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Preterm and early term birth linked to an increased risk of autism
Preterm and early birth is associated with an increased risk of autism independent of genetic or environmental factors, according to new research published in Pediatrics.
Although previous studies have linked preterm births to an increased risk of autism – one 2017 study published in Cerebral Cortex found that 27.4% of the children born extremely preterm were diagnosed with autism – Casey Crump, MD, PhD, said potential causality, sex-specific differences, and association with early-term births were still unclear.
“Preterm birth had previously been linked with higher risk of autism; however, several important questions remained unanswered,” said Dr. Crump, professor and vice chair for research at the department of family medicine and community health and professor of epidemiology in the department of population health science and policy at Icahn School of Medicine at Mount Sinai New York. “To our knowledge, [our study] is the largest to date of gestational age at birth in relation to autism, and one of the first to investigate sex-specific differences, early term birth, or the influence of shared familial factors.”
Dr. Crump and colleagues examined data from more than 4 million infants born in Sweden between 1973 and 2013 who were followed-up for autism spectrum disorder identified from nationwide outpatient and inpatient diagnoses through December 2015. Children born between 22 and 27 weeks were considered extremely preterm, those born between 28 and 33 week were characterized as very to moderate preterm, and those born between 34 and 36 weeks were considered late preterm. Early-term births are characterized as infants born between 37 and 38 weeks and children born between 39 and 41 weeks were considered term births.
They found that 6.1% of those born extremely preterm were diagnosed with autism. Meanwhile, autism spectrum disorder prevalences were 2.6% for very to moderate preterm, 1.9% for late preterm, 2.1% for all preterm, and 1.6% for early term, compared with 1.4% for term birth.
The researchers’ analysis showed that preterm and early birth were associated with a significantly increased risk of autism in males and females. Children who were born extremely preterm had an approximately fourfold increased risk of autism. Researchers also found that each additional week of gestation was associated with a 5% lower prevalence of autism spectrum disorder (ASD) on average.
“The elevated risk even in [late preterm] infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems ... and psychiatric disorders, some of which may extend to adulthood,” Elisabeth McGowan, MD, who was not involved in the study, said in a solicited editorial commentary about the study.
Dr. Crump believes the association between preterm birth and autism may be because of increased inflammatory marker levels. A 2009 study published in Reproductive Sciences found that increased proinflammatory cytokine levels have been associated with the timing and initiation of preterm birth, and also have been detected in the brain and cerebrospinal fluid of individuals with autism “and may play a key role in its pathogenesis,” Dr. Crump said.
“Inflammatory-driven alteration of neuronal connections during critical periods of brain development may be central to the development of autism,” Dr. Crump explained.
However, Dr. Crump said that, although the relative risks of autism were higher in those born preterm, the absolute risk of the condition is low.
“The report by Crump is in many ways a definitive accounting of the elevated rates of ASD in preterm infants,” said Dr. McGowan, associate professor of pediatrics at the Women and Infants Hospital, Providence, R.I. “And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous.”
ASD is a developmental condition that affects about 1 in 54 children, according to the Centers for Disease Control and Prevention. Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the CDC.
“Children born prematurely need early evaluation and long-term follow-up to facilitate timely detection and treatment of autism, especially those born at the earliest gestational ages,” Dr. Crump said in an interview. “In patients of all ages, gestational age at birth should be routinely included in history-taking and medical records to help identify in clinical practice those born preterm or early term. Such information can provide additional valuable context for understanding patients’ health and may facilitate earlier evaluation for autism and other neurodevelopmental conditions in those born prematurely.”
Dr. Crump and colleagues said more research is needed to understand the biologic mechanisms linking preterm birth with higher risks of autism, which “may reveal new targets for intervention at critical windows of neurodevelopment to improve the disease trajectory.”
Experts interviewed did not disclose any relevant financial relationships.
Preterm and early birth is associated with an increased risk of autism independent of genetic or environmental factors, according to new research published in Pediatrics.
Although previous studies have linked preterm births to an increased risk of autism – one 2017 study published in Cerebral Cortex found that 27.4% of the children born extremely preterm were diagnosed with autism – Casey Crump, MD, PhD, said potential causality, sex-specific differences, and association with early-term births were still unclear.
“Preterm birth had previously been linked with higher risk of autism; however, several important questions remained unanswered,” said Dr. Crump, professor and vice chair for research at the department of family medicine and community health and professor of epidemiology in the department of population health science and policy at Icahn School of Medicine at Mount Sinai New York. “To our knowledge, [our study] is the largest to date of gestational age at birth in relation to autism, and one of the first to investigate sex-specific differences, early term birth, or the influence of shared familial factors.”
Dr. Crump and colleagues examined data from more than 4 million infants born in Sweden between 1973 and 2013 who were followed-up for autism spectrum disorder identified from nationwide outpatient and inpatient diagnoses through December 2015. Children born between 22 and 27 weeks were considered extremely preterm, those born between 28 and 33 week were characterized as very to moderate preterm, and those born between 34 and 36 weeks were considered late preterm. Early-term births are characterized as infants born between 37 and 38 weeks and children born between 39 and 41 weeks were considered term births.
They found that 6.1% of those born extremely preterm were diagnosed with autism. Meanwhile, autism spectrum disorder prevalences were 2.6% for very to moderate preterm, 1.9% for late preterm, 2.1% for all preterm, and 1.6% for early term, compared with 1.4% for term birth.
The researchers’ analysis showed that preterm and early birth were associated with a significantly increased risk of autism in males and females. Children who were born extremely preterm had an approximately fourfold increased risk of autism. Researchers also found that each additional week of gestation was associated with a 5% lower prevalence of autism spectrum disorder (ASD) on average.
“The elevated risk even in [late preterm] infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems ... and psychiatric disorders, some of which may extend to adulthood,” Elisabeth McGowan, MD, who was not involved in the study, said in a solicited editorial commentary about the study.
Dr. Crump believes the association between preterm birth and autism may be because of increased inflammatory marker levels. A 2009 study published in Reproductive Sciences found that increased proinflammatory cytokine levels have been associated with the timing and initiation of preterm birth, and also have been detected in the brain and cerebrospinal fluid of individuals with autism “and may play a key role in its pathogenesis,” Dr. Crump said.
“Inflammatory-driven alteration of neuronal connections during critical periods of brain development may be central to the development of autism,” Dr. Crump explained.
However, Dr. Crump said that, although the relative risks of autism were higher in those born preterm, the absolute risk of the condition is low.
“The report by Crump is in many ways a definitive accounting of the elevated rates of ASD in preterm infants,” said Dr. McGowan, associate professor of pediatrics at the Women and Infants Hospital, Providence, R.I. “And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous.”
ASD is a developmental condition that affects about 1 in 54 children, according to the Centers for Disease Control and Prevention. Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the CDC.
“Children born prematurely need early evaluation and long-term follow-up to facilitate timely detection and treatment of autism, especially those born at the earliest gestational ages,” Dr. Crump said in an interview. “In patients of all ages, gestational age at birth should be routinely included in history-taking and medical records to help identify in clinical practice those born preterm or early term. Such information can provide additional valuable context for understanding patients’ health and may facilitate earlier evaluation for autism and other neurodevelopmental conditions in those born prematurely.”
Dr. Crump and colleagues said more research is needed to understand the biologic mechanisms linking preterm birth with higher risks of autism, which “may reveal new targets for intervention at critical windows of neurodevelopment to improve the disease trajectory.”
Experts interviewed did not disclose any relevant financial relationships.
Preterm and early birth is associated with an increased risk of autism independent of genetic or environmental factors, according to new research published in Pediatrics.
Although previous studies have linked preterm births to an increased risk of autism – one 2017 study published in Cerebral Cortex found that 27.4% of the children born extremely preterm were diagnosed with autism – Casey Crump, MD, PhD, said potential causality, sex-specific differences, and association with early-term births were still unclear.
“Preterm birth had previously been linked with higher risk of autism; however, several important questions remained unanswered,” said Dr. Crump, professor and vice chair for research at the department of family medicine and community health and professor of epidemiology in the department of population health science and policy at Icahn School of Medicine at Mount Sinai New York. “To our knowledge, [our study] is the largest to date of gestational age at birth in relation to autism, and one of the first to investigate sex-specific differences, early term birth, or the influence of shared familial factors.”
Dr. Crump and colleagues examined data from more than 4 million infants born in Sweden between 1973 and 2013 who were followed-up for autism spectrum disorder identified from nationwide outpatient and inpatient diagnoses through December 2015. Children born between 22 and 27 weeks were considered extremely preterm, those born between 28 and 33 week were characterized as very to moderate preterm, and those born between 34 and 36 weeks were considered late preterm. Early-term births are characterized as infants born between 37 and 38 weeks and children born between 39 and 41 weeks were considered term births.
They found that 6.1% of those born extremely preterm were diagnosed with autism. Meanwhile, autism spectrum disorder prevalences were 2.6% for very to moderate preterm, 1.9% for late preterm, 2.1% for all preterm, and 1.6% for early term, compared with 1.4% for term birth.
The researchers’ analysis showed that preterm and early birth were associated with a significantly increased risk of autism in males and females. Children who were born extremely preterm had an approximately fourfold increased risk of autism. Researchers also found that each additional week of gestation was associated with a 5% lower prevalence of autism spectrum disorder (ASD) on average.
“The elevated risk even in [late preterm] infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems ... and psychiatric disorders, some of which may extend to adulthood,” Elisabeth McGowan, MD, who was not involved in the study, said in a solicited editorial commentary about the study.
Dr. Crump believes the association between preterm birth and autism may be because of increased inflammatory marker levels. A 2009 study published in Reproductive Sciences found that increased proinflammatory cytokine levels have been associated with the timing and initiation of preterm birth, and also have been detected in the brain and cerebrospinal fluid of individuals with autism “and may play a key role in its pathogenesis,” Dr. Crump said.
“Inflammatory-driven alteration of neuronal connections during critical periods of brain development may be central to the development of autism,” Dr. Crump explained.
However, Dr. Crump said that, although the relative risks of autism were higher in those born preterm, the absolute risk of the condition is low.
“The report by Crump is in many ways a definitive accounting of the elevated rates of ASD in preterm infants,” said Dr. McGowan, associate professor of pediatrics at the Women and Infants Hospital, Providence, R.I. “And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous.”
ASD is a developmental condition that affects about 1 in 54 children, according to the Centers for Disease Control and Prevention. Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the CDC.
“Children born prematurely need early evaluation and long-term follow-up to facilitate timely detection and treatment of autism, especially those born at the earliest gestational ages,” Dr. Crump said in an interview. “In patients of all ages, gestational age at birth should be routinely included in history-taking and medical records to help identify in clinical practice those born preterm or early term. Such information can provide additional valuable context for understanding patients’ health and may facilitate earlier evaluation for autism and other neurodevelopmental conditions in those born prematurely.”
Dr. Crump and colleagues said more research is needed to understand the biologic mechanisms linking preterm birth with higher risks of autism, which “may reveal new targets for intervention at critical windows of neurodevelopment to improve the disease trajectory.”
Experts interviewed did not disclose any relevant financial relationships.
FROM PEDIATRICS
‘Reassuring’ findings for second-generation antipsychotics during pregnancy
Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.
Data from a large registry study of almost 2,000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio of 1.5 for major malformations.
“The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention’s national baseline rate of major malformations in the general population,” lead author Adele Viguera, MD, MPH, director of research for women’s mental health, Cleveland Clinic Neurological Institute, told this news organization.
“Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations,” Dr. Viguera said.
The findings were published online August 3 in the Journal of Clinical Psychiatry.
Safety data scarce
Despite the increasing use of SGAs to treat a “spectrum of psychiatric disorders,” relatively little data are available on the reproductive safety of these agents, Dr. Viguera said.
The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.
The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women’s Mental Health website.
Specific data collected are shown in the following table.
Since publication of the first results in 2015, the sample size for the trial has increased – and the absolute and relative risk for major malformations observed in the study population are “more precise,” the investigators note. The current study presented updated previous findings.
Demographic differences
Of the 1,906 women who enrolled as of April 2020, 1,311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.
Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs. 90%, respectively) and fewer had a college education (71.2% vs. 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs. 5.1%).
On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs. 21.4%, respectively).
The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.
Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).
The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).
Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.
Major clinical implication?
Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.
The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% confidence interval, 0.625-3.517).
The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs versus those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96-1.16).
Additionally, “a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups,” Dr. Viguera said
“A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy,” she added.
The concept of ‘satisficing’
Commenting on the study, Vivien Burt, MD, PhD, founder and director/consultant of the Women’s Life Center at the Resnick University of California, Los Angeles (UCLA) Neuropsychiatric Hospital, called the findings “reassuring.”
The results “support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness,” she said.
An accompanying editorial co-authored by Dr. Burt and colleague Sonya Rasminsky, MD, introduced the concept of “satisficing” – a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. “Satisficing” is a “decision-making strategy that aims for a satisfactory (‘good enough’) outcome rather than a perfect one.”
The concept applies to decision-making beyond the field of economics “and is critical to how physicians help patients make decisions when they are faced with multiple treatment options,” said Dr. Burt, a professor emeritus of psychiatry at UCLA.
“The goal of ‘satisficing’ is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with,” she noted.
The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were “overwhelmingly White, married, and well-educated women.”
They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will “further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding.”
The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper. Dr. Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and SAGE Therapeutics and receives adviser/consulting fees from Up-to-Date. Dr. Burt has been a consultant/speaker for Sage Therapeutics. Dr. Rasminsky has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.
Data from a large registry study of almost 2,000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio of 1.5 for major malformations.
“The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention’s national baseline rate of major malformations in the general population,” lead author Adele Viguera, MD, MPH, director of research for women’s mental health, Cleveland Clinic Neurological Institute, told this news organization.
“Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations,” Dr. Viguera said.
The findings were published online August 3 in the Journal of Clinical Psychiatry.
Safety data scarce
Despite the increasing use of SGAs to treat a “spectrum of psychiatric disorders,” relatively little data are available on the reproductive safety of these agents, Dr. Viguera said.
The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.
The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women’s Mental Health website.
Specific data collected are shown in the following table.
Since publication of the first results in 2015, the sample size for the trial has increased – and the absolute and relative risk for major malformations observed in the study population are “more precise,” the investigators note. The current study presented updated previous findings.
Demographic differences
Of the 1,906 women who enrolled as of April 2020, 1,311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.
Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs. 90%, respectively) and fewer had a college education (71.2% vs. 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs. 5.1%).
On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs. 21.4%, respectively).
The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.
Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).
The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).
Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.
Major clinical implication?
Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.
The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% confidence interval, 0.625-3.517).
The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs versus those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96-1.16).
Additionally, “a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups,” Dr. Viguera said
“A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy,” she added.
The concept of ‘satisficing’
Commenting on the study, Vivien Burt, MD, PhD, founder and director/consultant of the Women’s Life Center at the Resnick University of California, Los Angeles (UCLA) Neuropsychiatric Hospital, called the findings “reassuring.”
The results “support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness,” she said.
An accompanying editorial co-authored by Dr. Burt and colleague Sonya Rasminsky, MD, introduced the concept of “satisficing” – a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. “Satisficing” is a “decision-making strategy that aims for a satisfactory (‘good enough’) outcome rather than a perfect one.”
The concept applies to decision-making beyond the field of economics “and is critical to how physicians help patients make decisions when they are faced with multiple treatment options,” said Dr. Burt, a professor emeritus of psychiatry at UCLA.
“The goal of ‘satisficing’ is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with,” she noted.
The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were “overwhelmingly White, married, and well-educated women.”
They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will “further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding.”
The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper. Dr. Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and SAGE Therapeutics and receives adviser/consulting fees from Up-to-Date. Dr. Burt has been a consultant/speaker for Sage Therapeutics. Dr. Rasminsky has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.
Data from a large registry study of almost 2,000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio of 1.5 for major malformations.
“The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention’s national baseline rate of major malformations in the general population,” lead author Adele Viguera, MD, MPH, director of research for women’s mental health, Cleveland Clinic Neurological Institute, told this news organization.
“Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations,” Dr. Viguera said.
The findings were published online August 3 in the Journal of Clinical Psychiatry.
Safety data scarce
Despite the increasing use of SGAs to treat a “spectrum of psychiatric disorders,” relatively little data are available on the reproductive safety of these agents, Dr. Viguera said.
The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.
The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women’s Mental Health website.
Specific data collected are shown in the following table.
Since publication of the first results in 2015, the sample size for the trial has increased – and the absolute and relative risk for major malformations observed in the study population are “more precise,” the investigators note. The current study presented updated previous findings.
Demographic differences
Of the 1,906 women who enrolled as of April 2020, 1,311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.
Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs. 90%, respectively) and fewer had a college education (71.2% vs. 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs. 5.1%).
On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs. 21.4%, respectively).
The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.
Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).
The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).
Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.
Major clinical implication?
Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.
The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% confidence interval, 0.625-3.517).
The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs versus those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96-1.16).
Additionally, “a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups,” Dr. Viguera said
“A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy,” she added.
The concept of ‘satisficing’
Commenting on the study, Vivien Burt, MD, PhD, founder and director/consultant of the Women’s Life Center at the Resnick University of California, Los Angeles (UCLA) Neuropsychiatric Hospital, called the findings “reassuring.”
The results “support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness,” she said.
An accompanying editorial co-authored by Dr. Burt and colleague Sonya Rasminsky, MD, introduced the concept of “satisficing” – a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. “Satisficing” is a “decision-making strategy that aims for a satisfactory (‘good enough’) outcome rather than a perfect one.”
The concept applies to decision-making beyond the field of economics “and is critical to how physicians help patients make decisions when they are faced with multiple treatment options,” said Dr. Burt, a professor emeritus of psychiatry at UCLA.
“The goal of ‘satisficing’ is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with,” she noted.
The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were “overwhelmingly White, married, and well-educated women.”
They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will “further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding.”
The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper. Dr. Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and SAGE Therapeutics and receives adviser/consulting fees from Up-to-Date. Dr. Burt has been a consultant/speaker for Sage Therapeutics. Dr. Rasminsky has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘No justification’ for suicide warning on all antiseizure meds
, new research shows. “There appears to be no justification for the FDA to label every new antiseizure medication with a warning that it may increase risk of suicidality,” said study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia.
“How many patients are afraid of their medication and do not take it because of the warning – and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue,” Dr. Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.
The study was published online August 2 in JAMA Neurology.
Blanket warning
In 2008, the FDA issued an alert stating that antiseizure medications increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 antiseizure medications – carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.
The meta-analytic review showed that, compared with placebo, antiseizure medications nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases. As a result of the FDA study, all antiseizure medications that have been approved since 2008 carry a warning for suicidality.
However, subsequent analyses did not show the same results, Dr. Sperling and colleagues noted.
“Pivotal” antiseizure medication epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they noted.
Meta analysis showed no increased risk
Dr. Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five antiseizure medications approved since 2008. These antiseizure medications were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5,996 patients, including 4,000 who were treated with antiseizure medications and 1,996 who were treated with placebo.
Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers noted.
They found no evidence of increased risk for suicidal ideation (overall risk ratio, antiseizure medications vs. placebo: 0.75; 95% confidence interval: 0.35-1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30-1.87) overall or for any individual antiseizure medication.
Suicidal ideation occurred in 12 of 4,000 patients treated with antiseizure medications (0.30%), versus 7 of 1,996 patients treated with placebo (0.35%) (P = .74). Three patients who were treated with antiseizure medications attempted suicide; no patients who were treated with placebo attempted suicide (P = .22). There were no completed suicides.
“There is no current evidence that the five antiseizure medications evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning,” the investigators wrote. When prescribed for epilepsy, “evidence does not support the FDA’s labeling practice of a blanket assumption of increased suicidality,” said Dr. Sperling.
“Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable,” he said. “The results are not surprising. Different drugs affect cells in different ways. So there’s no reason to expect that every drug would increase suicide risk for every patient,” Dr. Sperling said in a statement.
“It’s important to recognize that epilepsy has many causes – perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others – and these underlying etiologies may well contribute to the presence of depression and suicidality in this population,” he said in an interview. “Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle,” he added.
Dr. Sperling said the FDA has accomplished “one useful thing with its warning – it highlighted that physicians and other health care providers must pay attention to their patients’ psychological state, ask questions, and treat accordingly.”
The study had no specific funding. Dr. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors’ disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
, new research shows. “There appears to be no justification for the FDA to label every new antiseizure medication with a warning that it may increase risk of suicidality,” said study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia.
“How many patients are afraid of their medication and do not take it because of the warning – and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue,” Dr. Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.
The study was published online August 2 in JAMA Neurology.
Blanket warning
In 2008, the FDA issued an alert stating that antiseizure medications increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 antiseizure medications – carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.
The meta-analytic review showed that, compared with placebo, antiseizure medications nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases. As a result of the FDA study, all antiseizure medications that have been approved since 2008 carry a warning for suicidality.
However, subsequent analyses did not show the same results, Dr. Sperling and colleagues noted.
“Pivotal” antiseizure medication epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they noted.
Meta analysis showed no increased risk
Dr. Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five antiseizure medications approved since 2008. These antiseizure medications were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5,996 patients, including 4,000 who were treated with antiseizure medications and 1,996 who were treated with placebo.
Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers noted.
They found no evidence of increased risk for suicidal ideation (overall risk ratio, antiseizure medications vs. placebo: 0.75; 95% confidence interval: 0.35-1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30-1.87) overall or for any individual antiseizure medication.
Suicidal ideation occurred in 12 of 4,000 patients treated with antiseizure medications (0.30%), versus 7 of 1,996 patients treated with placebo (0.35%) (P = .74). Three patients who were treated with antiseizure medications attempted suicide; no patients who were treated with placebo attempted suicide (P = .22). There were no completed suicides.
“There is no current evidence that the five antiseizure medications evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning,” the investigators wrote. When prescribed for epilepsy, “evidence does not support the FDA’s labeling practice of a blanket assumption of increased suicidality,” said Dr. Sperling.
“Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable,” he said. “The results are not surprising. Different drugs affect cells in different ways. So there’s no reason to expect that every drug would increase suicide risk for every patient,” Dr. Sperling said in a statement.
“It’s important to recognize that epilepsy has many causes – perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others – and these underlying etiologies may well contribute to the presence of depression and suicidality in this population,” he said in an interview. “Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle,” he added.
Dr. Sperling said the FDA has accomplished “one useful thing with its warning – it highlighted that physicians and other health care providers must pay attention to their patients’ psychological state, ask questions, and treat accordingly.”
The study had no specific funding. Dr. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors’ disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
, new research shows. “There appears to be no justification for the FDA to label every new antiseizure medication with a warning that it may increase risk of suicidality,” said study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia.
“How many patients are afraid of their medication and do not take it because of the warning – and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue,” Dr. Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.
The study was published online August 2 in JAMA Neurology.
Blanket warning
In 2008, the FDA issued an alert stating that antiseizure medications increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 antiseizure medications – carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.
The meta-analytic review showed that, compared with placebo, antiseizure medications nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases. As a result of the FDA study, all antiseizure medications that have been approved since 2008 carry a warning for suicidality.
However, subsequent analyses did not show the same results, Dr. Sperling and colleagues noted.
“Pivotal” antiseizure medication epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they noted.
Meta analysis showed no increased risk
Dr. Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five antiseizure medications approved since 2008. These antiseizure medications were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5,996 patients, including 4,000 who were treated with antiseizure medications and 1,996 who were treated with placebo.
Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers noted.
They found no evidence of increased risk for suicidal ideation (overall risk ratio, antiseizure medications vs. placebo: 0.75; 95% confidence interval: 0.35-1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30-1.87) overall or for any individual antiseizure medication.
Suicidal ideation occurred in 12 of 4,000 patients treated with antiseizure medications (0.30%), versus 7 of 1,996 patients treated with placebo (0.35%) (P = .74). Three patients who were treated with antiseizure medications attempted suicide; no patients who were treated with placebo attempted suicide (P = .22). There were no completed suicides.
“There is no current evidence that the five antiseizure medications evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning,” the investigators wrote. When prescribed for epilepsy, “evidence does not support the FDA’s labeling practice of a blanket assumption of increased suicidality,” said Dr. Sperling.
“Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable,” he said. “The results are not surprising. Different drugs affect cells in different ways. So there’s no reason to expect that every drug would increase suicide risk for every patient,” Dr. Sperling said in a statement.
“It’s important to recognize that epilepsy has many causes – perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others – and these underlying etiologies may well contribute to the presence of depression and suicidality in this population,” he said in an interview. “Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle,” he added.
Dr. Sperling said the FDA has accomplished “one useful thing with its warning – it highlighted that physicians and other health care providers must pay attention to their patients’ psychological state, ask questions, and treat accordingly.”
The study had no specific funding. Dr. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors’ disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
Wisdom may counter loneliness, burnout in older adults
Wisdom increases with age, and although this personality trait is regarded as nebulous by many, there is evidence that it has biological and neuropsychiatric underpinnings. It could even hold the key to reducing loneliness and burnout among older people.
Those were some of the key messages delivered by Tanya T. Nguyen, PhD, of the department of psychiatry at the University of California, San Diego, who spoke at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“To many people, wisdom remains a fuzzy concept that’s difficult to operationalize and measure. It’s analogous to the concepts of consciousness, emotions, and cognitions, which at one point were considered nonscientific, but today we accept them as biological and scientific entities,” Dr. Nguyen said during her talk at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
Interest in quantifying and studying wisdom has picked up in recent years, and Dr. Nguyen gave a definition with six elements that includes prosocial behaviors such as empathy and compassion, as well as emotional regulation, self-reflection, decisiveness, and social decision-making. She also included a spirituality component, though she conceded that this is controversial.
She noted that there are cultural variations in the definition of wisdom, but it has changed little over time, suggesting that it may be biological rather than cultural in nature, and therefore may have a neuropsychiatric underpinning.
Loss of some or all characteristics of wisdom occurs in some behaviors and disorders, including most markedly in the neurodegenerative disorder frontotemporal dementia (FTD), which is characterized by damage only in the prefrontal cortex and anterior temporal lobes. It usually occurs before age 60, and patients exhibit poor social awareness, impulsivity, antisocial behavior, and a lack of insight and empathy.
This and other lines of evidence have led to the suggestion that wisdom may be governed by processes in the prefrontal cortex and the limbic striatum. The prefrontal cortex controls executive functions such as planning, predicting, and anticipating events, as well as managing emotional reactions and impulses. “Thus, wisdom involves parts of the brain that balance cold, hard analytical reasoning with primitive desires and drives, which ultimately leads to self-regulation, social insight, theory of mind, and empathy,” said Dr. Nguyen.
Wisdom has long been associated with age, but age is also linked to cognitive decline. A recent discovery that the brain does not stop evolving at older age may help explain this contradiction. Brains develop in a back to front order, so that the prefrontal cortex is the last to mature. As we age, neural activity shifts from the occipital lobes to the prefrontal cortex and its executive decision-making power.
“The brain may recruit higher-order networks to the prefrontal cortex that are associated with wisdom development,” said Dr. Nguyen. She also pointed out that asymmetry between the left and right hemisphere is reduced with age, as tasks that relied on circuits from one hemisphere or another more often call upon both. “In order to make up for lost synapses and neurons with aging, active older adults use more neuronal networks from both hemispheres to perform the same mental activity,” Dr. Nguyen said.
Some interventions can improve scores in traits associated with wisdom in older adults, and could be an important contributor to improvements in health and longevity, said Dr. Nguyen. Randomized, controlled trials have demonstrated that psychosocial or behavioral interventions can improve elements of wisdom such as prosocial behaviors and emotional regulation, both in people with mental illness and in the general population, with moderate to large effect sizes. But such studies don’t prove an effect on overall wisdom.
The intervention achieved positive results in 89 participants in senior housing communities, though the effect sizes were small, possibly because of high baseline resilience. A subanalysis suggested that reduction in loneliness was mediated by an increase in compassion.
“One of the most striking findings from our research on wisdom is this consistent and very strongly negative correlation between wisdom and loneliness,” Dr. Nguyen said. She highlighted other U.S. nationwide and cross-cultural studies that showed inverse relationships between loneliness and wisdom.
Loneliness is an important topic because it can contribute to burnout and suicide rates.
“Loneliness has a profound effect on how we show up in the workplace, in school, and in our communities. And that leads to anxiety, depression, depersonalization, and emotional fatigue. All are key features of burnout. And together loneliness and burnout have contributed to increased rates of suicide by 30%, and opioid-related deaths almost sixfold since the late 1990s,” Dr. Nguyen said.
Loneliness also is associated with worse physical health, and it may be linked to wisdom. “Loneliness can be conceptualized as being caused and maintained by objective circumstances, such as physical or social distancing, and by thoughts, behaviors, and feelings surrounding those experiences, including biased perceptions of social relations, and a negative assessment of one’s social skills, which then results in a discrepancy between one’s desired and perceived social relationships, which then can contribute to social withdrawal,” Dr. Nguyen said.
Dr. Nguyen highlighted the AARP Foundation’s Experience Corps program, which recruits older adults to act as mentors and tutors for children in kindergarten through third grade. It involves 15 hours per week over an entire school year, with a focus on child literacy, development, and behavioral management skills. A study revealed a significant impact. “It showed improvements in children’s grades and happiness, as well as seniors’ mental and physical health,” Dr. Nguyen said.
Dr. Nguyen concluded that wisdom “may be a vaccine against compassion fatigue and burnout that drive today’s behavioral epidemics of loneliness, opioid abuse, and suicide. It’s a tool for our times. It’s nuanced, flexible, pragmatic, compassionate, and it presents a reasonable framework for getting along in the often messy world that we all share.”
Implications for psychiatrists
Henry A. Nasrallah, MD, who organized the conference, suggested that the benefits of wisdom may not be limited to patients. He pointed out that surgeons often retire at age 60 or 65 because of declining physical skills, while psychiatrists continue to practice.
“We develop more wisdom and better skills, and we can practice into our 60s and 70s. I know psychiatrists who practice sometimes into their 80s. It’s really a wonderful thing to know that what you do in life develops or enhances the neuroplasticity of certain brain regions. In our case, in psychiatry, it is the brain regions involved in wisdom,” commented Dr. Nasrallah, who is a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati.
Dr. Nguyen has no financial disclosures. Dr. Nasrallah has received grants from Abbott, AstraZeneca, Forest, Janssen, Lilly, Pfizer, and Shire, and advises Abbott, AstraZeneca, and Shire.
Wisdom increases with age, and although this personality trait is regarded as nebulous by many, there is evidence that it has biological and neuropsychiatric underpinnings. It could even hold the key to reducing loneliness and burnout among older people.
Those were some of the key messages delivered by Tanya T. Nguyen, PhD, of the department of psychiatry at the University of California, San Diego, who spoke at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“To many people, wisdom remains a fuzzy concept that’s difficult to operationalize and measure. It’s analogous to the concepts of consciousness, emotions, and cognitions, which at one point were considered nonscientific, but today we accept them as biological and scientific entities,” Dr. Nguyen said during her talk at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
Interest in quantifying and studying wisdom has picked up in recent years, and Dr. Nguyen gave a definition with six elements that includes prosocial behaviors such as empathy and compassion, as well as emotional regulation, self-reflection, decisiveness, and social decision-making. She also included a spirituality component, though she conceded that this is controversial.
She noted that there are cultural variations in the definition of wisdom, but it has changed little over time, suggesting that it may be biological rather than cultural in nature, and therefore may have a neuropsychiatric underpinning.
Loss of some or all characteristics of wisdom occurs in some behaviors and disorders, including most markedly in the neurodegenerative disorder frontotemporal dementia (FTD), which is characterized by damage only in the prefrontal cortex and anterior temporal lobes. It usually occurs before age 60, and patients exhibit poor social awareness, impulsivity, antisocial behavior, and a lack of insight and empathy.
This and other lines of evidence have led to the suggestion that wisdom may be governed by processes in the prefrontal cortex and the limbic striatum. The prefrontal cortex controls executive functions such as planning, predicting, and anticipating events, as well as managing emotional reactions and impulses. “Thus, wisdom involves parts of the brain that balance cold, hard analytical reasoning with primitive desires and drives, which ultimately leads to self-regulation, social insight, theory of mind, and empathy,” said Dr. Nguyen.
Wisdom has long been associated with age, but age is also linked to cognitive decline. A recent discovery that the brain does not stop evolving at older age may help explain this contradiction. Brains develop in a back to front order, so that the prefrontal cortex is the last to mature. As we age, neural activity shifts from the occipital lobes to the prefrontal cortex and its executive decision-making power.
“The brain may recruit higher-order networks to the prefrontal cortex that are associated with wisdom development,” said Dr. Nguyen. She also pointed out that asymmetry between the left and right hemisphere is reduced with age, as tasks that relied on circuits from one hemisphere or another more often call upon both. “In order to make up for lost synapses and neurons with aging, active older adults use more neuronal networks from both hemispheres to perform the same mental activity,” Dr. Nguyen said.
Some interventions can improve scores in traits associated with wisdom in older adults, and could be an important contributor to improvements in health and longevity, said Dr. Nguyen. Randomized, controlled trials have demonstrated that psychosocial or behavioral interventions can improve elements of wisdom such as prosocial behaviors and emotional regulation, both in people with mental illness and in the general population, with moderate to large effect sizes. But such studies don’t prove an effect on overall wisdom.
The intervention achieved positive results in 89 participants in senior housing communities, though the effect sizes were small, possibly because of high baseline resilience. A subanalysis suggested that reduction in loneliness was mediated by an increase in compassion.
“One of the most striking findings from our research on wisdom is this consistent and very strongly negative correlation between wisdom and loneliness,” Dr. Nguyen said. She highlighted other U.S. nationwide and cross-cultural studies that showed inverse relationships between loneliness and wisdom.
Loneliness is an important topic because it can contribute to burnout and suicide rates.
“Loneliness has a profound effect on how we show up in the workplace, in school, and in our communities. And that leads to anxiety, depression, depersonalization, and emotional fatigue. All are key features of burnout. And together loneliness and burnout have contributed to increased rates of suicide by 30%, and opioid-related deaths almost sixfold since the late 1990s,” Dr. Nguyen said.
Loneliness also is associated with worse physical health, and it may be linked to wisdom. “Loneliness can be conceptualized as being caused and maintained by objective circumstances, such as physical or social distancing, and by thoughts, behaviors, and feelings surrounding those experiences, including biased perceptions of social relations, and a negative assessment of one’s social skills, which then results in a discrepancy between one’s desired and perceived social relationships, which then can contribute to social withdrawal,” Dr. Nguyen said.
Dr. Nguyen highlighted the AARP Foundation’s Experience Corps program, which recruits older adults to act as mentors and tutors for children in kindergarten through third grade. It involves 15 hours per week over an entire school year, with a focus on child literacy, development, and behavioral management skills. A study revealed a significant impact. “It showed improvements in children’s grades and happiness, as well as seniors’ mental and physical health,” Dr. Nguyen said.
Dr. Nguyen concluded that wisdom “may be a vaccine against compassion fatigue and burnout that drive today’s behavioral epidemics of loneliness, opioid abuse, and suicide. It’s a tool for our times. It’s nuanced, flexible, pragmatic, compassionate, and it presents a reasonable framework for getting along in the often messy world that we all share.”
Implications for psychiatrists
Henry A. Nasrallah, MD, who organized the conference, suggested that the benefits of wisdom may not be limited to patients. He pointed out that surgeons often retire at age 60 or 65 because of declining physical skills, while psychiatrists continue to practice.
“We develop more wisdom and better skills, and we can practice into our 60s and 70s. I know psychiatrists who practice sometimes into their 80s. It’s really a wonderful thing to know that what you do in life develops or enhances the neuroplasticity of certain brain regions. In our case, in psychiatry, it is the brain regions involved in wisdom,” commented Dr. Nasrallah, who is a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati.
Dr. Nguyen has no financial disclosures. Dr. Nasrallah has received grants from Abbott, AstraZeneca, Forest, Janssen, Lilly, Pfizer, and Shire, and advises Abbott, AstraZeneca, and Shire.
Wisdom increases with age, and although this personality trait is regarded as nebulous by many, there is evidence that it has biological and neuropsychiatric underpinnings. It could even hold the key to reducing loneliness and burnout among older people.
Those were some of the key messages delivered by Tanya T. Nguyen, PhD, of the department of psychiatry at the University of California, San Diego, who spoke at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“To many people, wisdom remains a fuzzy concept that’s difficult to operationalize and measure. It’s analogous to the concepts of consciousness, emotions, and cognitions, which at one point were considered nonscientific, but today we accept them as biological and scientific entities,” Dr. Nguyen said during her talk at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
Interest in quantifying and studying wisdom has picked up in recent years, and Dr. Nguyen gave a definition with six elements that includes prosocial behaviors such as empathy and compassion, as well as emotional regulation, self-reflection, decisiveness, and social decision-making. She also included a spirituality component, though she conceded that this is controversial.
She noted that there are cultural variations in the definition of wisdom, but it has changed little over time, suggesting that it may be biological rather than cultural in nature, and therefore may have a neuropsychiatric underpinning.
Loss of some or all characteristics of wisdom occurs in some behaviors and disorders, including most markedly in the neurodegenerative disorder frontotemporal dementia (FTD), which is characterized by damage only in the prefrontal cortex and anterior temporal lobes. It usually occurs before age 60, and patients exhibit poor social awareness, impulsivity, antisocial behavior, and a lack of insight and empathy.
This and other lines of evidence have led to the suggestion that wisdom may be governed by processes in the prefrontal cortex and the limbic striatum. The prefrontal cortex controls executive functions such as planning, predicting, and anticipating events, as well as managing emotional reactions and impulses. “Thus, wisdom involves parts of the brain that balance cold, hard analytical reasoning with primitive desires and drives, which ultimately leads to self-regulation, social insight, theory of mind, and empathy,” said Dr. Nguyen.
Wisdom has long been associated with age, but age is also linked to cognitive decline. A recent discovery that the brain does not stop evolving at older age may help explain this contradiction. Brains develop in a back to front order, so that the prefrontal cortex is the last to mature. As we age, neural activity shifts from the occipital lobes to the prefrontal cortex and its executive decision-making power.
“The brain may recruit higher-order networks to the prefrontal cortex that are associated with wisdom development,” said Dr. Nguyen. She also pointed out that asymmetry between the left and right hemisphere is reduced with age, as tasks that relied on circuits from one hemisphere or another more often call upon both. “In order to make up for lost synapses and neurons with aging, active older adults use more neuronal networks from both hemispheres to perform the same mental activity,” Dr. Nguyen said.
Some interventions can improve scores in traits associated with wisdom in older adults, and could be an important contributor to improvements in health and longevity, said Dr. Nguyen. Randomized, controlled trials have demonstrated that psychosocial or behavioral interventions can improve elements of wisdom such as prosocial behaviors and emotional regulation, both in people with mental illness and in the general population, with moderate to large effect sizes. But such studies don’t prove an effect on overall wisdom.
The intervention achieved positive results in 89 participants in senior housing communities, though the effect sizes were small, possibly because of high baseline resilience. A subanalysis suggested that reduction in loneliness was mediated by an increase in compassion.
“One of the most striking findings from our research on wisdom is this consistent and very strongly negative correlation between wisdom and loneliness,” Dr. Nguyen said. She highlighted other U.S. nationwide and cross-cultural studies that showed inverse relationships between loneliness and wisdom.
Loneliness is an important topic because it can contribute to burnout and suicide rates.
“Loneliness has a profound effect on how we show up in the workplace, in school, and in our communities. And that leads to anxiety, depression, depersonalization, and emotional fatigue. All are key features of burnout. And together loneliness and burnout have contributed to increased rates of suicide by 30%, and opioid-related deaths almost sixfold since the late 1990s,” Dr. Nguyen said.
Loneliness also is associated with worse physical health, and it may be linked to wisdom. “Loneliness can be conceptualized as being caused and maintained by objective circumstances, such as physical or social distancing, and by thoughts, behaviors, and feelings surrounding those experiences, including biased perceptions of social relations, and a negative assessment of one’s social skills, which then results in a discrepancy between one’s desired and perceived social relationships, which then can contribute to social withdrawal,” Dr. Nguyen said.
Dr. Nguyen highlighted the AARP Foundation’s Experience Corps program, which recruits older adults to act as mentors and tutors for children in kindergarten through third grade. It involves 15 hours per week over an entire school year, with a focus on child literacy, development, and behavioral management skills. A study revealed a significant impact. “It showed improvements in children’s grades and happiness, as well as seniors’ mental and physical health,” Dr. Nguyen said.
Dr. Nguyen concluded that wisdom “may be a vaccine against compassion fatigue and burnout that drive today’s behavioral epidemics of loneliness, opioid abuse, and suicide. It’s a tool for our times. It’s nuanced, flexible, pragmatic, compassionate, and it presents a reasonable framework for getting along in the often messy world that we all share.”
Implications for psychiatrists
Henry A. Nasrallah, MD, who organized the conference, suggested that the benefits of wisdom may not be limited to patients. He pointed out that surgeons often retire at age 60 or 65 because of declining physical skills, while psychiatrists continue to practice.
“We develop more wisdom and better skills, and we can practice into our 60s and 70s. I know psychiatrists who practice sometimes into their 80s. It’s really a wonderful thing to know that what you do in life develops or enhances the neuroplasticity of certain brain regions. In our case, in psychiatry, it is the brain regions involved in wisdom,” commented Dr. Nasrallah, who is a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati.
Dr. Nguyen has no financial disclosures. Dr. Nasrallah has received grants from Abbott, AstraZeneca, Forest, Janssen, Lilly, Pfizer, and Shire, and advises Abbott, AstraZeneca, and Shire.
REPORTING FROM FOCUS ON NEUROPSYCHIATRY 2021
Brain memory signals appear to regulate metabolism
Rhythmic brain signals that help encode memories also appear to influence blood sugar levels and may regulate the timing of the release of hormones, early, pre-clinical research shows.
“Our study is the first to show how clusters of brain cell firing in the hippocampus may directly regulate metabolism,” senior author György Buzsáki, MD, PhD, professor, department of neuroscience and physiology, NYU Grossman School of Medicine and NYU Langone Health, said in a news release.
“Evidence suggests that the brain evolved, for reasons of efficiency, to use the same signals to achieve two very different functions in terms of memory and hormonal regulation,” added corresponding author David Tingley, PhD, a post-doctoral scholar in Dr. Buzsáki’s lab.
The study was published online August 11 in Nature.
It’s recently been discovered that populations of hippocampal neurons fire within milliseconds of each other in cycles. This firing pattern is called a “sharp wave ripple” for the shape it takes when captured graphically by electroencephalogram.
In their study, Dr. Buzsáki, Dr. Tingley, and colleagues observed that clusters of sharp wave ripples recorded from the hippocampus of rats were “reliably” and rapidly, followed by decreases in blood sugar concentrations in the animals.
“This correlation was not dependent on circadian, ultradian, or meal-triggered fluctuations; it could be mimicked with optogenetically induced ripples in the hippocampus, but not in the parietal cortex, and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum (LS), the major conduit between the hippocampus and hypothalamus,” the researchers report.
These observations suggest that hippocampal sharp wave ripples may regulate the timing of the release of hormones, possibly including insulin, by the pancreas and liver, as well as other hormones by the pituitary gland, the researchers note.
As sharp wave ripples mostly occur during non-rapid eye movement sleep, the impact of sleep disturbance on sharp wave ripples may provide a mechanistic link between poor sleep and high blood sugar levels seen in type 2 diabetes, they suggest.
“There are a couple of experimental studies showing that if you deprive a young healthy person from sleep [for 48 hours], their glucose tolerance resembles” that of a person with diabetes, Dr. Buzsáki noted in an interview.
Moving forward, the researchers will seek to extend their theory that several hormones could be affected by nightly sharp wave ripples.
The research was funded by National Institutes of Health. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Rhythmic brain signals that help encode memories also appear to influence blood sugar levels and may regulate the timing of the release of hormones, early, pre-clinical research shows.
“Our study is the first to show how clusters of brain cell firing in the hippocampus may directly regulate metabolism,” senior author György Buzsáki, MD, PhD, professor, department of neuroscience and physiology, NYU Grossman School of Medicine and NYU Langone Health, said in a news release.
“Evidence suggests that the brain evolved, for reasons of efficiency, to use the same signals to achieve two very different functions in terms of memory and hormonal regulation,” added corresponding author David Tingley, PhD, a post-doctoral scholar in Dr. Buzsáki’s lab.
The study was published online August 11 in Nature.
It’s recently been discovered that populations of hippocampal neurons fire within milliseconds of each other in cycles. This firing pattern is called a “sharp wave ripple” for the shape it takes when captured graphically by electroencephalogram.
In their study, Dr. Buzsáki, Dr. Tingley, and colleagues observed that clusters of sharp wave ripples recorded from the hippocampus of rats were “reliably” and rapidly, followed by decreases in blood sugar concentrations in the animals.
“This correlation was not dependent on circadian, ultradian, or meal-triggered fluctuations; it could be mimicked with optogenetically induced ripples in the hippocampus, but not in the parietal cortex, and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum (LS), the major conduit between the hippocampus and hypothalamus,” the researchers report.
These observations suggest that hippocampal sharp wave ripples may regulate the timing of the release of hormones, possibly including insulin, by the pancreas and liver, as well as other hormones by the pituitary gland, the researchers note.
As sharp wave ripples mostly occur during non-rapid eye movement sleep, the impact of sleep disturbance on sharp wave ripples may provide a mechanistic link between poor sleep and high blood sugar levels seen in type 2 diabetes, they suggest.
“There are a couple of experimental studies showing that if you deprive a young healthy person from sleep [for 48 hours], their glucose tolerance resembles” that of a person with diabetes, Dr. Buzsáki noted in an interview.
Moving forward, the researchers will seek to extend their theory that several hormones could be affected by nightly sharp wave ripples.
The research was funded by National Institutes of Health. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Rhythmic brain signals that help encode memories also appear to influence blood sugar levels and may regulate the timing of the release of hormones, early, pre-clinical research shows.
“Our study is the first to show how clusters of brain cell firing in the hippocampus may directly regulate metabolism,” senior author György Buzsáki, MD, PhD, professor, department of neuroscience and physiology, NYU Grossman School of Medicine and NYU Langone Health, said in a news release.
“Evidence suggests that the brain evolved, for reasons of efficiency, to use the same signals to achieve two very different functions in terms of memory and hormonal regulation,” added corresponding author David Tingley, PhD, a post-doctoral scholar in Dr. Buzsáki’s lab.
The study was published online August 11 in Nature.
It’s recently been discovered that populations of hippocampal neurons fire within milliseconds of each other in cycles. This firing pattern is called a “sharp wave ripple” for the shape it takes when captured graphically by electroencephalogram.
In their study, Dr. Buzsáki, Dr. Tingley, and colleagues observed that clusters of sharp wave ripples recorded from the hippocampus of rats were “reliably” and rapidly, followed by decreases in blood sugar concentrations in the animals.
“This correlation was not dependent on circadian, ultradian, or meal-triggered fluctuations; it could be mimicked with optogenetically induced ripples in the hippocampus, but not in the parietal cortex, and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum (LS), the major conduit between the hippocampus and hypothalamus,” the researchers report.
These observations suggest that hippocampal sharp wave ripples may regulate the timing of the release of hormones, possibly including insulin, by the pancreas and liver, as well as other hormones by the pituitary gland, the researchers note.
As sharp wave ripples mostly occur during non-rapid eye movement sleep, the impact of sleep disturbance on sharp wave ripples may provide a mechanistic link between poor sleep and high blood sugar levels seen in type 2 diabetes, they suggest.
“There are a couple of experimental studies showing that if you deprive a young healthy person from sleep [for 48 hours], their glucose tolerance resembles” that of a person with diabetes, Dr. Buzsáki noted in an interview.
Moving forward, the researchers will seek to extend their theory that several hormones could be affected by nightly sharp wave ripples.
The research was funded by National Institutes of Health. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FDA approves first drug for idiopathic hypersomnia
, the company announced in a news release.
It marks the second approval for Xywav. The FDA approved it last year for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy as young as 7 years of age.
This recent approval is the first for a treatment for idiopathic hypersomnia.
“Idiopathic hypersomnia can have a significant impact on the social, educational, and occupational functioning of people living with the condition,” Diane Powell, board chair and CEO of the Hypersomnia Foundation, noted in the release.
This FDA approval “is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder,” said Ms. Powell.
Low sodium oxybate product
Xywav is a novel oxybate product with a unique composition of cations. It contains 92% less sodium than sodium oxybate (Xyrem) at the recommended adult dosage range of 6 to 9 g, the company noted in a news release.
An estimated 37,000 people in the United States have been diagnosed with idiopathic hypersomnia, a neurologic sleep disorder characterized by chronic excessive daytime sleepiness.
Other symptoms of the disorder may include severe sleep inertia or sleep drunkenness (prolonged difficulty waking with frequent re-entries into sleep, confusion, and irritability), as well as prolonged, nonrestorative night-time sleep, cognitive impairment, and long and unrefreshing naps.
The approval was based on findings from a phase 3, double-blind, multicenter, placebo-controlled, randomized withdrawal study.
Results showed “statistically significant and clinically meaningful” differences compared with placebo in change in the primary endpoint of Epworth Sleepiness Scale score (P < .0001) and the secondary endpoints of Patient Global Impression of Change (P < .0001) and the Idiopathic Hypersomnia Severity Scale (P < .0001), the company reported.
The most common adverse reactions were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.
The novel agent can be administered once or twice nightly for the treatment of idiopathic hypersomnia in adults.
“To optimize response, a patient’s health care provider may consider prescribing a twice-nightly regimen in equally or unequally divided doses at bedtime and 2.5 to 4 hours later and gradually titrate Xywav so that a patient may receive an individualized dose and regimen based on efficacy and tolerability,” the company said.
Xywav carries a boxed warning because it is a central nervous system depressant and because there is potential for abuse and misuse. The drug is only available through a risk evaluation and mitigation strategy (REMS) program.
The company plans to make Xywav available to patients with idiopathic hypersomnia later this year following implementation of the REMS program.
A version of this article first appeared on Medscape.com.
, the company announced in a news release.
It marks the second approval for Xywav. The FDA approved it last year for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy as young as 7 years of age.
This recent approval is the first for a treatment for idiopathic hypersomnia.
“Idiopathic hypersomnia can have a significant impact on the social, educational, and occupational functioning of people living with the condition,” Diane Powell, board chair and CEO of the Hypersomnia Foundation, noted in the release.
This FDA approval “is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder,” said Ms. Powell.
Low sodium oxybate product
Xywav is a novel oxybate product with a unique composition of cations. It contains 92% less sodium than sodium oxybate (Xyrem) at the recommended adult dosage range of 6 to 9 g, the company noted in a news release.
An estimated 37,000 people in the United States have been diagnosed with idiopathic hypersomnia, a neurologic sleep disorder characterized by chronic excessive daytime sleepiness.
Other symptoms of the disorder may include severe sleep inertia or sleep drunkenness (prolonged difficulty waking with frequent re-entries into sleep, confusion, and irritability), as well as prolonged, nonrestorative night-time sleep, cognitive impairment, and long and unrefreshing naps.
The approval was based on findings from a phase 3, double-blind, multicenter, placebo-controlled, randomized withdrawal study.
Results showed “statistically significant and clinically meaningful” differences compared with placebo in change in the primary endpoint of Epworth Sleepiness Scale score (P < .0001) and the secondary endpoints of Patient Global Impression of Change (P < .0001) and the Idiopathic Hypersomnia Severity Scale (P < .0001), the company reported.
The most common adverse reactions were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.
The novel agent can be administered once or twice nightly for the treatment of idiopathic hypersomnia in adults.
“To optimize response, a patient’s health care provider may consider prescribing a twice-nightly regimen in equally or unequally divided doses at bedtime and 2.5 to 4 hours later and gradually titrate Xywav so that a patient may receive an individualized dose and regimen based on efficacy and tolerability,” the company said.
Xywav carries a boxed warning because it is a central nervous system depressant and because there is potential for abuse and misuse. The drug is only available through a risk evaluation and mitigation strategy (REMS) program.
The company plans to make Xywav available to patients with idiopathic hypersomnia later this year following implementation of the REMS program.
A version of this article first appeared on Medscape.com.
, the company announced in a news release.
It marks the second approval for Xywav. The FDA approved it last year for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy as young as 7 years of age.
This recent approval is the first for a treatment for idiopathic hypersomnia.
“Idiopathic hypersomnia can have a significant impact on the social, educational, and occupational functioning of people living with the condition,” Diane Powell, board chair and CEO of the Hypersomnia Foundation, noted in the release.
This FDA approval “is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder,” said Ms. Powell.
Low sodium oxybate product
Xywav is a novel oxybate product with a unique composition of cations. It contains 92% less sodium than sodium oxybate (Xyrem) at the recommended adult dosage range of 6 to 9 g, the company noted in a news release.
An estimated 37,000 people in the United States have been diagnosed with idiopathic hypersomnia, a neurologic sleep disorder characterized by chronic excessive daytime sleepiness.
Other symptoms of the disorder may include severe sleep inertia or sleep drunkenness (prolonged difficulty waking with frequent re-entries into sleep, confusion, and irritability), as well as prolonged, nonrestorative night-time sleep, cognitive impairment, and long and unrefreshing naps.
The approval was based on findings from a phase 3, double-blind, multicenter, placebo-controlled, randomized withdrawal study.
Results showed “statistically significant and clinically meaningful” differences compared with placebo in change in the primary endpoint of Epworth Sleepiness Scale score (P < .0001) and the secondary endpoints of Patient Global Impression of Change (P < .0001) and the Idiopathic Hypersomnia Severity Scale (P < .0001), the company reported.
The most common adverse reactions were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.
The novel agent can be administered once or twice nightly for the treatment of idiopathic hypersomnia in adults.
“To optimize response, a patient’s health care provider may consider prescribing a twice-nightly regimen in equally or unequally divided doses at bedtime and 2.5 to 4 hours later and gradually titrate Xywav so that a patient may receive an individualized dose and regimen based on efficacy and tolerability,” the company said.
Xywav carries a boxed warning because it is a central nervous system depressant and because there is potential for abuse and misuse. The drug is only available through a risk evaluation and mitigation strategy (REMS) program.
The company plans to make Xywav available to patients with idiopathic hypersomnia later this year following implementation of the REMS program.
A version of this article first appeared on Medscape.com.
Exercise tied to 50% reduction in mortality after stroke
, with a greater than 50% reduction in risk.
Lead study author Raed A. Joundi, MD, DPhil, of the University of Calgary (Alta.), said he expected results to show exercise was beneficial, but was surprised by the magnitude of the association between physical activity and lower mortality risk.
The impact of physical activity also differed significantly by age; those younger than 75 had a 79% reduction in mortality risk, compared with 32% in those age 75 and older.
“This is even after adjusting for factors such heart disease, respiratory conditions, smoking, and other functional limitations,” said Dr. Joundi.
The study was published online Aug. 11 in the journal Neurology.
For this analysis, the researchers used data on a cohort of people across Canada (excluding the province of Quebec) over 3-9 years. The 895 patients with prior stroke averaged 72 years of age, while the 97,805 in the control group had an average age of 63.
Weekly physical activity averages were evaluated using the self-reporting Canadian Community Health Survey, which was linked with administrative databases to evaluate the association of physical activity with long-term risk for mortality among stroke survivors, compared with controls.
Physical activity was measured in metabolic equivalents (METs); meeting minimum physical activity guidelines was defined as 10 MET-hours/week.
During the study period, more stroke patients than controls died (24.7% vs. 5.7%). However, those who met the physical activity guideline recommendations of 10 MET-hours/week had a lower mortality, both in the stroke survivor group (14.6% vs. 33.2%; adjusted hazard ratio, 0.46; 95% confidence interval, 0.29-0.73) and among control participants (3.6% vs. 7.9%; aHR 0.69; 95% CI, 0.62-0.76).
The largest absolute and relative reduction in mortality was among stroke respondents younger than 75 (10.5% vs. 29%; aHR, 0.21; 95% CI, 0.10-0.43), the researchers note.
There was a significant interaction with age for the stroke patients but not the control group.
“The greatest reduction in mortality was seen between 0 and 10 METs per week … so the main point is that something is better than nothing,” said Dr. Joundi.
Exercise guidelines for the future
Although current guidelines recommend physical activity in stroke survivors, investigators noted that these are largely based on studies in the general population. Therefore, the aim of this research was to get a better understanding of the role of physical activity in the health of stroke survivors in the community, which could ultimately be used to design improved public health campaigns and physical activity interventions.
Given that this is a large study of stroke survivors in the community, Dr. Joundi hopes the results will influence future activity guidelines for those who have suffered a stroke.
“We found a log-linear relationship between physical activity and mortality such that 10 MET-hours/week was associated with large reductions in mortality with most benefit achieved by 20 MET-hours/week,” the authors concluded. “These thresholds could be considered for use in future guidelines for stroke.”
Clinical trials are underway to provide evidence for the implementation of exercise programs after stroke, they add, and offering physical activity programs to stroke survivors in the community “is an increasing priority in the U.S., Canada, and Europe.”
“People are at higher risk of death early on after a stroke but also months and years later, so if we can identify a relatively low-cost and easy intervention like physical activity to improve health and reduce the risk of death for stroke survivors it would be important,” Dr. Joundi said.
Key barriers
Paul George, MD, PhD, a stroke and vascular neurologist at Stanford (Calif.) University, said findings such as these further strengthen the argument that physical exercise is important after stroke.
“Because the study looked specifically at stroke patients, it can provide further guidance on physical activity recommendations that we provide to our patients following stroke,” said Dr. George, who was not associated with the study.
Going forward, he said, more research is needed to identify specifically what is preventing stroke patients from exercising more. What is required, he said, is “future research to determine the key barriers to physical activity following stroke and methods to reduce these will also be important to increasing physical activity in stroke survivors.”
Dr. Joundi said determining how to tailor exercise recommendations to meet the wide range of capabilities of stroke survivors will be another key factor.
“Stroke survivors may have some disabilities, so we need to be able to engage them at an [exercise] level that’s possible for them,” he said.
The study did not include stroke survivors living in long-term care homes.
The study had no targeted funding. Coauthor Eric E. Smith, MD, MPH, reports royalties from UpToDate, and consulting fees from Alnylam, Biogen, and Javelin. Dr. Joundi and the other coauthors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with a greater than 50% reduction in risk.
Lead study author Raed A. Joundi, MD, DPhil, of the University of Calgary (Alta.), said he expected results to show exercise was beneficial, but was surprised by the magnitude of the association between physical activity and lower mortality risk.
The impact of physical activity also differed significantly by age; those younger than 75 had a 79% reduction in mortality risk, compared with 32% in those age 75 and older.
“This is even after adjusting for factors such heart disease, respiratory conditions, smoking, and other functional limitations,” said Dr. Joundi.
The study was published online Aug. 11 in the journal Neurology.
For this analysis, the researchers used data on a cohort of people across Canada (excluding the province of Quebec) over 3-9 years. The 895 patients with prior stroke averaged 72 years of age, while the 97,805 in the control group had an average age of 63.
Weekly physical activity averages were evaluated using the self-reporting Canadian Community Health Survey, which was linked with administrative databases to evaluate the association of physical activity with long-term risk for mortality among stroke survivors, compared with controls.
Physical activity was measured in metabolic equivalents (METs); meeting minimum physical activity guidelines was defined as 10 MET-hours/week.
During the study period, more stroke patients than controls died (24.7% vs. 5.7%). However, those who met the physical activity guideline recommendations of 10 MET-hours/week had a lower mortality, both in the stroke survivor group (14.6% vs. 33.2%; adjusted hazard ratio, 0.46; 95% confidence interval, 0.29-0.73) and among control participants (3.6% vs. 7.9%; aHR 0.69; 95% CI, 0.62-0.76).
The largest absolute and relative reduction in mortality was among stroke respondents younger than 75 (10.5% vs. 29%; aHR, 0.21; 95% CI, 0.10-0.43), the researchers note.
There was a significant interaction with age for the stroke patients but not the control group.
“The greatest reduction in mortality was seen between 0 and 10 METs per week … so the main point is that something is better than nothing,” said Dr. Joundi.
Exercise guidelines for the future
Although current guidelines recommend physical activity in stroke survivors, investigators noted that these are largely based on studies in the general population. Therefore, the aim of this research was to get a better understanding of the role of physical activity in the health of stroke survivors in the community, which could ultimately be used to design improved public health campaigns and physical activity interventions.
Given that this is a large study of stroke survivors in the community, Dr. Joundi hopes the results will influence future activity guidelines for those who have suffered a stroke.
“We found a log-linear relationship between physical activity and mortality such that 10 MET-hours/week was associated with large reductions in mortality with most benefit achieved by 20 MET-hours/week,” the authors concluded. “These thresholds could be considered for use in future guidelines for stroke.”
Clinical trials are underway to provide evidence for the implementation of exercise programs after stroke, they add, and offering physical activity programs to stroke survivors in the community “is an increasing priority in the U.S., Canada, and Europe.”
“People are at higher risk of death early on after a stroke but also months and years later, so if we can identify a relatively low-cost and easy intervention like physical activity to improve health and reduce the risk of death for stroke survivors it would be important,” Dr. Joundi said.
Key barriers
Paul George, MD, PhD, a stroke and vascular neurologist at Stanford (Calif.) University, said findings such as these further strengthen the argument that physical exercise is important after stroke.
“Because the study looked specifically at stroke patients, it can provide further guidance on physical activity recommendations that we provide to our patients following stroke,” said Dr. George, who was not associated with the study.
Going forward, he said, more research is needed to identify specifically what is preventing stroke patients from exercising more. What is required, he said, is “future research to determine the key barriers to physical activity following stroke and methods to reduce these will also be important to increasing physical activity in stroke survivors.”
Dr. Joundi said determining how to tailor exercise recommendations to meet the wide range of capabilities of stroke survivors will be another key factor.
“Stroke survivors may have some disabilities, so we need to be able to engage them at an [exercise] level that’s possible for them,” he said.
The study did not include stroke survivors living in long-term care homes.
The study had no targeted funding. Coauthor Eric E. Smith, MD, MPH, reports royalties from UpToDate, and consulting fees from Alnylam, Biogen, and Javelin. Dr. Joundi and the other coauthors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with a greater than 50% reduction in risk.
Lead study author Raed A. Joundi, MD, DPhil, of the University of Calgary (Alta.), said he expected results to show exercise was beneficial, but was surprised by the magnitude of the association between physical activity and lower mortality risk.
The impact of physical activity also differed significantly by age; those younger than 75 had a 79% reduction in mortality risk, compared with 32% in those age 75 and older.
“This is even after adjusting for factors such heart disease, respiratory conditions, smoking, and other functional limitations,” said Dr. Joundi.
The study was published online Aug. 11 in the journal Neurology.
For this analysis, the researchers used data on a cohort of people across Canada (excluding the province of Quebec) over 3-9 years. The 895 patients with prior stroke averaged 72 years of age, while the 97,805 in the control group had an average age of 63.
Weekly physical activity averages were evaluated using the self-reporting Canadian Community Health Survey, which was linked with administrative databases to evaluate the association of physical activity with long-term risk for mortality among stroke survivors, compared with controls.
Physical activity was measured in metabolic equivalents (METs); meeting minimum physical activity guidelines was defined as 10 MET-hours/week.
During the study period, more stroke patients than controls died (24.7% vs. 5.7%). However, those who met the physical activity guideline recommendations of 10 MET-hours/week had a lower mortality, both in the stroke survivor group (14.6% vs. 33.2%; adjusted hazard ratio, 0.46; 95% confidence interval, 0.29-0.73) and among control participants (3.6% vs. 7.9%; aHR 0.69; 95% CI, 0.62-0.76).
The largest absolute and relative reduction in mortality was among stroke respondents younger than 75 (10.5% vs. 29%; aHR, 0.21; 95% CI, 0.10-0.43), the researchers note.
There was a significant interaction with age for the stroke patients but not the control group.
“The greatest reduction in mortality was seen between 0 and 10 METs per week … so the main point is that something is better than nothing,” said Dr. Joundi.
Exercise guidelines for the future
Although current guidelines recommend physical activity in stroke survivors, investigators noted that these are largely based on studies in the general population. Therefore, the aim of this research was to get a better understanding of the role of physical activity in the health of stroke survivors in the community, which could ultimately be used to design improved public health campaigns and physical activity interventions.
Given that this is a large study of stroke survivors in the community, Dr. Joundi hopes the results will influence future activity guidelines for those who have suffered a stroke.
“We found a log-linear relationship between physical activity and mortality such that 10 MET-hours/week was associated with large reductions in mortality with most benefit achieved by 20 MET-hours/week,” the authors concluded. “These thresholds could be considered for use in future guidelines for stroke.”
Clinical trials are underway to provide evidence for the implementation of exercise programs after stroke, they add, and offering physical activity programs to stroke survivors in the community “is an increasing priority in the U.S., Canada, and Europe.”
“People are at higher risk of death early on after a stroke but also months and years later, so if we can identify a relatively low-cost and easy intervention like physical activity to improve health and reduce the risk of death for stroke survivors it would be important,” Dr. Joundi said.
Key barriers
Paul George, MD, PhD, a stroke and vascular neurologist at Stanford (Calif.) University, said findings such as these further strengthen the argument that physical exercise is important after stroke.
“Because the study looked specifically at stroke patients, it can provide further guidance on physical activity recommendations that we provide to our patients following stroke,” said Dr. George, who was not associated with the study.
Going forward, he said, more research is needed to identify specifically what is preventing stroke patients from exercising more. What is required, he said, is “future research to determine the key barriers to physical activity following stroke and methods to reduce these will also be important to increasing physical activity in stroke survivors.”
Dr. Joundi said determining how to tailor exercise recommendations to meet the wide range of capabilities of stroke survivors will be another key factor.
“Stroke survivors may have some disabilities, so we need to be able to engage them at an [exercise] level that’s possible for them,” he said.
The study did not include stroke survivors living in long-term care homes.
The study had no targeted funding. Coauthor Eric E. Smith, MD, MPH, reports royalties from UpToDate, and consulting fees from Alnylam, Biogen, and Javelin. Dr. Joundi and the other coauthors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Opioid prescribing laws having an impact
State laws capping initial opioid prescriptions to 7 days or less have led to a reduction in opioid prescribing, a new analysis of Medicare data shows.
While overall opioid prescribing has decreased, the reduction in states with legislation restricting opioid prescribing was “significantly greater than in states without such legislation,” study investigator Michael Brenner, MD, University of Michigan, Ann Arbor, said in an interview.
The study was published online August 9 in JAMA Internal Medicine.
Significant but limited effect
Because of rising concern around the opioid crisis, 23 states representing 43% of the U.S. population passed laws from 2016 through 2018 limiting initial opioid prescription to 7 days or less.
Using Medicare data from 2013 through 2018, Dr. Brenner and colleagues conducted a before-and-after study to assess the effect of these laws.
They found that on average, the number of days an opioid was prescribed for each Medicare beneficiary decreased by 11.6 days (from 44.2 days in 2013 to 32.7 days in 2018) in states that imposed duration limits, compared with 10.1 days in states without these laws (from 43.4 days in 2013 to 33.3 days in 2018).
Prior to the start of duration limits in 2016, days an opioid was prescribed were comparable among states.
After adjusting for state-level differences in race, urbanization, median income, tobacco and alcohol use, serious mental illness, and other factors, state laws limiting opioid prescriptions to 7 days or less were associated with a reduction in prescribing of 1.7 days per enrollee, “suggesting a significant but limited outcome” for these laws, the researchers note.
, but this was not significantly different in states with limit laws versus those without. However, state laws limiting duration led to a significant reduction in days of opioid prescribed among surgeons, dentists, pain specialists, and other specialists.
Inadequate pain control?
The researchers note the study was limited to Medicare beneficiaries; however, excess opioid prescribing is prevalent across all patient populations.
In addition, it’s not possible to tell from the data whether acute pain was adequately controlled with fewer pills.
“The question of adequacy of pain control is a crucial one that has been investigated extensively in prior work but was not possible to evaluate in this particular study,” said Dr. Brenner.
However, “ample evidence supports a role for reducing opioid prescribing and that such reduction can be achieved while ensuring that pain is adequately controlled with fewer pills,” he noted.
“A persistent misconception is that opioids are uniquely powerful and effective for controlling pain. Patients may perceive that effective analgesia is being withheld when opioids are not included in a regimen,” Dr. Brenner added.
“Yet, the evidence from meta-analyses derived from large numbers of randomized clinical trials finds that [nonsteroidal anti-inflammatory drugs] NSAIDS combined with acetaminophen provide similar or improved acute pain when compared to commonly prescribed opioid regimens, based on number-needed-to-treat analyses,” he added.
In a related editorial, Deborah Grady, MD, MPH, with University of California, San Francisco, and Mitchell H. Katz, MD, president and CEO of NYC Health + Hospitals, say the decrease in opioid prescribing with duration limits was “small but probably meaningful.”
Restricting initial prescriptions to seven or fewer days is “reasonable because patients with new onset of pain should be re-evaluated in a week if the pain continues,” they write.
However, Dr. Grady and Dr. Katz “worry” that restricting initial prescriptions to shorter periods, such as 3 or 5 days, as has occurred in six states, “may result in patients with acute pain going untreated or having to go to extraordinary effort to obtain adequate pain relief.”
In their view, the data from this study suggest that limiting initial prescriptions to seven or fewer days is “helpful, but we would not restrict any further given that we do not know how it affected patients with acute pain.”
The study had no specific funding. Dr. Brenner, Dr. Grady, and Dr. Katz have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
State laws capping initial opioid prescriptions to 7 days or less have led to a reduction in opioid prescribing, a new analysis of Medicare data shows.
While overall opioid prescribing has decreased, the reduction in states with legislation restricting opioid prescribing was “significantly greater than in states without such legislation,” study investigator Michael Brenner, MD, University of Michigan, Ann Arbor, said in an interview.
The study was published online August 9 in JAMA Internal Medicine.
Significant but limited effect
Because of rising concern around the opioid crisis, 23 states representing 43% of the U.S. population passed laws from 2016 through 2018 limiting initial opioid prescription to 7 days or less.
Using Medicare data from 2013 through 2018, Dr. Brenner and colleagues conducted a before-and-after study to assess the effect of these laws.
They found that on average, the number of days an opioid was prescribed for each Medicare beneficiary decreased by 11.6 days (from 44.2 days in 2013 to 32.7 days in 2018) in states that imposed duration limits, compared with 10.1 days in states without these laws (from 43.4 days in 2013 to 33.3 days in 2018).
Prior to the start of duration limits in 2016, days an opioid was prescribed were comparable among states.
After adjusting for state-level differences in race, urbanization, median income, tobacco and alcohol use, serious mental illness, and other factors, state laws limiting opioid prescriptions to 7 days or less were associated with a reduction in prescribing of 1.7 days per enrollee, “suggesting a significant but limited outcome” for these laws, the researchers note.
, but this was not significantly different in states with limit laws versus those without. However, state laws limiting duration led to a significant reduction in days of opioid prescribed among surgeons, dentists, pain specialists, and other specialists.
Inadequate pain control?
The researchers note the study was limited to Medicare beneficiaries; however, excess opioid prescribing is prevalent across all patient populations.
In addition, it’s not possible to tell from the data whether acute pain was adequately controlled with fewer pills.
“The question of adequacy of pain control is a crucial one that has been investigated extensively in prior work but was not possible to evaluate in this particular study,” said Dr. Brenner.
However, “ample evidence supports a role for reducing opioid prescribing and that such reduction can be achieved while ensuring that pain is adequately controlled with fewer pills,” he noted.
“A persistent misconception is that opioids are uniquely powerful and effective for controlling pain. Patients may perceive that effective analgesia is being withheld when opioids are not included in a regimen,” Dr. Brenner added.
“Yet, the evidence from meta-analyses derived from large numbers of randomized clinical trials finds that [nonsteroidal anti-inflammatory drugs] NSAIDS combined with acetaminophen provide similar or improved acute pain when compared to commonly prescribed opioid regimens, based on number-needed-to-treat analyses,” he added.
In a related editorial, Deborah Grady, MD, MPH, with University of California, San Francisco, and Mitchell H. Katz, MD, president and CEO of NYC Health + Hospitals, say the decrease in opioid prescribing with duration limits was “small but probably meaningful.”
Restricting initial prescriptions to seven or fewer days is “reasonable because patients with new onset of pain should be re-evaluated in a week if the pain continues,” they write.
However, Dr. Grady and Dr. Katz “worry” that restricting initial prescriptions to shorter periods, such as 3 or 5 days, as has occurred in six states, “may result in patients with acute pain going untreated or having to go to extraordinary effort to obtain adequate pain relief.”
In their view, the data from this study suggest that limiting initial prescriptions to seven or fewer days is “helpful, but we would not restrict any further given that we do not know how it affected patients with acute pain.”
The study had no specific funding. Dr. Brenner, Dr. Grady, and Dr. Katz have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
State laws capping initial opioid prescriptions to 7 days or less have led to a reduction in opioid prescribing, a new analysis of Medicare data shows.
While overall opioid prescribing has decreased, the reduction in states with legislation restricting opioid prescribing was “significantly greater than in states without such legislation,” study investigator Michael Brenner, MD, University of Michigan, Ann Arbor, said in an interview.
The study was published online August 9 in JAMA Internal Medicine.
Significant but limited effect
Because of rising concern around the opioid crisis, 23 states representing 43% of the U.S. population passed laws from 2016 through 2018 limiting initial opioid prescription to 7 days or less.
Using Medicare data from 2013 through 2018, Dr. Brenner and colleagues conducted a before-and-after study to assess the effect of these laws.
They found that on average, the number of days an opioid was prescribed for each Medicare beneficiary decreased by 11.6 days (from 44.2 days in 2013 to 32.7 days in 2018) in states that imposed duration limits, compared with 10.1 days in states without these laws (from 43.4 days in 2013 to 33.3 days in 2018).
Prior to the start of duration limits in 2016, days an opioid was prescribed were comparable among states.
After adjusting for state-level differences in race, urbanization, median income, tobacco and alcohol use, serious mental illness, and other factors, state laws limiting opioid prescriptions to 7 days or less were associated with a reduction in prescribing of 1.7 days per enrollee, “suggesting a significant but limited outcome” for these laws, the researchers note.
, but this was not significantly different in states with limit laws versus those without. However, state laws limiting duration led to a significant reduction in days of opioid prescribed among surgeons, dentists, pain specialists, and other specialists.
Inadequate pain control?
The researchers note the study was limited to Medicare beneficiaries; however, excess opioid prescribing is prevalent across all patient populations.
In addition, it’s not possible to tell from the data whether acute pain was adequately controlled with fewer pills.
“The question of adequacy of pain control is a crucial one that has been investigated extensively in prior work but was not possible to evaluate in this particular study,” said Dr. Brenner.
However, “ample evidence supports a role for reducing opioid prescribing and that such reduction can be achieved while ensuring that pain is adequately controlled with fewer pills,” he noted.
“A persistent misconception is that opioids are uniquely powerful and effective for controlling pain. Patients may perceive that effective analgesia is being withheld when opioids are not included in a regimen,” Dr. Brenner added.
“Yet, the evidence from meta-analyses derived from large numbers of randomized clinical trials finds that [nonsteroidal anti-inflammatory drugs] NSAIDS combined with acetaminophen provide similar or improved acute pain when compared to commonly prescribed opioid regimens, based on number-needed-to-treat analyses,” he added.
In a related editorial, Deborah Grady, MD, MPH, with University of California, San Francisco, and Mitchell H. Katz, MD, president and CEO of NYC Health + Hospitals, say the decrease in opioid prescribing with duration limits was “small but probably meaningful.”
Restricting initial prescriptions to seven or fewer days is “reasonable because patients with new onset of pain should be re-evaluated in a week if the pain continues,” they write.
However, Dr. Grady and Dr. Katz “worry” that restricting initial prescriptions to shorter periods, such as 3 or 5 days, as has occurred in six states, “may result in patients with acute pain going untreated or having to go to extraordinary effort to obtain adequate pain relief.”
In their view, the data from this study suggest that limiting initial prescriptions to seven or fewer days is “helpful, but we would not restrict any further given that we do not know how it affected patients with acute pain.”
The study had no specific funding. Dr. Brenner, Dr. Grady, and Dr. Katz have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Flavonoids dietary ‘powerhouses’ for cognitive decline prevention
, new research shows.
Among the different types of flavonoids, flavones (found in some spices and yellow or orange fruits and vegetables) and anthocyanins (found in blueberries, blackberries, and cherries) seem to have most protective effect, the researchers report.
“There is mounting evidence suggesting flavonoids are powerhouses when it comes to preventing your thinking skills from declining as you get older,” study investigator Walter Willett, MD, DrPH, Harvard University, Boston, said in a statement.
“Our results are exciting because they show that making simple changes to your diet could help prevent cognitive decline,” said Dr. Willett.
The study was published online July 28 in the journal Neurology.
Antioxidant punch
Flavonoids, naturally occurring phytochemicals found in plants, are strong antioxidants. Considering the likely role of oxidative stress in age-related cognitive decline, flavonoids have been proposed as a potentially important preventive.
For the study, Dr. Willett and colleagues prospectively examined associations between long-term dietary flavonoids (flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, polymeric flavonoids, and proanthocyanidins) and subjective cognitive decline in 49,493 women from the Nurses’ Health Study (1984-2006) and 27,842 men from the Health Professionals Follow-up Study (1986-2002).
Those in the highest quintile of flavonoid consumption consumed about 600 mg daily on average while those in the lowest quintile got only about 150 mg daily.
After adjusting for age, total energy intake, major nondietary factors, and specific dietary factors, a higher intake of total flavonoids was associated with lower likelihood of self-reported subjective cognitive decline during follow up.
Individuals in the highest quintile of daily consumption had about a 20% lower risk of subjective cognitive decline relative to peers in the lowest quintile (pooled multivariable-adjusted odds ratio: 0.81; 95% confidence interval, 0.76-0.89).
The strongest protective associations were found for flavones (OR, 0.62; 95% confidence interval, 0.57-0.68), flavanones (OR, 0.64; 95% CI, 0.58-0.68), and anthocyanins (OR, 0.76; 95% CI, 0.72-0.84) (P trend < .0001 for all groups).
“The people in our study who did the best over time ate an average of at least half a serving per day of foods like orange juice, oranges, peppers, celery, grapefruits, grapefruit juice, apples, and pears,” Dr. Willett said.
“While it is possible other phytochemicals are at work here, a colorful diet rich in flavonoids – and specifically flavones and anthocyanins – seems to be a good bet for promoting long-term brain health,” he added.
A limitation of the study is that participants reported on their diets and may not recall perfectly what they ate or how much.
Healthy diet best bet for brain health
Reached for comment, Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association, said this study “adds to our understanding of which elements of a healthy diet may be important in reducing dementia risk; flavonols may be one of those elements.”
“However, at this point, people should not put too much stock in specific nutrients – including subsets of flavonols – for reducing dementia risk until more research is done. Rather, they should focus on eating an overall healthy diet,” he said.
“It would be wonderful if a particular food or supplement could delay or prevent Alzheimer’s disease, but we do not have scientific evidence to support such claims. Randomized controlled clinical trials are necessary to evaluate whether any food or supplement has a scientifically proven beneficial effect,” Dr. Weber added.
For now, the Alzheimer’s Association “encourages everyone to eat a healthy and balanced diet as a way to help reduce the risk of cognitive decline,” Dr. Weber said.
“With more than 6 million Americans living with Alzheimer’s disease and other dementia today, there is a pressing need to test the effectiveness of a healthy lifestyle regimen to reduce risk of cognitive decline in a large and diverse population,” he added.
The Alzheimer’s Association has launched a 2-year clinical trial, called the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), to do just that.
“While we research that definitive lifestyle ‘recipe,’ there are things we can do today that may decrease our risk of cognitive decline as we age. Eating a heart-healthy diet, exercising regularly, and staying cognitively engaged are just a few,” Dr. Weber added.
Also weighing in, Taylor Wallace, PhD, adjunct professor, department of nutrition and food studies, George Mason University, Fairfax, Va., said the study results are not surprising.
“Scientific data on the ability of flavonoids to prevent age-related chronic diseases, including cognitive decline, has accumulated immensely over the last decade. This epidemiological study reinforces findings from smaller shorter-duration clinical trials and mechanistic studies,” said Dr. Wallace, who was not involved in the study.
“Flavonoids show great potential in reducing inflammation and oxidative stress in the body. They are also vasodilators that help improve blood flow, which is important for the cardiovascular and cerebrovascular systems,” he noted.
“Typically, foods rich in flavonoids are also nutrient-dense in vitamins, minerals, and dietary fiber (eg, fruits and vegetables). Anthocyanins in blueberries have long been known to prevent cognitive decline with age,” Dr. Wallace said.
Dr. Wallace was part of a 14-member panel of nutrition scientists who recently reviewed available evidence around fruit and vegetable intake and health.
“Our findings are consistent with this study in regard to cognitive decline and other disease states. Cruciferous vegetables, dark-green leafy vegetables, citrus fruits, and dark-colored berries seem to have superior effects on health promotion and disease prevention in general,” said Dr. Wallace.
This work was supported by grants from the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr. Weber has no relevant disclosures. Dr. Wallace is principal and chief executive officer of the Think Healthy Group; editor of the Journal of Dietary Supplements; and deputy editor-in-chief of the Journal of the American College of Nutrition.
A version of this article first appeared on Medscape.com.
, new research shows.
Among the different types of flavonoids, flavones (found in some spices and yellow or orange fruits and vegetables) and anthocyanins (found in blueberries, blackberries, and cherries) seem to have most protective effect, the researchers report.
“There is mounting evidence suggesting flavonoids are powerhouses when it comes to preventing your thinking skills from declining as you get older,” study investigator Walter Willett, MD, DrPH, Harvard University, Boston, said in a statement.
“Our results are exciting because they show that making simple changes to your diet could help prevent cognitive decline,” said Dr. Willett.
The study was published online July 28 in the journal Neurology.
Antioxidant punch
Flavonoids, naturally occurring phytochemicals found in plants, are strong antioxidants. Considering the likely role of oxidative stress in age-related cognitive decline, flavonoids have been proposed as a potentially important preventive.
For the study, Dr. Willett and colleagues prospectively examined associations between long-term dietary flavonoids (flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, polymeric flavonoids, and proanthocyanidins) and subjective cognitive decline in 49,493 women from the Nurses’ Health Study (1984-2006) and 27,842 men from the Health Professionals Follow-up Study (1986-2002).
Those in the highest quintile of flavonoid consumption consumed about 600 mg daily on average while those in the lowest quintile got only about 150 mg daily.
After adjusting for age, total energy intake, major nondietary factors, and specific dietary factors, a higher intake of total flavonoids was associated with lower likelihood of self-reported subjective cognitive decline during follow up.
Individuals in the highest quintile of daily consumption had about a 20% lower risk of subjective cognitive decline relative to peers in the lowest quintile (pooled multivariable-adjusted odds ratio: 0.81; 95% confidence interval, 0.76-0.89).
The strongest protective associations were found for flavones (OR, 0.62; 95% confidence interval, 0.57-0.68), flavanones (OR, 0.64; 95% CI, 0.58-0.68), and anthocyanins (OR, 0.76; 95% CI, 0.72-0.84) (P trend < .0001 for all groups).
“The people in our study who did the best over time ate an average of at least half a serving per day of foods like orange juice, oranges, peppers, celery, grapefruits, grapefruit juice, apples, and pears,” Dr. Willett said.
“While it is possible other phytochemicals are at work here, a colorful diet rich in flavonoids – and specifically flavones and anthocyanins – seems to be a good bet for promoting long-term brain health,” he added.
A limitation of the study is that participants reported on their diets and may not recall perfectly what they ate or how much.
Healthy diet best bet for brain health
Reached for comment, Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association, said this study “adds to our understanding of which elements of a healthy diet may be important in reducing dementia risk; flavonols may be one of those elements.”
“However, at this point, people should not put too much stock in specific nutrients – including subsets of flavonols – for reducing dementia risk until more research is done. Rather, they should focus on eating an overall healthy diet,” he said.
“It would be wonderful if a particular food or supplement could delay or prevent Alzheimer’s disease, but we do not have scientific evidence to support such claims. Randomized controlled clinical trials are necessary to evaluate whether any food or supplement has a scientifically proven beneficial effect,” Dr. Weber added.
For now, the Alzheimer’s Association “encourages everyone to eat a healthy and balanced diet as a way to help reduce the risk of cognitive decline,” Dr. Weber said.
“With more than 6 million Americans living with Alzheimer’s disease and other dementia today, there is a pressing need to test the effectiveness of a healthy lifestyle regimen to reduce risk of cognitive decline in a large and diverse population,” he added.
The Alzheimer’s Association has launched a 2-year clinical trial, called the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), to do just that.
“While we research that definitive lifestyle ‘recipe,’ there are things we can do today that may decrease our risk of cognitive decline as we age. Eating a heart-healthy diet, exercising regularly, and staying cognitively engaged are just a few,” Dr. Weber added.
Also weighing in, Taylor Wallace, PhD, adjunct professor, department of nutrition and food studies, George Mason University, Fairfax, Va., said the study results are not surprising.
“Scientific data on the ability of flavonoids to prevent age-related chronic diseases, including cognitive decline, has accumulated immensely over the last decade. This epidemiological study reinforces findings from smaller shorter-duration clinical trials and mechanistic studies,” said Dr. Wallace, who was not involved in the study.
“Flavonoids show great potential in reducing inflammation and oxidative stress in the body. They are also vasodilators that help improve blood flow, which is important for the cardiovascular and cerebrovascular systems,” he noted.
“Typically, foods rich in flavonoids are also nutrient-dense in vitamins, minerals, and dietary fiber (eg, fruits and vegetables). Anthocyanins in blueberries have long been known to prevent cognitive decline with age,” Dr. Wallace said.
Dr. Wallace was part of a 14-member panel of nutrition scientists who recently reviewed available evidence around fruit and vegetable intake and health.
“Our findings are consistent with this study in regard to cognitive decline and other disease states. Cruciferous vegetables, dark-green leafy vegetables, citrus fruits, and dark-colored berries seem to have superior effects on health promotion and disease prevention in general,” said Dr. Wallace.
This work was supported by grants from the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr. Weber has no relevant disclosures. Dr. Wallace is principal and chief executive officer of the Think Healthy Group; editor of the Journal of Dietary Supplements; and deputy editor-in-chief of the Journal of the American College of Nutrition.
A version of this article first appeared on Medscape.com.
, new research shows.
Among the different types of flavonoids, flavones (found in some spices and yellow or orange fruits and vegetables) and anthocyanins (found in blueberries, blackberries, and cherries) seem to have most protective effect, the researchers report.
“There is mounting evidence suggesting flavonoids are powerhouses when it comes to preventing your thinking skills from declining as you get older,” study investigator Walter Willett, MD, DrPH, Harvard University, Boston, said in a statement.
“Our results are exciting because they show that making simple changes to your diet could help prevent cognitive decline,” said Dr. Willett.
The study was published online July 28 in the journal Neurology.
Antioxidant punch
Flavonoids, naturally occurring phytochemicals found in plants, are strong antioxidants. Considering the likely role of oxidative stress in age-related cognitive decline, flavonoids have been proposed as a potentially important preventive.
For the study, Dr. Willett and colleagues prospectively examined associations between long-term dietary flavonoids (flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, polymeric flavonoids, and proanthocyanidins) and subjective cognitive decline in 49,493 women from the Nurses’ Health Study (1984-2006) and 27,842 men from the Health Professionals Follow-up Study (1986-2002).
Those in the highest quintile of flavonoid consumption consumed about 600 mg daily on average while those in the lowest quintile got only about 150 mg daily.
After adjusting for age, total energy intake, major nondietary factors, and specific dietary factors, a higher intake of total flavonoids was associated with lower likelihood of self-reported subjective cognitive decline during follow up.
Individuals in the highest quintile of daily consumption had about a 20% lower risk of subjective cognitive decline relative to peers in the lowest quintile (pooled multivariable-adjusted odds ratio: 0.81; 95% confidence interval, 0.76-0.89).
The strongest protective associations were found for flavones (OR, 0.62; 95% confidence interval, 0.57-0.68), flavanones (OR, 0.64; 95% CI, 0.58-0.68), and anthocyanins (OR, 0.76; 95% CI, 0.72-0.84) (P trend < .0001 for all groups).
“The people in our study who did the best over time ate an average of at least half a serving per day of foods like orange juice, oranges, peppers, celery, grapefruits, grapefruit juice, apples, and pears,” Dr. Willett said.
“While it is possible other phytochemicals are at work here, a colorful diet rich in flavonoids – and specifically flavones and anthocyanins – seems to be a good bet for promoting long-term brain health,” he added.
A limitation of the study is that participants reported on their diets and may not recall perfectly what they ate or how much.
Healthy diet best bet for brain health
Reached for comment, Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association, said this study “adds to our understanding of which elements of a healthy diet may be important in reducing dementia risk; flavonols may be one of those elements.”
“However, at this point, people should not put too much stock in specific nutrients – including subsets of flavonols – for reducing dementia risk until more research is done. Rather, they should focus on eating an overall healthy diet,” he said.
“It would be wonderful if a particular food or supplement could delay or prevent Alzheimer’s disease, but we do not have scientific evidence to support such claims. Randomized controlled clinical trials are necessary to evaluate whether any food or supplement has a scientifically proven beneficial effect,” Dr. Weber added.
For now, the Alzheimer’s Association “encourages everyone to eat a healthy and balanced diet as a way to help reduce the risk of cognitive decline,” Dr. Weber said.
“With more than 6 million Americans living with Alzheimer’s disease and other dementia today, there is a pressing need to test the effectiveness of a healthy lifestyle regimen to reduce risk of cognitive decline in a large and diverse population,” he added.
The Alzheimer’s Association has launched a 2-year clinical trial, called the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), to do just that.
“While we research that definitive lifestyle ‘recipe,’ there are things we can do today that may decrease our risk of cognitive decline as we age. Eating a heart-healthy diet, exercising regularly, and staying cognitively engaged are just a few,” Dr. Weber added.
Also weighing in, Taylor Wallace, PhD, adjunct professor, department of nutrition and food studies, George Mason University, Fairfax, Va., said the study results are not surprising.
“Scientific data on the ability of flavonoids to prevent age-related chronic diseases, including cognitive decline, has accumulated immensely over the last decade. This epidemiological study reinforces findings from smaller shorter-duration clinical trials and mechanistic studies,” said Dr. Wallace, who was not involved in the study.
“Flavonoids show great potential in reducing inflammation and oxidative stress in the body. They are also vasodilators that help improve blood flow, which is important for the cardiovascular and cerebrovascular systems,” he noted.
“Typically, foods rich in flavonoids are also nutrient-dense in vitamins, minerals, and dietary fiber (eg, fruits and vegetables). Anthocyanins in blueberries have long been known to prevent cognitive decline with age,” Dr. Wallace said.
Dr. Wallace was part of a 14-member panel of nutrition scientists who recently reviewed available evidence around fruit and vegetable intake and health.
“Our findings are consistent with this study in regard to cognitive decline and other disease states. Cruciferous vegetables, dark-green leafy vegetables, citrus fruits, and dark-colored berries seem to have superior effects on health promotion and disease prevention in general,” said Dr. Wallace.
This work was supported by grants from the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr. Weber has no relevant disclosures. Dr. Wallace is principal and chief executive officer of the Think Healthy Group; editor of the Journal of Dietary Supplements; and deputy editor-in-chief of the Journal of the American College of Nutrition.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Better CNS control in children with ALL: ‘Goldilocks’ approach
Treatment of central nervous system involvement in pediatric acute lymphoblastic leukemia (ALL) needs to be based on risk, and should no longer be applied in a one-size-fits all approach, say experts writing in an editorial published July 29 in the journal Blood.
“Because cure rates now exceed 90%, using neurotoxic drugs in non–risk-adapted protocols is unacceptable and a paradigm shift in treating CNS ALL is required,” write pediatric leukemia researchers Christina Halsey, PhD, of the University of Glasgow and Gabriele Escherich, MD, of the University Medical Center Hamburg-Eppendorf (Germany).
“We want to reach a Goldilocks point: not too much, not too little, but just right for every child,” they write.
The problem is that “the absence of clinically useful biomarkers prevents accurate risk stratification, resulting in universal use of intensive CNS-directed therapy. This therapy is likely to overtreat many children, exposing them to an unnecessary risk of toxicity,” including long-term cognitive deficits in 20%-40% of them, they point out.
The editorial accompanied a new study in which investigators in China focused on improving CNS control in children with ALL, which the editorialists said was step in the right direction.
In the Chinese Children’s Cancer Group ALL-2015 trial, investigators found that prephase dexamethasone, delayed intrathecal therapy, intravenous anesthesia to reduce traumatic lumbar punctures, and flow cytometry to accurately ascertain initial CNS involvement may improve CNS control.
The trial included 7,640 consecutive children up to age 18 treated from 2015 to 2019 across 20 major medical centers in China. Children received conventional remission induction and subsequent risk-directed therapy, including 16-22 triple intrathecal treatments. Prophylactic cranial irradiation was not used.
The 5-year event-free survival was 80.3% and overall survival 91.1%. The cumulative risk of isolated CNS relapse was 1.9% and of any CNS relapse 2.7%, comparable to reports from other major study groups, both with and without cranial radiation.
“We attributed our relatively good CNS control to the prephase treatment with dexamethasone, which reduced leukemia cells in blood and the CNS, and to the delayed intrathecal therapy until all (or a large proportion) of circulating leukemic blasts were cleared, thus reducing the consequence of traumatic lumbar puncture with blasts,” said the investigators, led by Jingyan Tang, MD, a hematologist/oncologist at the Shanghai (China) Children’s Medical Center.
“This approach of delayed administration of initial intrathecal therapy after prephase steroid treatment, if confirmed successful by additional studies, can be adopted readily,” they say.
The editorialists concur. The low rates of CNS relapse, despite omission of radiotherapy and inclusion of high-risk subgroups, “might suggest a potential protective effect of steroids before diagnostic lumbar puncture,” they said.
“However, flow cytometry is not sensitive enough to track disease response over time. In the bone marrow, minimal residual disease (MRD) is used to identify children at high or low risk of relapse and modify therapy accordingly. We desperately need a minimal residual disease equivalent for CNS leukemia to allow us to tailor therapy,” Dr. Halsey and Dr. Escherich say.
It’s not surprising that the use of anesthesia led to fewer traumatic lumbar punctures than in “frightened child[ren] undergoing such a painful procedure without anesthesia,” the study team notes. Its correlation with lower CNS relapses is probably because drug delivery was more accurate in sedated children, the editorialists add.
Female sex was also protective against relapse in cases where general anesthesia wasn’t used for lumbar puncture. “One could speculate that it is more difficult to restrict male patients than female patients for successful intrathecal therapy if they were not undergoing anesthesia during the procedure,” the investigators write.
“Unfortunately,” the editorialists add, rapid adoption of anesthesia for lumbar punctures “is tempered by the recent observation that repeated general anesthesia in children with ALL is associated with increased neurotoxicity.”
The work was supported by grants from the National Natural Science Foundation of China, National Cancer Institute, and others. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment of central nervous system involvement in pediatric acute lymphoblastic leukemia (ALL) needs to be based on risk, and should no longer be applied in a one-size-fits all approach, say experts writing in an editorial published July 29 in the journal Blood.
“Because cure rates now exceed 90%, using neurotoxic drugs in non–risk-adapted protocols is unacceptable and a paradigm shift in treating CNS ALL is required,” write pediatric leukemia researchers Christina Halsey, PhD, of the University of Glasgow and Gabriele Escherich, MD, of the University Medical Center Hamburg-Eppendorf (Germany).
“We want to reach a Goldilocks point: not too much, not too little, but just right for every child,” they write.
The problem is that “the absence of clinically useful biomarkers prevents accurate risk stratification, resulting in universal use of intensive CNS-directed therapy. This therapy is likely to overtreat many children, exposing them to an unnecessary risk of toxicity,” including long-term cognitive deficits in 20%-40% of them, they point out.
The editorial accompanied a new study in which investigators in China focused on improving CNS control in children with ALL, which the editorialists said was step in the right direction.
In the Chinese Children’s Cancer Group ALL-2015 trial, investigators found that prephase dexamethasone, delayed intrathecal therapy, intravenous anesthesia to reduce traumatic lumbar punctures, and flow cytometry to accurately ascertain initial CNS involvement may improve CNS control.
The trial included 7,640 consecutive children up to age 18 treated from 2015 to 2019 across 20 major medical centers in China. Children received conventional remission induction and subsequent risk-directed therapy, including 16-22 triple intrathecal treatments. Prophylactic cranial irradiation was not used.
The 5-year event-free survival was 80.3% and overall survival 91.1%. The cumulative risk of isolated CNS relapse was 1.9% and of any CNS relapse 2.7%, comparable to reports from other major study groups, both with and without cranial radiation.
“We attributed our relatively good CNS control to the prephase treatment with dexamethasone, which reduced leukemia cells in blood and the CNS, and to the delayed intrathecal therapy until all (or a large proportion) of circulating leukemic blasts were cleared, thus reducing the consequence of traumatic lumbar puncture with blasts,” said the investigators, led by Jingyan Tang, MD, a hematologist/oncologist at the Shanghai (China) Children’s Medical Center.
“This approach of delayed administration of initial intrathecal therapy after prephase steroid treatment, if confirmed successful by additional studies, can be adopted readily,” they say.
The editorialists concur. The low rates of CNS relapse, despite omission of radiotherapy and inclusion of high-risk subgroups, “might suggest a potential protective effect of steroids before diagnostic lumbar puncture,” they said.
“However, flow cytometry is not sensitive enough to track disease response over time. In the bone marrow, minimal residual disease (MRD) is used to identify children at high or low risk of relapse and modify therapy accordingly. We desperately need a minimal residual disease equivalent for CNS leukemia to allow us to tailor therapy,” Dr. Halsey and Dr. Escherich say.
It’s not surprising that the use of anesthesia led to fewer traumatic lumbar punctures than in “frightened child[ren] undergoing such a painful procedure without anesthesia,” the study team notes. Its correlation with lower CNS relapses is probably because drug delivery was more accurate in sedated children, the editorialists add.
Female sex was also protective against relapse in cases where general anesthesia wasn’t used for lumbar puncture. “One could speculate that it is more difficult to restrict male patients than female patients for successful intrathecal therapy if they were not undergoing anesthesia during the procedure,” the investigators write.
“Unfortunately,” the editorialists add, rapid adoption of anesthesia for lumbar punctures “is tempered by the recent observation that repeated general anesthesia in children with ALL is associated with increased neurotoxicity.”
The work was supported by grants from the National Natural Science Foundation of China, National Cancer Institute, and others. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment of central nervous system involvement in pediatric acute lymphoblastic leukemia (ALL) needs to be based on risk, and should no longer be applied in a one-size-fits all approach, say experts writing in an editorial published July 29 in the journal Blood.
“Because cure rates now exceed 90%, using neurotoxic drugs in non–risk-adapted protocols is unacceptable and a paradigm shift in treating CNS ALL is required,” write pediatric leukemia researchers Christina Halsey, PhD, of the University of Glasgow and Gabriele Escherich, MD, of the University Medical Center Hamburg-Eppendorf (Germany).
“We want to reach a Goldilocks point: not too much, not too little, but just right for every child,” they write.
The problem is that “the absence of clinically useful biomarkers prevents accurate risk stratification, resulting in universal use of intensive CNS-directed therapy. This therapy is likely to overtreat many children, exposing them to an unnecessary risk of toxicity,” including long-term cognitive deficits in 20%-40% of them, they point out.
The editorial accompanied a new study in which investigators in China focused on improving CNS control in children with ALL, which the editorialists said was step in the right direction.
In the Chinese Children’s Cancer Group ALL-2015 trial, investigators found that prephase dexamethasone, delayed intrathecal therapy, intravenous anesthesia to reduce traumatic lumbar punctures, and flow cytometry to accurately ascertain initial CNS involvement may improve CNS control.
The trial included 7,640 consecutive children up to age 18 treated from 2015 to 2019 across 20 major medical centers in China. Children received conventional remission induction and subsequent risk-directed therapy, including 16-22 triple intrathecal treatments. Prophylactic cranial irradiation was not used.
The 5-year event-free survival was 80.3% and overall survival 91.1%. The cumulative risk of isolated CNS relapse was 1.9% and of any CNS relapse 2.7%, comparable to reports from other major study groups, both with and without cranial radiation.
“We attributed our relatively good CNS control to the prephase treatment with dexamethasone, which reduced leukemia cells in blood and the CNS, and to the delayed intrathecal therapy until all (or a large proportion) of circulating leukemic blasts were cleared, thus reducing the consequence of traumatic lumbar puncture with blasts,” said the investigators, led by Jingyan Tang, MD, a hematologist/oncologist at the Shanghai (China) Children’s Medical Center.
“This approach of delayed administration of initial intrathecal therapy after prephase steroid treatment, if confirmed successful by additional studies, can be adopted readily,” they say.
The editorialists concur. The low rates of CNS relapse, despite omission of radiotherapy and inclusion of high-risk subgroups, “might suggest a potential protective effect of steroids before diagnostic lumbar puncture,” they said.
“However, flow cytometry is not sensitive enough to track disease response over time. In the bone marrow, minimal residual disease (MRD) is used to identify children at high or low risk of relapse and modify therapy accordingly. We desperately need a minimal residual disease equivalent for CNS leukemia to allow us to tailor therapy,” Dr. Halsey and Dr. Escherich say.
It’s not surprising that the use of anesthesia led to fewer traumatic lumbar punctures than in “frightened child[ren] undergoing such a painful procedure without anesthesia,” the study team notes. Its correlation with lower CNS relapses is probably because drug delivery was more accurate in sedated children, the editorialists add.
Female sex was also protective against relapse in cases where general anesthesia wasn’t used for lumbar puncture. “One could speculate that it is more difficult to restrict male patients than female patients for successful intrathecal therapy if they were not undergoing anesthesia during the procedure,” the investigators write.
“Unfortunately,” the editorialists add, rapid adoption of anesthesia for lumbar punctures “is tempered by the recent observation that repeated general anesthesia in children with ALL is associated with increased neurotoxicity.”
The work was supported by grants from the National Natural Science Foundation of China, National Cancer Institute, and others. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.