Neurology

Patients with psychotic disorders such as schizophrenia are more than twice as likely as those without a psychotic disorder to eventually develop dementia, new research suggests.

Results from a review and meta-analysis of almost 13 million total participants from nine countries showed that, across multiple different psychotic disorders, there was a 2.5-fold higher risk of developing dementia later in life compared with individuals who did not have a disorder. This was regardless of the age at which the patients first developed the mental illness.

Moreover, participants with a psychotic disorder tended to be younger than average when diagnosed with dementia. Two studies showed that those with psychotic disorders were more likely to be diagnosed with dementia as early as in their 60s.

“The findings add to a growing body of evidence linking psychiatric disorders with later cognitive decline and dementia,” senior investigator Jean Stafford, PhD, a research fellow at MRC Unit for Lifelong Health and Ageing, University College London, told this news organization.

Dr. Stafford noted that the results highlight the importance of being aware of and watchful for symptoms of cognitive decline in patients with psychotic disorders in mid- and late life.

“In addition, given that people with psychotic disorders are at higher risk of experiencing multiple health conditions, including dementia, managing overall physical and mental health in this group is crucial,” she said.

The findings were published online in Psychological Medicine.
 

Bringing the evidence together

There is increasing evidence that multiple psychiatric symptoms and diagnoses are associated with cognitive decline and dementia, with particularly strong evidence for late-life depression, Dr. Stafford said.

“However, the relationship between psychotic disorders and dementia is less well-established,” she added.

Last year, her team published a study showing a strong association between very late onset psychotic disorders, defined as first diagnosed after age 60 years, and increased risk for dementia in Swedish population register data.

“We also became aware of several other large studies on the topic published in the last few years and realized that an up-to-date systematic review and meta-analysis was needed to bring together the evidence, specifically focusing on longitudinal studies,” Dr. Stafford said.

The researchers searched four databases of prospective and retrospective longitudinal studies published through March 2022. Studies were required to focus on adults aged 18 years or older with a clinical diagnosis of a nonaffective psychotic disorder and a comparison group consisting of adults without a nonaffective psychotic disorder.

Of 9,496 papers, the investigators selected 11 published from 2003 to 2022 that met criteria for inclusion in their meta-analysis (12,997,101 participants), with follow-up periods ranging from 1.57 to 33 years.

The studies hailed from Denmark, Finland, Sweden, the United Kingdom, the United States, Australia, Taiwan, New Zealand, and Israel.

Random-effects meta-analyses were used to pool estimates across studies. The researchers assessed the risk of bias for each study. They also included two additional studies in the review, but not the meta-analysis, that focused specifically on late-onset acute and transient psychosis and late-onset delusional disorder.

The other studies focused on late-onset schizophrenia and/or very late onset schizophrenia-like psychoses, schizophrenia, psychotic disorders, and schizophrenia in older people.

Most studies investigated the incidence of all-cause dementia, although one study focused on the incidence of Alzheimer’s disease.
 

Potential mechanisms

The narrative review showed that most studies (n = 10) were of high methodological quality, although two were rated as fair and one as poor.

Almost all studies accounted for basic sociodemographic confounders. Several also adjusted for comorbidities, alcohol/substance use disorders, medications, smoking status, and income/education level.

Pooled estimates from the meta-analyzed studies showed that only one showed no significant association between psychotic disorders and dementia, whereas 10 reported increased risk (pooled risk ratio, 2.52; 95% confidence interval, 1.67-3.80; I², 99.7%).

Subgroup analyses showed higher risk in participants with typical and late-onset psychotic disorders (pooled RR, 2.10; 95% CI, 2.33-4.14; I², 77.5%; P = .004) vs. those with very late onset schizophrenia-like psychoses (pooled RR, 2.77; 95% CI, 1.74-4.40 I², 98.9%; P < .001).

The effect was larger in studies with a follow-up of less than 10 years vs. those with a follow-up of 10 years or more, and it was also greater in studies conducted in non-European vs. European countries (all P < .001).

Studies with more female participants (≥ 60%) showed higher risk compared with those that had a lower percentage of female participants. Studies published during or after 2020 showed a stronger association than those published before 2020 (all P < .001).

There was also a higher risk for dementia in studies investigating broader nonaffective psychotic disorders compared with studies investigating only schizophrenia, in prospective vs. retrospective studies, and in studies with a minimum age of less than 60 years at baseline vs. a minimum age of 60 or older (all P < .001).

“Several possible mechanisms could underlie these findings, although we were not able to directly test these in our review,” Dr. Stafford said. She noted that psychotic disorders and other psychiatric diagnoses may cause dementia.

“People with psychotic disorders such as schizophrenia are also at higher risk of health conditions including cardiovascular disease and diabetes, which are known risk factors for dementia and could underpin these associations,” said Dr. Stafford.

It is also possible “that psychotic symptoms could be early markers of dementia for some people, rather than causes,” she added.
 

Neuroimaging evidence lacking

Commenting on the study, Dilip V. Jeste, MD, former senior associate dean for healthy aging and senior care and distinguished professor of psychiatry and neurosciences at the University of California, San Diego, complimented the investigators for “an excellent article on an important but difficult topic.”

Limitations “pertain not to the meta-analysis but to the original studies,” said Dr. Jeste, who was not involved with the review. Diagnosing dementia in individuals with psychotic disorders is “challenging because cognitive deficits and behavioral symptoms in psychotic disorders may be misdiagnosed as dementia in some individuals – and vice versa,” he added.

Moreover, the studies did not specify the type of dementia, such as Alzheimer’s disease, vascular, Lewy body, frontotemporal, or mixed. Together, “they account for 90% of the dementias, and most patients with these dementias have brain abnormalities that can clearly be seen on MRI,” Dr. Jeste said.

However, patients with schizophrenia who are diagnosed with dementia “rarely show severe brain atrophy, even in specific regions commonly observed in nonpsychotic people with these dementias,” Dr. Jeste noted.

Thus, objective neuroimaging-based evidence for dementia and its subtype “is lacking in most of the published studies of persons with psychotic disorders diagnosed as having dementia,” he said.

There is a “clear need for comprehensive studies of dementia in people with psychotic disorders to understand the significance of the results,” Dr. Jeste concluded.

The review did not receive any funding. Dr. Stafford was supported by an NIHR-UCLH BRC Postdoctoral Bridging Fellowship and the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. Dr. Stafford was also the principal investigator in one of the studies meeting the inclusion criteria of the review. The other investigators and Dr. Jeste reported no relevant financial relationships.

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

Patients with psychotic disorders such as schizophrenia are more than twice as likely as those without a psychotic disorder to eventually develop dementia, new research suggests.

Results from a review and meta-analysis of almost 13 million total participants from nine countries showed that, across multiple different psychotic disorders, there was a 2.5-fold higher risk of developing dementia later in life compared with individuals who did not have a disorder. This was regardless of the age at which the patients first developed the mental illness.

Moreover, participants with a psychotic disorder tended to be younger than average when diagnosed with dementia. Two studies showed that those with psychotic disorders were more likely to be diagnosed with dementia as early as in their 60s.

“The findings add to a growing body of evidence linking psychiatric disorders with later cognitive decline and dementia,” senior investigator Jean Stafford, PhD, a research fellow at MRC Unit for Lifelong Health and Ageing, University College London, told this news organization.

Dr. Stafford noted that the results highlight the importance of being aware of and watchful for symptoms of cognitive decline in patients with psychotic disorders in mid- and late life.

“In addition, given that people with psychotic disorders are at higher risk of experiencing multiple health conditions, including dementia, managing overall physical and mental health in this group is crucial,” she said.

The findings were published online in Psychological Medicine.
 

Bringing the evidence together

There is increasing evidence that multiple psychiatric symptoms and diagnoses are associated with cognitive decline and dementia, with particularly strong evidence for late-life depression, Dr. Stafford said.

“However, the relationship between psychotic disorders and dementia is less well-established,” she added.

Last year, her team published a study showing a strong association between very late onset psychotic disorders, defined as first diagnosed after age 60 years, and increased risk for dementia in Swedish population register data.

“We also became aware of several other large studies on the topic published in the last few years and realized that an up-to-date systematic review and meta-analysis was needed to bring together the evidence, specifically focusing on longitudinal studies,” Dr. Stafford said.

The researchers searched four databases of prospective and retrospective longitudinal studies published through March 2022. Studies were required to focus on adults aged 18 years or older with a clinical diagnosis of a nonaffective psychotic disorder and a comparison group consisting of adults without a nonaffective psychotic disorder.

Of 9,496 papers, the investigators selected 11 published from 2003 to 2022 that met criteria for inclusion in their meta-analysis (12,997,101 participants), with follow-up periods ranging from 1.57 to 33 years.

The studies hailed from Denmark, Finland, Sweden, the United Kingdom, the United States, Australia, Taiwan, New Zealand, and Israel.

Random-effects meta-analyses were used to pool estimates across studies. The researchers assessed the risk of bias for each study. They also included two additional studies in the review, but not the meta-analysis, that focused specifically on late-onset acute and transient psychosis and late-onset delusional disorder.

The other studies focused on late-onset schizophrenia and/or very late onset schizophrenia-like psychoses, schizophrenia, psychotic disorders, and schizophrenia in older people.

Most studies investigated the incidence of all-cause dementia, although one study focused on the incidence of Alzheimer’s disease.
 

Potential mechanisms

The narrative review showed that most studies (n = 10) were of high methodological quality, although two were rated as fair and one as poor.

Almost all studies accounted for basic sociodemographic confounders. Several also adjusted for comorbidities, alcohol/substance use disorders, medications, smoking status, and income/education level.

Pooled estimates from the meta-analyzed studies showed that only one showed no significant association between psychotic disorders and dementia, whereas 10 reported increased risk (pooled risk ratio, 2.52; 95% confidence interval, 1.67-3.80; I², 99.7%).

Subgroup analyses showed higher risk in participants with typical and late-onset psychotic disorders (pooled RR, 2.10; 95% CI, 2.33-4.14; I², 77.5%; P = .004) vs. those with very late onset schizophrenia-like psychoses (pooled RR, 2.77; 95% CI, 1.74-4.40 I², 98.9%; P < .001).

The effect was larger in studies with a follow-up of less than 10 years vs. those with a follow-up of 10 years or more, and it was also greater in studies conducted in non-European vs. European countries (all P < .001).

Studies with more female participants (≥ 60%) showed higher risk compared with those that had a lower percentage of female participants. Studies published during or after 2020 showed a stronger association than those published before 2020 (all P < .001).

There was also a higher risk for dementia in studies investigating broader nonaffective psychotic disorders compared with studies investigating only schizophrenia, in prospective vs. retrospective studies, and in studies with a minimum age of less than 60 years at baseline vs. a minimum age of 60 or older (all P < .001).

“Several possible mechanisms could underlie these findings, although we were not able to directly test these in our review,” Dr. Stafford said. She noted that psychotic disorders and other psychiatric diagnoses may cause dementia.

“People with psychotic disorders such as schizophrenia are also at higher risk of health conditions including cardiovascular disease and diabetes, which are known risk factors for dementia and could underpin these associations,” said Dr. Stafford.

It is also possible “that psychotic symptoms could be early markers of dementia for some people, rather than causes,” she added.
 

Neuroimaging evidence lacking

Commenting on the study, Dilip V. Jeste, MD, former senior associate dean for healthy aging and senior care and distinguished professor of psychiatry and neurosciences at the University of California, San Diego, complimented the investigators for “an excellent article on an important but difficult topic.”

Limitations “pertain not to the meta-analysis but to the original studies,” said Dr. Jeste, who was not involved with the review. Diagnosing dementia in individuals with psychotic disorders is “challenging because cognitive deficits and behavioral symptoms in psychotic disorders may be misdiagnosed as dementia in some individuals – and vice versa,” he added.

Moreover, the studies did not specify the type of dementia, such as Alzheimer’s disease, vascular, Lewy body, frontotemporal, or mixed. Together, “they account for 90% of the dementias, and most patients with these dementias have brain abnormalities that can clearly be seen on MRI,” Dr. Jeste said.

However, patients with schizophrenia who are diagnosed with dementia “rarely show severe brain atrophy, even in specific regions commonly observed in nonpsychotic people with these dementias,” Dr. Jeste noted.

Thus, objective neuroimaging-based evidence for dementia and its subtype “is lacking in most of the published studies of persons with psychotic disorders diagnosed as having dementia,” he said.

There is a “clear need for comprehensive studies of dementia in people with psychotic disorders to understand the significance of the results,” Dr. Jeste concluded.

The review did not receive any funding. Dr. Stafford was supported by an NIHR-UCLH BRC Postdoctoral Bridging Fellowship and the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. Dr. Stafford was also the principal investigator in one of the studies meeting the inclusion criteria of the review. The other investigators and Dr. Jeste reported no relevant financial relationships.

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

Patients with psychotic disorders such as schizophrenia are more than twice as likely as those without a psychotic disorder to eventually develop dementia, new research suggests.

Results from a review and meta-analysis of almost 13 million total participants from nine countries showed that, across multiple different psychotic disorders, there was a 2.5-fold higher risk of developing dementia later in life compared with individuals who did not have a disorder. This was regardless of the age at which the patients first developed the mental illness.

Moreover, participants with a psychotic disorder tended to be younger than average when diagnosed with dementia. Two studies showed that those with psychotic disorders were more likely to be diagnosed with dementia as early as in their 60s.

“The findings add to a growing body of evidence linking psychiatric disorders with later cognitive decline and dementia,” senior investigator Jean Stafford, PhD, a research fellow at MRC Unit for Lifelong Health and Ageing, University College London, told this news organization.

Dr. Stafford noted that the results highlight the importance of being aware of and watchful for symptoms of cognitive decline in patients with psychotic disorders in mid- and late life.

“In addition, given that people with psychotic disorders are at higher risk of experiencing multiple health conditions, including dementia, managing overall physical and mental health in this group is crucial,” she said.

The findings were published online in Psychological Medicine.
 

Bringing the evidence together

There is increasing evidence that multiple psychiatric symptoms and diagnoses are associated with cognitive decline and dementia, with particularly strong evidence for late-life depression, Dr. Stafford said.

“However, the relationship between psychotic disorders and dementia is less well-established,” she added.

Last year, her team published a study showing a strong association between very late onset psychotic disorders, defined as first diagnosed after age 60 years, and increased risk for dementia in Swedish population register data.

“We also became aware of several other large studies on the topic published in the last few years and realized that an up-to-date systematic review and meta-analysis was needed to bring together the evidence, specifically focusing on longitudinal studies,” Dr. Stafford said.

The researchers searched four databases of prospective and retrospective longitudinal studies published through March 2022. Studies were required to focus on adults aged 18 years or older with a clinical diagnosis of a nonaffective psychotic disorder and a comparison group consisting of adults without a nonaffective psychotic disorder.

Of 9,496 papers, the investigators selected 11 published from 2003 to 2022 that met criteria for inclusion in their meta-analysis (12,997,101 participants), with follow-up periods ranging from 1.57 to 33 years.

The studies hailed from Denmark, Finland, Sweden, the United Kingdom, the United States, Australia, Taiwan, New Zealand, and Israel.

Random-effects meta-analyses were used to pool estimates across studies. The researchers assessed the risk of bias for each study. They also included two additional studies in the review, but not the meta-analysis, that focused specifically on late-onset acute and transient psychosis and late-onset delusional disorder.

The other studies focused on late-onset schizophrenia and/or very late onset schizophrenia-like psychoses, schizophrenia, psychotic disorders, and schizophrenia in older people.

Most studies investigated the incidence of all-cause dementia, although one study focused on the incidence of Alzheimer’s disease.
 

Potential mechanisms

The narrative review showed that most studies (n = 10) were of high methodological quality, although two were rated as fair and one as poor.

Almost all studies accounted for basic sociodemographic confounders. Several also adjusted for comorbidities, alcohol/substance use disorders, medications, smoking status, and income/education level.

Pooled estimates from the meta-analyzed studies showed that only one showed no significant association between psychotic disorders and dementia, whereas 10 reported increased risk (pooled risk ratio, 2.52; 95% confidence interval, 1.67-3.80; I², 99.7%).

Subgroup analyses showed higher risk in participants with typical and late-onset psychotic disorders (pooled RR, 2.10; 95% CI, 2.33-4.14; I², 77.5%; P = .004) vs. those with very late onset schizophrenia-like psychoses (pooled RR, 2.77; 95% CI, 1.74-4.40 I², 98.9%; P < .001).

The effect was larger in studies with a follow-up of less than 10 years vs. those with a follow-up of 10 years or more, and it was also greater in studies conducted in non-European vs. European countries (all P < .001).

Studies with more female participants (≥ 60%) showed higher risk compared with those that had a lower percentage of female participants. Studies published during or after 2020 showed a stronger association than those published before 2020 (all P < .001).

There was also a higher risk for dementia in studies investigating broader nonaffective psychotic disorders compared with studies investigating only schizophrenia, in prospective vs. retrospective studies, and in studies with a minimum age of less than 60 years at baseline vs. a minimum age of 60 or older (all P < .001).

“Several possible mechanisms could underlie these findings, although we were not able to directly test these in our review,” Dr. Stafford said. She noted that psychotic disorders and other psychiatric diagnoses may cause dementia.

“People with psychotic disorders such as schizophrenia are also at higher risk of health conditions including cardiovascular disease and diabetes, which are known risk factors for dementia and could underpin these associations,” said Dr. Stafford.

It is also possible “that psychotic symptoms could be early markers of dementia for some people, rather than causes,” she added.
 

Neuroimaging evidence lacking

Commenting on the study, Dilip V. Jeste, MD, former senior associate dean for healthy aging and senior care and distinguished professor of psychiatry and neurosciences at the University of California, San Diego, complimented the investigators for “an excellent article on an important but difficult topic.”

Limitations “pertain not to the meta-analysis but to the original studies,” said Dr. Jeste, who was not involved with the review. Diagnosing dementia in individuals with psychotic disorders is “challenging because cognitive deficits and behavioral symptoms in psychotic disorders may be misdiagnosed as dementia in some individuals – and vice versa,” he added.

Moreover, the studies did not specify the type of dementia, such as Alzheimer’s disease, vascular, Lewy body, frontotemporal, or mixed. Together, “they account for 90% of the dementias, and most patients with these dementias have brain abnormalities that can clearly be seen on MRI,” Dr. Jeste said.

However, patients with schizophrenia who are diagnosed with dementia “rarely show severe brain atrophy, even in specific regions commonly observed in nonpsychotic people with these dementias,” Dr. Jeste noted.

Thus, objective neuroimaging-based evidence for dementia and its subtype “is lacking in most of the published studies of persons with psychotic disorders diagnosed as having dementia,” he said.

There is a “clear need for comprehensive studies of dementia in people with psychotic disorders to understand the significance of the results,” Dr. Jeste concluded.

The review did not receive any funding. Dr. Stafford was supported by an NIHR-UCLH BRC Postdoctoral Bridging Fellowship and the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. Dr. Stafford was also the principal investigator in one of the studies meeting the inclusion criteria of the review. The other investigators and Dr. Jeste reported no relevant financial relationships.

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

Rates of subarachnoid hemorrhage (SAH) are increasing, particularly in Black people, new research suggests.

Results of a new study based on hospital discharge data show Black people have disproportionately high rates of SAH versus other racial groups. Compared with White and Hispanic people, who had an average of 10 cases per 100,000, or Asian people, with 8 per 100,000 people, Black people had an average of 15 cases per 100,000 population.

Whereas case rates held steady for other racial groups in the study over a 10-year period, Black people were the only racial group for whom SAH incidence increased over time, at a rate of 1.8% per year.

“Root causes of the higher SAH incidence in Black [people] are complex and likely extend beyond simple differences in risk factor characteristics to other socioeconomic factors including level of education, poverty level, lack of insurance, access to quality care, and structural racism,” study investigator Fadar Oliver Otite, MD, assistant professor of neurology at SUNY Upstate Medical University, Syracuse, said in an interview.

“Addressing this racial disparity will require multidisciplinary factors targeted not just at subarachnoid hemorrhage risk factors but also at socioeconomic equity,” he added.

The study was published online in Neurology.
 

Uncontrolled hypertension

The average incidence of SAH for all participants was 11 cases per 100,000 people. Men had an average rate of 10 cases and women an average rate of 13 cases per 100,000.

As expected, incidence increased with age: For middle-aged men, the average was four cases per 100,000 people whereas for men 65 and older, the average was 22 cases.

Dr. Otite and his team combined U.S. Census data with two state hospitalization databases in New York and Florida and found that there were nearly 40,000 people hospitalized for SAH between 2007 and 2017. To find annual incidences of SAH per 100,000 population, they calculated the number of SAH cases and the total adult population for the year.

“Smoking and hypertension are two of the strongest risk factors for subarachnoid hemorrhage,” Dr. Otite said. “Hypertension is more prevalent in Black people in the United States, and Black patients with hypertension are more likely to have it uncontrolled.”
 

Racism, toxic stress

Anjail Sharieff, MD, associate professor of neurology at UT Health, Houston, said aside from a high rate of common SAH risk factors such as hypertension, Black Americans also face a barrage of inequities to health education and quality health care that contributes to higher SAH rates.

“The impact of toxic stress related to racism and discrimination experiences, and chronic stress related to poverty, can contribute to hypertension in Black people,” Dr. Sharieff said, adding that these factors contribute to stroke risk and are not usually accounted for in studies.

Dr. Sharieff said many of her first-time patients end up in her office due to a heart attack or stroke because they were previously uninsured and did not have access to primary care. “We need to begin leveraging trust with people in communities – meeting people where they are,” to educate them about hypertension and other health issues, she said.

A shining example of community engagement to reduce hypertension in Black communities was the Cedars-Sinai Barbershop Study, where 52 barbershops in Los Angeles implemented blood pressure checks and interventions among customers. A year later, the project was still working.

“Once we can identify the health problems in Black communities,” said Dr. Sharieff, “we can treat them.”

Dr. Otite and Dr. Sharieff report no relevant financial relationships.

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

Rates of subarachnoid hemorrhage (SAH) are increasing, particularly in Black people, new research suggests.

Results of a new study based on hospital discharge data show Black people have disproportionately high rates of SAH versus other racial groups. Compared with White and Hispanic people, who had an average of 10 cases per 100,000, or Asian people, with 8 per 100,000 people, Black people had an average of 15 cases per 100,000 population.

Whereas case rates held steady for other racial groups in the study over a 10-year period, Black people were the only racial group for whom SAH incidence increased over time, at a rate of 1.8% per year.

“Root causes of the higher SAH incidence in Black [people] are complex and likely extend beyond simple differences in risk factor characteristics to other socioeconomic factors including level of education, poverty level, lack of insurance, access to quality care, and structural racism,” study investigator Fadar Oliver Otite, MD, assistant professor of neurology at SUNY Upstate Medical University, Syracuse, said in an interview.

“Addressing this racial disparity will require multidisciplinary factors targeted not just at subarachnoid hemorrhage risk factors but also at socioeconomic equity,” he added.

The study was published online in Neurology.
 

Uncontrolled hypertension

The average incidence of SAH for all participants was 11 cases per 100,000 people. Men had an average rate of 10 cases and women an average rate of 13 cases per 100,000.

As expected, incidence increased with age: For middle-aged men, the average was four cases per 100,000 people whereas for men 65 and older, the average was 22 cases.

Dr. Otite and his team combined U.S. Census data with two state hospitalization databases in New York and Florida and found that there were nearly 40,000 people hospitalized for SAH between 2007 and 2017. To find annual incidences of SAH per 100,000 population, they calculated the number of SAH cases and the total adult population for the year.

“Smoking and hypertension are two of the strongest risk factors for subarachnoid hemorrhage,” Dr. Otite said. “Hypertension is more prevalent in Black people in the United States, and Black patients with hypertension are more likely to have it uncontrolled.”
 

Racism, toxic stress

Anjail Sharieff, MD, associate professor of neurology at UT Health, Houston, said aside from a high rate of common SAH risk factors such as hypertension, Black Americans also face a barrage of inequities to health education and quality health care that contributes to higher SAH rates.

“The impact of toxic stress related to racism and discrimination experiences, and chronic stress related to poverty, can contribute to hypertension in Black people,” Dr. Sharieff said, adding that these factors contribute to stroke risk and are not usually accounted for in studies.

Dr. Sharieff said many of her first-time patients end up in her office due to a heart attack or stroke because they were previously uninsured and did not have access to primary care. “We need to begin leveraging trust with people in communities – meeting people where they are,” to educate them about hypertension and other health issues, she said.

A shining example of community engagement to reduce hypertension in Black communities was the Cedars-Sinai Barbershop Study, where 52 barbershops in Los Angeles implemented blood pressure checks and interventions among customers. A year later, the project was still working.

“Once we can identify the health problems in Black communities,” said Dr. Sharieff, “we can treat them.”

Dr. Otite and Dr. Sharieff report no relevant financial relationships.

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

Rates of subarachnoid hemorrhage (SAH) are increasing, particularly in Black people, new research suggests.

Results of a new study based on hospital discharge data show Black people have disproportionately high rates of SAH versus other racial groups. Compared with White and Hispanic people, who had an average of 10 cases per 100,000, or Asian people, with 8 per 100,000 people, Black people had an average of 15 cases per 100,000 population.

Whereas case rates held steady for other racial groups in the study over a 10-year period, Black people were the only racial group for whom SAH incidence increased over time, at a rate of 1.8% per year.

“Root causes of the higher SAH incidence in Black [people] are complex and likely extend beyond simple differences in risk factor characteristics to other socioeconomic factors including level of education, poverty level, lack of insurance, access to quality care, and structural racism,” study investigator Fadar Oliver Otite, MD, assistant professor of neurology at SUNY Upstate Medical University, Syracuse, said in an interview.

“Addressing this racial disparity will require multidisciplinary factors targeted not just at subarachnoid hemorrhage risk factors but also at socioeconomic equity,” he added.

The study was published online in Neurology.
 

Uncontrolled hypertension

The average incidence of SAH for all participants was 11 cases per 100,000 people. Men had an average rate of 10 cases and women an average rate of 13 cases per 100,000.

As expected, incidence increased with age: For middle-aged men, the average was four cases per 100,000 people whereas for men 65 and older, the average was 22 cases.

Dr. Otite and his team combined U.S. Census data with two state hospitalization databases in New York and Florida and found that there were nearly 40,000 people hospitalized for SAH between 2007 and 2017. To find annual incidences of SAH per 100,000 population, they calculated the number of SAH cases and the total adult population for the year.

“Smoking and hypertension are two of the strongest risk factors for subarachnoid hemorrhage,” Dr. Otite said. “Hypertension is more prevalent in Black people in the United States, and Black patients with hypertension are more likely to have it uncontrolled.”
 

Racism, toxic stress

Anjail Sharieff, MD, associate professor of neurology at UT Health, Houston, said aside from a high rate of common SAH risk factors such as hypertension, Black Americans also face a barrage of inequities to health education and quality health care that contributes to higher SAH rates.

“The impact of toxic stress related to racism and discrimination experiences, and chronic stress related to poverty, can contribute to hypertension in Black people,” Dr. Sharieff said, adding that these factors contribute to stroke risk and are not usually accounted for in studies.

Dr. Sharieff said many of her first-time patients end up in her office due to a heart attack or stroke because they were previously uninsured and did not have access to primary care. “We need to begin leveraging trust with people in communities – meeting people where they are,” to educate them about hypertension and other health issues, she said.

A shining example of community engagement to reduce hypertension in Black communities was the Cedars-Sinai Barbershop Study, where 52 barbershops in Los Angeles implemented blood pressure checks and interventions among customers. A year later, the project was still working.

“Once we can identify the health problems in Black communities,” said Dr. Sharieff, “we can treat them.”

Dr. Otite and Dr. Sharieff report no relevant financial relationships.

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

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

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

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

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

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

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

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

There’s some good overall news in a large analysis that looked at whether a mother’s COVID-19 infection or birth during the pandemic could affect a baby’s brain development.

Researchers studied 21,419 infants who had neurodevelopmental screening during the pandemic (from January 2020 to January 2021) and compared them with babies born before the pandemic (2015-2019).

They found in an analysis of eight studies that, generally, brain development in infants ages 6-12 months old was not changed by COVID-19.
 

Communication skill scores lower than prepandemic

However, one area did see a significant difference when they looked at answers to the Ages and Stages Questionnaire, 3rd edition (ASQ-3): Scores were lower in communication skills.

Compared with the prepandemic babies, the pandemic group of babies was more likely to have communication impairment (odds were 1.7 times higher).

Additionally, mothers’ SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment sector in offspring, with one exception: Odds were 3.5 times higher for fine motor impairment in the pandemic baby group.

The babies in this study were either exposed in the womb to the SARS-CoV-2 infection or screened during the pandemic regardless of whether they were exposed to the virus.

The study, led by Kamran Hessami, MD, with the Maternal Fetal Care Center at Boston Children’s Hospital and Harvard Medical School in Boston, was published in JAMA Network Open.
 

Potential reasons for lower communication skills

The study points to some factors of the pandemic that may be tied to impaired communication skills.

“Higher levels of COVID-19–related stress were reported for both mothers and fathers of infants aged 0-6 months and were associated with insensitive parenting practices, including decreased emotional responsiveness in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood,” they write. “Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.”

Viviana M. Fajardo Martinez, MD, with neonatal/perinatal medicine at University of California, Los Angeles, Health, told this publication her team is also studying child development before and after the pandemic over a 3-year period, and delayed communication skills is something she is seeing in clinic there.

She says some parents have been concerned, saying their babies aren’t talking enough or are behind in vocabulary.
 

Babies can catch up after 12 months

One thing she tells parents is that babies who are a bit delayed at 12 months can catch up.

Up to 18 months, they can catch up, she said, adding that they can be reevaluated then for improvement. If, at that point, the baby is not catching up, “that’s when we refer for early intervention,” she said.

Dr. Martinez also tells parents concerned about their infant’s communication skills that it’s important to talk, read, and sing to their child. She said amid pandemic stress, corners may have been cut in asking children to use language skills.

For instance, if a child points to an apple, a stressed parent may just give the child the apple instead of asking the child to request it by name and repeat the word several times.

She also said a limitation of this study is the use of the ASQ-3 questionnaire, which is filled out by parents. Answers are subjective, she notes, and sometimes differ between one child’s two parents. The questionnaire was commonly used during the pandemic because a more objective, professional evaluation has been more difficult.

However, a measure like the Bayley Scales of Infant and Toddler Development Screening Test adds objectivity and will likely give a better picture as research progresses, Dr. Martinez said. 
 

Some information missing

Andréane Lavallée, PhD, and Dani Dumitriu, MD, PhD, both with the department of pediatrics at Columbia University, New York, write in an invited commentary that the overall positive message of the study “should not make researchers complacent” and results should be viewed with caution.

They point out that the precise effects of this novel virus are still unclear and the age group and variables studied may not tell the whole story.

“It should be noted that this systematic review did not consider timing of exposure during pregnancy, maternal infection severity, or exposure to various SARS-CoV-2 variants – all factors that could eventually be proven to contribute to subtle adverse neurodevelopmental outcomes,” they write.

Additionally, past pandemics “such as the 1918 Spanish flu, 1964 rubella, and 2009 H1N1” have taught researchers to watch for increases in diagnoses such as autism spectrum disorder (ASD) and schizophrenia in subsequent years.

“ASD is generally diagnosed at age 3-5 years (and often not until early teens), while schizophrenia is generally diagnosed in mid-to-late 20s,” the editorialists point out. The authors agree and emphasize the need for long-term studies.

Authors report no relevant financial relationships. Editorialist Dr. Dumitriu reports grants from National Institute of Mental Health, the U.S. Centers for Disease Control and Prevention, and the W. K. Kellogg Foundation; and has received gift funds from Einhorn Collaborative during the conduct of the study to the Nurture Science Program, for which Dr Dumitriu serves as director. Dr. Dumitriu received personal fees from Medela outside the submitted work; and is the corresponding author for one of the studies (Shuffrey et al., 2022) included in the systematic review conducted by Dr. Hessami et al. Dr. Lavallée reports grants from the Canadian Institutes of Health Research. Dr. Martinez reports no relevant financial relationships.
 

There’s some good overall news in a large analysis that looked at whether a mother’s COVID-19 infection or birth during the pandemic could affect a baby’s brain development.

Researchers studied 21,419 infants who had neurodevelopmental screening during the pandemic (from January 2020 to January 2021) and compared them with babies born before the pandemic (2015-2019).

They found in an analysis of eight studies that, generally, brain development in infants ages 6-12 months old was not changed by COVID-19.
 

Communication skill scores lower than prepandemic

However, one area did see a significant difference when they looked at answers to the Ages and Stages Questionnaire, 3rd edition (ASQ-3): Scores were lower in communication skills.

Compared with the prepandemic babies, the pandemic group of babies was more likely to have communication impairment (odds were 1.7 times higher).

Additionally, mothers’ SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment sector in offspring, with one exception: Odds were 3.5 times higher for fine motor impairment in the pandemic baby group.

The babies in this study were either exposed in the womb to the SARS-CoV-2 infection or screened during the pandemic regardless of whether they were exposed to the virus.

The study, led by Kamran Hessami, MD, with the Maternal Fetal Care Center at Boston Children’s Hospital and Harvard Medical School in Boston, was published in JAMA Network Open.
 

Potential reasons for lower communication skills

The study points to some factors of the pandemic that may be tied to impaired communication skills.

“Higher levels of COVID-19–related stress were reported for both mothers and fathers of infants aged 0-6 months and were associated with insensitive parenting practices, including decreased emotional responsiveness in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood,” they write. “Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.”

Viviana M. Fajardo Martinez, MD, with neonatal/perinatal medicine at University of California, Los Angeles, Health, told this publication her team is also studying child development before and after the pandemic over a 3-year period, and delayed communication skills is something she is seeing in clinic there.

She says some parents have been concerned, saying their babies aren’t talking enough or are behind in vocabulary.
 

Babies can catch up after 12 months

One thing she tells parents is that babies who are a bit delayed at 12 months can catch up.

Up to 18 months, they can catch up, she said, adding that they can be reevaluated then for improvement. If, at that point, the baby is not catching up, “that’s when we refer for early intervention,” she said.

Dr. Martinez also tells parents concerned about their infant’s communication skills that it’s important to talk, read, and sing to their child. She said amid pandemic stress, corners may have been cut in asking children to use language skills.

For instance, if a child points to an apple, a stressed parent may just give the child the apple instead of asking the child to request it by name and repeat the word several times.

She also said a limitation of this study is the use of the ASQ-3 questionnaire, which is filled out by parents. Answers are subjective, she notes, and sometimes differ between one child’s two parents. The questionnaire was commonly used during the pandemic because a more objective, professional evaluation has been more difficult.

However, a measure like the Bayley Scales of Infant and Toddler Development Screening Test adds objectivity and will likely give a better picture as research progresses, Dr. Martinez said. 
 

Some information missing

Andréane Lavallée, PhD, and Dani Dumitriu, MD, PhD, both with the department of pediatrics at Columbia University, New York, write in an invited commentary that the overall positive message of the study “should not make researchers complacent” and results should be viewed with caution.

They point out that the precise effects of this novel virus are still unclear and the age group and variables studied may not tell the whole story.

“It should be noted that this systematic review did not consider timing of exposure during pregnancy, maternal infection severity, or exposure to various SARS-CoV-2 variants – all factors that could eventually be proven to contribute to subtle adverse neurodevelopmental outcomes,” they write.

Additionally, past pandemics “such as the 1918 Spanish flu, 1964 rubella, and 2009 H1N1” have taught researchers to watch for increases in diagnoses such as autism spectrum disorder (ASD) and schizophrenia in subsequent years.

“ASD is generally diagnosed at age 3-5 years (and often not until early teens), while schizophrenia is generally diagnosed in mid-to-late 20s,” the editorialists point out. The authors agree and emphasize the need for long-term studies.

Authors report no relevant financial relationships. Editorialist Dr. Dumitriu reports grants from National Institute of Mental Health, the U.S. Centers for Disease Control and Prevention, and the W. K. Kellogg Foundation; and has received gift funds from Einhorn Collaborative during the conduct of the study to the Nurture Science Program, for which Dr Dumitriu serves as director. Dr. Dumitriu received personal fees from Medela outside the submitted work; and is the corresponding author for one of the studies (Shuffrey et al., 2022) included in the systematic review conducted by Dr. Hessami et al. Dr. Lavallée reports grants from the Canadian Institutes of Health Research. Dr. Martinez reports no relevant financial relationships.
 

There’s some good overall news in a large analysis that looked at whether a mother’s COVID-19 infection or birth during the pandemic could affect a baby’s brain development.

Researchers studied 21,419 infants who had neurodevelopmental screening during the pandemic (from January 2020 to January 2021) and compared them with babies born before the pandemic (2015-2019).

They found in an analysis of eight studies that, generally, brain development in infants ages 6-12 months old was not changed by COVID-19.
 

Communication skill scores lower than prepandemic

However, one area did see a significant difference when they looked at answers to the Ages and Stages Questionnaire, 3rd edition (ASQ-3): Scores were lower in communication skills.

Compared with the prepandemic babies, the pandemic group of babies was more likely to have communication impairment (odds were 1.7 times higher).

Additionally, mothers’ SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment sector in offspring, with one exception: Odds were 3.5 times higher for fine motor impairment in the pandemic baby group.

The babies in this study were either exposed in the womb to the SARS-CoV-2 infection or screened during the pandemic regardless of whether they were exposed to the virus.

The study, led by Kamran Hessami, MD, with the Maternal Fetal Care Center at Boston Children’s Hospital and Harvard Medical School in Boston, was published in JAMA Network Open.
 

Potential reasons for lower communication skills

The study points to some factors of the pandemic that may be tied to impaired communication skills.

“Higher levels of COVID-19–related stress were reported for both mothers and fathers of infants aged 0-6 months and were associated with insensitive parenting practices, including decreased emotional responsiveness in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood,” they write. “Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.”

Viviana M. Fajardo Martinez, MD, with neonatal/perinatal medicine at University of California, Los Angeles, Health, told this publication her team is also studying child development before and after the pandemic over a 3-year period, and delayed communication skills is something she is seeing in clinic there.

She says some parents have been concerned, saying their babies aren’t talking enough or are behind in vocabulary.
 

Babies can catch up after 12 months

One thing she tells parents is that babies who are a bit delayed at 12 months can catch up.

Up to 18 months, they can catch up, she said, adding that they can be reevaluated then for improvement. If, at that point, the baby is not catching up, “that’s when we refer for early intervention,” she said.

Dr. Martinez also tells parents concerned about their infant’s communication skills that it’s important to talk, read, and sing to their child. She said amid pandemic stress, corners may have been cut in asking children to use language skills.

For instance, if a child points to an apple, a stressed parent may just give the child the apple instead of asking the child to request it by name and repeat the word several times.

She also said a limitation of this study is the use of the ASQ-3 questionnaire, which is filled out by parents. Answers are subjective, she notes, and sometimes differ between one child’s two parents. The questionnaire was commonly used during the pandemic because a more objective, professional evaluation has been more difficult.

However, a measure like the Bayley Scales of Infant and Toddler Development Screening Test adds objectivity and will likely give a better picture as research progresses, Dr. Martinez said. 
 

Some information missing

Andréane Lavallée, PhD, and Dani Dumitriu, MD, PhD, both with the department of pediatrics at Columbia University, New York, write in an invited commentary that the overall positive message of the study “should not make researchers complacent” and results should be viewed with caution.

They point out that the precise effects of this novel virus are still unclear and the age group and variables studied may not tell the whole story.

“It should be noted that this systematic review did not consider timing of exposure during pregnancy, maternal infection severity, or exposure to various SARS-CoV-2 variants – all factors that could eventually be proven to contribute to subtle adverse neurodevelopmental outcomes,” they write.

Additionally, past pandemics “such as the 1918 Spanish flu, 1964 rubella, and 2009 H1N1” have taught researchers to watch for increases in diagnoses such as autism spectrum disorder (ASD) and schizophrenia in subsequent years.

“ASD is generally diagnosed at age 3-5 years (and often not until early teens), while schizophrenia is generally diagnosed in mid-to-late 20s,” the editorialists point out. The authors agree and emphasize the need for long-term studies.

Authors report no relevant financial relationships. Editorialist Dr. Dumitriu reports grants from National Institute of Mental Health, the U.S. Centers for Disease Control and Prevention, and the W. K. Kellogg Foundation; and has received gift funds from Einhorn Collaborative during the conduct of the study to the Nurture Science Program, for which Dr Dumitriu serves as director. Dr. Dumitriu received personal fees from Medela outside the submitted work; and is the corresponding author for one of the studies (Shuffrey et al., 2022) included in the systematic review conducted by Dr. Hessami et al. Dr. Lavallée reports grants from the Canadian Institutes of Health Research. Dr. Martinez reports no relevant financial relationships.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

A 67-year-old man asks about what he can do to prevent dementia. He reports his mother had dementia, and he wants to do everything he can to prevent it. Which of the following has evidence of benefit?

A) Thiamine

B) Vitamin E

C) Multivitamin (MV)

D) Keto diet

E) Red wine
 

FDA-approved therapies for dementia

To date the actual therapies for dementia have been disappointing. Donepezil, the most prescribed medication for the treatment of dementia has a number-needed-to treat (NNT) over 17, and causes frequent side effects. Aducanumab was recently approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD), but controversy has arisen, as the clinical results were modest, and the price tag will be large – estimated at $30,000-$50,000/year.

Preventive options that may decrease the likelihood of dementia

Patients often ask the question stated above. Regarding how to respond to that question, choice C, MV, has some recent evidence of benefit. Baker and colleagues studied the effect of cocoa extract and multivitamins on cognitive function in the COSMOS-Mind trial.¹ A total of 2,262 people were enrolled, and over 90% completed baseline and at least one annual cognitive assessment. Cocoa extract had no impact on global cognition (confidence interval [CI], –.02-.08, P = .28), but MV supplementation did have a statistically significant impact on global cognition (CI, .02-.12, P less than .007).

Vitamin E has been enthusiastically endorsed in the past as a treatment to prevent cognitive decline. The most recent Cochrane review on vitamin E concluded there was no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.²

Exercise has long been a mainstay of our advice to patients as something they can do to help prevent dementia. Yu and colleagues did a meta-analysis of almost 400 randomized controlled trials and observational studies to grade the evidence on different interventions.³ They gave exercise a grade B for evidence of benefit.

A recent study addressed this issue, and I think it is helpful on quantifying how much exercise is needed. Del Pozo Cruz and colleagues did a prospective population-based cohort study of 78,000 adults aged 40-79, with an average of 6.9 years of follow up.⁴ The optimal step count was 9,826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal step count for benefit was 3,826 steps (HR, 0.75; 95% CI, 0.67-0.83).
 

Modifiable factors

The other major modifiable factors to consider are problems with special senses. Both vision loss and hearing loss have been associated with cognitive impairment.

Shang and colleagues published a meta-analysis of 14 cohort studies addressing vision impairment and cognitive function involving more than 6 million individuals.⁵ They concluded that vision impairment is associated with an increased risk of both dementia and cognitive impairment in older adults.

Loughrey and colleagues performed a meta-analysis of 36 studies addressing hearing loss and cognitive decline.⁶ They reported that, among cross-sectional studies, a significant association was found for cognitive impairment (odds ratio [OR], 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). A similar finding was present in prospective cohort studies with a significant association being found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59).

A 25-year prospective, population-based study of patients with hearing loss revealed a difference in the rate of change in MMSE score over the 25-year follow-up between participants with hearing loss not using hearing aids matched with controls who didn’t have hearing loss. Those with untreated hearing loss had more cognitive decline than that of patients without hearing loss.⁷ The subjects with hearing loss using a hearing aid had no difference in cognitive decline from controls.
 

Pearl

Several simple and safe interventions may protect our patients from cognitive decline. These include taking a daily multivitamin, walking more than 4,000 steps a day, and optimizing vision and hearing.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Baker LD et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement. 2022 Sep 14. doi: 10.1002/alz.12767.

2. Farina N et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854. doi: 10.1002/14651858.CD002854.pub5.

3. Yu JT et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-9.

4. Del Pozo Cruz B et al. Association of daily step count and intensity with incident dementia in 78,430 adults living in the UK. JAMA Neurol. 2022 Oct 1;79(10):1059-63.

5. Shang X et al. The association between vision impairment and incidence of dementia and cognitive impairment: A systematic review and meta-analysis. Ophthalmology. 2021 Aug;128(8):1135-49.

6. Loughrey DG et al. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):115-26.

7. Amieva H et al. Self-reported hearing loss, hearing aids, and cognitive decline in elderly adults: A 25-year study. J Am Geriatr Soc. 2015 Oct;63(10):2099-104.

A 67-year-old man asks about what he can do to prevent dementia. He reports his mother had dementia, and he wants to do everything he can to prevent it. Which of the following has evidence of benefit?

A) Thiamine

B) Vitamin E

C) Multivitamin (MV)

D) Keto diet

E) Red wine
 

FDA-approved therapies for dementia

To date the actual therapies for dementia have been disappointing. Donepezil, the most prescribed medication for the treatment of dementia has a number-needed-to treat (NNT) over 17, and causes frequent side effects. Aducanumab was recently approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD), but controversy has arisen, as the clinical results were modest, and the price tag will be large – estimated at $30,000-$50,000/year.

Preventive options that may decrease the likelihood of dementia

Patients often ask the question stated above. Regarding how to respond to that question, choice C, MV, has some recent evidence of benefit. Baker and colleagues studied the effect of cocoa extract and multivitamins on cognitive function in the COSMOS-Mind trial.¹ A total of 2,262 people were enrolled, and over 90% completed baseline and at least one annual cognitive assessment. Cocoa extract had no impact on global cognition (confidence interval [CI], –.02-.08, P = .28), but MV supplementation did have a statistically significant impact on global cognition (CI, .02-.12, P less than .007).

Vitamin E has been enthusiastically endorsed in the past as a treatment to prevent cognitive decline. The most recent Cochrane review on vitamin E concluded there was no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.²

Exercise has long been a mainstay of our advice to patients as something they can do to help prevent dementia. Yu and colleagues did a meta-analysis of almost 400 randomized controlled trials and observational studies to grade the evidence on different interventions.³ They gave exercise a grade B for evidence of benefit.

A recent study addressed this issue, and I think it is helpful on quantifying how much exercise is needed. Del Pozo Cruz and colleagues did a prospective population-based cohort study of 78,000 adults aged 40-79, with an average of 6.9 years of follow up.⁴ The optimal step count was 9,826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal step count for benefit was 3,826 steps (HR, 0.75; 95% CI, 0.67-0.83).
 

Modifiable factors

The other major modifiable factors to consider are problems with special senses. Both vision loss and hearing loss have been associated with cognitive impairment.

Shang and colleagues published a meta-analysis of 14 cohort studies addressing vision impairment and cognitive function involving more than 6 million individuals.⁵ They concluded that vision impairment is associated with an increased risk of both dementia and cognitive impairment in older adults.

Loughrey and colleagues performed a meta-analysis of 36 studies addressing hearing loss and cognitive decline.⁶ They reported that, among cross-sectional studies, a significant association was found for cognitive impairment (odds ratio [OR], 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). A similar finding was present in prospective cohort studies with a significant association being found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59).

A 25-year prospective, population-based study of patients with hearing loss revealed a difference in the rate of change in MMSE score over the 25-year follow-up between participants with hearing loss not using hearing aids matched with controls who didn’t have hearing loss. Those with untreated hearing loss had more cognitive decline than that of patients without hearing loss.⁷ The subjects with hearing loss using a hearing aid had no difference in cognitive decline from controls.
 

Pearl

Several simple and safe interventions may protect our patients from cognitive decline. These include taking a daily multivitamin, walking more than 4,000 steps a day, and optimizing vision and hearing.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Baker LD et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement. 2022 Sep 14. doi: 10.1002/alz.12767.

2. Farina N et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854. doi: 10.1002/14651858.CD002854.pub5.

3. Yu JT et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-9.

4. Del Pozo Cruz B et al. Association of daily step count and intensity with incident dementia in 78,430 adults living in the UK. JAMA Neurol. 2022 Oct 1;79(10):1059-63.

5. Shang X et al. The association between vision impairment and incidence of dementia and cognitive impairment: A systematic review and meta-analysis. Ophthalmology. 2021 Aug;128(8):1135-49.

6. Loughrey DG et al. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):115-26.

7. Amieva H et al. Self-reported hearing loss, hearing aids, and cognitive decline in elderly adults: A 25-year study. J Am Geriatr Soc. 2015 Oct;63(10):2099-104.

A 67-year-old man asks about what he can do to prevent dementia. He reports his mother had dementia, and he wants to do everything he can to prevent it. Which of the following has evidence of benefit?

A) Thiamine

B) Vitamin E

C) Multivitamin (MV)

D) Keto diet

E) Red wine
 

FDA-approved therapies for dementia

To date the actual therapies for dementia have been disappointing. Donepezil, the most prescribed medication for the treatment of dementia has a number-needed-to treat (NNT) over 17, and causes frequent side effects. Aducanumab was recently approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD), but controversy has arisen, as the clinical results were modest, and the price tag will be large – estimated at $30,000-$50,000/year.

Preventive options that may decrease the likelihood of dementia

Patients often ask the question stated above. Regarding how to respond to that question, choice C, MV, has some recent evidence of benefit. Baker and colleagues studied the effect of cocoa extract and multivitamins on cognitive function in the COSMOS-Mind trial.¹ A total of 2,262 people were enrolled, and over 90% completed baseline and at least one annual cognitive assessment. Cocoa extract had no impact on global cognition (confidence interval [CI], –.02-.08, P = .28), but MV supplementation did have a statistically significant impact on global cognition (CI, .02-.12, P less than .007).

Vitamin E has been enthusiastically endorsed in the past as a treatment to prevent cognitive decline. The most recent Cochrane review on vitamin E concluded there was no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.²

Exercise has long been a mainstay of our advice to patients as something they can do to help prevent dementia. Yu and colleagues did a meta-analysis of almost 400 randomized controlled trials and observational studies to grade the evidence on different interventions.³ They gave exercise a grade B for evidence of benefit.

A recent study addressed this issue, and I think it is helpful on quantifying how much exercise is needed. Del Pozo Cruz and colleagues did a prospective population-based cohort study of 78,000 adults aged 40-79, with an average of 6.9 years of follow up.⁴ The optimal step count was 9,826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal step count for benefit was 3,826 steps (HR, 0.75; 95% CI, 0.67-0.83).
 

Modifiable factors

The other major modifiable factors to consider are problems with special senses. Both vision loss and hearing loss have been associated with cognitive impairment.

Shang and colleagues published a meta-analysis of 14 cohort studies addressing vision impairment and cognitive function involving more than 6 million individuals.⁵ They concluded that vision impairment is associated with an increased risk of both dementia and cognitive impairment in older adults.

Loughrey and colleagues performed a meta-analysis of 36 studies addressing hearing loss and cognitive decline.⁶ They reported that, among cross-sectional studies, a significant association was found for cognitive impairment (odds ratio [OR], 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). A similar finding was present in prospective cohort studies with a significant association being found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59).

A 25-year prospective, population-based study of patients with hearing loss revealed a difference in the rate of change in MMSE score over the 25-year follow-up between participants with hearing loss not using hearing aids matched with controls who didn’t have hearing loss. Those with untreated hearing loss had more cognitive decline than that of patients without hearing loss.⁷ The subjects with hearing loss using a hearing aid had no difference in cognitive decline from controls.
 

Pearl

Several simple and safe interventions may protect our patients from cognitive decline. These include taking a daily multivitamin, walking more than 4,000 steps a day, and optimizing vision and hearing.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Baker LD et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement. 2022 Sep 14. doi: 10.1002/alz.12767.

2. Farina N et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854. doi: 10.1002/14651858.CD002854.pub5.

3. Yu JT et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-9.

4. Del Pozo Cruz B et al. Association of daily step count and intensity with incident dementia in 78,430 adults living in the UK. JAMA Neurol. 2022 Oct 1;79(10):1059-63.

5. Shang X et al. The association between vision impairment and incidence of dementia and cognitive impairment: A systematic review and meta-analysis. Ophthalmology. 2021 Aug;128(8):1135-49.

6. Loughrey DG et al. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):115-26.

7. Amieva H et al. Self-reported hearing loss, hearing aids, and cognitive decline in elderly adults: A 25-year study. J Am Geriatr Soc. 2015 Oct;63(10):2099-104.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Words including death, die, dying, or stillborn were frequently replaced by euphemisms in meetings between clinicians and families of critically ill children, based on data from 33 family meetings that involved discussions of death.

Clear communication is essential in discussing death with patients and families and current consensus guidelines recommend against use of euphemisms; data also suggest that patients and families prefer clear and direct language, wrote Margaret H. Barlet, of Duke University, Durham, N.C., and colleagues.

However, data on the language used in discussions of death in neonatal or pediatric contexts are limited, they said.

In a study published in JAMA Network Open, the researchers reviewed conversations between clinicians and parents of critically ill children. The study participants included 20 parents of 13 infants with neurological conditions who were hospitalized in a pediatric ICU in a single center in the southeastern United States between September 2018 and September 2020. Family meetings were scheduled to discuss prognosis and whether to start, not start, or discontinue life-sustaining treatment. The discussions were recorded, transcribed, and deidentified. The median age of the parents was 28.5 years; 60% identified as Black, 40% as White, and 10% as Asian; with some selecting more than one race.

For all 13 infants, one parent identified as the infant’s mother, and another parent identified as the father for seven of the infants. The median gestational age of the infants was 37 weeks; 54% were female, and the median hospital stay was 86 days.

Twelve infants (92%) required mechanical ventilation, six required chest compressions, and five had a do-not-attempt resuscitation order placed. Two infants died during the hospital admission process.

The primary outcome of the study was language used to reference death during family meetings between doctors and families. In the family conversations, death was referenced 406 times (275 times by clinicians and 131 times by family members).

Families were more likely than were clinicians to use the words die, death, dying, or stillborn; these terms appeared in 19 of 131 references by families and 13 of 275 references by clinicians (15% vs. 5%).

In addition to a category for use of words such as die, death, dying, or stillborn, the researchers identified four types of euphemisms used in place of these terms. They characterized the types of euphemisms as survival framing (for example, not live), colloquialisms (for example, pass away), medical jargon or use of physiologic terms (for example, code event or irrecoverable heart rate drop) and the use of pronouns without an antecedent (for example, it might happen soon).

Overall, 92% of references to death in the conversations were euphemistic. Medical jargon was the most common type of euphemism used by clinicians (118 of 275 references, 43%), while colloquialism was the most common type used by family members (44 of 131 references, 34%).

The results are consistent with limited research on this topic and show the high rates of euphemistic language used in discussions of death, the researchers wrote in their discussion. “Although our work did not directly evaluate the comparative clarity of different ways to reference death, our results raise questions about what language is most clear,” they said. The researchers proposed that their classification of euphemistic language may provide a framework for the use of language in discussions of death and may prompt clinicians to notice the language they use and hear from patients and families. “Empirically evaluating the perceived clarity of euphemism types and their effects on shared decision-making should be a priority for future study and should be used to inform interventions for improving communication in this context,” they said.

The findings were limited by several factors including the use of data from a single institution and the exclusion of non-English speaking families, the researchers noted. In addition, the researchers studied only what was said, therefore “questions about speaker motivation, listener understanding, and the effects of language choice on decision-making remain unanswered,” they added.

However, the results reflect the frequent use of euphemisms by both clinicians and families, and more research is needed to assess the effect of language on understanding, decision-making, and doctor-patient relationships, the researchers concluded.
 

Euphemisms can create confusion but may increase empathy

“Ms. Barlet and colleagues provide further consideration of types of speech that may obscure a clinician’s intended meaning or distract from their true point in the context of family discussions about critically ill patients,” Michael B. Pitt, MD, of the University of Minnesota, Minneapolis, and colleagues wrote in an accompanying editorial. Using a euphemism such as “pass on” instead of “die” may be an intentional choice by physicians to use less harsh language but it may still cause confusion, they noted.

The study showed how frequently physicians use euphemisms to talk about death but was distinctive in the inclusion of data on language use by families as well, they said.

“This pattern of use identified among the infants’ families may indicate that despite the clinical recommendation that end-of-life discussions avoid the use of euphemisms, it may be worth noting and responding to families’ language preferences accordingly once it is clear they have expressed understanding that the clinician is speaking of death,” they said. For example, if a family is consistently using softer terminology, clinicians should consider responding with similar terms, rather than using medical jargon or the words death or dying, they wrote.

“As the authors note, family preferences for this type of discussion are an important target for future research aimed at optimizing family-centered communication,” the editorialists added.
 

Families seek clarity in communication

“Clinicians have an important role in helping parents of seriously ill children understand their child’s health condition and make value-driven decisions about care,” Jennifer W. Mack, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston, said in an interview. “The words that clinicians use can have a significant impact on the knowledge parents take away from encounters and the decisions they make. While there is evidence of euphemistic language in the adult setting, there is limited information about this in children,” said Dr. Mack, a pediatric hematologist/oncologist who was not involved in the study.

Dr. Mack said she was not entirely surprised that in the current study, clinician language often includes medical jargon and an avoidance of direct language about death. “This is consistent with what I have seen in clinical practice,” she said. “One striking aspect of the study is that parents used terms like death or die more often than clinicians, and they sometimes used these terms as a way to clarify what the clinician was saying. This suggests to me that parents often want clarity, even if the information is very difficult,” she said.

The key message of the study is that clinicians should pay attention to the words they use to talk about the possibility of death and recognize the tendency of many clinicians to fall back on medical jargon, said Dr. Mack.

“My personal belief is that it is possible to be both clear and compassionate, and clinicians should strive for both in these conversations, to support families and help them make their best decisions for their children,” she said. “We need to remember a single communication strategy or choice of words is not likely to feel supportive to every family; what is helpful for one family may feel painful to another,” she emphasized. “Being willing to listen to the needs they express and their own language choice can help us to be responsive to individual needs,” she added.

An important next step for research is to learn more about what families experience as supportive during conversations with clinicians about death and dying, Dr. Mack said.

The study was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and the Doris Duke Charitable Foundation. The researchers, editorial authors, and Dr. Mack had no financial conflicts to disclose.

Words including death, die, dying, or stillborn were frequently replaced by euphemisms in meetings between clinicians and families of critically ill children, based on data from 33 family meetings that involved discussions of death.

Clear communication is essential in discussing death with patients and families and current consensus guidelines recommend against use of euphemisms; data also suggest that patients and families prefer clear and direct language, wrote Margaret H. Barlet, of Duke University, Durham, N.C., and colleagues.

However, data on the language used in discussions of death in neonatal or pediatric contexts are limited, they said.

In a study published in JAMA Network Open, the researchers reviewed conversations between clinicians and parents of critically ill children. The study participants included 20 parents of 13 infants with neurological conditions who were hospitalized in a pediatric ICU in a single center in the southeastern United States between September 2018 and September 2020. Family meetings were scheduled to discuss prognosis and whether to start, not start, or discontinue life-sustaining treatment. The discussions were recorded, transcribed, and deidentified. The median age of the parents was 28.5 years; 60% identified as Black, 40% as White, and 10% as Asian; with some selecting more than one race.

For all 13 infants, one parent identified as the infant’s mother, and another parent identified as the father for seven of the infants. The median gestational age of the infants was 37 weeks; 54% were female, and the median hospital stay was 86 days.

Twelve infants (92%) required mechanical ventilation, six required chest compressions, and five had a do-not-attempt resuscitation order placed. Two infants died during the hospital admission process.

The primary outcome of the study was language used to reference death during family meetings between doctors and families. In the family conversations, death was referenced 406 times (275 times by clinicians and 131 times by family members).

Families were more likely than were clinicians to use the words die, death, dying, or stillborn; these terms appeared in 19 of 131 references by families and 13 of 275 references by clinicians (15% vs. 5%).

In addition to a category for use of words such as die, death, dying, or stillborn, the researchers identified four types of euphemisms used in place of these terms. They characterized the types of euphemisms as survival framing (for example, not live), colloquialisms (for example, pass away), medical jargon or use of physiologic terms (for example, code event or irrecoverable heart rate drop) and the use of pronouns without an antecedent (for example, it might happen soon).

Overall, 92% of references to death in the conversations were euphemistic. Medical jargon was the most common type of euphemism used by clinicians (118 of 275 references, 43%), while colloquialism was the most common type used by family members (44 of 131 references, 34%).

The results are consistent with limited research on this topic and show the high rates of euphemistic language used in discussions of death, the researchers wrote in their discussion. “Although our work did not directly evaluate the comparative clarity of different ways to reference death, our results raise questions about what language is most clear,” they said. The researchers proposed that their classification of euphemistic language may provide a framework for the use of language in discussions of death and may prompt clinicians to notice the language they use and hear from patients and families. “Empirically evaluating the perceived clarity of euphemism types and their effects on shared decision-making should be a priority for future study and should be used to inform interventions for improving communication in this context,” they said.

The findings were limited by several factors including the use of data from a single institution and the exclusion of non-English speaking families, the researchers noted. In addition, the researchers studied only what was said, therefore “questions about speaker motivation, listener understanding, and the effects of language choice on decision-making remain unanswered,” they added.

However, the results reflect the frequent use of euphemisms by both clinicians and families, and more research is needed to assess the effect of language on understanding, decision-making, and doctor-patient relationships, the researchers concluded.
 

Euphemisms can create confusion but may increase empathy

“Ms. Barlet and colleagues provide further consideration of types of speech that may obscure a clinician’s intended meaning or distract from their true point in the context of family discussions about critically ill patients,” Michael B. Pitt, MD, of the University of Minnesota, Minneapolis, and colleagues wrote in an accompanying editorial. Using a euphemism such as “pass on” instead of “die” may be an intentional choice by physicians to use less harsh language but it may still cause confusion, they noted.

The study showed how frequently physicians use euphemisms to talk about death but was distinctive in the inclusion of data on language use by families as well, they said.

“This pattern of use identified among the infants’ families may indicate that despite the clinical recommendation that end-of-life discussions avoid the use of euphemisms, it may be worth noting and responding to families’ language preferences accordingly once it is clear they have expressed understanding that the clinician is speaking of death,” they said. For example, if a family is consistently using softer terminology, clinicians should consider responding with similar terms, rather than using medical jargon or the words death or dying, they wrote.

“As the authors note, family preferences for this type of discussion are an important target for future research aimed at optimizing family-centered communication,” the editorialists added.
 

Families seek clarity in communication

“Clinicians have an important role in helping parents of seriously ill children understand their child’s health condition and make value-driven decisions about care,” Jennifer W. Mack, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston, said in an interview. “The words that clinicians use can have a significant impact on the knowledge parents take away from encounters and the decisions they make. While there is evidence of euphemistic language in the adult setting, there is limited information about this in children,” said Dr. Mack, a pediatric hematologist/oncologist who was not involved in the study.

Dr. Mack said she was not entirely surprised that in the current study, clinician language often includes medical jargon and an avoidance of direct language about death. “This is consistent with what I have seen in clinical practice,” she said. “One striking aspect of the study is that parents used terms like death or die more often than clinicians, and they sometimes used these terms as a way to clarify what the clinician was saying. This suggests to me that parents often want clarity, even if the information is very difficult,” she said.

The key message of the study is that clinicians should pay attention to the words they use to talk about the possibility of death and recognize the tendency of many clinicians to fall back on medical jargon, said Dr. Mack.

“My personal belief is that it is possible to be both clear and compassionate, and clinicians should strive for both in these conversations, to support families and help them make their best decisions for their children,” she said. “We need to remember a single communication strategy or choice of words is not likely to feel supportive to every family; what is helpful for one family may feel painful to another,” she emphasized. “Being willing to listen to the needs they express and their own language choice can help us to be responsive to individual needs,” she added.

An important next step for research is to learn more about what families experience as supportive during conversations with clinicians about death and dying, Dr. Mack said.

The study was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and the Doris Duke Charitable Foundation. The researchers, editorial authors, and Dr. Mack had no financial conflicts to disclose.

Words including death, die, dying, or stillborn were frequently replaced by euphemisms in meetings between clinicians and families of critically ill children, based on data from 33 family meetings that involved discussions of death.

Clear communication is essential in discussing death with patients and families and current consensus guidelines recommend against use of euphemisms; data also suggest that patients and families prefer clear and direct language, wrote Margaret H. Barlet, of Duke University, Durham, N.C., and colleagues.

However, data on the language used in discussions of death in neonatal or pediatric contexts are limited, they said.

In a study published in JAMA Network Open, the researchers reviewed conversations between clinicians and parents of critically ill children. The study participants included 20 parents of 13 infants with neurological conditions who were hospitalized in a pediatric ICU in a single center in the southeastern United States between September 2018 and September 2020. Family meetings were scheduled to discuss prognosis and whether to start, not start, or discontinue life-sustaining treatment. The discussions were recorded, transcribed, and deidentified. The median age of the parents was 28.5 years; 60% identified as Black, 40% as White, and 10% as Asian; with some selecting more than one race.

For all 13 infants, one parent identified as the infant’s mother, and another parent identified as the father for seven of the infants. The median gestational age of the infants was 37 weeks; 54% were female, and the median hospital stay was 86 days.

Twelve infants (92%) required mechanical ventilation, six required chest compressions, and five had a do-not-attempt resuscitation order placed. Two infants died during the hospital admission process.

The primary outcome of the study was language used to reference death during family meetings between doctors and families. In the family conversations, death was referenced 406 times (275 times by clinicians and 131 times by family members).

Families were more likely than were clinicians to use the words die, death, dying, or stillborn; these terms appeared in 19 of 131 references by families and 13 of 275 references by clinicians (15% vs. 5%).

In addition to a category for use of words such as die, death, dying, or stillborn, the researchers identified four types of euphemisms used in place of these terms. They characterized the types of euphemisms as survival framing (for example, not live), colloquialisms (for example, pass away), medical jargon or use of physiologic terms (for example, code event or irrecoverable heart rate drop) and the use of pronouns without an antecedent (for example, it might happen soon).

Overall, 92% of references to death in the conversations were euphemistic. Medical jargon was the most common type of euphemism used by clinicians (118 of 275 references, 43%), while colloquialism was the most common type used by family members (44 of 131 references, 34%).

The results are consistent with limited research on this topic and show the high rates of euphemistic language used in discussions of death, the researchers wrote in their discussion. “Although our work did not directly evaluate the comparative clarity of different ways to reference death, our results raise questions about what language is most clear,” they said. The researchers proposed that their classification of euphemistic language may provide a framework for the use of language in discussions of death and may prompt clinicians to notice the language they use and hear from patients and families. “Empirically evaluating the perceived clarity of euphemism types and their effects on shared decision-making should be a priority for future study and should be used to inform interventions for improving communication in this context,” they said.

The findings were limited by several factors including the use of data from a single institution and the exclusion of non-English speaking families, the researchers noted. In addition, the researchers studied only what was said, therefore “questions about speaker motivation, listener understanding, and the effects of language choice on decision-making remain unanswered,” they added.

However, the results reflect the frequent use of euphemisms by both clinicians and families, and more research is needed to assess the effect of language on understanding, decision-making, and doctor-patient relationships, the researchers concluded.
 

Euphemisms can create confusion but may increase empathy

“Ms. Barlet and colleagues provide further consideration of types of speech that may obscure a clinician’s intended meaning or distract from their true point in the context of family discussions about critically ill patients,” Michael B. Pitt, MD, of the University of Minnesota, Minneapolis, and colleagues wrote in an accompanying editorial. Using a euphemism such as “pass on” instead of “die” may be an intentional choice by physicians to use less harsh language but it may still cause confusion, they noted.

The study showed how frequently physicians use euphemisms to talk about death but was distinctive in the inclusion of data on language use by families as well, they said.

“This pattern of use identified among the infants’ families may indicate that despite the clinical recommendation that end-of-life discussions avoid the use of euphemisms, it may be worth noting and responding to families’ language preferences accordingly once it is clear they have expressed understanding that the clinician is speaking of death,” they said. For example, if a family is consistently using softer terminology, clinicians should consider responding with similar terms, rather than using medical jargon or the words death or dying, they wrote.

“As the authors note, family preferences for this type of discussion are an important target for future research aimed at optimizing family-centered communication,” the editorialists added.
 

Families seek clarity in communication

“Clinicians have an important role in helping parents of seriously ill children understand their child’s health condition and make value-driven decisions about care,” Jennifer W. Mack, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston, said in an interview. “The words that clinicians use can have a significant impact on the knowledge parents take away from encounters and the decisions they make. While there is evidence of euphemistic language in the adult setting, there is limited information about this in children,” said Dr. Mack, a pediatric hematologist/oncologist who was not involved in the study.

Dr. Mack said she was not entirely surprised that in the current study, clinician language often includes medical jargon and an avoidance of direct language about death. “This is consistent with what I have seen in clinical practice,” she said. “One striking aspect of the study is that parents used terms like death or die more often than clinicians, and they sometimes used these terms as a way to clarify what the clinician was saying. This suggests to me that parents often want clarity, even if the information is very difficult,” she said.

The key message of the study is that clinicians should pay attention to the words they use to talk about the possibility of death and recognize the tendency of many clinicians to fall back on medical jargon, said Dr. Mack.

“My personal belief is that it is possible to be both clear and compassionate, and clinicians should strive for both in these conversations, to support families and help them make their best decisions for their children,” she said. “We need to remember a single communication strategy or choice of words is not likely to feel supportive to every family; what is helpful for one family may feel painful to another,” she emphasized. “Being willing to listen to the needs they express and their own language choice can help us to be responsive to individual needs,” she added.

An important next step for research is to learn more about what families experience as supportive during conversations with clinicians about death and dying, Dr. Mack said.

The study was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and the Doris Duke Charitable Foundation. The researchers, editorial authors, and Dr. Mack had no financial conflicts to disclose.

CINCINNATI – Neurology and psychiatry have an inherent kinship, as one often deals with the brain and the other always focuses on the mind. The two fields can be intertwined, since neurological conditions are often associated with psychiatric comorbidities amid complex relationships: For example, a young patient with a neurological disorder may experience anxiety due to life changes, his or her diagnosis, or altered biological pathways from the condition or medications used to treat it.

As a result, psychiatric comorbidities are often seen among pediatric patients with neurological conditions, and pediatric neurologists can play an important role in diagnosis and management of such disorders, according to Devin McNulty, PhD, who spoke on the topic at the 2022 annual meeting of the Child Neurology Society.
 

The ‘second pandemic’

Mental health conditions represent about 16% of the global burden of disease among people aged 10-19, and the COVID-19 pandemic has drastically worsened the problem, as shutdowns, school loss, and economic struggles have added to the burden. “I think we’ve really seen mental health as sort of the second pandemic. We’ve seen this in Chicago in our emergency room, and in outpatient clinics wait-lists are really high. I think adolescents are specifically at risk,” said Dr. McNulty during her talk. She is an assistant professor of psychiatry and behavioral sciences at Northwestern University and a child psychiatrist at Ann & Robert H. Lurie Children’s Hospital of Chicago.

Common diagnoses include major depressive order, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, somatic symptom disorder, and functional neurological symptom disorder. The last can appear as neurological symptoms that are not consistent with neurological medical conditions, such as attacks or seizures, abnormal movements, sensory loss or gain, weakness or paralysis, or speech and swallowing issues. It is the second most commonly diagnosed disorder in neurology clinics and accounts for 10% of neurology hospitalizations, and it leads to high rates of health care utilization and functional impairment.

Overall, children with neurological conditions are at about a 5-fold increased risk for depression and anxiety disorders, with a range of contributing risk factors. These include biological factors like medication use, neurological dysfunction, and genetic vulnerability. Psychological factors include stressors, the child’s reaction to the diagnosis and illness, and the level of his or her coping skills. Psychiatric comorbidities may also be triggered by social factors such as familial stress, peer rejection and social isolation, and barriers to treatment for the neurological condition. As just one example, overprotective parenting behavior, while adaptive in moderation, can create a sort of feedback loop that can lead to separation anxiety.
 

A unique opportunity

“There’s an overlap,” Dr. McNulty said, “because the origin is often multifactorial.” A young patient has a medical condition, which can be chronic or disabling, and the age of onset and diagnosis comes during a critical developmental period. “Then we have issues such as the impact of treatments, whether that’s medication side effects or medical visits. And then disease-related environmental changes, such as family factors, social changes, and impact on school,” said Dr. McNulty.

Child neurologists are in a unique position to identify and ensure treatment of these psychiatric comorbidities, according to Dr. McNulty. “Child neurologists will see psychiatric symptoms in their patient population, and pediatric providers have a unique capacity and ability to treat these patients, especially when you’re seeing patients on a frequent basis. You get to know these patients and their families really well,” she said.

She specifically pointed to three areas: psychosocial screening, differential diagnosis, and treatment and management.

There are broad-based screening measures that can be useful, such as the Strengths and Difficulties Questionnaire and the Pediatric Symptom Checklist. Disorder-specific screening tools include the PHQ-9 (depression), GAD7 (anxiety), Vanderbilt (ADHD), and PROMIS measures for anxiety and depression. “The idea behind the screening measure is that all patients would fill this out and then if a patient screens positive, they would benefit from a more thorough evaluation and history,” said Dr. McNulty.

However, she noted that screening shouldn’t necessarily be a one-off effort. Research has shown that sequential screening is the most powerful strategy. “Then you can get a baseline of a patient’s emotional and behavioral functioning, and it’s actually the changes in some of these screening measures that might give them most clinical information,” said Dr. McNulty.

In fact, on October 11, 2022, the U.S. Preventive Services Task Force announced a recommendation that all children starting at age 8 should be screened for anxiety disorders. It is already recommended to screen children aged 12 and over for depressive disorders, although these documents are aimed primarily at pediatricians or primary care clinics. The American Academy of Neurology has also recommended routine screening of psychiatric and behavioral disorders among children with epilepsy.
 

A unique perspective

Once a disorder is identified, neurologists can bring a unique perspective to treatment. The neurologist can use his or her knowledge of the disease state to assess whether symptoms are due to poor adjustment to the neurological condition, a primary psychiatric disorder, or the biological underpinnings of the illness or prescribed medications. “I think their neurologist can sort of help tease that apart, [using] their knowledge of neurologic disorders and pathways and medications in a way that psychologists might not be able to do on their own,” said Dr. McNulty.

She also emphasized that there are effective treatments for psychiatric disorders, including cognitive behavioral therapy and various pharmacotherapy options. Other approaches for treating comorbid neurological and psychiatric disorders may include building adaptive coping skills, psychoeducation, and incorporating changes to the family or school environment.

During the Q&A period, one person commented that there should be more psychiatric training for neurology residents. “We do work with the same brain, so I completely agree with that,” said Dr. McNulty.

She was also asked how to identify psychiatric symptoms in nonverbal patients. “One thing that I pay close attention to when I ask parents about (their child) is changes in their physical (attributes). Oftentimes in anxiety in folks who are not severely impaired, if we’re feeling anxious we might be breathing a little faster, or we might get a little sweaty. So looking for physical manifestations is one thing. And then sometimes I’ll tell the parents, if we’re not quite sure, I’ll say ‘I’m not sure, but this is very common given the disorder that you have. Can we check?’ I’m always very clear that I may not be nailing it, but then when we go after it with targeted treatment and we see it getting better, we can say ‘Aha!’ ”

Dr. McNulty has no relevant financial disclosures.
 

CINCINNATI – Neurology and psychiatry have an inherent kinship, as one often deals with the brain and the other always focuses on the mind. The two fields can be intertwined, since neurological conditions are often associated with psychiatric comorbidities amid complex relationships: For example, a young patient with a neurological disorder may experience anxiety due to life changes, his or her diagnosis, or altered biological pathways from the condition or medications used to treat it.

As a result, psychiatric comorbidities are often seen among pediatric patients with neurological conditions, and pediatric neurologists can play an important role in diagnosis and management of such disorders, according to Devin McNulty, PhD, who spoke on the topic at the 2022 annual meeting of the Child Neurology Society.
 

The ‘second pandemic’

Mental health conditions represent about 16% of the global burden of disease among people aged 10-19, and the COVID-19 pandemic has drastically worsened the problem, as shutdowns, school loss, and economic struggles have added to the burden. “I think we’ve really seen mental health as sort of the second pandemic. We’ve seen this in Chicago in our emergency room, and in outpatient clinics wait-lists are really high. I think adolescents are specifically at risk,” said Dr. McNulty during her talk. She is an assistant professor of psychiatry and behavioral sciences at Northwestern University and a child psychiatrist at Ann & Robert H. Lurie Children’s Hospital of Chicago.

Common diagnoses include major depressive order, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, somatic symptom disorder, and functional neurological symptom disorder. The last can appear as neurological symptoms that are not consistent with neurological medical conditions, such as attacks or seizures, abnormal movements, sensory loss or gain, weakness or paralysis, or speech and swallowing issues. It is the second most commonly diagnosed disorder in neurology clinics and accounts for 10% of neurology hospitalizations, and it leads to high rates of health care utilization and functional impairment.

Overall, children with neurological conditions are at about a 5-fold increased risk for depression and anxiety disorders, with a range of contributing risk factors. These include biological factors like medication use, neurological dysfunction, and genetic vulnerability. Psychological factors include stressors, the child’s reaction to the diagnosis and illness, and the level of his or her coping skills. Psychiatric comorbidities may also be triggered by social factors such as familial stress, peer rejection and social isolation, and barriers to treatment for the neurological condition. As just one example, overprotective parenting behavior, while adaptive in moderation, can create a sort of feedback loop that can lead to separation anxiety.
 

A unique opportunity

“There’s an overlap,” Dr. McNulty said, “because the origin is often multifactorial.” A young patient has a medical condition, which can be chronic or disabling, and the age of onset and diagnosis comes during a critical developmental period. “Then we have issues such as the impact of treatments, whether that’s medication side effects or medical visits. And then disease-related environmental changes, such as family factors, social changes, and impact on school,” said Dr. McNulty.

Child neurologists are in a unique position to identify and ensure treatment of these psychiatric comorbidities, according to Dr. McNulty. “Child neurologists will see psychiatric symptoms in their patient population, and pediatric providers have a unique capacity and ability to treat these patients, especially when you’re seeing patients on a frequent basis. You get to know these patients and their families really well,” she said.

She specifically pointed to three areas: psychosocial screening, differential diagnosis, and treatment and management.

There are broad-based screening measures that can be useful, such as the Strengths and Difficulties Questionnaire and the Pediatric Symptom Checklist. Disorder-specific screening tools include the PHQ-9 (depression), GAD7 (anxiety), Vanderbilt (ADHD), and PROMIS measures for anxiety and depression. “The idea behind the screening measure is that all patients would fill this out and then if a patient screens positive, they would benefit from a more thorough evaluation and history,” said Dr. McNulty.

However, she noted that screening shouldn’t necessarily be a one-off effort. Research has shown that sequential screening is the most powerful strategy. “Then you can get a baseline of a patient’s emotional and behavioral functioning, and it’s actually the changes in some of these screening measures that might give them most clinical information,” said Dr. McNulty.

In fact, on October 11, 2022, the U.S. Preventive Services Task Force announced a recommendation that all children starting at age 8 should be screened for anxiety disorders. It is already recommended to screen children aged 12 and over for depressive disorders, although these documents are aimed primarily at pediatricians or primary care clinics. The American Academy of Neurology has also recommended routine screening of psychiatric and behavioral disorders among children with epilepsy.
 

A unique perspective

Once a disorder is identified, neurologists can bring a unique perspective to treatment. The neurologist can use his or her knowledge of the disease state to assess whether symptoms are due to poor adjustment to the neurological condition, a primary psychiatric disorder, or the biological underpinnings of the illness or prescribed medications. “I think their neurologist can sort of help tease that apart, [using] their knowledge of neurologic disorders and pathways and medications in a way that psychologists might not be able to do on their own,” said Dr. McNulty.

She also emphasized that there are effective treatments for psychiatric disorders, including cognitive behavioral therapy and various pharmacotherapy options. Other approaches for treating comorbid neurological and psychiatric disorders may include building adaptive coping skills, psychoeducation, and incorporating changes to the family or school environment.

During the Q&A period, one person commented that there should be more psychiatric training for neurology residents. “We do work with the same brain, so I completely agree with that,” said Dr. McNulty.

She was also asked how to identify psychiatric symptoms in nonverbal patients. “One thing that I pay close attention to when I ask parents about (their child) is changes in their physical (attributes). Oftentimes in anxiety in folks who are not severely impaired, if we’re feeling anxious we might be breathing a little faster, or we might get a little sweaty. So looking for physical manifestations is one thing. And then sometimes I’ll tell the parents, if we’re not quite sure, I’ll say ‘I’m not sure, but this is very common given the disorder that you have. Can we check?’ I’m always very clear that I may not be nailing it, but then when we go after it with targeted treatment and we see it getting better, we can say ‘Aha!’ ”

Dr. McNulty has no relevant financial disclosures.
 

CINCINNATI – Neurology and psychiatry have an inherent kinship, as one often deals with the brain and the other always focuses on the mind. The two fields can be intertwined, since neurological conditions are often associated with psychiatric comorbidities amid complex relationships: For example, a young patient with a neurological disorder may experience anxiety due to life changes, his or her diagnosis, or altered biological pathways from the condition or medications used to treat it.

As a result, psychiatric comorbidities are often seen among pediatric patients with neurological conditions, and pediatric neurologists can play an important role in diagnosis and management of such disorders, according to Devin McNulty, PhD, who spoke on the topic at the 2022 annual meeting of the Child Neurology Society.
 

The ‘second pandemic’

Mental health conditions represent about 16% of the global burden of disease among people aged 10-19, and the COVID-19 pandemic has drastically worsened the problem, as shutdowns, school loss, and economic struggles have added to the burden. “I think we’ve really seen mental health as sort of the second pandemic. We’ve seen this in Chicago in our emergency room, and in outpatient clinics wait-lists are really high. I think adolescents are specifically at risk,” said Dr. McNulty during her talk. She is an assistant professor of psychiatry and behavioral sciences at Northwestern University and a child psychiatrist at Ann & Robert H. Lurie Children’s Hospital of Chicago.

Common diagnoses include major depressive order, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, somatic symptom disorder, and functional neurological symptom disorder. The last can appear as neurological symptoms that are not consistent with neurological medical conditions, such as attacks or seizures, abnormal movements, sensory loss or gain, weakness or paralysis, or speech and swallowing issues. It is the second most commonly diagnosed disorder in neurology clinics and accounts for 10% of neurology hospitalizations, and it leads to high rates of health care utilization and functional impairment.

Overall, children with neurological conditions are at about a 5-fold increased risk for depression and anxiety disorders, with a range of contributing risk factors. These include biological factors like medication use, neurological dysfunction, and genetic vulnerability. Psychological factors include stressors, the child’s reaction to the diagnosis and illness, and the level of his or her coping skills. Psychiatric comorbidities may also be triggered by social factors such as familial stress, peer rejection and social isolation, and barriers to treatment for the neurological condition. As just one example, overprotective parenting behavior, while adaptive in moderation, can create a sort of feedback loop that can lead to separation anxiety.
 

A unique opportunity

“There’s an overlap,” Dr. McNulty said, “because the origin is often multifactorial.” A young patient has a medical condition, which can be chronic or disabling, and the age of onset and diagnosis comes during a critical developmental period. “Then we have issues such as the impact of treatments, whether that’s medication side effects or medical visits. And then disease-related environmental changes, such as family factors, social changes, and impact on school,” said Dr. McNulty.

Child neurologists are in a unique position to identify and ensure treatment of these psychiatric comorbidities, according to Dr. McNulty. “Child neurologists will see psychiatric symptoms in their patient population, and pediatric providers have a unique capacity and ability to treat these patients, especially when you’re seeing patients on a frequent basis. You get to know these patients and their families really well,” she said.

She specifically pointed to three areas: psychosocial screening, differential diagnosis, and treatment and management.

There are broad-based screening measures that can be useful, such as the Strengths and Difficulties Questionnaire and the Pediatric Symptom Checklist. Disorder-specific screening tools include the PHQ-9 (depression), GAD7 (anxiety), Vanderbilt (ADHD), and PROMIS measures for anxiety and depression. “The idea behind the screening measure is that all patients would fill this out and then if a patient screens positive, they would benefit from a more thorough evaluation and history,” said Dr. McNulty.

However, she noted that screening shouldn’t necessarily be a one-off effort. Research has shown that sequential screening is the most powerful strategy. “Then you can get a baseline of a patient’s emotional and behavioral functioning, and it’s actually the changes in some of these screening measures that might give them most clinical information,” said Dr. McNulty.

In fact, on October 11, 2022, the U.S. Preventive Services Task Force announced a recommendation that all children starting at age 8 should be screened for anxiety disorders. It is already recommended to screen children aged 12 and over for depressive disorders, although these documents are aimed primarily at pediatricians or primary care clinics. The American Academy of Neurology has also recommended routine screening of psychiatric and behavioral disorders among children with epilepsy.
 

A unique perspective

Once a disorder is identified, neurologists can bring a unique perspective to treatment. The neurologist can use his or her knowledge of the disease state to assess whether symptoms are due to poor adjustment to the neurological condition, a primary psychiatric disorder, or the biological underpinnings of the illness or prescribed medications. “I think their neurologist can sort of help tease that apart, [using] their knowledge of neurologic disorders and pathways and medications in a way that psychologists might not be able to do on their own,” said Dr. McNulty.

She also emphasized that there are effective treatments for psychiatric disorders, including cognitive behavioral therapy and various pharmacotherapy options. Other approaches for treating comorbid neurological and psychiatric disorders may include building adaptive coping skills, psychoeducation, and incorporating changes to the family or school environment.

During the Q&A period, one person commented that there should be more psychiatric training for neurology residents. “We do work with the same brain, so I completely agree with that,” said Dr. McNulty.

She was also asked how to identify psychiatric symptoms in nonverbal patients. “One thing that I pay close attention to when I ask parents about (their child) is changes in their physical (attributes). Oftentimes in anxiety in folks who are not severely impaired, if we’re feeling anxious we might be breathing a little faster, or we might get a little sweaty. So looking for physical manifestations is one thing. And then sometimes I’ll tell the parents, if we’re not quite sure, I’ll say ‘I’m not sure, but this is very common given the disorder that you have. Can we check?’ I’m always very clear that I may not be nailing it, but then when we go after it with targeted treatment and we see it getting better, we can say ‘Aha!’ ”

Dr. McNulty has no relevant financial disclosures.