own guidelines.

The former note “the need for a skilled mental health clinician in providing comprehensive exploration of a child or adolescent’s biopsychosocial context,” Dr. Pang says.

However, it’s difficult not to see the contrast in stance when the new RANZCP statement maintains: “Research on gender dysphoria is still emerging. There are polarized views and mixed evidence regarding treatment options for people presenting with gender identity concerns, especially children and young people.”

Dr. Pang says the RCH guidelines do, however, recognize the need for further research in the field.

“I look forward to being able to incorporate such research, including from our own Trans20 study, into future revisions of our guidelines,” he told this news organization.
 

Watch your backs with affirmative therapy: Will there be a compromise?

Dr. Morris says there will obviously be cases where “the child might transition with a medical intervention, but that wouldn’t be the first step.”

And yet, he adds, “There are those who push the pro-trans view that everyone should be allowed to transition, and the doctors are only technicians that provide hormones with no questions asked.” 

But from a doctor’s perspective, clinicians will still be held responsible in medical and legal terms for the treatments given, he stressed.

“I don’t think they will ever not be accountable for that. They will always need to determine in their own mind whether their actions have positive value that outweigh any disadvantages,” Dr. Morris continues.

The RANZCP statement does, in fact, stress just this.

All health care professionals need to “be aware of ethical and medicolegal dilemmas” pertaining to affirmative therapy, it indicates. “Psychiatrists should practice within the relevant laws and accepted professional standards in relation to assessing capacity and obtaining consent...”

Dr. Morris hopes there will ultimately be many more checks and balances in place and that courts and clinicians will need to step back and not assume every child who seeks to transition is doing it as a result of pure gender dysphoria.

He predicts that things will end in a compromise. 

“In my view, this compromise will treat children with respect and approach them like any other patient that presents with a condition that requires proper assessment and treatment.”

“In the end, some cases will be transitioned, but there will be fewer than [are] transitioned at the moment,” he predicts.

Dr. Morris has reported no relevant financial relationships. Dr. Pang is a member of the Australian Professional Association for Trans Health and its research committee.

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

After a concussion, resuming aerobic exercise relatively early on – at an intensity that does not worsen symptoms – may help young athletes recover sooner, compared with stretching, a randomized controlled trial (RCT) shows.

Douglas Levere/University at Buffalo

The study adds to emerging evidence that clinicians should prescribe exercise, rather than strict rest, to facilitate concussion recovery, researchers said.

Tamara McLeod, PhD, ATC, professor and director of athletic training programs at A.T. Still University in Mesa, Ariz., hopes the findings help clinicians see that “this is an approach that should be taken.”

“Too often with concussion, patients are given a laundry list of things they are NOT allowed to do,” including sports, school, and social activities, said Dr. McLeod, who was not involved in the study.

The research, published in The Lancet Child & Adolescent Health, largely replicates the findings of a prior trial while addressing limitations of the previous study’s design, researchers said.

For the trial, John J. Leddy, MD, with the State University of New York at Buffalo and colleagues recruited 118 male and female adolescent athletes aged 13-18 years who had had a sport-related concussion in the past 10 days. Investigators at three community and hospital-affiliated sports medicine concussion centers in the United States randomly assigned the athletes to individualized subsymptom-threshold aerobic exercise (61 participants) or stretching exercise (57 participants) at least 20 minutes per day for up to 4 weeks. Aerobic exercise included walking, jogging, or stationary cycling at home.

“It is important that the general clinician community appreciates that prolonged rest and avoidance of physical activity until spontaneous symptom resolution is no longer an acceptable approach to caring for adolescents with concussion,” Dr. Leddy and coauthors said.

The investigators improved on the “the scientific rigor of their previous RCT by including intention-to-treat and per-protocol analyses, daily symptom reporting, objective exercise adherence measurements, and greater heterogeneity of concussion severity,” said Carolyn A. Emery, PhD, and Jonathan Smirl, PhD, both with the University of Calgary (Alta.), in a related commentary. The new study is the first to show that early targeted heart rate subsymptom-threshold aerobic exercise, relative to stretching, shortened recovery time within 4 weeks after sport-related concussion (hazard ratio, 0.52) when controlling for sex, study site, and average daily exercise time, Dr. Emery and Dr. Smirl said.

A larger proportion of athletes assigned to stretching did not recover by 4 weeks, compared with those assigned to aerobic exercise (32% vs. 21%). The median time to full recovery was longer for the stretching group than for the aerobic exercise group (19 days vs. 14 days).

Among athletes who adhered to their assigned regimens, the differences were more pronounced: The median recovery time was 21 days for the stretching group, compared with 12 days for the aerobic exercise group. The rate of postconcussion symptoms beyond 28 days was 9% in the aerobic exercise group versus 31% in the stretching group, among adherent participants.

More research is needed to establish the efficacy of postconcussion aerobic exercise in adults and for nonsport injury, the researchers noted. Possible mechanisms underlying aerobic exercise’s benefits could include increased parasympathetic autonomic tone, improved cerebral blood flow regulation, or enhanced neuron repair, they suggested.

The right amount and timing of exercise, and doing so at an intensity that does not exacerbate symptoms, may be key. Other research has suggested that too much exercise, too soon may delay recovery, Dr. Emery said in an interview. “But there is now a lot of evidence to support low and moderate levels of physical activity to expedite recovery,” she said.

The study was funded by the American Medical Society for Sports Medicine. The study and commentary authors and Dr. McLeod had no disclosures.

[email protected]

After a concussion, resuming aerobic exercise relatively early on – at an intensity that does not worsen symptoms – may help young athletes recover sooner, compared with stretching, a randomized controlled trial (RCT) shows.

Douglas Levere/University at Buffalo

The study adds to emerging evidence that clinicians should prescribe exercise, rather than strict rest, to facilitate concussion recovery, researchers said.

Tamara McLeod, PhD, ATC, professor and director of athletic training programs at A.T. Still University in Mesa, Ariz., hopes the findings help clinicians see that “this is an approach that should be taken.”

“Too often with concussion, patients are given a laundry list of things they are NOT allowed to do,” including sports, school, and social activities, said Dr. McLeod, who was not involved in the study.

The research, published in The Lancet Child & Adolescent Health, largely replicates the findings of a prior trial while addressing limitations of the previous study’s design, researchers said.

For the trial, John J. Leddy, MD, with the State University of New York at Buffalo and colleagues recruited 118 male and female adolescent athletes aged 13-18 years who had had a sport-related concussion in the past 10 days. Investigators at three community and hospital-affiliated sports medicine concussion centers in the United States randomly assigned the athletes to individualized subsymptom-threshold aerobic exercise (61 participants) or stretching exercise (57 participants) at least 20 minutes per day for up to 4 weeks. Aerobic exercise included walking, jogging, or stationary cycling at home.

“It is important that the general clinician community appreciates that prolonged rest and avoidance of physical activity until spontaneous symptom resolution is no longer an acceptable approach to caring for adolescents with concussion,” Dr. Leddy and coauthors said.

The investigators improved on the “the scientific rigor of their previous RCT by including intention-to-treat and per-protocol analyses, daily symptom reporting, objective exercise adherence measurements, and greater heterogeneity of concussion severity,” said Carolyn A. Emery, PhD, and Jonathan Smirl, PhD, both with the University of Calgary (Alta.), in a related commentary. The new study is the first to show that early targeted heart rate subsymptom-threshold aerobic exercise, relative to stretching, shortened recovery time within 4 weeks after sport-related concussion (hazard ratio, 0.52) when controlling for sex, study site, and average daily exercise time, Dr. Emery and Dr. Smirl said.

A larger proportion of athletes assigned to stretching did not recover by 4 weeks, compared with those assigned to aerobic exercise (32% vs. 21%). The median time to full recovery was longer for the stretching group than for the aerobic exercise group (19 days vs. 14 days).

Among athletes who adhered to their assigned regimens, the differences were more pronounced: The median recovery time was 21 days for the stretching group, compared with 12 days for the aerobic exercise group. The rate of postconcussion symptoms beyond 28 days was 9% in the aerobic exercise group versus 31% in the stretching group, among adherent participants.

More research is needed to establish the efficacy of postconcussion aerobic exercise in adults and for nonsport injury, the researchers noted. Possible mechanisms underlying aerobic exercise’s benefits could include increased parasympathetic autonomic tone, improved cerebral blood flow regulation, or enhanced neuron repair, they suggested.

The right amount and timing of exercise, and doing so at an intensity that does not exacerbate symptoms, may be key. Other research has suggested that too much exercise, too soon may delay recovery, Dr. Emery said in an interview. “But there is now a lot of evidence to support low and moderate levels of physical activity to expedite recovery,” she said.

The study was funded by the American Medical Society for Sports Medicine. The study and commentary authors and Dr. McLeod had no disclosures.

[email protected]

After a concussion, resuming aerobic exercise relatively early on – at an intensity that does not worsen symptoms – may help young athletes recover sooner, compared with stretching, a randomized controlled trial (RCT) shows.

Douglas Levere/University at Buffalo

The study adds to emerging evidence that clinicians should prescribe exercise, rather than strict rest, to facilitate concussion recovery, researchers said.

Tamara McLeod, PhD, ATC, professor and director of athletic training programs at A.T. Still University in Mesa, Ariz., hopes the findings help clinicians see that “this is an approach that should be taken.”

“Too often with concussion, patients are given a laundry list of things they are NOT allowed to do,” including sports, school, and social activities, said Dr. McLeod, who was not involved in the study.

The research, published in The Lancet Child & Adolescent Health, largely replicates the findings of a prior trial while addressing limitations of the previous study’s design, researchers said.

For the trial, John J. Leddy, MD, with the State University of New York at Buffalo and colleagues recruited 118 male and female adolescent athletes aged 13-18 years who had had a sport-related concussion in the past 10 days. Investigators at three community and hospital-affiliated sports medicine concussion centers in the United States randomly assigned the athletes to individualized subsymptom-threshold aerobic exercise (61 participants) or stretching exercise (57 participants) at least 20 minutes per day for up to 4 weeks. Aerobic exercise included walking, jogging, or stationary cycling at home.

“It is important that the general clinician community appreciates that prolonged rest and avoidance of physical activity until spontaneous symptom resolution is no longer an acceptable approach to caring for adolescents with concussion,” Dr. Leddy and coauthors said.

The investigators improved on the “the scientific rigor of their previous RCT by including intention-to-treat and per-protocol analyses, daily symptom reporting, objective exercise adherence measurements, and greater heterogeneity of concussion severity,” said Carolyn A. Emery, PhD, and Jonathan Smirl, PhD, both with the University of Calgary (Alta.), in a related commentary. The new study is the first to show that early targeted heart rate subsymptom-threshold aerobic exercise, relative to stretching, shortened recovery time within 4 weeks after sport-related concussion (hazard ratio, 0.52) when controlling for sex, study site, and average daily exercise time, Dr. Emery and Dr. Smirl said.

A larger proportion of athletes assigned to stretching did not recover by 4 weeks, compared with those assigned to aerobic exercise (32% vs. 21%). The median time to full recovery was longer for the stretching group than for the aerobic exercise group (19 days vs. 14 days).

Among athletes who adhered to their assigned regimens, the differences were more pronounced: The median recovery time was 21 days for the stretching group, compared with 12 days for the aerobic exercise group. The rate of postconcussion symptoms beyond 28 days was 9% in the aerobic exercise group versus 31% in the stretching group, among adherent participants.

More research is needed to establish the efficacy of postconcussion aerobic exercise in adults and for nonsport injury, the researchers noted. Possible mechanisms underlying aerobic exercise’s benefits could include increased parasympathetic autonomic tone, improved cerebral blood flow regulation, or enhanced neuron repair, they suggested.

The right amount and timing of exercise, and doing so at an intensity that does not exacerbate symptoms, may be key. Other research has suggested that too much exercise, too soon may delay recovery, Dr. Emery said in an interview. “But there is now a lot of evidence to support low and moderate levels of physical activity to expedite recovery,” she said.

The study was funded by the American Medical Society for Sports Medicine. The study and commentary authors and Dr. McLeod had no disclosures.

[email protected]

The presence of benzene has prompted voluntary company recalls of antifungal foot sprays and sunscreen products, all aerosol spray products.

mark wragg/iStockphoto.com

Bayer has voluntarily recalled batches of its Lotrimin and Tinactin products because of benzene detected in some samples, according to an Oct. 1 company announcement, available on the Food and Drug Administration website. “It is important to note that Bayer’s decision to voluntarily recall these products is a precautionary measure and that the levels detected are not expected to cause adverse health consequences in consumers,” the announcement said.

Benzene is classified as a human carcinogen present in the environment from both natural sources and human activity, and it has been shown to cause cancer with long-term exposure.

The products included in the recall – all in aerosol spray cans – are unexpired Lotrimin and Tinactin sprays with lot numbers starting with TN, CV, or NAA that were distributed to consumer venues between September 2018 and September 2021. The over-the-counter products are Lotrimin Anti-Fungal Athlete’s Foot Powder Spray, Lotrimin Anti-Fungal Jock Itch (AFJI) Athlete’s Foot Powder Spray, Lotrimin Anti-Fungal (AF) Athlete’s Foot Deodorant Powder Spray, Lotrimin AF Athlete’s Foot Liquid Spray, Lotrimin AF Athlete’s Foot Daily Prevention Deodorant Powder Spray, Tinactin Jock Itch (JI) Powder Spray, Tinactin Athlete’s Foot Deodorant Powder Spray, Tinactin Athlete’s Foot Powder Spray, and Tinactin Athlete’s Foot Liquid Spray.

Bayer has received no reports of adverse events related to the recall. The company also reported no concerns with its antifungal creams or other products.

In addition, Coppertone has issued a voluntary recall of specific lots of five spray sunscreen products because of the presence of benzene, according to a Sept. 30th company announcement, also posted on the FDA website. The recall includes Pure&Simple spray for babies, children, and adults; Coppertone Sport Mineral Spray; and Travel-sized Coppertone Sport spray. The specific lots were manufactured between January and June 2021, and are listed on the company announcement.

“Daily exposure to benzene at the levels detected in these affected Coppertone aerosol sunscreen spray products would not be expected to cause adverse health consequences based on generally accepted exposure modeling by numerous regulatory agencies,” according to the announcement. Coppertone has received no reports of adverse events related to the recall.

In the announcement, Coppertone advised consumers to discontinue use of the impacted products, dispose of the aerosol cans properly, and contact their physician or health care provider if they experience any problems related to the sunscreen sprays.

In May 2021, online pharmacy Valisure, which routinely tests their medications, petitioned the FDA to recall specific sunscreens after detecting high benzene levels in several brands and batches of sunscreen products. The FDA evaluated the petition, but the agency itself did not issue any recalls of sunscreens.

Clinicians are advised to report any adverse events to the FDA’s MedWatch Adverse Event Reporting program either online or by regular mail or fax using this form.

The presence of benzene has prompted voluntary company recalls of antifungal foot sprays and sunscreen products, all aerosol spray products.

mark wragg/iStockphoto.com

Bayer has voluntarily recalled batches of its Lotrimin and Tinactin products because of benzene detected in some samples, according to an Oct. 1 company announcement, available on the Food and Drug Administration website. “It is important to note that Bayer’s decision to voluntarily recall these products is a precautionary measure and that the levels detected are not expected to cause adverse health consequences in consumers,” the announcement said.

Benzene is classified as a human carcinogen present in the environment from both natural sources and human activity, and it has been shown to cause cancer with long-term exposure.

The products included in the recall – all in aerosol spray cans – are unexpired Lotrimin and Tinactin sprays with lot numbers starting with TN, CV, or NAA that were distributed to consumer venues between September 2018 and September 2021. The over-the-counter products are Lotrimin Anti-Fungal Athlete’s Foot Powder Spray, Lotrimin Anti-Fungal Jock Itch (AFJI) Athlete’s Foot Powder Spray, Lotrimin Anti-Fungal (AF) Athlete’s Foot Deodorant Powder Spray, Lotrimin AF Athlete’s Foot Liquid Spray, Lotrimin AF Athlete’s Foot Daily Prevention Deodorant Powder Spray, Tinactin Jock Itch (JI) Powder Spray, Tinactin Athlete’s Foot Deodorant Powder Spray, Tinactin Athlete’s Foot Powder Spray, and Tinactin Athlete’s Foot Liquid Spray.

Bayer has received no reports of adverse events related to the recall. The company also reported no concerns with its antifungal creams or other products.

In addition, Coppertone has issued a voluntary recall of specific lots of five spray sunscreen products because of the presence of benzene, according to a Sept. 30th company announcement, also posted on the FDA website. The recall includes Pure&Simple spray for babies, children, and adults; Coppertone Sport Mineral Spray; and Travel-sized Coppertone Sport spray. The specific lots were manufactured between January and June 2021, and are listed on the company announcement.

“Daily exposure to benzene at the levels detected in these affected Coppertone aerosol sunscreen spray products would not be expected to cause adverse health consequences based on generally accepted exposure modeling by numerous regulatory agencies,” according to the announcement. Coppertone has received no reports of adverse events related to the recall.

In the announcement, Coppertone advised consumers to discontinue use of the impacted products, dispose of the aerosol cans properly, and contact their physician or health care provider if they experience any problems related to the sunscreen sprays.

In May 2021, online pharmacy Valisure, which routinely tests their medications, petitioned the FDA to recall specific sunscreens after detecting high benzene levels in several brands and batches of sunscreen products. The FDA evaluated the petition, but the agency itself did not issue any recalls of sunscreens.

Clinicians are advised to report any adverse events to the FDA’s MedWatch Adverse Event Reporting program either online or by regular mail or fax using this form.

The presence of benzene has prompted voluntary company recalls of antifungal foot sprays and sunscreen products, all aerosol spray products.

mark wragg/iStockphoto.com

Bayer has voluntarily recalled batches of its Lotrimin and Tinactin products because of benzene detected in some samples, according to an Oct. 1 company announcement, available on the Food and Drug Administration website. “It is important to note that Bayer’s decision to voluntarily recall these products is a precautionary measure and that the levels detected are not expected to cause adverse health consequences in consumers,” the announcement said.

Benzene is classified as a human carcinogen present in the environment from both natural sources and human activity, and it has been shown to cause cancer with long-term exposure.

The products included in the recall – all in aerosol spray cans – are unexpired Lotrimin and Tinactin sprays with lot numbers starting with TN, CV, or NAA that were distributed to consumer venues between September 2018 and September 2021. The over-the-counter products are Lotrimin Anti-Fungal Athlete’s Foot Powder Spray, Lotrimin Anti-Fungal Jock Itch (AFJI) Athlete’s Foot Powder Spray, Lotrimin Anti-Fungal (AF) Athlete’s Foot Deodorant Powder Spray, Lotrimin AF Athlete’s Foot Liquid Spray, Lotrimin AF Athlete’s Foot Daily Prevention Deodorant Powder Spray, Tinactin Jock Itch (JI) Powder Spray, Tinactin Athlete’s Foot Deodorant Powder Spray, Tinactin Athlete’s Foot Powder Spray, and Tinactin Athlete’s Foot Liquid Spray.

Bayer has received no reports of adverse events related to the recall. The company also reported no concerns with its antifungal creams or other products.

In addition, Coppertone has issued a voluntary recall of specific lots of five spray sunscreen products because of the presence of benzene, according to a Sept. 30th company announcement, also posted on the FDA website. The recall includes Pure&Simple spray for babies, children, and adults; Coppertone Sport Mineral Spray; and Travel-sized Coppertone Sport spray. The specific lots were manufactured between January and June 2021, and are listed on the company announcement.

“Daily exposure to benzene at the levels detected in these affected Coppertone aerosol sunscreen spray products would not be expected to cause adverse health consequences based on generally accepted exposure modeling by numerous regulatory agencies,” according to the announcement. Coppertone has received no reports of adverse events related to the recall.

In the announcement, Coppertone advised consumers to discontinue use of the impacted products, dispose of the aerosol cans properly, and contact their physician or health care provider if they experience any problems related to the sunscreen sprays.

In May 2021, online pharmacy Valisure, which routinely tests their medications, petitioned the FDA to recall specific sunscreens after detecting high benzene levels in several brands and batches of sunscreen products. The FDA evaluated the petition, but the agency itself did not issue any recalls of sunscreens.

Clinicians are advised to report any adverse events to the FDA’s MedWatch Adverse Event Reporting program either online or by regular mail or fax using this form.

Anthem Blue Cross, the country’s second-biggest health insurance company, is behind on billions of dollars in payments owed to hospitals and doctors because of onerous new reimbursement rules, computer problems and mishandled claims, say hospital officials in multiple states.

Anthem, like other big insurers, is using the COVID-19 crisis as cover to institute “egregious” policies that harm patients and pinch hospital finances, said Molly Smith, group vice president at the American Hospital Association. “There’s this sense of ‘Everyone’s distracted. We can get this through.’ ”

Hospitals are also dealing with a spike in retroactive claims denials by UnitedHealthcare, the biggest health insurer, for ED care, the AHA said.

Disputes between insurers and hospitals are nothing new. But this fight sticks more patients in the middle, worried they’ll have to pay unresolved claims. Hospitals say it is hurting their finances as many cope with COVID surges – even after the industry has received tens of billions of dollars in emergency assistance from the federal government.

“We recognize there have been some challenges” to prompt payments caused by claims-processing changes and “a new set of dynamics” amid the pandemic, Anthem spokesperson Colin Manning said in an email. “We apologize for any delays or inconvenience this may have caused.”

Virginia law requires insurers to pay claims within 40 days. In a Sept. 24 letter to state insurance regulators, VCU Health, a system that operates a large teaching hospital in Richmond associated with Virginia Commonwealth University, said Anthem owes it $385 million. More than 40% of the claims are more than 90 days old, VCU said.

For all Virginia hospitals, Anthem’s late, unpaid claims amount to “hundreds of millions of dollars,” the Virginia Hospital and Healthcare Association said in a June 23 letter to state regulators.

Nationwide, the payment delays “are creating an untenable situation,” the American Hospital Association said in a Sept. 9 letter to Anthem CEO Gail Boudreaux. “Patients are facing greater hurdles to accessing care; clinicians are burning out on unnecessary administrative tasks; and the system is straining to finance the personnel and supplies” needed to fight Covid.

Complaints about Anthem extend “from sea to shining sea, from New Hampshire to California,” AHA CEO Rick Pollack told KHN.

Substantial payment delays can be seen on Anthem’s books. On June 30, 2019, before the pandemic, 43% of the insurer’s medical bills for that quarter were unpaid, according to regulatory filings. Two years later that figure had risen to 53% – a difference of $2.5 billion.

Anthem profits were $4.6 billion in 2020 and $3.5 billion in the first half of 2021.

Alexis Thurber, who lives near Seattle, was insured by Anthem when she got an $18,192 hospital bill in May for radiation therapy that doctors said was essential to treat her breast cancer.

The treatments were “experimental” and “not medically necessary,” Anthem said, according to Ms. Thurber. She spent much of the summer trying to get the insurer to pay up – placing two dozen phone calls, spending hours on hold, sending multiple emails and enduring unmeasurable stress and worry. It finally covered the claim months later.

“It’s so egregious. It’s a game they’re playing,” said Ms. Thurber, 51, whose cancer was diagnosed in November. “Trying to get true help was impossible.”

Privacy rules prevent Anthem from commenting on Ms. Thurber’s case, said Anthem spokesperson Colin Manning.

When insurers fail to promptly pay medical bills, patients are left in the lurch. They might first get a notice saying payment is pending or denied. A hospital might bill them for treatment they thought would be covered. Hospitals and doctors often sue patients whose insurance didn’t pay up.

Hospitals point to a variety of Anthem practices contributing to payment delays or denials, including new layers of document requirements, prior-authorization hurdles for routine procedures and requirements that doctors themselves – not support staffers – speak to insurance gatekeepers. “This requires providers to literally leave the patient[’s] bedside to get on the phone with Anthem,” AHA said in its letter.

Anthem often hinders coverage for outpatient surgery, specialty pharmacy and other services in health systems listed as in network, amounting to a “bait and switch” on Anthem members, AHA officials said.

“Demanding that patients be treated outside of the hospital setting, against the advice of the patient’s in-network treating physician, appears to be motivated by a desire to drive up Empire’s profits,” the Greater New York Hospital Association wrote in an April letter to Empire Blue Cross, which is owned by Anthem.

Anthem officials pushed back in a recent letter to the AHA, saying the insurer’s changing rules are intended partly to control excessive prices charged by hospitals for specialty drugs and nonemergency surgery, screening and diagnostic procedures.

Severe problems with Anthem’s new claims management system surfaced months ago and “persist without meaningful improvement,” AHA said in its letter.

Claims have gotten lost in Anthem’s computers, and in some cases VCU Health has had to print medical records and mail them to get paid, VCU said in its letter. The cash slowdown imposes “an unmanageable disruption that threatens to undermine our financial footing,” VCU said.

United denied $31,557 in claims for Emily Long’s care after she was struck in June by a motorcycle in New York City. She needed surgery to repair a fractured cheekbone. United said there was a lack of documentation for “medical necessity” – an “incredibly aggravating” response on top of the distress of the accident, Ms. Long said.

The Brooklyn hospital that treated Ms. Long was “paid appropriately under her plan and within the required time frame,” said United spokesperson Maria Gordon Shydlo. “The facility has the right to appeal the decision.”

United’s unpaid claims came to 54% as of June 30, about the same level as 2 years previously.

When Erin Conlisk initially had trouble gaining approval for a piece of medical equipment for her elderly father this summer, United employees told her the insurer’s entire prior-authorization database had gone down for weeks, said Ms. Conlisk, who lives in California.

“There was a brief issue with our prior-authorization process in mid-July, which was resolved quickly,” Gordon Shydlo said.

When asked by Wall Street analysts about the payment backups, Anthem executives said it partly reflects their decision to increase financial reserves amid the health crisis.

“Really a ton of uncertainty associated with this environment,” John Gallina, the company’s chief financial officer, said on a conference call in July. “We’ve tried to be extremely prudent and conservative in our approach.”

During the pandemic, hospitals have benefited from two extraordinary cash infusions. They and other medical providers have received more than $100 billion through the CARES Act of 2020 and the American Rescue Plan of 2021. Last year United, Anthem and other insurers accelerated billions in hospital reimbursements.

The federal payments enriched many of the biggest, wealthiest systems while poorer hospitals serving low-income patients and rural areas struggled.

Those are the systems most hurt now by insurer payment delays, hospital officials said. Federal relief funds “have been a lifeline, but they don’t make people whole in terms of the losses from increased expenses and lost revenue as a result of the COVID experience,” Mr. Pollack said.

Several health systems declined to comment about claims payment delays or didn’t respond to a reporter’s queries. Among individual hospitals “there is a deep fear of talking on the record about your largest business partner,” AHA’s Ms. Smith said.

Alexis Thurber worried she might have to pay her $18,192 radiation bill herself, and she’s not confident her Anthem policy will do a better job next time of covering the cost of her care.

“It makes me not want to go to the doctor anymore,” she said. “I’m scared to get another mammogram because you can’t rely on it.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Anthem Blue Cross, the country’s second-biggest health insurance company, is behind on billions of dollars in payments owed to hospitals and doctors because of onerous new reimbursement rules, computer problems and mishandled claims, say hospital officials in multiple states.

Anthem, like other big insurers, is using the COVID-19 crisis as cover to institute “egregious” policies that harm patients and pinch hospital finances, said Molly Smith, group vice president at the American Hospital Association. “There’s this sense of ‘Everyone’s distracted. We can get this through.’ ”

Hospitals are also dealing with a spike in retroactive claims denials by UnitedHealthcare, the biggest health insurer, for ED care, the AHA said.

Disputes between insurers and hospitals are nothing new. But this fight sticks more patients in the middle, worried they’ll have to pay unresolved claims. Hospitals say it is hurting their finances as many cope with COVID surges – even after the industry has received tens of billions of dollars in emergency assistance from the federal government.

“We recognize there have been some challenges” to prompt payments caused by claims-processing changes and “a new set of dynamics” amid the pandemic, Anthem spokesperson Colin Manning said in an email. “We apologize for any delays or inconvenience this may have caused.”

Virginia law requires insurers to pay claims within 40 days. In a Sept. 24 letter to state insurance regulators, VCU Health, a system that operates a large teaching hospital in Richmond associated with Virginia Commonwealth University, said Anthem owes it $385 million. More than 40% of the claims are more than 90 days old, VCU said.

For all Virginia hospitals, Anthem’s late, unpaid claims amount to “hundreds of millions of dollars,” the Virginia Hospital and Healthcare Association said in a June 23 letter to state regulators.

Nationwide, the payment delays “are creating an untenable situation,” the American Hospital Association said in a Sept. 9 letter to Anthem CEO Gail Boudreaux. “Patients are facing greater hurdles to accessing care; clinicians are burning out on unnecessary administrative tasks; and the system is straining to finance the personnel and supplies” needed to fight Covid.

Complaints about Anthem extend “from sea to shining sea, from New Hampshire to California,” AHA CEO Rick Pollack told KHN.

Substantial payment delays can be seen on Anthem’s books. On June 30, 2019, before the pandemic, 43% of the insurer’s medical bills for that quarter were unpaid, according to regulatory filings. Two years later that figure had risen to 53% – a difference of $2.5 billion.

Anthem profits were $4.6 billion in 2020 and $3.5 billion in the first half of 2021.

Alexis Thurber, who lives near Seattle, was insured by Anthem when she got an $18,192 hospital bill in May for radiation therapy that doctors said was essential to treat her breast cancer.

The treatments were “experimental” and “not medically necessary,” Anthem said, according to Ms. Thurber. She spent much of the summer trying to get the insurer to pay up – placing two dozen phone calls, spending hours on hold, sending multiple emails and enduring unmeasurable stress and worry. It finally covered the claim months later.

“It’s so egregious. It’s a game they’re playing,” said Ms. Thurber, 51, whose cancer was diagnosed in November. “Trying to get true help was impossible.”

Privacy rules prevent Anthem from commenting on Ms. Thurber’s case, said Anthem spokesperson Colin Manning.

When insurers fail to promptly pay medical bills, patients are left in the lurch. They might first get a notice saying payment is pending or denied. A hospital might bill them for treatment they thought would be covered. Hospitals and doctors often sue patients whose insurance didn’t pay up.

Hospitals point to a variety of Anthem practices contributing to payment delays or denials, including new layers of document requirements, prior-authorization hurdles for routine procedures and requirements that doctors themselves – not support staffers – speak to insurance gatekeepers. “This requires providers to literally leave the patient[’s] bedside to get on the phone with Anthem,” AHA said in its letter.

Anthem often hinders coverage for outpatient surgery, specialty pharmacy and other services in health systems listed as in network, amounting to a “bait and switch” on Anthem members, AHA officials said.

“Demanding that patients be treated outside of the hospital setting, against the advice of the patient’s in-network treating physician, appears to be motivated by a desire to drive up Empire’s profits,” the Greater New York Hospital Association wrote in an April letter to Empire Blue Cross, which is owned by Anthem.

Anthem officials pushed back in a recent letter to the AHA, saying the insurer’s changing rules are intended partly to control excessive prices charged by hospitals for specialty drugs and nonemergency surgery, screening and diagnostic procedures.

Severe problems with Anthem’s new claims management system surfaced months ago and “persist without meaningful improvement,” AHA said in its letter.

Claims have gotten lost in Anthem’s computers, and in some cases VCU Health has had to print medical records and mail them to get paid, VCU said in its letter. The cash slowdown imposes “an unmanageable disruption that threatens to undermine our financial footing,” VCU said.

United denied $31,557 in claims for Emily Long’s care after she was struck in June by a motorcycle in New York City. She needed surgery to repair a fractured cheekbone. United said there was a lack of documentation for “medical necessity” – an “incredibly aggravating” response on top of the distress of the accident, Ms. Long said.

The Brooklyn hospital that treated Ms. Long was “paid appropriately under her plan and within the required time frame,” said United spokesperson Maria Gordon Shydlo. “The facility has the right to appeal the decision.”

United’s unpaid claims came to 54% as of June 30, about the same level as 2 years previously.

When Erin Conlisk initially had trouble gaining approval for a piece of medical equipment for her elderly father this summer, United employees told her the insurer’s entire prior-authorization database had gone down for weeks, said Ms. Conlisk, who lives in California.

“There was a brief issue with our prior-authorization process in mid-July, which was resolved quickly,” Gordon Shydlo said.

When asked by Wall Street analysts about the payment backups, Anthem executives said it partly reflects their decision to increase financial reserves amid the health crisis.

“Really a ton of uncertainty associated with this environment,” John Gallina, the company’s chief financial officer, said on a conference call in July. “We’ve tried to be extremely prudent and conservative in our approach.”

During the pandemic, hospitals have benefited from two extraordinary cash infusions. They and other medical providers have received more than $100 billion through the CARES Act of 2020 and the American Rescue Plan of 2021. Last year United, Anthem and other insurers accelerated billions in hospital reimbursements.

The federal payments enriched many of the biggest, wealthiest systems while poorer hospitals serving low-income patients and rural areas struggled.

Those are the systems most hurt now by insurer payment delays, hospital officials said. Federal relief funds “have been a lifeline, but they don’t make people whole in terms of the losses from increased expenses and lost revenue as a result of the COVID experience,” Mr. Pollack said.

Several health systems declined to comment about claims payment delays or didn’t respond to a reporter’s queries. Among individual hospitals “there is a deep fear of talking on the record about your largest business partner,” AHA’s Ms. Smith said.

Alexis Thurber worried she might have to pay her $18,192 radiation bill herself, and she’s not confident her Anthem policy will do a better job next time of covering the cost of her care.

“It makes me not want to go to the doctor anymore,” she said. “I’m scared to get another mammogram because you can’t rely on it.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Anthem Blue Cross, the country’s second-biggest health insurance company, is behind on billions of dollars in payments owed to hospitals and doctors because of onerous new reimbursement rules, computer problems and mishandled claims, say hospital officials in multiple states.

Anthem, like other big insurers, is using the COVID-19 crisis as cover to institute “egregious” policies that harm patients and pinch hospital finances, said Molly Smith, group vice president at the American Hospital Association. “There’s this sense of ‘Everyone’s distracted. We can get this through.’ ”

Hospitals are also dealing with a spike in retroactive claims denials by UnitedHealthcare, the biggest health insurer, for ED care, the AHA said.

Disputes between insurers and hospitals are nothing new. But this fight sticks more patients in the middle, worried they’ll have to pay unresolved claims. Hospitals say it is hurting their finances as many cope with COVID surges – even after the industry has received tens of billions of dollars in emergency assistance from the federal government.

“We recognize there have been some challenges” to prompt payments caused by claims-processing changes and “a new set of dynamics” amid the pandemic, Anthem spokesperson Colin Manning said in an email. “We apologize for any delays or inconvenience this may have caused.”

Virginia law requires insurers to pay claims within 40 days. In a Sept. 24 letter to state insurance regulators, VCU Health, a system that operates a large teaching hospital in Richmond associated with Virginia Commonwealth University, said Anthem owes it $385 million. More than 40% of the claims are more than 90 days old, VCU said.

For all Virginia hospitals, Anthem’s late, unpaid claims amount to “hundreds of millions of dollars,” the Virginia Hospital and Healthcare Association said in a June 23 letter to state regulators.

Nationwide, the payment delays “are creating an untenable situation,” the American Hospital Association said in a Sept. 9 letter to Anthem CEO Gail Boudreaux. “Patients are facing greater hurdles to accessing care; clinicians are burning out on unnecessary administrative tasks; and the system is straining to finance the personnel and supplies” needed to fight Covid.

Complaints about Anthem extend “from sea to shining sea, from New Hampshire to California,” AHA CEO Rick Pollack told KHN.

Substantial payment delays can be seen on Anthem’s books. On June 30, 2019, before the pandemic, 43% of the insurer’s medical bills for that quarter were unpaid, according to regulatory filings. Two years later that figure had risen to 53% – a difference of $2.5 billion.

Anthem profits were $4.6 billion in 2020 and $3.5 billion in the first half of 2021.

Alexis Thurber, who lives near Seattle, was insured by Anthem when she got an $18,192 hospital bill in May for radiation therapy that doctors said was essential to treat her breast cancer.

The treatments were “experimental” and “not medically necessary,” Anthem said, according to Ms. Thurber. She spent much of the summer trying to get the insurer to pay up – placing two dozen phone calls, spending hours on hold, sending multiple emails and enduring unmeasurable stress and worry. It finally covered the claim months later.

“It’s so egregious. It’s a game they’re playing,” said Ms. Thurber, 51, whose cancer was diagnosed in November. “Trying to get true help was impossible.”

Privacy rules prevent Anthem from commenting on Ms. Thurber’s case, said Anthem spokesperson Colin Manning.

When insurers fail to promptly pay medical bills, patients are left in the lurch. They might first get a notice saying payment is pending or denied. A hospital might bill them for treatment they thought would be covered. Hospitals and doctors often sue patients whose insurance didn’t pay up.

Hospitals point to a variety of Anthem practices contributing to payment delays or denials, including new layers of document requirements, prior-authorization hurdles for routine procedures and requirements that doctors themselves – not support staffers – speak to insurance gatekeepers. “This requires providers to literally leave the patient[’s] bedside to get on the phone with Anthem,” AHA said in its letter.

Anthem often hinders coverage for outpatient surgery, specialty pharmacy and other services in health systems listed as in network, amounting to a “bait and switch” on Anthem members, AHA officials said.

“Demanding that patients be treated outside of the hospital setting, against the advice of the patient’s in-network treating physician, appears to be motivated by a desire to drive up Empire’s profits,” the Greater New York Hospital Association wrote in an April letter to Empire Blue Cross, which is owned by Anthem.

Anthem officials pushed back in a recent letter to the AHA, saying the insurer’s changing rules are intended partly to control excessive prices charged by hospitals for specialty drugs and nonemergency surgery, screening and diagnostic procedures.

Severe problems with Anthem’s new claims management system surfaced months ago and “persist without meaningful improvement,” AHA said in its letter.

Claims have gotten lost in Anthem’s computers, and in some cases VCU Health has had to print medical records and mail them to get paid, VCU said in its letter. The cash slowdown imposes “an unmanageable disruption that threatens to undermine our financial footing,” VCU said.

United denied $31,557 in claims for Emily Long’s care after she was struck in June by a motorcycle in New York City. She needed surgery to repair a fractured cheekbone. United said there was a lack of documentation for “medical necessity” – an “incredibly aggravating” response on top of the distress of the accident, Ms. Long said.

The Brooklyn hospital that treated Ms. Long was “paid appropriately under her plan and within the required time frame,” said United spokesperson Maria Gordon Shydlo. “The facility has the right to appeal the decision.”

United’s unpaid claims came to 54% as of June 30, about the same level as 2 years previously.

When Erin Conlisk initially had trouble gaining approval for a piece of medical equipment for her elderly father this summer, United employees told her the insurer’s entire prior-authorization database had gone down for weeks, said Ms. Conlisk, who lives in California.

“There was a brief issue with our prior-authorization process in mid-July, which was resolved quickly,” Gordon Shydlo said.

When asked by Wall Street analysts about the payment backups, Anthem executives said it partly reflects their decision to increase financial reserves amid the health crisis.

“Really a ton of uncertainty associated with this environment,” John Gallina, the company’s chief financial officer, said on a conference call in July. “We’ve tried to be extremely prudent and conservative in our approach.”

During the pandemic, hospitals have benefited from two extraordinary cash infusions. They and other medical providers have received more than $100 billion through the CARES Act of 2020 and the American Rescue Plan of 2021. Last year United, Anthem and other insurers accelerated billions in hospital reimbursements.

The federal payments enriched many of the biggest, wealthiest systems while poorer hospitals serving low-income patients and rural areas struggled.

Those are the systems most hurt now by insurer payment delays, hospital officials said. Federal relief funds “have been a lifeline, but they don’t make people whole in terms of the losses from increased expenses and lost revenue as a result of the COVID experience,” Mr. Pollack said.

Several health systems declined to comment about claims payment delays or didn’t respond to a reporter’s queries. Among individual hospitals “there is a deep fear of talking on the record about your largest business partner,” AHA’s Ms. Smith said.

Alexis Thurber worried she might have to pay her $18,192 radiation bill herself, and she’s not confident her Anthem policy will do a better job next time of covering the cost of her care.

“It makes me not want to go to the doctor anymore,” she said. “I’m scared to get another mammogram because you can’t rely on it.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

A federal judge has paused the recent Texas abortion law that bans nearly all abortions in the state.

Robert Pitman, a federal district court judge in Austin, sided with the Biden administration and granted the Justice Department’s request to halt enforcement of the new law. The Biden administration sued to stop the law, and Mr. Pitman’s decision pauses the law while it moves through federal courts, The New York Times reported.

In a 113-page ruling, Mr. Pitman criticized the law, also known as Senate Bill 8, for delegating enforcement to private individuals, who can sue anyone who performs abortions or “aids and abets” them. Plaintiffs are encouraged to file lawsuits because they recover legal fees and $10,000 if they win.

“From the moment S.B. 8 went into effect, women have been unlawfully prevented from exercising control over their own lives in ways that are protected by the Constitution,” Mr. Pitman wrote in the ruling.

“This court will not sanction one more day of this offensive deprivation of such an important right,” he said.

The Texas law bans abortions once fetal cardiac activity can be detected, which is usually around 6 weeks of pregnancy. Women may not know they’re pregnant yet during that time frame.

It’s not yet clear what effect Mr. Pitman’s ruling will have on women in Texas, the Times reported. Since the law went into effect about a month ago, women have sought abortion providers in other states. Mr. Pitman’s ruling pauses the enforcement of the law, but clinics may still face retroactive lawsuits for abortions provided while the law was temporarily suspended.

Whole Woman’s Health, which operates four clinics in Texas, said Wednesday that it was “making plans to resume abortion care up to 18 weeks as soon as possible,” the newspaper reported. The Center for Reproductive Rights also said that clinics “hope to resume full abortion services as soon as they are able.”

Late Oct. 6, Texas said it would appeal the ruling. The U.S. Court of Appeals for the Fifth Circuit is one of the most conservative in the country, according to the Times, and another decision could come soon.

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

A federal judge has paused the recent Texas abortion law that bans nearly all abortions in the state.

Robert Pitman, a federal district court judge in Austin, sided with the Biden administration and granted the Justice Department’s request to halt enforcement of the new law. The Biden administration sued to stop the law, and Mr. Pitman’s decision pauses the law while it moves through federal courts, The New York Times reported.

In a 113-page ruling, Mr. Pitman criticized the law, also known as Senate Bill 8, for delegating enforcement to private individuals, who can sue anyone who performs abortions or “aids and abets” them. Plaintiffs are encouraged to file lawsuits because they recover legal fees and $10,000 if they win.

“From the moment S.B. 8 went into effect, women have been unlawfully prevented from exercising control over their own lives in ways that are protected by the Constitution,” Mr. Pitman wrote in the ruling.

“This court will not sanction one more day of this offensive deprivation of such an important right,” he said.

The Texas law bans abortions once fetal cardiac activity can be detected, which is usually around 6 weeks of pregnancy. Women may not know they’re pregnant yet during that time frame.

It’s not yet clear what effect Mr. Pitman’s ruling will have on women in Texas, the Times reported. Since the law went into effect about a month ago, women have sought abortion providers in other states. Mr. Pitman’s ruling pauses the enforcement of the law, but clinics may still face retroactive lawsuits for abortions provided while the law was temporarily suspended.

Whole Woman’s Health, which operates four clinics in Texas, said Wednesday that it was “making plans to resume abortion care up to 18 weeks as soon as possible,” the newspaper reported. The Center for Reproductive Rights also said that clinics “hope to resume full abortion services as soon as they are able.”

Late Oct. 6, Texas said it would appeal the ruling. The U.S. Court of Appeals for the Fifth Circuit is one of the most conservative in the country, according to the Times, and another decision could come soon.

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

A federal judge has paused the recent Texas abortion law that bans nearly all abortions in the state.

Robert Pitman, a federal district court judge in Austin, sided with the Biden administration and granted the Justice Department’s request to halt enforcement of the new law. The Biden administration sued to stop the law, and Mr. Pitman’s decision pauses the law while it moves through federal courts, The New York Times reported.

In a 113-page ruling, Mr. Pitman criticized the law, also known as Senate Bill 8, for delegating enforcement to private individuals, who can sue anyone who performs abortions or “aids and abets” them. Plaintiffs are encouraged to file lawsuits because they recover legal fees and $10,000 if they win.

“From the moment S.B. 8 went into effect, women have been unlawfully prevented from exercising control over their own lives in ways that are protected by the Constitution,” Mr. Pitman wrote in the ruling.

“This court will not sanction one more day of this offensive deprivation of such an important right,” he said.

The Texas law bans abortions once fetal cardiac activity can be detected, which is usually around 6 weeks of pregnancy. Women may not know they’re pregnant yet during that time frame.

It’s not yet clear what effect Mr. Pitman’s ruling will have on women in Texas, the Times reported. Since the law went into effect about a month ago, women have sought abortion providers in other states. Mr. Pitman’s ruling pauses the enforcement of the law, but clinics may still face retroactive lawsuits for abortions provided while the law was temporarily suspended.

Whole Woman’s Health, which operates four clinics in Texas, said Wednesday that it was “making plans to resume abortion care up to 18 weeks as soon as possible,” the newspaper reported. The Center for Reproductive Rights also said that clinics “hope to resume full abortion services as soon as they are able.”

Late Oct. 6, Texas said it would appeal the ruling. The U.S. Court of Appeals for the Fifth Circuit is one of the most conservative in the country, according to the Times, and another decision could come soon.

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

Pfizer asked the FDA on Thursday to expand emergency use authorization of its COVID-19 vaccine to children ages 5 to 11.

The request comes after the drugmaker submitted clinical trial data to the FDA on Sept. 28. Pfizer said the study of 2,268 children showed the vaccine was safe and produced a robust immune response.

Participants in the studies received a lower dose of the vaccine, 10 micrograms. Their response 2 weeks after a second dose was reportedly equal to the immune protection in a control group of 16- to 25-year-olds who received the fully approved 30-microgram doses.

Currently, the Pfizer EUA applies to 12- to 15-year-olds and people eligible for a Pfizer booster shot. The drugmaker received full FDA approval for the vaccine for Americans 16 years and older in August.

The filing for authorization in 5- to 11-year-olds comes as overall cases of COVID-19 in the United States continue to decline. The decrease includes a drop in new cases in children for the fourth consecutive week, according to analysis of data from the American Academy of Pediatrics and the Children’s Hospital Association.

The next step is an FDA decision on whether to expand the current emergency use authorization (EUA) for teenagers to the younger age group.

Timing of any official word from the agency is unknown. But possibly in anticipation of today’s filing, the FDA already scheduled a meeting of its Vaccines and Related Biological Products Advisory Committee for Oct. 25.

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

Pfizer asked the FDA on Thursday to expand emergency use authorization of its COVID-19 vaccine to children ages 5 to 11.

The request comes after the drugmaker submitted clinical trial data to the FDA on Sept. 28. Pfizer said the study of 2,268 children showed the vaccine was safe and produced a robust immune response.

Participants in the studies received a lower dose of the vaccine, 10 micrograms. Their response 2 weeks after a second dose was reportedly equal to the immune protection in a control group of 16- to 25-year-olds who received the fully approved 30-microgram doses.

Currently, the Pfizer EUA applies to 12- to 15-year-olds and people eligible for a Pfizer booster shot. The drugmaker received full FDA approval for the vaccine for Americans 16 years and older in August.

The filing for authorization in 5- to 11-year-olds comes as overall cases of COVID-19 in the United States continue to decline. The decrease includes a drop in new cases in children for the fourth consecutive week, according to analysis of data from the American Academy of Pediatrics and the Children’s Hospital Association.

The next step is an FDA decision on whether to expand the current emergency use authorization (EUA) for teenagers to the younger age group.

Timing of any official word from the agency is unknown. But possibly in anticipation of today’s filing, the FDA already scheduled a meeting of its Vaccines and Related Biological Products Advisory Committee for Oct. 25.

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

Pfizer asked the FDA on Thursday to expand emergency use authorization of its COVID-19 vaccine to children ages 5 to 11.

The request comes after the drugmaker submitted clinical trial data to the FDA on Sept. 28. Pfizer said the study of 2,268 children showed the vaccine was safe and produced a robust immune response.

Participants in the studies received a lower dose of the vaccine, 10 micrograms. Their response 2 weeks after a second dose was reportedly equal to the immune protection in a control group of 16- to 25-year-olds who received the fully approved 30-microgram doses.

Currently, the Pfizer EUA applies to 12- to 15-year-olds and people eligible for a Pfizer booster shot. The drugmaker received full FDA approval for the vaccine for Americans 16 years and older in August.

The filing for authorization in 5- to 11-year-olds comes as overall cases of COVID-19 in the United States continue to decline. The decrease includes a drop in new cases in children for the fourth consecutive week, according to analysis of data from the American Academy of Pediatrics and the Children’s Hospital Association.

The next step is an FDA decision on whether to expand the current emergency use authorization (EUA) for teenagers to the younger age group.

Timing of any official word from the agency is unknown. But possibly in anticipation of today’s filing, the FDA already scheduled a meeting of its Vaccines and Related Biological Products Advisory Committee for Oct. 25.

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

A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, new research suggests.

In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.

After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.

“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.

“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
 

“Exciting early evidence”

“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.

“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.

Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.

“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”

However, she said in an interview that “a lack of safe human agents made translation tricky.”

As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.

The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”

Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.

In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m², and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).

On day 6 of treatment administration, all participants underwent 3T MRI.

Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.

During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
 

Better memory

In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.

However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.

Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).

Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.

There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).

“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.

“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.

Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.

“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.

“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
 

Generalizable findings?

Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”

He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.

“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.

“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.

The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.

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

A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, new research suggests.

In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.

After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.

“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.

“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
 

“Exciting early evidence”

“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.

“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.

Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.

“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”

However, she said in an interview that “a lack of safe human agents made translation tricky.”

As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.

The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”

Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.

In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m², and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).

On day 6 of treatment administration, all participants underwent 3T MRI.

Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.

During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
 

Better memory

In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.

However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.

Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).

Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.

There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).

“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.

“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.

Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.

“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.

“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
 

Generalizable findings?

Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”

He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.

“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.

“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.

The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.

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

A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, new research suggests.

In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.

After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.

“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.

“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
 

“Exciting early evidence”

“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.

“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.

Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.

“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”

However, she said in an interview that “a lack of safe human agents made translation tricky.”

As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.

The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”

Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.

In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m², and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).

On day 6 of treatment administration, all participants underwent 3T MRI.

Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.

During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
 

Better memory

In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.

However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.

Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).

Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.

There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).

“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.

“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.

Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.

“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.

“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
 

Generalizable findings?

Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”

He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.

“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.

“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.

The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.

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

An 8-year-old girl who was infected with SARS-CoV-2 died after developing an extremely rare condition known as acute fulminant cerebral edema (AFCE), according to pediatric neurologists who are urging colleagues to watch out for similar cases.

At least one other child in the United States has died after becoming infected with the virus and developing cerebral edema. “The rapid and devastating clinical course in both of these cases highlights the need for early recognition of a cerebral edema and AFCE as potential complications of COVID-19 in pediatric patients,” the neurologists wrote.

The case was highlighted in a poster presented at the annual meeting of the Child Neurology Society and in a report published earlier this year in Child Neurology Open.

According to pediatric neurologist Timothy Gershon, MD, PhD , of the University of North Carolina at Chapel Hill, the child appeared in clinic in July 2020. She had been healthy but was suffering from 1 day of fever, seizure-like activity (generalized convulsions and drooling), anorexia, and lethargy.

The girl, who was subsequently diagnosed with COVID-19, deteriorated in the hospital. “She received IV dexamethasone in attempts to reduce cerebral edema,” the neurologists wrote. “Regarding immunomodulatory therapy, she received intravenous immunoglobulin (2 g/kg), anakinra, and hydrocortisone; despite approval for remdesivir and COVID-19 convalescent plasma, these were ultimately withheld due to poor prognosis.”

Brain death examinations at 24 and 48 hours after cardiac arrest were consistent with brain death, they reported.

Neurologists believe the patient suffered from AFCE, “an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema.” They add that “AFCE occurs as a rare complication of a variety of common pediatric infections, and a CNS [central nervous system] pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema.”

Neurologists offered a case definition of the “recently recognized” AFCE earlier this year.

“This was an extremely rare rapid progression to cerebral edema. I think it was related to the patient’s COVID infection, but why this patient got it and others don’t is unknown,” Dr. Gershon said in an interview. “The full spectrum of neurological complications of COVID were not yet known [at the time]. We didn’t know, and still don’t know, what the causative links are between COVID and suddenly having seizures and brain swelling.”

He said he’d treat a similar patient differently now and give dexamethasone earlier in the clinical course, although “there is no data to tell us if any therapy could have reversed it.” Specifically, he said, “I’d give dexamethasone at the first sign of brain involvement, using the dosing recommended for cerebral edema, and try to get the MRI earlier in the course.”

Dr. Gershon and colleagues noted another case of fatal cerebral edema in a child, a 7-year-old boy who was treated in New York state. That case “shows that fatal cerebral edema may complicate pediatric multisystem inflammatory syndrome,” they wrote.

Pediatric critical care specialist Preetha Krishnan, MD, of Randall Children’s Hospital at Legacy Emanuel in Portland, Ore., helped develop the new definition of AFCE. In an interview, she said AFCE is difficult to diagnose because the signs/symptoms – such as fever, altered sensorium, and seizures – are found in other conditions such as febrile status epilepticus with a viral illness. 
“The key to recognition of AFCE is that unlike other disease processes, these children have rapid neurologic progression,” she said. “In addition, many of our AFCE patients also had vomiting and/or headache, which in retrospect was likely an indication of elevated ICP [intracranial pressure] rather than viral infection.”
She added that “if a child with fever, seizures, and encephalopathy has cerebral edema on imaging and/or has neurologic progression, AFCE should be considered. Most of our cases of AFCE had fulminant progression within the first 3 days of their head imaging noting cerebral edema. There are other neurologic diseases, such as acute necrotizing encephalopathy of childhood, that also have progressive signs/symptoms, but head imaging and lab work should help differentiate many of these etiologies.”
In regard to treatment, she said, “our unit would likely err on the side of providing as much neuroprotective measures as is reasonable, such as maintaining normothermia, consideration of hyperosmolar therapy, maintaining normocarbia and normoxemia, managing seizures, etc. I would recommend getting the entire neurocritical care team involved in the management discussion. This varies by center, but will likely include neurology, ID [infectious disease], possibly neurosurgery, and PICU.”
As for the new case report, Krishnan said COVID-19 has been linked to neurologic complications, “so it does not surprise me that AFCE is part of the neurologic spectrum of disease.”
No funding was reported, and the authors report no relevant disclosures. Dr. Krishnan has no disclosures.

An 8-year-old girl who was infected with SARS-CoV-2 died after developing an extremely rare condition known as acute fulminant cerebral edema (AFCE), according to pediatric neurologists who are urging colleagues to watch out for similar cases.

At least one other child in the United States has died after becoming infected with the virus and developing cerebral edema. “The rapid and devastating clinical course in both of these cases highlights the need for early recognition of a cerebral edema and AFCE as potential complications of COVID-19 in pediatric patients,” the neurologists wrote.

The case was highlighted in a poster presented at the annual meeting of the Child Neurology Society and in a report published earlier this year in Child Neurology Open.

According to pediatric neurologist Timothy Gershon, MD, PhD , of the University of North Carolina at Chapel Hill, the child appeared in clinic in July 2020. She had been healthy but was suffering from 1 day of fever, seizure-like activity (generalized convulsions and drooling), anorexia, and lethargy.

The girl, who was subsequently diagnosed with COVID-19, deteriorated in the hospital. “She received IV dexamethasone in attempts to reduce cerebral edema,” the neurologists wrote. “Regarding immunomodulatory therapy, she received intravenous immunoglobulin (2 g/kg), anakinra, and hydrocortisone; despite approval for remdesivir and COVID-19 convalescent plasma, these were ultimately withheld due to poor prognosis.”

Brain death examinations at 24 and 48 hours after cardiac arrest were consistent with brain death, they reported.

Neurologists believe the patient suffered from AFCE, “an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema.” They add that “AFCE occurs as a rare complication of a variety of common pediatric infections, and a CNS [central nervous system] pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema.”

Neurologists offered a case definition of the “recently recognized” AFCE earlier this year.

“This was an extremely rare rapid progression to cerebral edema. I think it was related to the patient’s COVID infection, but why this patient got it and others don’t is unknown,” Dr. Gershon said in an interview. “The full spectrum of neurological complications of COVID were not yet known [at the time]. We didn’t know, and still don’t know, what the causative links are between COVID and suddenly having seizures and brain swelling.”

He said he’d treat a similar patient differently now and give dexamethasone earlier in the clinical course, although “there is no data to tell us if any therapy could have reversed it.” Specifically, he said, “I’d give dexamethasone at the first sign of brain involvement, using the dosing recommended for cerebral edema, and try to get the MRI earlier in the course.”

Dr. Gershon and colleagues noted another case of fatal cerebral edema in a child, a 7-year-old boy who was treated in New York state. That case “shows that fatal cerebral edema may complicate pediatric multisystem inflammatory syndrome,” they wrote.

Pediatric critical care specialist Preetha Krishnan, MD, of Randall Children’s Hospital at Legacy Emanuel in Portland, Ore., helped develop the new definition of AFCE. In an interview, she said AFCE is difficult to diagnose because the signs/symptoms – such as fever, altered sensorium, and seizures – are found in other conditions such as febrile status epilepticus with a viral illness. 
“The key to recognition of AFCE is that unlike other disease processes, these children have rapid neurologic progression,” she said. “In addition, many of our AFCE patients also had vomiting and/or headache, which in retrospect was likely an indication of elevated ICP [intracranial pressure] rather than viral infection.”
She added that “if a child with fever, seizures, and encephalopathy has cerebral edema on imaging and/or has neurologic progression, AFCE should be considered. Most of our cases of AFCE had fulminant progression within the first 3 days of their head imaging noting cerebral edema. There are other neurologic diseases, such as acute necrotizing encephalopathy of childhood, that also have progressive signs/symptoms, but head imaging and lab work should help differentiate many of these etiologies.”
In regard to treatment, she said, “our unit would likely err on the side of providing as much neuroprotective measures as is reasonable, such as maintaining normothermia, consideration of hyperosmolar therapy, maintaining normocarbia and normoxemia, managing seizures, etc. I would recommend getting the entire neurocritical care team involved in the management discussion. This varies by center, but will likely include neurology, ID [infectious disease], possibly neurosurgery, and PICU.”
As for the new case report, Krishnan said COVID-19 has been linked to neurologic complications, “so it does not surprise me that AFCE is part of the neurologic spectrum of disease.”
No funding was reported, and the authors report no relevant disclosures. Dr. Krishnan has no disclosures.

An 8-year-old girl who was infected with SARS-CoV-2 died after developing an extremely rare condition known as acute fulminant cerebral edema (AFCE), according to pediatric neurologists who are urging colleagues to watch out for similar cases.

At least one other child in the United States has died after becoming infected with the virus and developing cerebral edema. “The rapid and devastating clinical course in both of these cases highlights the need for early recognition of a cerebral edema and AFCE as potential complications of COVID-19 in pediatric patients,” the neurologists wrote.

The case was highlighted in a poster presented at the annual meeting of the Child Neurology Society and in a report published earlier this year in Child Neurology Open.

According to pediatric neurologist Timothy Gershon, MD, PhD , of the University of North Carolina at Chapel Hill, the child appeared in clinic in July 2020. She had been healthy but was suffering from 1 day of fever, seizure-like activity (generalized convulsions and drooling), anorexia, and lethargy.

The girl, who was subsequently diagnosed with COVID-19, deteriorated in the hospital. “She received IV dexamethasone in attempts to reduce cerebral edema,” the neurologists wrote. “Regarding immunomodulatory therapy, she received intravenous immunoglobulin (2 g/kg), anakinra, and hydrocortisone; despite approval for remdesivir and COVID-19 convalescent plasma, these were ultimately withheld due to poor prognosis.”

Brain death examinations at 24 and 48 hours after cardiac arrest were consistent with brain death, they reported.

Neurologists believe the patient suffered from AFCE, “an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema.” They add that “AFCE occurs as a rare complication of a variety of common pediatric infections, and a CNS [central nervous system] pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema.”

Neurologists offered a case definition of the “recently recognized” AFCE earlier this year.

“This was an extremely rare rapid progression to cerebral edema. I think it was related to the patient’s COVID infection, but why this patient got it and others don’t is unknown,” Dr. Gershon said in an interview. “The full spectrum of neurological complications of COVID were not yet known [at the time]. We didn’t know, and still don’t know, what the causative links are between COVID and suddenly having seizures and brain swelling.”

He said he’d treat a similar patient differently now and give dexamethasone earlier in the clinical course, although “there is no data to tell us if any therapy could have reversed it.” Specifically, he said, “I’d give dexamethasone at the first sign of brain involvement, using the dosing recommended for cerebral edema, and try to get the MRI earlier in the course.”

Dr. Gershon and colleagues noted another case of fatal cerebral edema in a child, a 7-year-old boy who was treated in New York state. That case “shows that fatal cerebral edema may complicate pediatric multisystem inflammatory syndrome,” they wrote.

Pediatric critical care specialist Preetha Krishnan, MD, of Randall Children’s Hospital at Legacy Emanuel in Portland, Ore., helped develop the new definition of AFCE. In an interview, she said AFCE is difficult to diagnose because the signs/symptoms – such as fever, altered sensorium, and seizures – are found in other conditions such as febrile status epilepticus with a viral illness. 
“The key to recognition of AFCE is that unlike other disease processes, these children have rapid neurologic progression,” she said. “In addition, many of our AFCE patients also had vomiting and/or headache, which in retrospect was likely an indication of elevated ICP [intracranial pressure] rather than viral infection.”
She added that “if a child with fever, seizures, and encephalopathy has cerebral edema on imaging and/or has neurologic progression, AFCE should be considered. Most of our cases of AFCE had fulminant progression within the first 3 days of their head imaging noting cerebral edema. There are other neurologic diseases, such as acute necrotizing encephalopathy of childhood, that also have progressive signs/symptoms, but head imaging and lab work should help differentiate many of these etiologies.”
In regard to treatment, she said, “our unit would likely err on the side of providing as much neuroprotective measures as is reasonable, such as maintaining normothermia, consideration of hyperosmolar therapy, maintaining normocarbia and normoxemia, managing seizures, etc. I would recommend getting the entire neurocritical care team involved in the management discussion. This varies by center, but will likely include neurology, ID [infectious disease], possibly neurosurgery, and PICU.”
As for the new case report, Krishnan said COVID-19 has been linked to neurologic complications, “so it does not surprise me that AFCE is part of the neurologic spectrum of disease.”
No funding was reported, and the authors report no relevant disclosures. Dr. Krishnan has no disclosures.

Newborns of pregnant women who were treated with selective serotonin reuptake inhibitors during the third trimester are almost three times as likely to develop neonatal encephalopathy (NE), although the overall risk remains extremely low, a new study finds.

The findings were presented in a poster at the 50th annual meeting of the Child Neurology Society.

“Our work showed that neonates exposed to SSRI in utero had higher risks of neonatal encephalopathy even when adjusting for confounders such as maternal mental health disorders and age. SSRIs could cause side effects such as encephalopathy in neonates, and these risks need to be balanced carefully with the potential benefits of treatment to the mother,” study lead author Marie Cornet, MD, a neonatology fellow with Benioff Children’s Hospital at the University of California, San Francisco, said in an interview.

According to Dr. Cornet, “we know that SSRI exposure in utero is associated with increased risks of respiratory distress at birth, need for positive-pressure ventilation, and an abnormal neurologic exam.” The researchers launched the new study to determine if the estimated 4%-8% of pregnant women who take SSRIs may be putting their newborns at greater risk of NE.

The researchers retrospectively tracked 305,426 infants who were born in the Kaiser Permanente Northern California health system (≥35 weeks) from 2011 to 2019. The mothers had an average age of 31 years, and approximately 34.7% were White, 34.7% of unknown race, 23.3% Asian, and 6.2% Black.

The researchers defined NE as a “5-minute APGAR score <7 and abnormal level of consciousness, activity, tone, or reflexes.”

A total of 8,024 infants (2.6%) had mothers who used SSRIs in the third trimester, and 510 (0.17%) were determined to have had NE.

After adjustment for maternal depression or anxiety, maternal age, race, and hospital, exposed neonates had 2.7 times higher odds of NE (odds ratio, 2.7).

Each 25 mg per day increase in the dose of SSRIs, as equalized to doses of sertraline (Zoloft), was linked to a significant 31% increase in the odds of developing NE (OR, 1.31).

The study doesn’t examine the benefits of SSRI treatment in pregnancy. Those taking SSRIs were much more likely to have depression during pregnancy (76.5% vs. 13.5%) and anxiety (56.7% vs. 6.9%), compared with those who did not take the drug.

The possible connection between SSRIs and NE is unclear. “SSRIs may contribute to NE by a withdrawal mechanism or by a toxicity mechanism. It is also possible that SSRIs themselves are not responsible for encephalopathy, or that the severity of maternal mental health is itself responsible for increased neonatal encephalopathy,” Dr. Cornet said. “However, we believe we adjusted our results thoroughly for that. Furthermore, in this cohort, neonates born from mothers with untreated depression were not at higher risk of encephalopathy than neonates born to mothers without depression.”

She added: “When infants have acidosis or require prolonged resuscitation after birth, they get treated with therapeutic hypothermia. This invasive treatment was shown to decrease mortality and morbidity in neonates with hypoxic-ischemic encephalopathy. However, therapeutic hypothermia may not be helpful in infants with encephalopathy due to other causes than acute hypoxia-ischemia, such as infection, inflammation, genetic conditions, or exposure to toxins. In the case of SSRIs, our results show that, while neonates often have encephalopathy, this encephalopathy is often mild and self-resolved. We did not see a statistically significant increase in acidosis or treatment with therapeutic hypothermia.”

In the future neurologists should consider SSRI use as a potential cause in cases of NE, Dr. Cornet said. “If there are no signs of hypoxic-ischemic encephalopathy – no evidence of acidosis, acute perinatal event – treatment with therapeutic hypothermia may not be indicated.”

Dr. Cornet said more research is in the works. “Studying the long-term side effect of SSRIs on neonatal brain development and injury is essential,” she said. “We plan to compare brain injury in neonates exposed and unexposed to SSRIs and examine long-term outcomes to assess if the effect of SSRI exposure is transient or has a lasting impact.”

This study was funded by the Thrasher Early Career Research Grant and by the Newborn Brain Research Innovation Award at UCSF. The authors have no relevant disclosures.
 

Newborns of pregnant women who were treated with selective serotonin reuptake inhibitors during the third trimester are almost three times as likely to develop neonatal encephalopathy (NE), although the overall risk remains extremely low, a new study finds.

The findings were presented in a poster at the 50th annual meeting of the Child Neurology Society.

“Our work showed that neonates exposed to SSRI in utero had higher risks of neonatal encephalopathy even when adjusting for confounders such as maternal mental health disorders and age. SSRIs could cause side effects such as encephalopathy in neonates, and these risks need to be balanced carefully with the potential benefits of treatment to the mother,” study lead author Marie Cornet, MD, a neonatology fellow with Benioff Children’s Hospital at the University of California, San Francisco, said in an interview.

According to Dr. Cornet, “we know that SSRI exposure in utero is associated with increased risks of respiratory distress at birth, need for positive-pressure ventilation, and an abnormal neurologic exam.” The researchers launched the new study to determine if the estimated 4%-8% of pregnant women who take SSRIs may be putting their newborns at greater risk of NE.

The researchers retrospectively tracked 305,426 infants who were born in the Kaiser Permanente Northern California health system (≥35 weeks) from 2011 to 2019. The mothers had an average age of 31 years, and approximately 34.7% were White, 34.7% of unknown race, 23.3% Asian, and 6.2% Black.

The researchers defined NE as a “5-minute APGAR score <7 and abnormal level of consciousness, activity, tone, or reflexes.”

A total of 8,024 infants (2.6%) had mothers who used SSRIs in the third trimester, and 510 (0.17%) were determined to have had NE.

After adjustment for maternal depression or anxiety, maternal age, race, and hospital, exposed neonates had 2.7 times higher odds of NE (odds ratio, 2.7).

Each 25 mg per day increase in the dose of SSRIs, as equalized to doses of sertraline (Zoloft), was linked to a significant 31% increase in the odds of developing NE (OR, 1.31).

The study doesn’t examine the benefits of SSRI treatment in pregnancy. Those taking SSRIs were much more likely to have depression during pregnancy (76.5% vs. 13.5%) and anxiety (56.7% vs. 6.9%), compared with those who did not take the drug.

The possible connection between SSRIs and NE is unclear. “SSRIs may contribute to NE by a withdrawal mechanism or by a toxicity mechanism. It is also possible that SSRIs themselves are not responsible for encephalopathy, or that the severity of maternal mental health is itself responsible for increased neonatal encephalopathy,” Dr. Cornet said. “However, we believe we adjusted our results thoroughly for that. Furthermore, in this cohort, neonates born from mothers with untreated depression were not at higher risk of encephalopathy than neonates born to mothers without depression.”

She added: “When infants have acidosis or require prolonged resuscitation after birth, they get treated with therapeutic hypothermia. This invasive treatment was shown to decrease mortality and morbidity in neonates with hypoxic-ischemic encephalopathy. However, therapeutic hypothermia may not be helpful in infants with encephalopathy due to other causes than acute hypoxia-ischemia, such as infection, inflammation, genetic conditions, or exposure to toxins. In the case of SSRIs, our results show that, while neonates often have encephalopathy, this encephalopathy is often mild and self-resolved. We did not see a statistically significant increase in acidosis or treatment with therapeutic hypothermia.”

In the future neurologists should consider SSRI use as a potential cause in cases of NE, Dr. Cornet said. “If there are no signs of hypoxic-ischemic encephalopathy – no evidence of acidosis, acute perinatal event – treatment with therapeutic hypothermia may not be indicated.”

Dr. Cornet said more research is in the works. “Studying the long-term side effect of SSRIs on neonatal brain development and injury is essential,” she said. “We plan to compare brain injury in neonates exposed and unexposed to SSRIs and examine long-term outcomes to assess if the effect of SSRI exposure is transient or has a lasting impact.”

This study was funded by the Thrasher Early Career Research Grant and by the Newborn Brain Research Innovation Award at UCSF. The authors have no relevant disclosures.
 

Newborns of pregnant women who were treated with selective serotonin reuptake inhibitors during the third trimester are almost three times as likely to develop neonatal encephalopathy (NE), although the overall risk remains extremely low, a new study finds.

The findings were presented in a poster at the 50th annual meeting of the Child Neurology Society.

“Our work showed that neonates exposed to SSRI in utero had higher risks of neonatal encephalopathy even when adjusting for confounders such as maternal mental health disorders and age. SSRIs could cause side effects such as encephalopathy in neonates, and these risks need to be balanced carefully with the potential benefits of treatment to the mother,” study lead author Marie Cornet, MD, a neonatology fellow with Benioff Children’s Hospital at the University of California, San Francisco, said in an interview.

According to Dr. Cornet, “we know that SSRI exposure in utero is associated with increased risks of respiratory distress at birth, need for positive-pressure ventilation, and an abnormal neurologic exam.” The researchers launched the new study to determine if the estimated 4%-8% of pregnant women who take SSRIs may be putting their newborns at greater risk of NE.

The researchers retrospectively tracked 305,426 infants who were born in the Kaiser Permanente Northern California health system (≥35 weeks) from 2011 to 2019. The mothers had an average age of 31 years, and approximately 34.7% were White, 34.7% of unknown race, 23.3% Asian, and 6.2% Black.

The researchers defined NE as a “5-minute APGAR score <7 and abnormal level of consciousness, activity, tone, or reflexes.”

A total of 8,024 infants (2.6%) had mothers who used SSRIs in the third trimester, and 510 (0.17%) were determined to have had NE.

After adjustment for maternal depression or anxiety, maternal age, race, and hospital, exposed neonates had 2.7 times higher odds of NE (odds ratio, 2.7).

Each 25 mg per day increase in the dose of SSRIs, as equalized to doses of sertraline (Zoloft), was linked to a significant 31% increase in the odds of developing NE (OR, 1.31).

The study doesn’t examine the benefits of SSRI treatment in pregnancy. Those taking SSRIs were much more likely to have depression during pregnancy (76.5% vs. 13.5%) and anxiety (56.7% vs. 6.9%), compared with those who did not take the drug.

The possible connection between SSRIs and NE is unclear. “SSRIs may contribute to NE by a withdrawal mechanism or by a toxicity mechanism. It is also possible that SSRIs themselves are not responsible for encephalopathy, or that the severity of maternal mental health is itself responsible for increased neonatal encephalopathy,” Dr. Cornet said. “However, we believe we adjusted our results thoroughly for that. Furthermore, in this cohort, neonates born from mothers with untreated depression were not at higher risk of encephalopathy than neonates born to mothers without depression.”

She added: “When infants have acidosis or require prolonged resuscitation after birth, they get treated with therapeutic hypothermia. This invasive treatment was shown to decrease mortality and morbidity in neonates with hypoxic-ischemic encephalopathy. However, therapeutic hypothermia may not be helpful in infants with encephalopathy due to other causes than acute hypoxia-ischemia, such as infection, inflammation, genetic conditions, or exposure to toxins. In the case of SSRIs, our results show that, while neonates often have encephalopathy, this encephalopathy is often mild and self-resolved. We did not see a statistically significant increase in acidosis or treatment with therapeutic hypothermia.”

In the future neurologists should consider SSRI use as a potential cause in cases of NE, Dr. Cornet said. “If there are no signs of hypoxic-ischemic encephalopathy – no evidence of acidosis, acute perinatal event – treatment with therapeutic hypothermia may not be indicated.”

Dr. Cornet said more research is in the works. “Studying the long-term side effect of SSRIs on neonatal brain development and injury is essential,” she said. “We plan to compare brain injury in neonates exposed and unexposed to SSRIs and examine long-term outcomes to assess if the effect of SSRI exposure is transient or has a lasting impact.”

This study was funded by the Thrasher Early Career Research Grant and by the Newborn Brain Research Innovation Award at UCSF. The authors have no relevant disclosures.
 

Soon after Merck announced on Oct. 1 that it would ask federal regulators for emergency use authorization (EUA) for its auspicious new COVID-19 pill, the accolades began.

Former Food and Drug Administration chief Scott Gottlieb, MD, told CNBC the drug was “a profound game changer.” Top infectious disease expert Anthony S. Fauci, MD, called the early data “impressive.” The World Health Organization termed it “certainly good news,” while saying it awaits more data.

Merck, partnering with Ridgeback Biotherapeutics on the investigational oral antiviral medicine molnupiravir, plans to submit applications to regulatory agencies worldwide, hoping to deliver the first oral antiviral medication for COVID-19. 

Interim clinical trial results show that the drug may slash the risk for hospitalization or death by 50% in those with mild to moderate COVID-19.

When the results were found to be so favorable, the study was halted at the recommendation of an independent data-monitoring committee and in consultation with the FDA.

That initial enthusiasm is now tempered with some perspective on the pros and cons. “This anticipated drug has gotten a little more hype than it deserves,” said William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tenn. He and others suggest a reality check.

“It’s not exactly a home run, like penicillin for strep throat,” agreed Carl Fichtenbaum, MD, professor of infectious diseases at the University of Cincinnati, who is investigating a similar pill for a rival company, Atea, partnering with Roche. 

“But it is encouraging,” he said. “It will probably be an incremental improvement on what we have.” The fact that it can be taken at home is a plus: “Anything we can do to keep people from getting sicker is a good thing.”

“The data show in this higher risk group [those who were studied had at least one risk factor for severe COVID-19, such as age or a medical condition], it reduces the risk of advancing to severe disease by 50%,” Dr. Schaffner said. While that’s a clear benefit for half, it of course leaves the other half without benefit, he said.

Others critiqued the predicted cost of the drug. The U.S. government has already agreed to pay about $700 per patient, according to a new report from Harvard T. H. Chan School of Public Health, Boston, and King’s College Hospital, London. That analysis concluded that the actual cost of production for the 5-day course is $17.74.

“We fully expect that having an oral treatment that reduces the risk of hospitalizations will be significantly cost effective for society,” Melissa Moody, a Merck spokesperson, told this news organization. “We are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”

Merck expects to produce 10 million courses of treatment by the end of the year, with additional doses expected to be produced in 2022, according to a company press release. Earlier in 2021, Merck finalized its agreement with the U.S. government to supply about 1.7 million courses of the drug at the $700 price, once an EUA or FDA approval is given.

Merck also has supply and purchase agreements with other governments worldwide, pending regulatory approval.
 

Study details

Details about the study findings came from a Merck press release. In the planned interim analysis, Merck and Ridgeback evaluated data from 775 patients initially enrolled in the phase 3 MOVe-OUT trial.

All adults had lab-confirmed mild to moderate COVID-19, and reported onset of symptoms within 5 days of being randomly assigned to the drug or placebo. All had at least one risk factor linked with poor disease outcome (such as older age or obesity).

The drug is a ribonucleoside and works by creating mutations in the virus’s genome, halting the ability of the virus to replicate.

Through day 29 of the study, the drug reduced the risk or hospitalization or death by about 50%. While 7.3% of those who received the drug either died or were hospitalized by day 29, 14.1% of those on placebo did, a statistically significant difference (P = .0012).

Side effects were similar in both groups, with 35% of the drug-treated and 40% of the placebo group reporting some side effect, Merck reported. Adverse drug-related events were 12% in the drug group and 11% in the placebo group. While 1.3% of the drug-treated group quit the study because of an adverse event, 3.4% of the placebo group quit.
 

Pros, cons, and unknowns

The ability to take the drug orally, and at home, is a definite plus, Dr. Schaffner said,  compared with the monoclonal antibody treatment currently approved that must be given intravenously or subcutaneously and in certain locations.

More people could be reached and helped with the option of an at-home, oral medicine, he and others agreed.

The regimen for molnupiravir is four pills, two times daily, for 5 days, even if symptoms are mild. As with other prescription drugs, “there will always be folks who don’t comply completely” with the prescribed regimen, Dr. Schaffner said. With this pill, that might be especially true if the symptoms are very mild.

The 50% reduction is not as effective as the benefit often quoted for monoclonal antibody treatment. In clinical trials of Regeneron’s monoclonal antibody treatment, the regimen reduced COVID-19–related hospitalization or death in high-risk patients by 70%.

Even so, the new pill could change the pandemic’s course, others say. “I think molnupiravir has the potential to change how we take care of people who have COVID and risk factors for developing severe disease,” Rajesh Tim Gandhi, MD, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization. 

“What we’ll need to do, however, is make sure that people get tested quickly after they develop symptoms and, if they’re confirmed to have COVID, start on the pills within 5 days of developing symptoms,” he said, while warning that more data are needed about the drug and the trial results.

Another concern is that the promise of a pill will stall vaccination rates, with some people figuring why get vaccinated when they can obtain the pill if they do get sick.

Relying on treatment alone won’t work, Dr. Schaffner said. “Let’s [also] focus on prevention, which is the vaccine. We have to keep working both sides of the street.”

Dr. Gandhi added: “It’s important to remember that even though molnupiravir reduced the likelihood of hospitalization and death, a number of people who received the drug still got sick enough to end up in the hospital.”

Also unknown, he said, is how severe their disease was and whether they will develop long COVID.

The Merck study included only unvaccinated people. Might it work for those vaccinated people who get a breakthrough infection? “From a purely scientific perspective, there is no reason to believe molnupiravir would not work in people who are vaccinated, but the overall efficacy on top of the vaccine is likely dependent on how well they were able to mount a protective immune response to the vaccine,” Ms. Moody said. Still, Merck believes the pill could be of benefit for these infections too, she added.

As for the expected cost, Ms. Moody said that the company takes into account a number of factors in setting pricing, “but fundamentally we look at the impact of the disease, the benefits that the drug delivers to patients and to society, and at supporting ongoing drug development.”
 

On Merck’s heels: Pfizer, Roche, Atea

Pfizer is studying an antiviral pill, PF-07321332, a protease inhibitor that blocks the protease enzymes and halts replication of the virus.

In addition to studying the drug in infected patients at high risk of severe illness and in those at typical risk, Pfizer launched a phase 2-3 study in late September that will enroll people who live in the same household as a person with a confirmed, symptomatic COVID-19 infection to see if the drug can prevent disease in those who have been exposed.

Atea and Roche’s COVID pill, AT527, is in phase 3 trials as well. AT527 is an inhibitor of polymerase, an enzyme many viruses have, to stop replications. Atea is evaluating the drug to reduce disease “burden” and for both pre- and postexposure prevention.
 

Big picture: Role of COVID-19 pills

It may be necessary to target the coronavirus with more than one antiviral agent, said Dr. Fichtenbaum, a principal investigator for the AT527 trials. 

“Sometimes viruses require two or three active agents to control their replication,” he said, citing information gleaned from other viral research, such as HIV. For control of HIV infection, a cocktail or combination of antivirals is often recommended.

That may well be the case for COVID-19, Dr. Fichtenbaum said. The goal would be to attack the virus at more than one pathway.

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

Soon after Merck announced on Oct. 1 that it would ask federal regulators for emergency use authorization (EUA) for its auspicious new COVID-19 pill, the accolades began.

Former Food and Drug Administration chief Scott Gottlieb, MD, told CNBC the drug was “a profound game changer.” Top infectious disease expert Anthony S. Fauci, MD, called the early data “impressive.” The World Health Organization termed it “certainly good news,” while saying it awaits more data.

Merck, partnering with Ridgeback Biotherapeutics on the investigational oral antiviral medicine molnupiravir, plans to submit applications to regulatory agencies worldwide, hoping to deliver the first oral antiviral medication for COVID-19. 

Interim clinical trial results show that the drug may slash the risk for hospitalization or death by 50% in those with mild to moderate COVID-19.

When the results were found to be so favorable, the study was halted at the recommendation of an independent data-monitoring committee and in consultation with the FDA.

That initial enthusiasm is now tempered with some perspective on the pros and cons. “This anticipated drug has gotten a little more hype than it deserves,” said William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tenn. He and others suggest a reality check.

“It’s not exactly a home run, like penicillin for strep throat,” agreed Carl Fichtenbaum, MD, professor of infectious diseases at the University of Cincinnati, who is investigating a similar pill for a rival company, Atea, partnering with Roche. 

“But it is encouraging,” he said. “It will probably be an incremental improvement on what we have.” The fact that it can be taken at home is a plus: “Anything we can do to keep people from getting sicker is a good thing.”

“The data show in this higher risk group [those who were studied had at least one risk factor for severe COVID-19, such as age or a medical condition], it reduces the risk of advancing to severe disease by 50%,” Dr. Schaffner said. While that’s a clear benefit for half, it of course leaves the other half without benefit, he said.

Others critiqued the predicted cost of the drug. The U.S. government has already agreed to pay about $700 per patient, according to a new report from Harvard T. H. Chan School of Public Health, Boston, and King’s College Hospital, London. That analysis concluded that the actual cost of production for the 5-day course is $17.74.

“We fully expect that having an oral treatment that reduces the risk of hospitalizations will be significantly cost effective for society,” Melissa Moody, a Merck spokesperson, told this news organization. “We are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”

Merck expects to produce 10 million courses of treatment by the end of the year, with additional doses expected to be produced in 2022, according to a company press release. Earlier in 2021, Merck finalized its agreement with the U.S. government to supply about 1.7 million courses of the drug at the $700 price, once an EUA or FDA approval is given.

Merck also has supply and purchase agreements with other governments worldwide, pending regulatory approval.
 

Study details

Details about the study findings came from a Merck press release. In the planned interim analysis, Merck and Ridgeback evaluated data from 775 patients initially enrolled in the phase 3 MOVe-OUT trial.

All adults had lab-confirmed mild to moderate COVID-19, and reported onset of symptoms within 5 days of being randomly assigned to the drug or placebo. All had at least one risk factor linked with poor disease outcome (such as older age or obesity).

The drug is a ribonucleoside and works by creating mutations in the virus’s genome, halting the ability of the virus to replicate.

Through day 29 of the study, the drug reduced the risk or hospitalization or death by about 50%. While 7.3% of those who received the drug either died or were hospitalized by day 29, 14.1% of those on placebo did, a statistically significant difference (P = .0012).

Side effects were similar in both groups, with 35% of the drug-treated and 40% of the placebo group reporting some side effect, Merck reported. Adverse drug-related events were 12% in the drug group and 11% in the placebo group. While 1.3% of the drug-treated group quit the study because of an adverse event, 3.4% of the placebo group quit.
 

Pros, cons, and unknowns

The ability to take the drug orally, and at home, is a definite plus, Dr. Schaffner said,  compared with the monoclonal antibody treatment currently approved that must be given intravenously or subcutaneously and in certain locations.

More people could be reached and helped with the option of an at-home, oral medicine, he and others agreed.

The regimen for molnupiravir is four pills, two times daily, for 5 days, even if symptoms are mild. As with other prescription drugs, “there will always be folks who don’t comply completely” with the prescribed regimen, Dr. Schaffner said. With this pill, that might be especially true if the symptoms are very mild.

The 50% reduction is not as effective as the benefit often quoted for monoclonal antibody treatment. In clinical trials of Regeneron’s monoclonal antibody treatment, the regimen reduced COVID-19–related hospitalization or death in high-risk patients by 70%.

Even so, the new pill could change the pandemic’s course, others say. “I think molnupiravir has the potential to change how we take care of people who have COVID and risk factors for developing severe disease,” Rajesh Tim Gandhi, MD, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization. 

“What we’ll need to do, however, is make sure that people get tested quickly after they develop symptoms and, if they’re confirmed to have COVID, start on the pills within 5 days of developing symptoms,” he said, while warning that more data are needed about the drug and the trial results.

Another concern is that the promise of a pill will stall vaccination rates, with some people figuring why get vaccinated when they can obtain the pill if they do get sick.

Relying on treatment alone won’t work, Dr. Schaffner said. “Let’s [also] focus on prevention, which is the vaccine. We have to keep working both sides of the street.”

Dr. Gandhi added: “It’s important to remember that even though molnupiravir reduced the likelihood of hospitalization and death, a number of people who received the drug still got sick enough to end up in the hospital.”

Also unknown, he said, is how severe their disease was and whether they will develop long COVID.

The Merck study included only unvaccinated people. Might it work for those vaccinated people who get a breakthrough infection? “From a purely scientific perspective, there is no reason to believe molnupiravir would not work in people who are vaccinated, but the overall efficacy on top of the vaccine is likely dependent on how well they were able to mount a protective immune response to the vaccine,” Ms. Moody said. Still, Merck believes the pill could be of benefit for these infections too, she added.

As for the expected cost, Ms. Moody said that the company takes into account a number of factors in setting pricing, “but fundamentally we look at the impact of the disease, the benefits that the drug delivers to patients and to society, and at supporting ongoing drug development.”
 

On Merck’s heels: Pfizer, Roche, Atea

Pfizer is studying an antiviral pill, PF-07321332, a protease inhibitor that blocks the protease enzymes and halts replication of the virus.

In addition to studying the drug in infected patients at high risk of severe illness and in those at typical risk, Pfizer launched a phase 2-3 study in late September that will enroll people who live in the same household as a person with a confirmed, symptomatic COVID-19 infection to see if the drug can prevent disease in those who have been exposed.

Atea and Roche’s COVID pill, AT527, is in phase 3 trials as well. AT527 is an inhibitor of polymerase, an enzyme many viruses have, to stop replications. Atea is evaluating the drug to reduce disease “burden” and for both pre- and postexposure prevention.
 

Big picture: Role of COVID-19 pills

It may be necessary to target the coronavirus with more than one antiviral agent, said Dr. Fichtenbaum, a principal investigator for the AT527 trials. 

“Sometimes viruses require two or three active agents to control their replication,” he said, citing information gleaned from other viral research, such as HIV. For control of HIV infection, a cocktail or combination of antivirals is often recommended.

That may well be the case for COVID-19, Dr. Fichtenbaum said. The goal would be to attack the virus at more than one pathway.

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

Soon after Merck announced on Oct. 1 that it would ask federal regulators for emergency use authorization (EUA) for its auspicious new COVID-19 pill, the accolades began.

Former Food and Drug Administration chief Scott Gottlieb, MD, told CNBC the drug was “a profound game changer.” Top infectious disease expert Anthony S. Fauci, MD, called the early data “impressive.” The World Health Organization termed it “certainly good news,” while saying it awaits more data.

Merck, partnering with Ridgeback Biotherapeutics on the investigational oral antiviral medicine molnupiravir, plans to submit applications to regulatory agencies worldwide, hoping to deliver the first oral antiviral medication for COVID-19. 

Interim clinical trial results show that the drug may slash the risk for hospitalization or death by 50% in those with mild to moderate COVID-19.

When the results were found to be so favorable, the study was halted at the recommendation of an independent data-monitoring committee and in consultation with the FDA.

That initial enthusiasm is now tempered with some perspective on the pros and cons. “This anticipated drug has gotten a little more hype than it deserves,” said William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tenn. He and others suggest a reality check.

“It’s not exactly a home run, like penicillin for strep throat,” agreed Carl Fichtenbaum, MD, professor of infectious diseases at the University of Cincinnati, who is investigating a similar pill for a rival company, Atea, partnering with Roche. 

“But it is encouraging,” he said. “It will probably be an incremental improvement on what we have.” The fact that it can be taken at home is a plus: “Anything we can do to keep people from getting sicker is a good thing.”

“The data show in this higher risk group [those who were studied had at least one risk factor for severe COVID-19, such as age or a medical condition], it reduces the risk of advancing to severe disease by 50%,” Dr. Schaffner said. While that’s a clear benefit for half, it of course leaves the other half without benefit, he said.

Others critiqued the predicted cost of the drug. The U.S. government has already agreed to pay about $700 per patient, according to a new report from Harvard T. H. Chan School of Public Health, Boston, and King’s College Hospital, London. That analysis concluded that the actual cost of production for the 5-day course is $17.74.

“We fully expect that having an oral treatment that reduces the risk of hospitalizations will be significantly cost effective for society,” Melissa Moody, a Merck spokesperson, told this news organization. “We are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”

Merck expects to produce 10 million courses of treatment by the end of the year, with additional doses expected to be produced in 2022, according to a company press release. Earlier in 2021, Merck finalized its agreement with the U.S. government to supply about 1.7 million courses of the drug at the $700 price, once an EUA or FDA approval is given.

Merck also has supply and purchase agreements with other governments worldwide, pending regulatory approval.
 

Study details

Details about the study findings came from a Merck press release. In the planned interim analysis, Merck and Ridgeback evaluated data from 775 patients initially enrolled in the phase 3 MOVe-OUT trial.

All adults had lab-confirmed mild to moderate COVID-19, and reported onset of symptoms within 5 days of being randomly assigned to the drug or placebo. All had at least one risk factor linked with poor disease outcome (such as older age or obesity).

The drug is a ribonucleoside and works by creating mutations in the virus’s genome, halting the ability of the virus to replicate.

Through day 29 of the study, the drug reduced the risk or hospitalization or death by about 50%. While 7.3% of those who received the drug either died or were hospitalized by day 29, 14.1% of those on placebo did, a statistically significant difference (P = .0012).

Side effects were similar in both groups, with 35% of the drug-treated and 40% of the placebo group reporting some side effect, Merck reported. Adverse drug-related events were 12% in the drug group and 11% in the placebo group. While 1.3% of the drug-treated group quit the study because of an adverse event, 3.4% of the placebo group quit.
 

Pros, cons, and unknowns

The ability to take the drug orally, and at home, is a definite plus, Dr. Schaffner said,  compared with the monoclonal antibody treatment currently approved that must be given intravenously or subcutaneously and in certain locations.

More people could be reached and helped with the option of an at-home, oral medicine, he and others agreed.

The regimen for molnupiravir is four pills, two times daily, for 5 days, even if symptoms are mild. As with other prescription drugs, “there will always be folks who don’t comply completely” with the prescribed regimen, Dr. Schaffner said. With this pill, that might be especially true if the symptoms are very mild.

The 50% reduction is not as effective as the benefit often quoted for monoclonal antibody treatment. In clinical trials of Regeneron’s monoclonal antibody treatment, the regimen reduced COVID-19–related hospitalization or death in high-risk patients by 70%.

Even so, the new pill could change the pandemic’s course, others say. “I think molnupiravir has the potential to change how we take care of people who have COVID and risk factors for developing severe disease,” Rajesh Tim Gandhi, MD, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization. 

“What we’ll need to do, however, is make sure that people get tested quickly after they develop symptoms and, if they’re confirmed to have COVID, start on the pills within 5 days of developing symptoms,” he said, while warning that more data are needed about the drug and the trial results.

Another concern is that the promise of a pill will stall vaccination rates, with some people figuring why get vaccinated when they can obtain the pill if they do get sick.

Relying on treatment alone won’t work, Dr. Schaffner said. “Let’s [also] focus on prevention, which is the vaccine. We have to keep working both sides of the street.”

Dr. Gandhi added: “It’s important to remember that even though molnupiravir reduced the likelihood of hospitalization and death, a number of people who received the drug still got sick enough to end up in the hospital.”

Also unknown, he said, is how severe their disease was and whether they will develop long COVID.

The Merck study included only unvaccinated people. Might it work for those vaccinated people who get a breakthrough infection? “From a purely scientific perspective, there is no reason to believe molnupiravir would not work in people who are vaccinated, but the overall efficacy on top of the vaccine is likely dependent on how well they were able to mount a protective immune response to the vaccine,” Ms. Moody said. Still, Merck believes the pill could be of benefit for these infections too, she added.

As for the expected cost, Ms. Moody said that the company takes into account a number of factors in setting pricing, “but fundamentally we look at the impact of the disease, the benefits that the drug delivers to patients and to society, and at supporting ongoing drug development.”
 

On Merck’s heels: Pfizer, Roche, Atea

Pfizer is studying an antiviral pill, PF-07321332, a protease inhibitor that blocks the protease enzymes and halts replication of the virus.

In addition to studying the drug in infected patients at high risk of severe illness and in those at typical risk, Pfizer launched a phase 2-3 study in late September that will enroll people who live in the same household as a person with a confirmed, symptomatic COVID-19 infection to see if the drug can prevent disease in those who have been exposed.

Atea and Roche’s COVID pill, AT527, is in phase 3 trials as well. AT527 is an inhibitor of polymerase, an enzyme many viruses have, to stop replications. Atea is evaluating the drug to reduce disease “burden” and for both pre- and postexposure prevention.
 

Big picture: Role of COVID-19 pills

It may be necessary to target the coronavirus with more than one antiviral agent, said Dr. Fichtenbaum, a principal investigator for the AT527 trials. 

“Sometimes viruses require two or three active agents to control their replication,” he said, citing information gleaned from other viral research, such as HIV. For control of HIV infection, a cocktail or combination of antivirals is often recommended.

That may well be the case for COVID-19, Dr. Fichtenbaum said. The goal would be to attack the virus at more than one pathway.

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