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Relapse risk increased with antidepressant discontinuation
a new study shows.
The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that “many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime,” said lead investigator Gemma Lewis, PhD, from University College London, in an interview.
The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.
The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients – 70% – had been using the drugs for more than 3 years, the researchers wrote.
Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.
Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).
The definition of relapse was answering yes to either of the following two questions:
- Have you had a spell of feeling sad, miserable, or depressed?
- Have you been unable to enjoy or take an interest in things as much as you usually do?
Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.
By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.
“We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year,” Dr. Lewis said.
Who can stop medications without relapsing is unknown
“Many people can stop their medication without relapsing, though at present we cannot identify who those people are,” noted Dr. Lewis.
“Our study did not investigate who is at higher risk of relapse … but this is something we will focus on in the future,” she said.
For primary care clinicians whose patients are considering discontinuation of antidepressant medication, “current best practice is to engage with patients’ priorities and collaborate in coming to a decision,” she noted.
“For the individual patient, it is only possible to know about the average likelihood of relapse – and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care.”
Findings are ‘important’ but ‘disappointing’
In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as “important but disappointing.”
“They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” he explained.
Dr. Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.
“It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression,” he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.
“I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission,” he wrote. “For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy.”
Protective effect of antidepressants was clear
“This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.
“The protective effect of antidepressant medication here was clear – those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year.”
Side effects can be significant
“It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse,” Dr. Skolnik said. “While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects.”
“So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient’s informed decision of what they would like to do,” he said.
The study was funded by the U.K. National Institute for Health Research
Dr. Lewis, Dr. Jackson, and Dr. Skolnik reported no conflicts of interest.
a new study shows.
The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that “many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime,” said lead investigator Gemma Lewis, PhD, from University College London, in an interview.
The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.
The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients – 70% – had been using the drugs for more than 3 years, the researchers wrote.
Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.
Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).
The definition of relapse was answering yes to either of the following two questions:
- Have you had a spell of feeling sad, miserable, or depressed?
- Have you been unable to enjoy or take an interest in things as much as you usually do?
Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.
By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.
“We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year,” Dr. Lewis said.
Who can stop medications without relapsing is unknown
“Many people can stop their medication without relapsing, though at present we cannot identify who those people are,” noted Dr. Lewis.
“Our study did not investigate who is at higher risk of relapse … but this is something we will focus on in the future,” she said.
For primary care clinicians whose patients are considering discontinuation of antidepressant medication, “current best practice is to engage with patients’ priorities and collaborate in coming to a decision,” she noted.
“For the individual patient, it is only possible to know about the average likelihood of relapse – and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care.”
Findings are ‘important’ but ‘disappointing’
In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as “important but disappointing.”
“They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” he explained.
Dr. Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.
“It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression,” he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.
“I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission,” he wrote. “For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy.”
Protective effect of antidepressants was clear
“This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.
“The protective effect of antidepressant medication here was clear – those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year.”
Side effects can be significant
“It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse,” Dr. Skolnik said. “While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects.”
“So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient’s informed decision of what they would like to do,” he said.
The study was funded by the U.K. National Institute for Health Research
Dr. Lewis, Dr. Jackson, and Dr. Skolnik reported no conflicts of interest.
a new study shows.
The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that “many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime,” said lead investigator Gemma Lewis, PhD, from University College London, in an interview.
The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.
The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients – 70% – had been using the drugs for more than 3 years, the researchers wrote.
Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.
Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).
The definition of relapse was answering yes to either of the following two questions:
- Have you had a spell of feeling sad, miserable, or depressed?
- Have you been unable to enjoy or take an interest in things as much as you usually do?
Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.
By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.
“We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year,” Dr. Lewis said.
Who can stop medications without relapsing is unknown
“Many people can stop their medication without relapsing, though at present we cannot identify who those people are,” noted Dr. Lewis.
“Our study did not investigate who is at higher risk of relapse … but this is something we will focus on in the future,” she said.
For primary care clinicians whose patients are considering discontinuation of antidepressant medication, “current best practice is to engage with patients’ priorities and collaborate in coming to a decision,” she noted.
“For the individual patient, it is only possible to know about the average likelihood of relapse – and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care.”
Findings are ‘important’ but ‘disappointing’
In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as “important but disappointing.”
“They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” he explained.
Dr. Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.
“It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression,” he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.
“I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission,” he wrote. “For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy.”
Protective effect of antidepressants was clear
“This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.
“The protective effect of antidepressant medication here was clear – those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year.”
Side effects can be significant
“It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse,” Dr. Skolnik said. “While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects.”
“So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient’s informed decision of what they would like to do,” he said.
The study was funded by the U.K. National Institute for Health Research
Dr. Lewis, Dr. Jackson, and Dr. Skolnik reported no conflicts of interest.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Parent-led intervention linked with decreased autism symptoms in at-risk infants
These findings, which were published in JAMA Pediatrics, were the first evidence worldwide that a preemptive intervention during infancy could lead to such a significant improvement in children’s social development, resulting in “three times fewer diagnoses of autism at age 3,” said lead author Andrew Whitehouse, PhD, in a statement.
“No trial of a preemptive infant intervention, applied prior to diagnosis, has to date shown such an effect to impact diagnostic outcomes – until now,” he said.
Study intervention is a nontraditonal approach
Dr. Whitehouse, who is professor of Autism Research at Telethon Kids and University of Western Australia, and Director of CliniKids in Perth, said the intervention is a departure from traditional approaches. “Traditionally, therapy seeks to train children to learn ‘typical’ behaviors,” he said in an email. “The difference of this therapy is that we help parents understand the unique abilities of their baby, and to use these strengths as a foundation for future development.”
Dr. Whitehouse’s study included 103 children (aged approximately 12 months), who displayed at least three of five behaviors indicating a high likelihood of ASD as defined by the Social Attention and Communication Surveillance–Revised (SACS-R) 12-month checklist. The infants were randomized to receive either usual care or the intervention, which is called the iBASIS–Video Interaction to Promote Positive Parenting (iBASIS-VIPP). Usual care was delivered by community physicians, whereas the intervention involved 10 sessions delivered at home by a trained therapist.
“The iBASIS-VIPP uses video-feedback as a means of helping parents recognize their baby’s communication cues so they can respond in a way that builds their social communication development,” Dr. Whitehouse explained in an interview. “The therapist then provides guidance to the parent as to how their baby is communicating with them, and they can communicate back to have back-and-forth conversations.”
“We know these back-and-forth conversations are crucial to support early social communication development, and are a precursor to more complex skills, such as verbal language,” he added.
Reassessment of the children at age 3 years showed a “small but enduring” benefit of the intervention, noted the authors. Children in the intervention group had a reduction in ASD symptom severity (P = .04), and reduced odds of ASD classification, compared with children receiving usual care (6.7% vs. 20.5%; odds ratio, 0.18; P = .02).
The findings provide “initial evidence of efficacy for a new clinical model that uses a specific developmentally focused intervention,” noted the authors. “The children falling below the diagnostic threshold still had developmental difficulties, but by working with each child’s unique differences, rather than trying to counter them, the therapy has effectively supported their development through the early childhood years,” noted Dr. Whitehouse in a statement.
Other research has shown benefits of new study approach
This is a “solid” study, “but, as acknowledged by the authors, the main effects are small in magnitude, and longer-term outcomes will be important to capture,” said Jessica Brian, PhD, C Psych, associate professor in the department of pediatrics at the University of Toronto, colead at the Autism Research Centre, and psychologist and clinician-investigator at Holland Bloorview Kids Rehab Hospital in Toronto.
Dr. Brian said she and her coauthors of a paper published in Autism Research and others have shown that the kind of approach used in the new study can be helpful for enhancing different areas of toddler development, but “the specific finding of reduced likelihood of a clinical ASD diagnosis is a bit different.”
The goal of reducing the likelihood of an ASD diagnosis “needs to be considered carefully, from the perspective of autism acceptance,” she added. “From an acceptance lens, the primary objective of early intervention in ASD might be better positioned as aiming to enhance or support a young child’s development, help them make developmental progress, build on their strengths, optimize outcomes, or reduce impairment. … I think the authors do a good job of balancing this perspective.”
New study shows value of parent-mediated interventions
Overall, Dr. Brian, who coauthored the Canadian Paediatric Society’s position statement on ASD diagnosis, lauded the findings as good news.
“It shows the value of using parent-mediated interventions, which are far less costly and are more resource-efficient than most therapist-delivered models.”
“In cases where parent-mediated approaches are made available to families prior to diagnosis, there is potential for strong effects, when the brain is most amenable to learning. Such models may also be an ideal fit before diagnosis, since they are less resource-intensive than therapist-delivered models, which may only be funded by governments once a diagnosis is confirmed,” she said.
“Finally, parent-mediated programs have the potential to support parents during what, for many families, is a particularly challenging time as they identify their child’s developmental differences or receive a diagnosis. Such programs have potential to increase parents’ confidence in parenting a young child with unique learning needs.”
What Dr. Brian thought was missing from the paper was acknowledgment that, “despite early developmental gains from parent-mediated interventions, it is likely that most children with ASD will need additional supports throughout development.”
This study was sponsored by the Telethon Kids Institute. Dr. Whitehouse reported no conflicts of interest. Dr. Brian codeveloped a parent-mediated intervention for toddlers with probable or confirmed ASD (the Social ABCs), for which she does not receive any royalties.
These findings, which were published in JAMA Pediatrics, were the first evidence worldwide that a preemptive intervention during infancy could lead to such a significant improvement in children’s social development, resulting in “three times fewer diagnoses of autism at age 3,” said lead author Andrew Whitehouse, PhD, in a statement.
“No trial of a preemptive infant intervention, applied prior to diagnosis, has to date shown such an effect to impact diagnostic outcomes – until now,” he said.
Study intervention is a nontraditonal approach
Dr. Whitehouse, who is professor of Autism Research at Telethon Kids and University of Western Australia, and Director of CliniKids in Perth, said the intervention is a departure from traditional approaches. “Traditionally, therapy seeks to train children to learn ‘typical’ behaviors,” he said in an email. “The difference of this therapy is that we help parents understand the unique abilities of their baby, and to use these strengths as a foundation for future development.”
Dr. Whitehouse’s study included 103 children (aged approximately 12 months), who displayed at least three of five behaviors indicating a high likelihood of ASD as defined by the Social Attention and Communication Surveillance–Revised (SACS-R) 12-month checklist. The infants were randomized to receive either usual care or the intervention, which is called the iBASIS–Video Interaction to Promote Positive Parenting (iBASIS-VIPP). Usual care was delivered by community physicians, whereas the intervention involved 10 sessions delivered at home by a trained therapist.
“The iBASIS-VIPP uses video-feedback as a means of helping parents recognize their baby’s communication cues so they can respond in a way that builds their social communication development,” Dr. Whitehouse explained in an interview. “The therapist then provides guidance to the parent as to how their baby is communicating with them, and they can communicate back to have back-and-forth conversations.”
“We know these back-and-forth conversations are crucial to support early social communication development, and are a precursor to more complex skills, such as verbal language,” he added.
Reassessment of the children at age 3 years showed a “small but enduring” benefit of the intervention, noted the authors. Children in the intervention group had a reduction in ASD symptom severity (P = .04), and reduced odds of ASD classification, compared with children receiving usual care (6.7% vs. 20.5%; odds ratio, 0.18; P = .02).
The findings provide “initial evidence of efficacy for a new clinical model that uses a specific developmentally focused intervention,” noted the authors. “The children falling below the diagnostic threshold still had developmental difficulties, but by working with each child’s unique differences, rather than trying to counter them, the therapy has effectively supported their development through the early childhood years,” noted Dr. Whitehouse in a statement.
Other research has shown benefits of new study approach
This is a “solid” study, “but, as acknowledged by the authors, the main effects are small in magnitude, and longer-term outcomes will be important to capture,” said Jessica Brian, PhD, C Psych, associate professor in the department of pediatrics at the University of Toronto, colead at the Autism Research Centre, and psychologist and clinician-investigator at Holland Bloorview Kids Rehab Hospital in Toronto.
Dr. Brian said she and her coauthors of a paper published in Autism Research and others have shown that the kind of approach used in the new study can be helpful for enhancing different areas of toddler development, but “the specific finding of reduced likelihood of a clinical ASD diagnosis is a bit different.”
The goal of reducing the likelihood of an ASD diagnosis “needs to be considered carefully, from the perspective of autism acceptance,” she added. “From an acceptance lens, the primary objective of early intervention in ASD might be better positioned as aiming to enhance or support a young child’s development, help them make developmental progress, build on their strengths, optimize outcomes, or reduce impairment. … I think the authors do a good job of balancing this perspective.”
New study shows value of parent-mediated interventions
Overall, Dr. Brian, who coauthored the Canadian Paediatric Society’s position statement on ASD diagnosis, lauded the findings as good news.
“It shows the value of using parent-mediated interventions, which are far less costly and are more resource-efficient than most therapist-delivered models.”
“In cases where parent-mediated approaches are made available to families prior to diagnosis, there is potential for strong effects, when the brain is most amenable to learning. Such models may also be an ideal fit before diagnosis, since they are less resource-intensive than therapist-delivered models, which may only be funded by governments once a diagnosis is confirmed,” she said.
“Finally, parent-mediated programs have the potential to support parents during what, for many families, is a particularly challenging time as they identify their child’s developmental differences or receive a diagnosis. Such programs have potential to increase parents’ confidence in parenting a young child with unique learning needs.”
What Dr. Brian thought was missing from the paper was acknowledgment that, “despite early developmental gains from parent-mediated interventions, it is likely that most children with ASD will need additional supports throughout development.”
This study was sponsored by the Telethon Kids Institute. Dr. Whitehouse reported no conflicts of interest. Dr. Brian codeveloped a parent-mediated intervention for toddlers with probable or confirmed ASD (the Social ABCs), for which she does not receive any royalties.
These findings, which were published in JAMA Pediatrics, were the first evidence worldwide that a preemptive intervention during infancy could lead to such a significant improvement in children’s social development, resulting in “three times fewer diagnoses of autism at age 3,” said lead author Andrew Whitehouse, PhD, in a statement.
“No trial of a preemptive infant intervention, applied prior to diagnosis, has to date shown such an effect to impact diagnostic outcomes – until now,” he said.
Study intervention is a nontraditonal approach
Dr. Whitehouse, who is professor of Autism Research at Telethon Kids and University of Western Australia, and Director of CliniKids in Perth, said the intervention is a departure from traditional approaches. “Traditionally, therapy seeks to train children to learn ‘typical’ behaviors,” he said in an email. “The difference of this therapy is that we help parents understand the unique abilities of their baby, and to use these strengths as a foundation for future development.”
Dr. Whitehouse’s study included 103 children (aged approximately 12 months), who displayed at least three of five behaviors indicating a high likelihood of ASD as defined by the Social Attention and Communication Surveillance–Revised (SACS-R) 12-month checklist. The infants were randomized to receive either usual care or the intervention, which is called the iBASIS–Video Interaction to Promote Positive Parenting (iBASIS-VIPP). Usual care was delivered by community physicians, whereas the intervention involved 10 sessions delivered at home by a trained therapist.
“The iBASIS-VIPP uses video-feedback as a means of helping parents recognize their baby’s communication cues so they can respond in a way that builds their social communication development,” Dr. Whitehouse explained in an interview. “The therapist then provides guidance to the parent as to how their baby is communicating with them, and they can communicate back to have back-and-forth conversations.”
“We know these back-and-forth conversations are crucial to support early social communication development, and are a precursor to more complex skills, such as verbal language,” he added.
Reassessment of the children at age 3 years showed a “small but enduring” benefit of the intervention, noted the authors. Children in the intervention group had a reduction in ASD symptom severity (P = .04), and reduced odds of ASD classification, compared with children receiving usual care (6.7% vs. 20.5%; odds ratio, 0.18; P = .02).
The findings provide “initial evidence of efficacy for a new clinical model that uses a specific developmentally focused intervention,” noted the authors. “The children falling below the diagnostic threshold still had developmental difficulties, but by working with each child’s unique differences, rather than trying to counter them, the therapy has effectively supported their development through the early childhood years,” noted Dr. Whitehouse in a statement.
Other research has shown benefits of new study approach
This is a “solid” study, “but, as acknowledged by the authors, the main effects are small in magnitude, and longer-term outcomes will be important to capture,” said Jessica Brian, PhD, C Psych, associate professor in the department of pediatrics at the University of Toronto, colead at the Autism Research Centre, and psychologist and clinician-investigator at Holland Bloorview Kids Rehab Hospital in Toronto.
Dr. Brian said she and her coauthors of a paper published in Autism Research and others have shown that the kind of approach used in the new study can be helpful for enhancing different areas of toddler development, but “the specific finding of reduced likelihood of a clinical ASD diagnosis is a bit different.”
The goal of reducing the likelihood of an ASD diagnosis “needs to be considered carefully, from the perspective of autism acceptance,” she added. “From an acceptance lens, the primary objective of early intervention in ASD might be better positioned as aiming to enhance or support a young child’s development, help them make developmental progress, build on their strengths, optimize outcomes, or reduce impairment. … I think the authors do a good job of balancing this perspective.”
New study shows value of parent-mediated interventions
Overall, Dr. Brian, who coauthored the Canadian Paediatric Society’s position statement on ASD diagnosis, lauded the findings as good news.
“It shows the value of using parent-mediated interventions, which are far less costly and are more resource-efficient than most therapist-delivered models.”
“In cases where parent-mediated approaches are made available to families prior to diagnosis, there is potential for strong effects, when the brain is most amenable to learning. Such models may also be an ideal fit before diagnosis, since they are less resource-intensive than therapist-delivered models, which may only be funded by governments once a diagnosis is confirmed,” she said.
“Finally, parent-mediated programs have the potential to support parents during what, for many families, is a particularly challenging time as they identify their child’s developmental differences or receive a diagnosis. Such programs have potential to increase parents’ confidence in parenting a young child with unique learning needs.”
What Dr. Brian thought was missing from the paper was acknowledgment that, “despite early developmental gains from parent-mediated interventions, it is likely that most children with ASD will need additional supports throughout development.”
This study was sponsored by the Telethon Kids Institute. Dr. Whitehouse reported no conflicts of interest. Dr. Brian codeveloped a parent-mediated intervention for toddlers with probable or confirmed ASD (the Social ABCs), for which she does not receive any royalties.
FROM JAMA PEDIATRICS
Study: Use urine sampling more broadly to rule out pediatric UTI
of diagnostic test accuracy studies in ambulatory care (Ann Fam Med 2021;19:437-46).
“Urine sampling is often restricted to children with clinical features such as pain while urinating, frequent urination or children presenting with fever without any abnormalities found on clinical examination,” said lead author Jan Y. Verbakel, MD, PhD, from the University of Leuven (Belgium) in an interview. “Our study findings suggest that, in children, pain while urinating or frequent urination are less accurate than in adults and increase the probability of UTI only moderately.”
Urine sampling “should be applied more broadly in ambulatory care, given that appropriate sampling techniques are available,” he and his coauthors advised in the paper.
Methods and results
The analysis included 35 studies, involving a total of 78,427 patients, which provided information on 58 clinical features and 6 prediction rules of UTI, compared with urine culture. For urine sampling, most studies used catheterization (n = 23), suprapubic aspiration (n = 17), or midstream catch (n = 14), and fewer studies used clean catch (n = 7), bag specimens (n = 5), or diaper pads (n = 2).
The study showed that only three features substantially decreased the likelihood of UTI: being circumcised, the presence of stridor, and the presence of diaper rash. “In febrile children, finding an apparent source of infection decreased the probability of UTI; however, this was not useful for ruling out UTI by itself,” the authors noted.
Additionally, they found that red flags for UTI were cloudy or malodorous urine, hematuria, no fluid intake, suprapubic tenderness, and loin tenderness.
Study implications
“We recommend to sample urine in children that have one or more features that increase the probability of UTI … and less so pain while urinating, frequent urination, urgency, bed wetting, or previous UTI history,” said Dr. Verbakel, who is also a researcher at the University of Oxford (England).
In terms of prediction rules, the analysis showed the Diagnosis of Urinary Tract Infection in Young Children (DUTY) score, Gorelick Scale score, and UTIcalc might be useful to identify which children should have urine sampling, the authors stated in the paper.
Specifically, a DUTY clean-catch score of less than one point was useful for ruling out UTI in children aged less than 5 years, and in girls aged less than 3 years with unexplained fever. The Gorelick Scale score was useful for ruling out UTI when less than two of five variables were present.
“The present meta-analyses confirm that few clinical features are useful for diagnosing or ruling out UTI without further urine analysis. Signs and symptoms combined in a clinical prediction rule, such as with the DUTY or UTIcalc score, might increase accuracy for ruling out UTI; however, these should be validated externally,” Dr. Verbakel said in an interview.
Is urine sampling guideline too broad?
Commenting on the new paper, Martin Koyle, MD, former division chief of urology at the Hospital for Sick Children and professor of surgery at the University of Toronto, expressed concern that unexplained fever is not included as a “differentiating” red flag.
“Many contemporary guidelines define fever as an important diagnostic symptom, as the goal truly is to differentiate lower urinary tract from actual kidney infection, the latter thought to be more important for severity of illness, and potential for developing kidney damage,” he said in an interview. “It begs the question as to which nonfebrile patients who don’t have symptoms related to the respiratory tract for instance [for example, stridor], should be under suspicion for an afebrile urinary tract infection, and have their urine sampled. This paper does not answer that question.”
Dr. Koyle added that an overly broad guideline for urine sampling could come at a cost, and he raised the following questions.
“Will there be an overdiagnosis based on urines alone? Will this lead to overtreatment, often unnecessary, just because there is a positive urine specimen or asymptomatic bacteriuria? Will overtreatment lead to resistant bacteria and side effects related to antibiotics? Will such treatment actually prevent clinical illness and/or renal damage?”
The study authors and Dr. Koyle reported no conflicts of interest.
of diagnostic test accuracy studies in ambulatory care (Ann Fam Med 2021;19:437-46).
“Urine sampling is often restricted to children with clinical features such as pain while urinating, frequent urination or children presenting with fever without any abnormalities found on clinical examination,” said lead author Jan Y. Verbakel, MD, PhD, from the University of Leuven (Belgium) in an interview. “Our study findings suggest that, in children, pain while urinating or frequent urination are less accurate than in adults and increase the probability of UTI only moderately.”
Urine sampling “should be applied more broadly in ambulatory care, given that appropriate sampling techniques are available,” he and his coauthors advised in the paper.
Methods and results
The analysis included 35 studies, involving a total of 78,427 patients, which provided information on 58 clinical features and 6 prediction rules of UTI, compared with urine culture. For urine sampling, most studies used catheterization (n = 23), suprapubic aspiration (n = 17), or midstream catch (n = 14), and fewer studies used clean catch (n = 7), bag specimens (n = 5), or diaper pads (n = 2).
The study showed that only three features substantially decreased the likelihood of UTI: being circumcised, the presence of stridor, and the presence of diaper rash. “In febrile children, finding an apparent source of infection decreased the probability of UTI; however, this was not useful for ruling out UTI by itself,” the authors noted.
Additionally, they found that red flags for UTI were cloudy or malodorous urine, hematuria, no fluid intake, suprapubic tenderness, and loin tenderness.
Study implications
“We recommend to sample urine in children that have one or more features that increase the probability of UTI … and less so pain while urinating, frequent urination, urgency, bed wetting, or previous UTI history,” said Dr. Verbakel, who is also a researcher at the University of Oxford (England).
In terms of prediction rules, the analysis showed the Diagnosis of Urinary Tract Infection in Young Children (DUTY) score, Gorelick Scale score, and UTIcalc might be useful to identify which children should have urine sampling, the authors stated in the paper.
Specifically, a DUTY clean-catch score of less than one point was useful for ruling out UTI in children aged less than 5 years, and in girls aged less than 3 years with unexplained fever. The Gorelick Scale score was useful for ruling out UTI when less than two of five variables were present.
“The present meta-analyses confirm that few clinical features are useful for diagnosing or ruling out UTI without further urine analysis. Signs and symptoms combined in a clinical prediction rule, such as with the DUTY or UTIcalc score, might increase accuracy for ruling out UTI; however, these should be validated externally,” Dr. Verbakel said in an interview.
Is urine sampling guideline too broad?
Commenting on the new paper, Martin Koyle, MD, former division chief of urology at the Hospital for Sick Children and professor of surgery at the University of Toronto, expressed concern that unexplained fever is not included as a “differentiating” red flag.
“Many contemporary guidelines define fever as an important diagnostic symptom, as the goal truly is to differentiate lower urinary tract from actual kidney infection, the latter thought to be more important for severity of illness, and potential for developing kidney damage,” he said in an interview. “It begs the question as to which nonfebrile patients who don’t have symptoms related to the respiratory tract for instance [for example, stridor], should be under suspicion for an afebrile urinary tract infection, and have their urine sampled. This paper does not answer that question.”
Dr. Koyle added that an overly broad guideline for urine sampling could come at a cost, and he raised the following questions.
“Will there be an overdiagnosis based on urines alone? Will this lead to overtreatment, often unnecessary, just because there is a positive urine specimen or asymptomatic bacteriuria? Will overtreatment lead to resistant bacteria and side effects related to antibiotics? Will such treatment actually prevent clinical illness and/or renal damage?”
The study authors and Dr. Koyle reported no conflicts of interest.
of diagnostic test accuracy studies in ambulatory care (Ann Fam Med 2021;19:437-46).
“Urine sampling is often restricted to children with clinical features such as pain while urinating, frequent urination or children presenting with fever without any abnormalities found on clinical examination,” said lead author Jan Y. Verbakel, MD, PhD, from the University of Leuven (Belgium) in an interview. “Our study findings suggest that, in children, pain while urinating or frequent urination are less accurate than in adults and increase the probability of UTI only moderately.”
Urine sampling “should be applied more broadly in ambulatory care, given that appropriate sampling techniques are available,” he and his coauthors advised in the paper.
Methods and results
The analysis included 35 studies, involving a total of 78,427 patients, which provided information on 58 clinical features and 6 prediction rules of UTI, compared with urine culture. For urine sampling, most studies used catheterization (n = 23), suprapubic aspiration (n = 17), or midstream catch (n = 14), and fewer studies used clean catch (n = 7), bag specimens (n = 5), or diaper pads (n = 2).
The study showed that only three features substantially decreased the likelihood of UTI: being circumcised, the presence of stridor, and the presence of diaper rash. “In febrile children, finding an apparent source of infection decreased the probability of UTI; however, this was not useful for ruling out UTI by itself,” the authors noted.
Additionally, they found that red flags for UTI were cloudy or malodorous urine, hematuria, no fluid intake, suprapubic tenderness, and loin tenderness.
Study implications
“We recommend to sample urine in children that have one or more features that increase the probability of UTI … and less so pain while urinating, frequent urination, urgency, bed wetting, or previous UTI history,” said Dr. Verbakel, who is also a researcher at the University of Oxford (England).
In terms of prediction rules, the analysis showed the Diagnosis of Urinary Tract Infection in Young Children (DUTY) score, Gorelick Scale score, and UTIcalc might be useful to identify which children should have urine sampling, the authors stated in the paper.
Specifically, a DUTY clean-catch score of less than one point was useful for ruling out UTI in children aged less than 5 years, and in girls aged less than 3 years with unexplained fever. The Gorelick Scale score was useful for ruling out UTI when less than two of five variables were present.
“The present meta-analyses confirm that few clinical features are useful for diagnosing or ruling out UTI without further urine analysis. Signs and symptoms combined in a clinical prediction rule, such as with the DUTY or UTIcalc score, might increase accuracy for ruling out UTI; however, these should be validated externally,” Dr. Verbakel said in an interview.
Is urine sampling guideline too broad?
Commenting on the new paper, Martin Koyle, MD, former division chief of urology at the Hospital for Sick Children and professor of surgery at the University of Toronto, expressed concern that unexplained fever is not included as a “differentiating” red flag.
“Many contemporary guidelines define fever as an important diagnostic symptom, as the goal truly is to differentiate lower urinary tract from actual kidney infection, the latter thought to be more important for severity of illness, and potential for developing kidney damage,” he said in an interview. “It begs the question as to which nonfebrile patients who don’t have symptoms related to the respiratory tract for instance [for example, stridor], should be under suspicion for an afebrile urinary tract infection, and have their urine sampled. This paper does not answer that question.”
Dr. Koyle added that an overly broad guideline for urine sampling could come at a cost, and he raised the following questions.
“Will there be an overdiagnosis based on urines alone? Will this lead to overtreatment, often unnecessary, just because there is a positive urine specimen or asymptomatic bacteriuria? Will overtreatment lead to resistant bacteria and side effects related to antibiotics? Will such treatment actually prevent clinical illness and/or renal damage?”
The study authors and Dr. Koyle reported no conflicts of interest.
Pandemic-related school closures tied to mental health inequities
Back-to-school jitters are heightened this year, as children head back to the risk of COVID transmission in class, but one upside to the return of in-person school may be better mental health for students.
New research shows that virtual schooling, which dominated in many districts last year, was associated with worse mental health outcomes for students – especially older ones – and youth from Black, Hispanic, or lower-income families were hit hardest because they experienced the most closures.
“Schools with lower funding may have had more difficulty meeting guidelines for safe reopening, including updates to ventilation systems and finding the physical space to create safe distancing between children,” explained lead author Matt Hawrilenko, PhD, of the department of psychiatry and behavioral sciences at the University of Washington, Seattle, in an interview.
“In the context of complex school reopening decisions that balance competing risks and benefits, these findings suggest that allocating funding to support safe in-person instruction may reduce mental health inequities associated with race/ethnicity and income,” he and his coauthors noted in the study, published in JAMA Network Open. “Ensuring that all students have access to additional educational and mental health resources must be an important public health priority, met with appropriate funding and work force augmentation, during and beyond the COVID-19 pandemic.”
The study used a cross-sectional population-based survey of 2,324 parents of school-age children in the United States. It was administered in English and Spanish via web and telephone between Dec. 2 and Dec. 21, 2020, and used the parent-report version of the Strengths and Difficulties Questionnaire (SDQ) to assess mental health difficulties of one child per family in four domains: emotional problems, peer problems, conduct, and hyperactivity. Parents were also asked about what kind of schooling their child had received in the last year (remote, in-person, or hybrid) and about demographic information such as child age, gender, household income, parent race and ethnicity, and parent education.
The results showed that, during the 2020 school year, 58.0% of children attended school remotely, 24% attended fully in person, and 18.0% attended in a hybrid format. “Fully remote schooling was strongly patterned along lines of parent race and ethnicity as well as income,” the authors noted. “Parents of 336 children attending school in person (65.8%) but of 597 children attending school fully remotely (44.5%) were White, whereas all other racial/ethnic groups had larger proportions of children attending school fully remotely (P < .001).”
In terms of mental health, the findings showed that older children who attended school remotely had more difficulties, compared with those who attended in-person – but among younger children, remote learning was comparable or slightly better for mental health.
Specifically, “a child aged 17 years attending school remotely would be expected to have a total difficulty score 2.4 points higher than a child of the same age attending school in person, corresponding to a small effect size in favor of in-person schooling,” the authors wrote. “Conversely, a child aged 4 years attending school remotely would be expected to have a total difficulty score 0.5 points lower than a child of the same age attending school in person, corresponding to a very small effect size in favor of remote schooling.”
Age of child proves critical
“Our best estimate is that remote schooling was associated with no difference in mental health difficulties at age 6, and with slightly more difficulties with each year of age after that, with differences most clearly apparent for high school–aged kids,” explained Dr. Hawrilenko, adding the finding suggests that school reopenings should prioritize older children.
However, “what kids are doing at home matters,” he added. “In the youngest age group, the biggest work kids are doing in school and childcare settings is social and emotional development. … Finding opportunities for regular, safe social interactions with peers – perhaps during outdoor playdates – can help them build those skills.”
He emphasized with the anticipated starts and stutters of the new school year there is an important role that doctors can play.
“First, they can help families assess their own risk profile, and whether it makes sense for their children to attend school in person or remotely [to the extent that is an option]. Second, they can help families think through how school closures might impact their child specifically. For those kids who wind up with long chunks of remote schooling, scheduling in regular interactions with other kids in safe ways could make a big difference. Another driver of child anxiety might be learning loss, and this is a good place to reinforce that not every mental health problem needs a mental health solution.
“A lot of kids might be rightfully anxious about having fallen behind over the pandemic. These kids are preparing to transition to college or to the workforce and may be feeling increasingly behind while approaching these moments of transition. Pointing families toward the resources to help them navigate these issues could go a long way to helping quell child anxiety.”
Research helps fill vacuum
Elizabeth A. Stuart, PhD, who was not involved in the study, said in an interview that this research is particularly valuable because there have been very few data on this topic, especially on a large-scale national sample.
“Sadly, many of the results are not surprising,” said Dr. Stuart, a statistician and professor of mental health at Johns Hopkins University, Baltimore. “Data have shown significant mental health challenges for adults during the pandemic, and it is not surprising that children and youth would experience that as well, especially for those whose daily routines and structures changed dramatically and who were not able to be interacting in-person with teachers, staff, and classmates. This is an important reminder that schools provide not just academic instruction for students, but that the social interactions and other services (such as behavioral health supports, meals, and connections with other social services) students might receive in school are crucial.
“It has been heartening to see a stronger commitment to getting students safely back into school this fall across the country, and that the Centers for Disease Control and Prevention highlighted the benefits of in-person schooling in their COVID-19–related guidance for schools.”
Dr. Stuart added that, as students return to classes, it will be important for schools to tackle ongoing mental health challenges.
“Some students may be struggling in obvious ways; for others it may be harder to identify. It will also be important to continue to monitor children’s and youth mental health … as returning to in-person school may bring its own challenges. ”
Dr. Hawrilenko agreed.
“From a policy perspective, I am quite frankly terrified about how these inequities – in particular, learning loss – might play out long after school closures are a distant memory,” he said. “It is critical to provide schools the resources not just to minimize risk when reopening, but additional funding for workforce augmentation – both for mental health staffing and for additional educational support – to help students navigate the months and years over which they transition back into the classroom.”
Dr. Hawrilenko and Dr. Stuart had no disclosures.
Back-to-school jitters are heightened this year, as children head back to the risk of COVID transmission in class, but one upside to the return of in-person school may be better mental health for students.
New research shows that virtual schooling, which dominated in many districts last year, was associated with worse mental health outcomes for students – especially older ones – and youth from Black, Hispanic, or lower-income families were hit hardest because they experienced the most closures.
“Schools with lower funding may have had more difficulty meeting guidelines for safe reopening, including updates to ventilation systems and finding the physical space to create safe distancing between children,” explained lead author Matt Hawrilenko, PhD, of the department of psychiatry and behavioral sciences at the University of Washington, Seattle, in an interview.
“In the context of complex school reopening decisions that balance competing risks and benefits, these findings suggest that allocating funding to support safe in-person instruction may reduce mental health inequities associated with race/ethnicity and income,” he and his coauthors noted in the study, published in JAMA Network Open. “Ensuring that all students have access to additional educational and mental health resources must be an important public health priority, met with appropriate funding and work force augmentation, during and beyond the COVID-19 pandemic.”
The study used a cross-sectional population-based survey of 2,324 parents of school-age children in the United States. It was administered in English and Spanish via web and telephone between Dec. 2 and Dec. 21, 2020, and used the parent-report version of the Strengths and Difficulties Questionnaire (SDQ) to assess mental health difficulties of one child per family in four domains: emotional problems, peer problems, conduct, and hyperactivity. Parents were also asked about what kind of schooling their child had received in the last year (remote, in-person, or hybrid) and about demographic information such as child age, gender, household income, parent race and ethnicity, and parent education.
The results showed that, during the 2020 school year, 58.0% of children attended school remotely, 24% attended fully in person, and 18.0% attended in a hybrid format. “Fully remote schooling was strongly patterned along lines of parent race and ethnicity as well as income,” the authors noted. “Parents of 336 children attending school in person (65.8%) but of 597 children attending school fully remotely (44.5%) were White, whereas all other racial/ethnic groups had larger proportions of children attending school fully remotely (P < .001).”
In terms of mental health, the findings showed that older children who attended school remotely had more difficulties, compared with those who attended in-person – but among younger children, remote learning was comparable or slightly better for mental health.
Specifically, “a child aged 17 years attending school remotely would be expected to have a total difficulty score 2.4 points higher than a child of the same age attending school in person, corresponding to a small effect size in favor of in-person schooling,” the authors wrote. “Conversely, a child aged 4 years attending school remotely would be expected to have a total difficulty score 0.5 points lower than a child of the same age attending school in person, corresponding to a very small effect size in favor of remote schooling.”
Age of child proves critical
“Our best estimate is that remote schooling was associated with no difference in mental health difficulties at age 6, and with slightly more difficulties with each year of age after that, with differences most clearly apparent for high school–aged kids,” explained Dr. Hawrilenko, adding the finding suggests that school reopenings should prioritize older children.
However, “what kids are doing at home matters,” he added. “In the youngest age group, the biggest work kids are doing in school and childcare settings is social and emotional development. … Finding opportunities for regular, safe social interactions with peers – perhaps during outdoor playdates – can help them build those skills.”
He emphasized with the anticipated starts and stutters of the new school year there is an important role that doctors can play.
“First, they can help families assess their own risk profile, and whether it makes sense for their children to attend school in person or remotely [to the extent that is an option]. Second, they can help families think through how school closures might impact their child specifically. For those kids who wind up with long chunks of remote schooling, scheduling in regular interactions with other kids in safe ways could make a big difference. Another driver of child anxiety might be learning loss, and this is a good place to reinforce that not every mental health problem needs a mental health solution.
“A lot of kids might be rightfully anxious about having fallen behind over the pandemic. These kids are preparing to transition to college or to the workforce and may be feeling increasingly behind while approaching these moments of transition. Pointing families toward the resources to help them navigate these issues could go a long way to helping quell child anxiety.”
Research helps fill vacuum
Elizabeth A. Stuart, PhD, who was not involved in the study, said in an interview that this research is particularly valuable because there have been very few data on this topic, especially on a large-scale national sample.
“Sadly, many of the results are not surprising,” said Dr. Stuart, a statistician and professor of mental health at Johns Hopkins University, Baltimore. “Data have shown significant mental health challenges for adults during the pandemic, and it is not surprising that children and youth would experience that as well, especially for those whose daily routines and structures changed dramatically and who were not able to be interacting in-person with teachers, staff, and classmates. This is an important reminder that schools provide not just academic instruction for students, but that the social interactions and other services (such as behavioral health supports, meals, and connections with other social services) students might receive in school are crucial.
“It has been heartening to see a stronger commitment to getting students safely back into school this fall across the country, and that the Centers for Disease Control and Prevention highlighted the benefits of in-person schooling in their COVID-19–related guidance for schools.”
Dr. Stuart added that, as students return to classes, it will be important for schools to tackle ongoing mental health challenges.
“Some students may be struggling in obvious ways; for others it may be harder to identify. It will also be important to continue to monitor children’s and youth mental health … as returning to in-person school may bring its own challenges. ”
Dr. Hawrilenko agreed.
“From a policy perspective, I am quite frankly terrified about how these inequities – in particular, learning loss – might play out long after school closures are a distant memory,” he said. “It is critical to provide schools the resources not just to minimize risk when reopening, but additional funding for workforce augmentation – both for mental health staffing and for additional educational support – to help students navigate the months and years over which they transition back into the classroom.”
Dr. Hawrilenko and Dr. Stuart had no disclosures.
Back-to-school jitters are heightened this year, as children head back to the risk of COVID transmission in class, but one upside to the return of in-person school may be better mental health for students.
New research shows that virtual schooling, which dominated in many districts last year, was associated with worse mental health outcomes for students – especially older ones – and youth from Black, Hispanic, or lower-income families were hit hardest because they experienced the most closures.
“Schools with lower funding may have had more difficulty meeting guidelines for safe reopening, including updates to ventilation systems and finding the physical space to create safe distancing between children,” explained lead author Matt Hawrilenko, PhD, of the department of psychiatry and behavioral sciences at the University of Washington, Seattle, in an interview.
“In the context of complex school reopening decisions that balance competing risks and benefits, these findings suggest that allocating funding to support safe in-person instruction may reduce mental health inequities associated with race/ethnicity and income,” he and his coauthors noted in the study, published in JAMA Network Open. “Ensuring that all students have access to additional educational and mental health resources must be an important public health priority, met with appropriate funding and work force augmentation, during and beyond the COVID-19 pandemic.”
The study used a cross-sectional population-based survey of 2,324 parents of school-age children in the United States. It was administered in English and Spanish via web and telephone between Dec. 2 and Dec. 21, 2020, and used the parent-report version of the Strengths and Difficulties Questionnaire (SDQ) to assess mental health difficulties of one child per family in four domains: emotional problems, peer problems, conduct, and hyperactivity. Parents were also asked about what kind of schooling their child had received in the last year (remote, in-person, or hybrid) and about demographic information such as child age, gender, household income, parent race and ethnicity, and parent education.
The results showed that, during the 2020 school year, 58.0% of children attended school remotely, 24% attended fully in person, and 18.0% attended in a hybrid format. “Fully remote schooling was strongly patterned along lines of parent race and ethnicity as well as income,” the authors noted. “Parents of 336 children attending school in person (65.8%) but of 597 children attending school fully remotely (44.5%) were White, whereas all other racial/ethnic groups had larger proportions of children attending school fully remotely (P < .001).”
In terms of mental health, the findings showed that older children who attended school remotely had more difficulties, compared with those who attended in-person – but among younger children, remote learning was comparable or slightly better for mental health.
Specifically, “a child aged 17 years attending school remotely would be expected to have a total difficulty score 2.4 points higher than a child of the same age attending school in person, corresponding to a small effect size in favor of in-person schooling,” the authors wrote. “Conversely, a child aged 4 years attending school remotely would be expected to have a total difficulty score 0.5 points lower than a child of the same age attending school in person, corresponding to a very small effect size in favor of remote schooling.”
Age of child proves critical
“Our best estimate is that remote schooling was associated with no difference in mental health difficulties at age 6, and with slightly more difficulties with each year of age after that, with differences most clearly apparent for high school–aged kids,” explained Dr. Hawrilenko, adding the finding suggests that school reopenings should prioritize older children.
However, “what kids are doing at home matters,” he added. “In the youngest age group, the biggest work kids are doing in school and childcare settings is social and emotional development. … Finding opportunities for regular, safe social interactions with peers – perhaps during outdoor playdates – can help them build those skills.”
He emphasized with the anticipated starts and stutters of the new school year there is an important role that doctors can play.
“First, they can help families assess their own risk profile, and whether it makes sense for their children to attend school in person or remotely [to the extent that is an option]. Second, they can help families think through how school closures might impact their child specifically. For those kids who wind up with long chunks of remote schooling, scheduling in regular interactions with other kids in safe ways could make a big difference. Another driver of child anxiety might be learning loss, and this is a good place to reinforce that not every mental health problem needs a mental health solution.
“A lot of kids might be rightfully anxious about having fallen behind over the pandemic. These kids are preparing to transition to college or to the workforce and may be feeling increasingly behind while approaching these moments of transition. Pointing families toward the resources to help them navigate these issues could go a long way to helping quell child anxiety.”
Research helps fill vacuum
Elizabeth A. Stuart, PhD, who was not involved in the study, said in an interview that this research is particularly valuable because there have been very few data on this topic, especially on a large-scale national sample.
“Sadly, many of the results are not surprising,” said Dr. Stuart, a statistician and professor of mental health at Johns Hopkins University, Baltimore. “Data have shown significant mental health challenges for adults during the pandemic, and it is not surprising that children and youth would experience that as well, especially for those whose daily routines and structures changed dramatically and who were not able to be interacting in-person with teachers, staff, and classmates. This is an important reminder that schools provide not just academic instruction for students, but that the social interactions and other services (such as behavioral health supports, meals, and connections with other social services) students might receive in school are crucial.
“It has been heartening to see a stronger commitment to getting students safely back into school this fall across the country, and that the Centers for Disease Control and Prevention highlighted the benefits of in-person schooling in their COVID-19–related guidance for schools.”
Dr. Stuart added that, as students return to classes, it will be important for schools to tackle ongoing mental health challenges.
“Some students may be struggling in obvious ways; for others it may be harder to identify. It will also be important to continue to monitor children’s and youth mental health … as returning to in-person school may bring its own challenges. ”
Dr. Hawrilenko agreed.
“From a policy perspective, I am quite frankly terrified about how these inequities – in particular, learning loss – might play out long after school closures are a distant memory,” he said. “It is critical to provide schools the resources not just to minimize risk when reopening, but additional funding for workforce augmentation – both for mental health staffing and for additional educational support – to help students navigate the months and years over which they transition back into the classroom.”
Dr. Hawrilenko and Dr. Stuart had no disclosures.
FROM JAMA NETWORK OPEN
Modest calorie reduction plus exercise linked with improved vascular health
Finding applies to seniors with obesity, who were part of a new study
The authors of the paper, published in Circulation, found a link between greater vascular benefits and exercise with modest – rather than intense – calorie restriction (CR) in elderly individuals with obesity.
“The finding that higher-intensity calorie restriction may not be necessary or advised has important implications for weight loss recommendations,” noted Tina E. Brinkley, Ph.D., lead author of the study and associate professor of gerontology and geriatric medicine at the Sticht Center for Healthy Aging and Alzheimer’s Prevention at Wake Forest University in Winston-Salem, N.C.
It’s “not entirely clear” why greater calorie restriction did not translate to greater vascular benefit, but it “could be related in part to potentially adverse effects of severe CR on vascular function,” she noted. “These findings have important implications for reducing cardiovascular risk with nonpharmacological interventions in high-risk populations.”
Methods and findings
The study included 160 men and women aged 65-79 years, with a body mass index (BMI) of 30 to 45 kg/m2. The subjects were randomized to one of three groups for 20 weeks of aerobic exercise only, aerobic exercise plus moderate CR, or aerobic exercise plus more intensive CR. Their exercise regimen involved 30 minutes of supervised treadmill walking for 4 days per week at 65%-70% of heart rate reserve.
Subjects in the moderate CR group decreased caloric intake by 250 kcals a day, while the intense calorie reduction group cut 600 kcals per day. Their meals contained less than 30% of calories from fat and at least 0.8 g of protein per kg of ideal body weight. They were also provided with supplemental calcium (1,200 mg/day) and vitamin D (800 IU/day).
Cardiovascular magnetic resonance imaging was used to assess various aspects of aortic structure and function, including aortic arch pulse wave velocity, aortic distensibility and dimensions, and periaortic fat.
Weight loss was greater among subjects with CR plus exercise, compared with that of patients in the exercise-only group. The degree of weight loss was not significantly different between those with moderate versus intense CR ( 8.02 kg vs. 8.98 kg).
Among the exercise-only group, researchers observed no changes in aortic stiffness. However, adding moderate CR significantly improved this measure, while intense CR did not.
Specifically, subjects in the moderate-CR group had a “robust” 21% increase in distensibility in the descending aorta (DA), and an 8% decrease in aortic arch pulse wave velocity, whereas there were no significant vascular changes in the intense-CR group.
Bests results seen in exercise plus modest CR group
“Collectively, these data suggest that combining exercise with modest CR (as opposed to more intensive CR or no CR) provides the greatest benefit for proximal aortic stiffness, while also optimizing weight loss and improvements in body composition and body fat distribution,” noted the authors in their paper.
“Our data support the growing number of studies indicating that intentional weight loss can be safe for older adults with obesity and extend our previous findings, suggesting that obesity may blunt the beneficial effects of exercise for not only cardiorespiratory fitness, but likely vascular health as well.”
William E. Kraus, MD, professor in the Department of Medicine, Division of Cardiology at Duke University Medical Center, in Durham, NC, described the study as important and interesting for several reasons.
“First, it demonstrates one can change aortic vascular function with a combined diet and exercise program, even in older, obese Americans. This implies it is never too late to make meaningful lifestyle changes that will benefit cardiovascular health,” he said. “Second, it is among an increasing number of studies demonstrating that more is not always better than less in exercise and diet lifestyle changes - and in fact the converse is true.”
“This gives hope that more people can benefit from modest lifestyle changes - in this case following guidelines for physical activity and only a modest reduction of 250 kilocalories per day resulted in benefit,” Dr. Kraus added.
The authors of the paper and Dr. Kraus disclosed no conflicts of interest.
Finding applies to seniors with obesity, who were part of a new study
Finding applies to seniors with obesity, who were part of a new study
The authors of the paper, published in Circulation, found a link between greater vascular benefits and exercise with modest – rather than intense – calorie restriction (CR) in elderly individuals with obesity.
“The finding that higher-intensity calorie restriction may not be necessary or advised has important implications for weight loss recommendations,” noted Tina E. Brinkley, Ph.D., lead author of the study and associate professor of gerontology and geriatric medicine at the Sticht Center for Healthy Aging and Alzheimer’s Prevention at Wake Forest University in Winston-Salem, N.C.
It’s “not entirely clear” why greater calorie restriction did not translate to greater vascular benefit, but it “could be related in part to potentially adverse effects of severe CR on vascular function,” she noted. “These findings have important implications for reducing cardiovascular risk with nonpharmacological interventions in high-risk populations.”
Methods and findings
The study included 160 men and women aged 65-79 years, with a body mass index (BMI) of 30 to 45 kg/m2. The subjects were randomized to one of three groups for 20 weeks of aerobic exercise only, aerobic exercise plus moderate CR, or aerobic exercise plus more intensive CR. Their exercise regimen involved 30 minutes of supervised treadmill walking for 4 days per week at 65%-70% of heart rate reserve.
Subjects in the moderate CR group decreased caloric intake by 250 kcals a day, while the intense calorie reduction group cut 600 kcals per day. Their meals contained less than 30% of calories from fat and at least 0.8 g of protein per kg of ideal body weight. They were also provided with supplemental calcium (1,200 mg/day) and vitamin D (800 IU/day).
Cardiovascular magnetic resonance imaging was used to assess various aspects of aortic structure and function, including aortic arch pulse wave velocity, aortic distensibility and dimensions, and periaortic fat.
Weight loss was greater among subjects with CR plus exercise, compared with that of patients in the exercise-only group. The degree of weight loss was not significantly different between those with moderate versus intense CR ( 8.02 kg vs. 8.98 kg).
Among the exercise-only group, researchers observed no changes in aortic stiffness. However, adding moderate CR significantly improved this measure, while intense CR did not.
Specifically, subjects in the moderate-CR group had a “robust” 21% increase in distensibility in the descending aorta (DA), and an 8% decrease in aortic arch pulse wave velocity, whereas there were no significant vascular changes in the intense-CR group.
Bests results seen in exercise plus modest CR group
“Collectively, these data suggest that combining exercise with modest CR (as opposed to more intensive CR or no CR) provides the greatest benefit for proximal aortic stiffness, while also optimizing weight loss and improvements in body composition and body fat distribution,” noted the authors in their paper.
“Our data support the growing number of studies indicating that intentional weight loss can be safe for older adults with obesity and extend our previous findings, suggesting that obesity may blunt the beneficial effects of exercise for not only cardiorespiratory fitness, but likely vascular health as well.”
William E. Kraus, MD, professor in the Department of Medicine, Division of Cardiology at Duke University Medical Center, in Durham, NC, described the study as important and interesting for several reasons.
“First, it demonstrates one can change aortic vascular function with a combined diet and exercise program, even in older, obese Americans. This implies it is never too late to make meaningful lifestyle changes that will benefit cardiovascular health,” he said. “Second, it is among an increasing number of studies demonstrating that more is not always better than less in exercise and diet lifestyle changes - and in fact the converse is true.”
“This gives hope that more people can benefit from modest lifestyle changes - in this case following guidelines for physical activity and only a modest reduction of 250 kilocalories per day resulted in benefit,” Dr. Kraus added.
The authors of the paper and Dr. Kraus disclosed no conflicts of interest.
The authors of the paper, published in Circulation, found a link between greater vascular benefits and exercise with modest – rather than intense – calorie restriction (CR) in elderly individuals with obesity.
“The finding that higher-intensity calorie restriction may not be necessary or advised has important implications for weight loss recommendations,” noted Tina E. Brinkley, Ph.D., lead author of the study and associate professor of gerontology and geriatric medicine at the Sticht Center for Healthy Aging and Alzheimer’s Prevention at Wake Forest University in Winston-Salem, N.C.
It’s “not entirely clear” why greater calorie restriction did not translate to greater vascular benefit, but it “could be related in part to potentially adverse effects of severe CR on vascular function,” she noted. “These findings have important implications for reducing cardiovascular risk with nonpharmacological interventions in high-risk populations.”
Methods and findings
The study included 160 men and women aged 65-79 years, with a body mass index (BMI) of 30 to 45 kg/m2. The subjects were randomized to one of three groups for 20 weeks of aerobic exercise only, aerobic exercise plus moderate CR, or aerobic exercise plus more intensive CR. Their exercise regimen involved 30 minutes of supervised treadmill walking for 4 days per week at 65%-70% of heart rate reserve.
Subjects in the moderate CR group decreased caloric intake by 250 kcals a day, while the intense calorie reduction group cut 600 kcals per day. Their meals contained less than 30% of calories from fat and at least 0.8 g of protein per kg of ideal body weight. They were also provided with supplemental calcium (1,200 mg/day) and vitamin D (800 IU/day).
Cardiovascular magnetic resonance imaging was used to assess various aspects of aortic structure and function, including aortic arch pulse wave velocity, aortic distensibility and dimensions, and periaortic fat.
Weight loss was greater among subjects with CR plus exercise, compared with that of patients in the exercise-only group. The degree of weight loss was not significantly different between those with moderate versus intense CR ( 8.02 kg vs. 8.98 kg).
Among the exercise-only group, researchers observed no changes in aortic stiffness. However, adding moderate CR significantly improved this measure, while intense CR did not.
Specifically, subjects in the moderate-CR group had a “robust” 21% increase in distensibility in the descending aorta (DA), and an 8% decrease in aortic arch pulse wave velocity, whereas there were no significant vascular changes in the intense-CR group.
Bests results seen in exercise plus modest CR group
“Collectively, these data suggest that combining exercise with modest CR (as opposed to more intensive CR or no CR) provides the greatest benefit for proximal aortic stiffness, while also optimizing weight loss and improvements in body composition and body fat distribution,” noted the authors in their paper.
“Our data support the growing number of studies indicating that intentional weight loss can be safe for older adults with obesity and extend our previous findings, suggesting that obesity may blunt the beneficial effects of exercise for not only cardiorespiratory fitness, but likely vascular health as well.”
William E. Kraus, MD, professor in the Department of Medicine, Division of Cardiology at Duke University Medical Center, in Durham, NC, described the study as important and interesting for several reasons.
“First, it demonstrates one can change aortic vascular function with a combined diet and exercise program, even in older, obese Americans. This implies it is never too late to make meaningful lifestyle changes that will benefit cardiovascular health,” he said. “Second, it is among an increasing number of studies demonstrating that more is not always better than less in exercise and diet lifestyle changes - and in fact the converse is true.”
“This gives hope that more people can benefit from modest lifestyle changes - in this case following guidelines for physical activity and only a modest reduction of 250 kilocalories per day resulted in benefit,” Dr. Kraus added.
The authors of the paper and Dr. Kraus disclosed no conflicts of interest.
FROM CIRCULATION
Revised dispatch system boosts bystander CPR in those with limited English
The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.
The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).
The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).
But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).
“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.
While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.
“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.
“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.
The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.
Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.
There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.
The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”
That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.
“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”
Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.
“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”
None of the authors or editorialists reported any conflicts of interest.
The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.
The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).
The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).
But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).
“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.
While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.
“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.
“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.
The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.
Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.
There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.
The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”
That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.
“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”
Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.
“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”
None of the authors or editorialists reported any conflicts of interest.
The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.
The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).
The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).
But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).
“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.
While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.
“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.
“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.
The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.
Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.
There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.
The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”
That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.
“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”
Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.
“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”
None of the authors or editorialists reported any conflicts of interest.
FROM JAMA NETWORK OPEN
Study points to best treatments for depression in primary care
according to a network meta-analysis (NMA) comparing either and both approaches with control conditions in the primary care setting.
The findings are important, since the majority of depressed patients are treated by primary care physicians, yet relatively few randomized trials of treatment have focused on this setting, noted senior study author Pim Cuijpers, PhD, from Vrije Universiteit Amsterdam, and colleagues, in the paper, which was published in Annals of Family Medicine.
“The main message is that clinicians should certainly consider psychotherapy instead of pharmacotherapy, because this is preferred by most patients, and when possible, combined treatments should be the preferred choice because the outcomes are considerably better,” he said in an interview. Either way, he emphasized that “preference of patients is very important and all three treatments are better than usual care.”
The NMA included studies comparing psychotherapy, antidepressant medication, or a combination of both, with control conditions (defined as usual care, wait list, or pill placebo) in adult primary care patients with depression.
Patients could have major depression, persistent mood disorders (dysthymia), both, or high scores on self-rating depression scales. The primary outcome of the NMA was response, defined as a 50% improvement in the Hamilton Depression Rating scores (HAM-D).
A total of 58 studies met inclusion criteria, involving 9,301 patients.
Treatment options compared
Compared with usual care, both psychotherapy alone and pharmacotherapy alone had significantly better response rates, with no significant difference between them (relative risk, 1.60 and RR, 1.65, respectively). The combination of psychotherapy and pharmacotherapy was even better (RR, 2.15), whereas the wait list was less effective (RR, 0.68).
When comparing combined therapy with psychotherapy or pharmacotherapy, the superiority of combination therapy over psychotherapy was only slightly statistically significant (RR, 1.35; 95% confidence interval, 1.00-1.81), while pharmacotherapy was only slightly inferior (RR, 1.30; 95% CI, 0.98-1.73).
“The significance level is not very high, which is related to statistical power,” said Dr. Cuijpers. “But the mean benefit is quite substantial in my opinion, with a 35% higher chance of response in the combined treatment, compared to psychotherapy alone.”
Looking at the outcome of remission, (normally defined as a score of 7 or less on the HAM-D), the outcomes were “comparable to those for response, with the exception that combined treatment was not significantly different from psychotherapy,” they wrote.
One important caveat is that several studies included in the NMA included patients with moderate to severe depression, a population that is different from the usual primary care population of depressed patients who have mild to moderate symptoms. Antidepressant medications are also assumed to work better against more severe symptoms, added the authors. “The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA.”
Among other limitations, the authors noted that studies included mixed populations of patients with dysthymia and major depression; they also made no distinction between different types of antidepressants.
Psychotherapies unknown, but meta-analysis is still useful
Commenting on these findings, Neil Skolnik, MD, professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, said this is “an important study, confirming and extending the conclusions” of a systematic review published in 2016 as a Clinical Practice Guideline from the American College of Physicians.
“Unfortunately, the authors did not specify what type of psychotherapy was studied in the meta-analysis, so we have to look elsewhere if we want to advise our patients on what type of psychotherapy to seek, since there are important differences between different types of therapy,” he said.
Still, he described the study as providing “helpful information for the practicing clinician, as it gives us solid information with which to engage and advise patients in a shared decision-making process for effective treatment of depression.”
“Some patients will choose psychotherapy, some will choose medications. They can make either choice with the confidence that both approaches are effective,” Dr. Skolnik elaborated. “In addition, if psychotherapy does not seem to be sufficiently helping we are on solid ground adding an antidepressant medication to psychotherapy, with this data showing that the combined treatment works better than psychotherapy alone.”
Dr. Cuijpers receives allowances for his memberships on the board of directors of Mind, Fonds Psychische Gezondheid, and Korrelatie, and for being chair of the PACO committee of the Raad voor Civiel-militaire Zorg en Onderzoek of the Dutch Ministry of Defense. He also serves as deputy editor of Depression and Anxiety and associate editor of Psychological Bulletin, and he receives royalties for books he has authored or coauthored. He received grants from the European Union, ZonMw, and PFGV. Another study author reported receiving personal fees from Mitsubishi-Tanabe, MSD, and Shionogi and a grant from Mitsubishi-Tanabe outside the submitted work. One author has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, and Angelini Pharmam, while another reported receiving personal fees from Boehringer Ingelheim, Kyowa Kirin, ASKA Pharmaceutical, and Toyota Motor Corporation outside the submitted work. The other authors and Dr. Skolnik reported no conflicts.
according to a network meta-analysis (NMA) comparing either and both approaches with control conditions in the primary care setting.
The findings are important, since the majority of depressed patients are treated by primary care physicians, yet relatively few randomized trials of treatment have focused on this setting, noted senior study author Pim Cuijpers, PhD, from Vrije Universiteit Amsterdam, and colleagues, in the paper, which was published in Annals of Family Medicine.
“The main message is that clinicians should certainly consider psychotherapy instead of pharmacotherapy, because this is preferred by most patients, and when possible, combined treatments should be the preferred choice because the outcomes are considerably better,” he said in an interview. Either way, he emphasized that “preference of patients is very important and all three treatments are better than usual care.”
The NMA included studies comparing psychotherapy, antidepressant medication, or a combination of both, with control conditions (defined as usual care, wait list, or pill placebo) in adult primary care patients with depression.
Patients could have major depression, persistent mood disorders (dysthymia), both, or high scores on self-rating depression scales. The primary outcome of the NMA was response, defined as a 50% improvement in the Hamilton Depression Rating scores (HAM-D).
A total of 58 studies met inclusion criteria, involving 9,301 patients.
Treatment options compared
Compared with usual care, both psychotherapy alone and pharmacotherapy alone had significantly better response rates, with no significant difference between them (relative risk, 1.60 and RR, 1.65, respectively). The combination of psychotherapy and pharmacotherapy was even better (RR, 2.15), whereas the wait list was less effective (RR, 0.68).
When comparing combined therapy with psychotherapy or pharmacotherapy, the superiority of combination therapy over psychotherapy was only slightly statistically significant (RR, 1.35; 95% confidence interval, 1.00-1.81), while pharmacotherapy was only slightly inferior (RR, 1.30; 95% CI, 0.98-1.73).
“The significance level is not very high, which is related to statistical power,” said Dr. Cuijpers. “But the mean benefit is quite substantial in my opinion, with a 35% higher chance of response in the combined treatment, compared to psychotherapy alone.”
Looking at the outcome of remission, (normally defined as a score of 7 or less on the HAM-D), the outcomes were “comparable to those for response, with the exception that combined treatment was not significantly different from psychotherapy,” they wrote.
One important caveat is that several studies included in the NMA included patients with moderate to severe depression, a population that is different from the usual primary care population of depressed patients who have mild to moderate symptoms. Antidepressant medications are also assumed to work better against more severe symptoms, added the authors. “The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA.”
Among other limitations, the authors noted that studies included mixed populations of patients with dysthymia and major depression; they also made no distinction between different types of antidepressants.
Psychotherapies unknown, but meta-analysis is still useful
Commenting on these findings, Neil Skolnik, MD, professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, said this is “an important study, confirming and extending the conclusions” of a systematic review published in 2016 as a Clinical Practice Guideline from the American College of Physicians.
“Unfortunately, the authors did not specify what type of psychotherapy was studied in the meta-analysis, so we have to look elsewhere if we want to advise our patients on what type of psychotherapy to seek, since there are important differences between different types of therapy,” he said.
Still, he described the study as providing “helpful information for the practicing clinician, as it gives us solid information with which to engage and advise patients in a shared decision-making process for effective treatment of depression.”
“Some patients will choose psychotherapy, some will choose medications. They can make either choice with the confidence that both approaches are effective,” Dr. Skolnik elaborated. “In addition, if psychotherapy does not seem to be sufficiently helping we are on solid ground adding an antidepressant medication to psychotherapy, with this data showing that the combined treatment works better than psychotherapy alone.”
Dr. Cuijpers receives allowances for his memberships on the board of directors of Mind, Fonds Psychische Gezondheid, and Korrelatie, and for being chair of the PACO committee of the Raad voor Civiel-militaire Zorg en Onderzoek of the Dutch Ministry of Defense. He also serves as deputy editor of Depression and Anxiety and associate editor of Psychological Bulletin, and he receives royalties for books he has authored or coauthored. He received grants from the European Union, ZonMw, and PFGV. Another study author reported receiving personal fees from Mitsubishi-Tanabe, MSD, and Shionogi and a grant from Mitsubishi-Tanabe outside the submitted work. One author has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, and Angelini Pharmam, while another reported receiving personal fees from Boehringer Ingelheim, Kyowa Kirin, ASKA Pharmaceutical, and Toyota Motor Corporation outside the submitted work. The other authors and Dr. Skolnik reported no conflicts.
according to a network meta-analysis (NMA) comparing either and both approaches with control conditions in the primary care setting.
The findings are important, since the majority of depressed patients are treated by primary care physicians, yet relatively few randomized trials of treatment have focused on this setting, noted senior study author Pim Cuijpers, PhD, from Vrije Universiteit Amsterdam, and colleagues, in the paper, which was published in Annals of Family Medicine.
“The main message is that clinicians should certainly consider psychotherapy instead of pharmacotherapy, because this is preferred by most patients, and when possible, combined treatments should be the preferred choice because the outcomes are considerably better,” he said in an interview. Either way, he emphasized that “preference of patients is very important and all three treatments are better than usual care.”
The NMA included studies comparing psychotherapy, antidepressant medication, or a combination of both, with control conditions (defined as usual care, wait list, or pill placebo) in adult primary care patients with depression.
Patients could have major depression, persistent mood disorders (dysthymia), both, or high scores on self-rating depression scales. The primary outcome of the NMA was response, defined as a 50% improvement in the Hamilton Depression Rating scores (HAM-D).
A total of 58 studies met inclusion criteria, involving 9,301 patients.
Treatment options compared
Compared with usual care, both psychotherapy alone and pharmacotherapy alone had significantly better response rates, with no significant difference between them (relative risk, 1.60 and RR, 1.65, respectively). The combination of psychotherapy and pharmacotherapy was even better (RR, 2.15), whereas the wait list was less effective (RR, 0.68).
When comparing combined therapy with psychotherapy or pharmacotherapy, the superiority of combination therapy over psychotherapy was only slightly statistically significant (RR, 1.35; 95% confidence interval, 1.00-1.81), while pharmacotherapy was only slightly inferior (RR, 1.30; 95% CI, 0.98-1.73).
“The significance level is not very high, which is related to statistical power,” said Dr. Cuijpers. “But the mean benefit is quite substantial in my opinion, with a 35% higher chance of response in the combined treatment, compared to psychotherapy alone.”
Looking at the outcome of remission, (normally defined as a score of 7 or less on the HAM-D), the outcomes were “comparable to those for response, with the exception that combined treatment was not significantly different from psychotherapy,” they wrote.
One important caveat is that several studies included in the NMA included patients with moderate to severe depression, a population that is different from the usual primary care population of depressed patients who have mild to moderate symptoms. Antidepressant medications are also assumed to work better against more severe symptoms, added the authors. “The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA.”
Among other limitations, the authors noted that studies included mixed populations of patients with dysthymia and major depression; they also made no distinction between different types of antidepressants.
Psychotherapies unknown, but meta-analysis is still useful
Commenting on these findings, Neil Skolnik, MD, professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, said this is “an important study, confirming and extending the conclusions” of a systematic review published in 2016 as a Clinical Practice Guideline from the American College of Physicians.
“Unfortunately, the authors did not specify what type of psychotherapy was studied in the meta-analysis, so we have to look elsewhere if we want to advise our patients on what type of psychotherapy to seek, since there are important differences between different types of therapy,” he said.
Still, he described the study as providing “helpful information for the practicing clinician, as it gives us solid information with which to engage and advise patients in a shared decision-making process for effective treatment of depression.”
“Some patients will choose psychotherapy, some will choose medications. They can make either choice with the confidence that both approaches are effective,” Dr. Skolnik elaborated. “In addition, if psychotherapy does not seem to be sufficiently helping we are on solid ground adding an antidepressant medication to psychotherapy, with this data showing that the combined treatment works better than psychotherapy alone.”
Dr. Cuijpers receives allowances for his memberships on the board of directors of Mind, Fonds Psychische Gezondheid, and Korrelatie, and for being chair of the PACO committee of the Raad voor Civiel-militaire Zorg en Onderzoek of the Dutch Ministry of Defense. He also serves as deputy editor of Depression and Anxiety and associate editor of Psychological Bulletin, and he receives royalties for books he has authored or coauthored. He received grants from the European Union, ZonMw, and PFGV. Another study author reported receiving personal fees from Mitsubishi-Tanabe, MSD, and Shionogi and a grant from Mitsubishi-Tanabe outside the submitted work. One author has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, and Angelini Pharmam, while another reported receiving personal fees from Boehringer Ingelheim, Kyowa Kirin, ASKA Pharmaceutical, and Toyota Motor Corporation outside the submitted work. The other authors and Dr. Skolnik reported no conflicts.
FROM ANNALS OF FAMILY MEDICINE
Transcranial brain stimulation can modulate placebo and nocebo experiences
, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).
“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.
The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”
Testing the hypothesis
The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.
The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).
All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.
Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.
The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.
“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
Proof of concept
Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”
Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.
“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”
Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.
, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).
“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.
The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”
Testing the hypothesis
The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.
The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).
All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.
Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.
The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.
“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
Proof of concept
Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”
Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.
“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”
Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.
, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).
“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.
The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”
Testing the hypothesis
The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.
The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).
All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.
Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.
The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.
“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
Proof of concept
Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”
Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.
“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”
Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.
FROM PNAS
Green light puts the stop on migraine
, according to results of a small study from the University of Arizona, Tucson.
“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”
“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.
The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.
The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
White versus green
The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.
Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.
The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.
The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.
On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).
“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.
“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
Better than white light
Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.
The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.
, according to results of a small study from the University of Arizona, Tucson.
“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”
“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.
The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.
The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
White versus green
The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.
Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.
The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.
The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.
On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).
“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.
“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
Better than white light
Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.
The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.
, according to results of a small study from the University of Arizona, Tucson.
“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”
“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.
The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.
The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
White versus green
The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.
Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.
The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.
The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.
On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).
“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.
“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
Better than white light
Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.
The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.
FROM CEPHALALGIA
Risdiplam study shows promise for spinal muscular atrophy
, according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A phase 2-3 open-label study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The first oral treatment option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
, according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A phase 2-3 open-label study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The first oral treatment option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
, according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A phase 2-3 open-label study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The first oral treatment option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE