MDedge Psychiatry

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

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

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

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

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

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

A group of experts representing various international professional societies has drafted a consensus statement on the determination of brain death or death by neurologic criteria (BD/DNC). The document, a result of the World Brain Death Project, surveys the clinical aspects of this determination, such as clinical testing, apnea testing, and the number of examinations required, as well as its social and legal aspects, including documentation, qualifications for making the determination, and religious attitudes toward BD/DNC.

The recommendations are the minimum criteria for BD/DNC, and countries and professional societies may choose to adopt stricter criteria, the authors noted. Seventeen supplements to the consensus statement contain detailed reports on topics the statement examines, including focuses on both adults and children.

“Perhaps the most important points of this project are, first, to show the worldwide acceptance of the concept of BD/DNC and what the minimum requirements are for BD/DNC,” said corresponding author Gene Sung, MD, MPH, director of the neurocritical care and stroke division at the University of Southern California, Los Angeles. Second, “this standard is centered around a clinical determination without the need for other testing.”

The consensus document and supplements were published online Aug. 3 in JAMA.

Comprehensive review

A lack of rigor has led to many differences in the determination of BD/DNC, said Dr. Sung. “Some of the variance that is common are the numbers of exams and examiners that are required and whether ancillary tests are required for determination of BD/DNC. In addition, a lot of guidelines and protocols that are in use are not thorough in detailing how to do the examinations and what to do in different circumstances.”

Professional societies such as the World Federation of Intensive and Critical Care recruited experts in BD/DNC to develop recommendations, which were based on relevant articles that they identified during a literature search. “We wanted to develop a fairly comprehensive document that, along with the 17 supplements, builds a foundation to show how to determine BD/DNC – what the minimum clinical criteria needed are and what to do in special circumstances,” Dr. Sung said.

Major sections of the statement include recommendations for the minimum clinical standards for the determination of BD/DNC in adults and children.

Determination must begin by establishing that the patient has sustained an irreversible brain injury that resulted in the loss of all brain function, according to the authors. Confounders such as pharmacologic paralysis and the effect of CNS depressant medications should be ruled out.

In addition, clinical evaluation must include an assessment for coma and an evaluation for brain stem areflexia. Among other criteria, the pupils should be fixed and nonresponsive to light, the face should not move in response to noxious cranial stimulation, and the gag and cough reflexes should be absent. Apnea testing is recommended to evaluate the responsiveness of respiratory centers in the medulla.

Although the definition of BD/DNC is the same in children as in adults, less evidence is available for the determination of BD/DNC in the very young. The authors thus advised a cautious approach to the evaluation of infants and younger children.

Recommendations vary by age and often require serial examinations, including apnea testing, they noted.

Ancillary testing

The consensus statement also reviews ancillary testing, which the authors recommend be required when the minimum clinical examination, including the apnea test, cannot be completed and when it is in the presence of confounding conditions that cannot be resolved.

The authors recommended digital subtraction angiography, radionuclide studies, and transcranial Doppler ultrasonography as ancillary tests based on blood flow in the brain. However, CT angiography and magnetic resonance angiography not be used.

A lack of guidance makes performing an apnea test in patients receiving extracorporeal membrane oxygenation (ECMO) challenging, according to the authors. Nevertheless, they recommended that the same principles of BD/DNC be applied to adults and children receiving ECMO.

They further recommended a period of preoxygenation before the apnea test, and the document describes in detail the method for administering this test to people receiving ECMO.

Another potentially challenging situation pointed out in the consensus document is the determination of BD/DNC in patients who have been treated with targeted temperature management. Therapeutic hypothermia, particularly if it is preceded or accompanied by sedation, can temporarily impair brain stem reflexes, thus mimicking BD/DNC.

The new document includes a flowchart and step-by-step recommendations as well as suggestions for determining BD/DNC under these circumstances.

Among document limitations acknowledged by the authors is the lack of high-quality data from randomized, controlled trials on which to base their recommendations.

In addition, economic, technological, or personnel limitations may reduce the available options for ancillary testing, they added. Also, the recommendations do not incorporate contributions from patients or social or religious groups, although the authors were mindful of their concerns.

To promote the national and international harmonization of BD/DNC criteria, “medical societies and countries can evaluate their own policies in relation to this document and fix any deficiencies,” Dr. Sung said.

“Many countries do not have any BD/DNC policies and can use the documents from this project to create their own. There may need to be discussions with legal, governmental, religious, and societal leaders to help understand and accept BD/DNC and to help enact policies in different communities,” he added.

Divergent definitions

The determination of death is not simply a scientific question, but also a philosophical, religious, and cultural question, wrote Robert D. Truog, MD, director of the Harvard Center for Bioethics, Boston, and colleagues in an accompanying editorial. Future research should consider cultural differences over these questions.

“Most important is that there be a clear and logical consistency between the definition of death and the tests that are used to diagnose it,” Dr. Truog said.

The concept of whole brain death was advanced as an equivalent to biological death, “such that, when the brain dies, the body literally disintegrates, just as it does after cardiac arrest,” but evidence indicates that this claim is untrue, Dr. Truog said. Current tests also do not diagnose the death of the whole brain.

Another hypothesis is that brain stem death represents the irreversible loss of consciousness and the capacity for spontaneous respiration.

“Instead of focusing on biology, [this definition] focuses on values and is based on the claim that when a person is in a state of irreversible apneic unconsciousness, we may consider them to be dead,” said Dr. Truog. He and his coeditorialists argued that the concept of whole brain death should be replaced with that of brain stem death.

“This report should be a call for our profession, as well as for federal and state lawmakers, to reform our laws so that they are consistent with our diagnostic criteria,” Dr. Truog said.

“The most straightforward way of doing this would be to change U.S. law and adopt the British standard of brain stem death, and then refine our testing to make the diagnosis of irreversible apneic unconsciousness as reliable and safe as possible,” he concluded.

The drafting of the consensus statement was not supported by outside funding. Dr. Sung reported no relevant financial relationships. Dr. Truog reported receiving compensation from Sanofi and Covance for participating in data and safety monitoring boards unrelated to the consensus document.

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

A group of experts representing various international professional societies has drafted a consensus statement on the determination of brain death or death by neurologic criteria (BD/DNC). The document, a result of the World Brain Death Project, surveys the clinical aspects of this determination, such as clinical testing, apnea testing, and the number of examinations required, as well as its social and legal aspects, including documentation, qualifications for making the determination, and religious attitudes toward BD/DNC.

The recommendations are the minimum criteria for BD/DNC, and countries and professional societies may choose to adopt stricter criteria, the authors noted. Seventeen supplements to the consensus statement contain detailed reports on topics the statement examines, including focuses on both adults and children.

“Perhaps the most important points of this project are, first, to show the worldwide acceptance of the concept of BD/DNC and what the minimum requirements are for BD/DNC,” said corresponding author Gene Sung, MD, MPH, director of the neurocritical care and stroke division at the University of Southern California, Los Angeles. Second, “this standard is centered around a clinical determination without the need for other testing.”

The consensus document and supplements were published online Aug. 3 in JAMA.

Comprehensive review

A lack of rigor has led to many differences in the determination of BD/DNC, said Dr. Sung. “Some of the variance that is common are the numbers of exams and examiners that are required and whether ancillary tests are required for determination of BD/DNC. In addition, a lot of guidelines and protocols that are in use are not thorough in detailing how to do the examinations and what to do in different circumstances.”

Professional societies such as the World Federation of Intensive and Critical Care recruited experts in BD/DNC to develop recommendations, which were based on relevant articles that they identified during a literature search. “We wanted to develop a fairly comprehensive document that, along with the 17 supplements, builds a foundation to show how to determine BD/DNC – what the minimum clinical criteria needed are and what to do in special circumstances,” Dr. Sung said.

Major sections of the statement include recommendations for the minimum clinical standards for the determination of BD/DNC in adults and children.

Determination must begin by establishing that the patient has sustained an irreversible brain injury that resulted in the loss of all brain function, according to the authors. Confounders such as pharmacologic paralysis and the effect of CNS depressant medications should be ruled out.

In addition, clinical evaluation must include an assessment for coma and an evaluation for brain stem areflexia. Among other criteria, the pupils should be fixed and nonresponsive to light, the face should not move in response to noxious cranial stimulation, and the gag and cough reflexes should be absent. Apnea testing is recommended to evaluate the responsiveness of respiratory centers in the medulla.

Although the definition of BD/DNC is the same in children as in adults, less evidence is available for the determination of BD/DNC in the very young. The authors thus advised a cautious approach to the evaluation of infants and younger children.

Recommendations vary by age and often require serial examinations, including apnea testing, they noted.

Ancillary testing

The consensus statement also reviews ancillary testing, which the authors recommend be required when the minimum clinical examination, including the apnea test, cannot be completed and when it is in the presence of confounding conditions that cannot be resolved.

The authors recommended digital subtraction angiography, radionuclide studies, and transcranial Doppler ultrasonography as ancillary tests based on blood flow in the brain. However, CT angiography and magnetic resonance angiography not be used.

A lack of guidance makes performing an apnea test in patients receiving extracorporeal membrane oxygenation (ECMO) challenging, according to the authors. Nevertheless, they recommended that the same principles of BD/DNC be applied to adults and children receiving ECMO.

They further recommended a period of preoxygenation before the apnea test, and the document describes in detail the method for administering this test to people receiving ECMO.

Another potentially challenging situation pointed out in the consensus document is the determination of BD/DNC in patients who have been treated with targeted temperature management. Therapeutic hypothermia, particularly if it is preceded or accompanied by sedation, can temporarily impair brain stem reflexes, thus mimicking BD/DNC.

The new document includes a flowchart and step-by-step recommendations as well as suggestions for determining BD/DNC under these circumstances.

Among document limitations acknowledged by the authors is the lack of high-quality data from randomized, controlled trials on which to base their recommendations.

In addition, economic, technological, or personnel limitations may reduce the available options for ancillary testing, they added. Also, the recommendations do not incorporate contributions from patients or social or religious groups, although the authors were mindful of their concerns.

To promote the national and international harmonization of BD/DNC criteria, “medical societies and countries can evaluate their own policies in relation to this document and fix any deficiencies,” Dr. Sung said.

“Many countries do not have any BD/DNC policies and can use the documents from this project to create their own. There may need to be discussions with legal, governmental, religious, and societal leaders to help understand and accept BD/DNC and to help enact policies in different communities,” he added.

Divergent definitions

The determination of death is not simply a scientific question, but also a philosophical, religious, and cultural question, wrote Robert D. Truog, MD, director of the Harvard Center for Bioethics, Boston, and colleagues in an accompanying editorial. Future research should consider cultural differences over these questions.

“Most important is that there be a clear and logical consistency between the definition of death and the tests that are used to diagnose it,” Dr. Truog said.

The concept of whole brain death was advanced as an equivalent to biological death, “such that, when the brain dies, the body literally disintegrates, just as it does after cardiac arrest,” but evidence indicates that this claim is untrue, Dr. Truog said. Current tests also do not diagnose the death of the whole brain.

Another hypothesis is that brain stem death represents the irreversible loss of consciousness and the capacity for spontaneous respiration.

“Instead of focusing on biology, [this definition] focuses on values and is based on the claim that when a person is in a state of irreversible apneic unconsciousness, we may consider them to be dead,” said Dr. Truog. He and his coeditorialists argued that the concept of whole brain death should be replaced with that of brain stem death.

“This report should be a call for our profession, as well as for federal and state lawmakers, to reform our laws so that they are consistent with our diagnostic criteria,” Dr. Truog said.

“The most straightforward way of doing this would be to change U.S. law and adopt the British standard of brain stem death, and then refine our testing to make the diagnosis of irreversible apneic unconsciousness as reliable and safe as possible,” he concluded.

The drafting of the consensus statement was not supported by outside funding. Dr. Sung reported no relevant financial relationships. Dr. Truog reported receiving compensation from Sanofi and Covance for participating in data and safety monitoring boards unrelated to the consensus document.

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

A group of experts representing various international professional societies has drafted a consensus statement on the determination of brain death or death by neurologic criteria (BD/DNC). The document, a result of the World Brain Death Project, surveys the clinical aspects of this determination, such as clinical testing, apnea testing, and the number of examinations required, as well as its social and legal aspects, including documentation, qualifications for making the determination, and religious attitudes toward BD/DNC.

The recommendations are the minimum criteria for BD/DNC, and countries and professional societies may choose to adopt stricter criteria, the authors noted. Seventeen supplements to the consensus statement contain detailed reports on topics the statement examines, including focuses on both adults and children.

“Perhaps the most important points of this project are, first, to show the worldwide acceptance of the concept of BD/DNC and what the minimum requirements are for BD/DNC,” said corresponding author Gene Sung, MD, MPH, director of the neurocritical care and stroke division at the University of Southern California, Los Angeles. Second, “this standard is centered around a clinical determination without the need for other testing.”

The consensus document and supplements were published online Aug. 3 in JAMA.

Comprehensive review

A lack of rigor has led to many differences in the determination of BD/DNC, said Dr. Sung. “Some of the variance that is common are the numbers of exams and examiners that are required and whether ancillary tests are required for determination of BD/DNC. In addition, a lot of guidelines and protocols that are in use are not thorough in detailing how to do the examinations and what to do in different circumstances.”

Professional societies such as the World Federation of Intensive and Critical Care recruited experts in BD/DNC to develop recommendations, which were based on relevant articles that they identified during a literature search. “We wanted to develop a fairly comprehensive document that, along with the 17 supplements, builds a foundation to show how to determine BD/DNC – what the minimum clinical criteria needed are and what to do in special circumstances,” Dr. Sung said.

Major sections of the statement include recommendations for the minimum clinical standards for the determination of BD/DNC in adults and children.

Determination must begin by establishing that the patient has sustained an irreversible brain injury that resulted in the loss of all brain function, according to the authors. Confounders such as pharmacologic paralysis and the effect of CNS depressant medications should be ruled out.

In addition, clinical evaluation must include an assessment for coma and an evaluation for brain stem areflexia. Among other criteria, the pupils should be fixed and nonresponsive to light, the face should not move in response to noxious cranial stimulation, and the gag and cough reflexes should be absent. Apnea testing is recommended to evaluate the responsiveness of respiratory centers in the medulla.

Although the definition of BD/DNC is the same in children as in adults, less evidence is available for the determination of BD/DNC in the very young. The authors thus advised a cautious approach to the evaluation of infants and younger children.

Recommendations vary by age and often require serial examinations, including apnea testing, they noted.

Ancillary testing

The consensus statement also reviews ancillary testing, which the authors recommend be required when the minimum clinical examination, including the apnea test, cannot be completed and when it is in the presence of confounding conditions that cannot be resolved.

The authors recommended digital subtraction angiography, radionuclide studies, and transcranial Doppler ultrasonography as ancillary tests based on blood flow in the brain. However, CT angiography and magnetic resonance angiography not be used.

A lack of guidance makes performing an apnea test in patients receiving extracorporeal membrane oxygenation (ECMO) challenging, according to the authors. Nevertheless, they recommended that the same principles of BD/DNC be applied to adults and children receiving ECMO.

They further recommended a period of preoxygenation before the apnea test, and the document describes in detail the method for administering this test to people receiving ECMO.

Another potentially challenging situation pointed out in the consensus document is the determination of BD/DNC in patients who have been treated with targeted temperature management. Therapeutic hypothermia, particularly if it is preceded or accompanied by sedation, can temporarily impair brain stem reflexes, thus mimicking BD/DNC.

The new document includes a flowchart and step-by-step recommendations as well as suggestions for determining BD/DNC under these circumstances.

Among document limitations acknowledged by the authors is the lack of high-quality data from randomized, controlled trials on which to base their recommendations.

In addition, economic, technological, or personnel limitations may reduce the available options for ancillary testing, they added. Also, the recommendations do not incorporate contributions from patients or social or religious groups, although the authors were mindful of their concerns.

To promote the national and international harmonization of BD/DNC criteria, “medical societies and countries can evaluate their own policies in relation to this document and fix any deficiencies,” Dr. Sung said.

“Many countries do not have any BD/DNC policies and can use the documents from this project to create their own. There may need to be discussions with legal, governmental, religious, and societal leaders to help understand and accept BD/DNC and to help enact policies in different communities,” he added.

Divergent definitions

The determination of death is not simply a scientific question, but also a philosophical, religious, and cultural question, wrote Robert D. Truog, MD, director of the Harvard Center for Bioethics, Boston, and colleagues in an accompanying editorial. Future research should consider cultural differences over these questions.

“Most important is that there be a clear and logical consistency between the definition of death and the tests that are used to diagnose it,” Dr. Truog said.

The concept of whole brain death was advanced as an equivalent to biological death, “such that, when the brain dies, the body literally disintegrates, just as it does after cardiac arrest,” but evidence indicates that this claim is untrue, Dr. Truog said. Current tests also do not diagnose the death of the whole brain.

Another hypothesis is that brain stem death represents the irreversible loss of consciousness and the capacity for spontaneous respiration.

“Instead of focusing on biology, [this definition] focuses on values and is based on the claim that when a person is in a state of irreversible apneic unconsciousness, we may consider them to be dead,” said Dr. Truog. He and his coeditorialists argued that the concept of whole brain death should be replaced with that of brain stem death.

“This report should be a call for our profession, as well as for federal and state lawmakers, to reform our laws so that they are consistent with our diagnostic criteria,” Dr. Truog said.

“The most straightforward way of doing this would be to change U.S. law and adopt the British standard of brain stem death, and then refine our testing to make the diagnosis of irreversible apneic unconsciousness as reliable and safe as possible,” he concluded.

The drafting of the consensus statement was not supported by outside funding. Dr. Sung reported no relevant financial relationships. Dr. Truog reported receiving compensation from Sanofi and Covance for participating in data and safety monitoring boards unrelated to the consensus document.

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

September every year means one thing to students across the country: Summer break is over, and it is time to go back to school. For LGBTQ youth, this can be both a blessing and a curse. Schools can be a refuge from being stuck at home with unsupportive family, but it also can mean returning to hallways full of harassment from other students and/or staff. Groups such as a gender-sexuality alliance (GSA) or a chapter of the Gay, Lesbian, and Straight Education Network (GLSEN) can provide a safe space for these students at school. Pediatricians can play an important role in ensuring that their patients know about access to these resources.

SolStock/E+

Gender-sexuality alliances, or gay-straight alliances as they have been more commonly known, have been around since the late 1980s. The first one was founded at Concord Academy in Massachusetts in 1988 by a straight student who was upset at how her gay classmates were being treated. Today’s GSAs continue this mission to create a welcoming environment for students of all gender identities and sexual orientations to gather, increase awareness on their campus of LGBTQ issues, and make the school environment safer for all students. According to the GSA network, there are over 4,000 active GSAs today in the United States located in 40 states.¹

GLSEN was founded in 1990 initially as a network of gay and lesbian educators who wanted to create safer spaces in schools for LGBTQ students. Over the last 30 years, GLSEN continues to support this mission but has expanded into research and advocacy as well. There are currently 43 chapters of GLSEN in 30 states.² GLSEN sponsors a number of national events throughout the year to raise awareness of LGBTQ issues in schools, including No Name Calling Week and the Day of Silence. Many chapters provide mentoring to local GSAs and volunteering as a mentor can be a great way for pediatricians to become involved in their local schools.

You may be asking yourself, why are GSAs important? According to GLSEN’s 2017 National School Climate Survey, nearly 35% of LGBTQ students missed at least 1 day of school in the previous month because of feeling unsafe, and nearly 57% of students reported hearing homophobic remarks from teachers and staff at their school.³ Around 10% of LGBTQ students reported being physically assaulted based on their sexual orientation and/or gender identity. Those LGBTQ students who experienced discrimination based on their sexual orientation and/or gender identity were more likely to have lower grade point averages and were more likely to be disciplined than those students who had not experienced discrimination.³ The cumulative effect of these negative experiences at school lead a sizable portion of affected students to drop out of school and possibly not pursue postsecondary education. This then leads to decreased job opportunities or career advancement, which could then lead to unemployment or low-wage jobs. Creating safe spaces for education to take place can have a lasting effect on the lives of LGBTQ students.

The 53% of students who reported having a GSA at their school in the National School Climate survey were less likely to report hearing negative comments about LGBTQ students, were less likely to miss school, experienced lower levels of victimization, and reported higher levels of supportive teachers and staff. All of these factors taken together ensure that LGBTQ students are more likely to complete their high school education. Russell B. Toomey, PhD, and colleagues were able to show that LGBTQ students with a perceived effective GSA were two times more likely than those without an effective GSA to attain a college education.⁴ Research also has shown that the presence of a GSA can have a beneficial impact on reducing bullying in general for all students, whether they identify as LGBTQ or not.⁵

What active steps can a pediatrician take to support their LGBTQ students? First, encourage your patients and families to talk to their schools about starting a GSA at their campus. If the families run into trouble from the school, have your social workers help them connect with legal resources, as many court cases have established precedent that public schools cannot have a blanket ban on GSAs solely because they focus on LGBTQ issues. Second, if your patient has a GSA at their school and seems to be struggling with his/her sexual orientation and/or gender identity, encourage that student to consider attending their GSA so that they are able to spend time with other students like themselves. Third, as many schools will be starting virtually this year, you can provide your LGBTQ patients with a list of local online groups that students can participate in virtually if their school’s GSA is not meeting (see my LGBTQ Youth Consult column entitled, “Resources for LGBTQ youth during challenging times” at mdedge.com/pediatrics for a few ideas).* Lastly, be an active advocate in your own local school district for the inclusion of comprehensive nondiscrimination policies and the presence of GSAs for students. These small steps can go a long way to helping your LGBTQ patients thrive and succeed in school.

Dr. Cooper is assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas. Dr. Cooper has no relevant financial disclosures. Email him at [email protected].

References

1. gsanetwork.org/mission-vision-history/.

2. www.glsen.org/find_chapter?field_chapter_state_target_id=All.

3. live-glsen-website.pantheonsite.io/sites/default/files/2019-10/GLSEN-2017-National-School-Climate-Survey-NSCS-Full-Report.pdf.

4. Appl Dev Sci. 2011 Nov 7;15(4):175-85.

5.www.usnews.com/news/articles/2016-08-04/gay-straight-alliances-in-schools-pay-off-for-all-students-study-finds.

*This article was updated 8/17/2020.

September every year means one thing to students across the country: Summer break is over, and it is time to go back to school. For LGBTQ youth, this can be both a blessing and a curse. Schools can be a refuge from being stuck at home with unsupportive family, but it also can mean returning to hallways full of harassment from other students and/or staff. Groups such as a gender-sexuality alliance (GSA) or a chapter of the Gay, Lesbian, and Straight Education Network (GLSEN) can provide a safe space for these students at school. Pediatricians can play an important role in ensuring that their patients know about access to these resources.

SolStock/E+

Gender-sexuality alliances, or gay-straight alliances as they have been more commonly known, have been around since the late 1980s. The first one was founded at Concord Academy in Massachusetts in 1988 by a straight student who was upset at how her gay classmates were being treated. Today’s GSAs continue this mission to create a welcoming environment for students of all gender identities and sexual orientations to gather, increase awareness on their campus of LGBTQ issues, and make the school environment safer for all students. According to the GSA network, there are over 4,000 active GSAs today in the United States located in 40 states.¹

GLSEN was founded in 1990 initially as a network of gay and lesbian educators who wanted to create safer spaces in schools for LGBTQ students. Over the last 30 years, GLSEN continues to support this mission but has expanded into research and advocacy as well. There are currently 43 chapters of GLSEN in 30 states.² GLSEN sponsors a number of national events throughout the year to raise awareness of LGBTQ issues in schools, including No Name Calling Week and the Day of Silence. Many chapters provide mentoring to local GSAs and volunteering as a mentor can be a great way for pediatricians to become involved in their local schools.

You may be asking yourself, why are GSAs important? According to GLSEN’s 2017 National School Climate Survey, nearly 35% of LGBTQ students missed at least 1 day of school in the previous month because of feeling unsafe, and nearly 57% of students reported hearing homophobic remarks from teachers and staff at their school.³ Around 10% of LGBTQ students reported being physically assaulted based on their sexual orientation and/or gender identity. Those LGBTQ students who experienced discrimination based on their sexual orientation and/or gender identity were more likely to have lower grade point averages and were more likely to be disciplined than those students who had not experienced discrimination.³ The cumulative effect of these negative experiences at school lead a sizable portion of affected students to drop out of school and possibly not pursue postsecondary education. This then leads to decreased job opportunities or career advancement, which could then lead to unemployment or low-wage jobs. Creating safe spaces for education to take place can have a lasting effect on the lives of LGBTQ students.

The 53% of students who reported having a GSA at their school in the National School Climate survey were less likely to report hearing negative comments about LGBTQ students, were less likely to miss school, experienced lower levels of victimization, and reported higher levels of supportive teachers and staff. All of these factors taken together ensure that LGBTQ students are more likely to complete their high school education. Russell B. Toomey, PhD, and colleagues were able to show that LGBTQ students with a perceived effective GSA were two times more likely than those without an effective GSA to attain a college education.⁴ Research also has shown that the presence of a GSA can have a beneficial impact on reducing bullying in general for all students, whether they identify as LGBTQ or not.⁵

What active steps can a pediatrician take to support their LGBTQ students? First, encourage your patients and families to talk to their schools about starting a GSA at their campus. If the families run into trouble from the school, have your social workers help them connect with legal resources, as many court cases have established precedent that public schools cannot have a blanket ban on GSAs solely because they focus on LGBTQ issues. Second, if your patient has a GSA at their school and seems to be struggling with his/her sexual orientation and/or gender identity, encourage that student to consider attending their GSA so that they are able to spend time with other students like themselves. Third, as many schools will be starting virtually this year, you can provide your LGBTQ patients with a list of local online groups that students can participate in virtually if their school’s GSA is not meeting (see my LGBTQ Youth Consult column entitled, “Resources for LGBTQ youth during challenging times” at mdedge.com/pediatrics for a few ideas).* Lastly, be an active advocate in your own local school district for the inclusion of comprehensive nondiscrimination policies and the presence of GSAs for students. These small steps can go a long way to helping your LGBTQ patients thrive and succeed in school.

Dr. Cooper is assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas. Dr. Cooper has no relevant financial disclosures. Email him at [email protected].

References

1. gsanetwork.org/mission-vision-history/.

2. www.glsen.org/find_chapter?field_chapter_state_target_id=All.

3. live-glsen-website.pantheonsite.io/sites/default/files/2019-10/GLSEN-2017-National-School-Climate-Survey-NSCS-Full-Report.pdf.

4. Appl Dev Sci. 2011 Nov 7;15(4):175-85.

5.www.usnews.com/news/articles/2016-08-04/gay-straight-alliances-in-schools-pay-off-for-all-students-study-finds.

*This article was updated 8/17/2020.

September every year means one thing to students across the country: Summer break is over, and it is time to go back to school. For LGBTQ youth, this can be both a blessing and a curse. Schools can be a refuge from being stuck at home with unsupportive family, but it also can mean returning to hallways full of harassment from other students and/or staff. Groups such as a gender-sexuality alliance (GSA) or a chapter of the Gay, Lesbian, and Straight Education Network (GLSEN) can provide a safe space for these students at school. Pediatricians can play an important role in ensuring that their patients know about access to these resources.

SolStock/E+

Gender-sexuality alliances, or gay-straight alliances as they have been more commonly known, have been around since the late 1980s. The first one was founded at Concord Academy in Massachusetts in 1988 by a straight student who was upset at how her gay classmates were being treated. Today’s GSAs continue this mission to create a welcoming environment for students of all gender identities and sexual orientations to gather, increase awareness on their campus of LGBTQ issues, and make the school environment safer for all students. According to the GSA network, there are over 4,000 active GSAs today in the United States located in 40 states.¹

GLSEN was founded in 1990 initially as a network of gay and lesbian educators who wanted to create safer spaces in schools for LGBTQ students. Over the last 30 years, GLSEN continues to support this mission but has expanded into research and advocacy as well. There are currently 43 chapters of GLSEN in 30 states.² GLSEN sponsors a number of national events throughout the year to raise awareness of LGBTQ issues in schools, including No Name Calling Week and the Day of Silence. Many chapters provide mentoring to local GSAs and volunteering as a mentor can be a great way for pediatricians to become involved in their local schools.

You may be asking yourself, why are GSAs important? According to GLSEN’s 2017 National School Climate Survey, nearly 35% of LGBTQ students missed at least 1 day of school in the previous month because of feeling unsafe, and nearly 57% of students reported hearing homophobic remarks from teachers and staff at their school.³ Around 10% of LGBTQ students reported being physically assaulted based on their sexual orientation and/or gender identity. Those LGBTQ students who experienced discrimination based on their sexual orientation and/or gender identity were more likely to have lower grade point averages and were more likely to be disciplined than those students who had not experienced discrimination.³ The cumulative effect of these negative experiences at school lead a sizable portion of affected students to drop out of school and possibly not pursue postsecondary education. This then leads to decreased job opportunities or career advancement, which could then lead to unemployment or low-wage jobs. Creating safe spaces for education to take place can have a lasting effect on the lives of LGBTQ students.

The 53% of students who reported having a GSA at their school in the National School Climate survey were less likely to report hearing negative comments about LGBTQ students, were less likely to miss school, experienced lower levels of victimization, and reported higher levels of supportive teachers and staff. All of these factors taken together ensure that LGBTQ students are more likely to complete their high school education. Russell B. Toomey, PhD, and colleagues were able to show that LGBTQ students with a perceived effective GSA were two times more likely than those without an effective GSA to attain a college education.⁴ Research also has shown that the presence of a GSA can have a beneficial impact on reducing bullying in general for all students, whether they identify as LGBTQ or not.⁵

What active steps can a pediatrician take to support their LGBTQ students? First, encourage your patients and families to talk to their schools about starting a GSA at their campus. If the families run into trouble from the school, have your social workers help them connect with legal resources, as many court cases have established precedent that public schools cannot have a blanket ban on GSAs solely because they focus on LGBTQ issues. Second, if your patient has a GSA at their school and seems to be struggling with his/her sexual orientation and/or gender identity, encourage that student to consider attending their GSA so that they are able to spend time with other students like themselves. Third, as many schools will be starting virtually this year, you can provide your LGBTQ patients with a list of local online groups that students can participate in virtually if their school’s GSA is not meeting (see my LGBTQ Youth Consult column entitled, “Resources for LGBTQ youth during challenging times” at mdedge.com/pediatrics for a few ideas).* Lastly, be an active advocate in your own local school district for the inclusion of comprehensive nondiscrimination policies and the presence of GSAs for students. These small steps can go a long way to helping your LGBTQ patients thrive and succeed in school.

Dr. Cooper is assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas. Dr. Cooper has no relevant financial disclosures. Email him at [email protected].

References

1. gsanetwork.org/mission-vision-history/.

2. www.glsen.org/find_chapter?field_chapter_state_target_id=All.

3. live-glsen-website.pantheonsite.io/sites/default/files/2019-10/GLSEN-2017-National-School-Climate-Survey-NSCS-Full-Report.pdf.

4. Appl Dev Sci. 2011 Nov 7;15(4):175-85.

5.www.usnews.com/news/articles/2016-08-04/gay-straight-alliances-in-schools-pay-off-for-all-students-study-finds.

*This article was updated 8/17/2020.

For some patients, a bout of COVID-19 may not be over after hospital discharge, acute symptoms subside, or a couple of tests for SARS-CoV-2 come back negative. Those who have reached these milestones of conquering the disease may find that their recovery journey has only begun. Debilitating symptoms such as fatigue, headache, and dyspnea may linger for weeks or longer. Patients with persistent symptoms, often referred to as “long haulers” in reference to the duration of their recovery, are looking for answers about their condition and when their COVID-19 illness will finally resolve.

Long-haul patients organize

What started as an accumulation of anecdotal evidence in social media, blogs, and the mainstream press about slow recovery and long-lasting symptoms of COVID-19 is now the focus of clinical trials in the population of recovering patients. Projects such as the COVID Symptom Study, initiated by the Massachusetts General Hospital, Boston; the Harvard School of Public Health, Boston; King’s College London; and Stanford (Calif.) University, are collecting data on symptoms from millions of patients and will eventually contribute to a better understanding of prolonged recovery.

Patients looking for answers have created groups on social media such as Facebook to exchange information about their experiences (e.g., Survivor Corps, COVID-19 Support Group, COVID-19 Recovered Survivors). Recovering patients have created patient-led research organizations (Body Politic COVID-19 Support Group) to explore persistent symptoms and begin to create data for research.
 

Some data on lingering symptoms

A small study of 143 previously hospitalized, recovering patients in Italy found that 87.4% of the cohort had at least one persistent symptom 2 months or longer after initial onset and at more than a month after discharge. In this sample, only 5% had been intubated. (JAMA 2020 Jul 9. doi: 10.1001/jama.2020.12603).

One study found that even patients who have had relatively mild symptoms and were not hospitalized can have persistent symptoms. The Centers for Disease Control and Prevention conducted a survey of adults who tested positive for the positive reverse transcription–polymerase chain reaction test for SARS-CoV-2 and found that, among the 292 respondents, 35% were still feeling the impact of the disease 2-3 weeks after testing. Fatigue (71%), cough (61%), and headache (61%) were the most commonly reported symptoms. The survey found that delayed recovery was evident in nearly a quarter of 18- to 34-year-olds and in a third of 35- to 49-year-olds who were not sick enough to require hospitalization (MMWR. 2020 Jul 24. doi: 10.15585/mmwr.mm6930e1).

Sachin Gupta, MD, FCCP, ATSF, a pulmonologist and member of the CHEST Physician editorial advisory board, has treated patients with COVID-19 and shared some of his thoughts on the problem of prolonged symptoms of COVID-19.
 

Q: Should clinicians expect to see COVID-19 patients who have symptoms persisting weeks after they are diagnosed?

Dr. Gupta: I think clinicians, especially in primary care, are already seeing many patients with lingering symptoms, both respiratory and nonrespiratory related, and debility. A few patients here in the San Francisco Bay Area that I have spoken with 4-6 weeks out from their acute illness have complained of persisting, though improving, fatigue and cough. Early studies are confirming this as a topical issue. There may be other long-lasting sequelae of COVID-19 beyond the common mild lingering symptoms. It will also be important to consider (and get more data on) to what degree asymptomatic patients develop some degree of mild inflammatory and subsequent fibrotic changes in organs like the lungs and heart

Q: How does the recovery phase of COVID-19 compare with recovery from severe influenza or ARDS?

Dr. Gupta: Most prior influenza and acute respiratory distress syndrome (ARDS) studies have provided initial follow-up at 3 months and beyond, so technically speaking, it is a little difficult to compare the symptomatology patterns in the JAMA study of 2 months on follow-up. Nevertheless, the key takeaway is that, even though few patients in the study had ARDS requiring intubation (severe disease), many patients with milder disease had significant lingering symptoms (55% with three or more symptoms) at 2 months.

This fits logically with the premise, which we have some limited data on with ARDS (N Engl J Med. 2003;348:683-93. doi: 10.1056/NEJMoa022450) and severe influenza infection survivors (Nature Sci Rep. 2017;7:17275. doi: 10.1038/s41598-017-17497-6) that varying degrees of the inflammation cascade triggered by certain viruses can lead to changes in important patient-reported outcomes, and objective measures such as pulmonary function over the long term.

Q: What can you do for patients with lingering symptoms of COVID-19 or what can you tell them about their symptoms?

Dr. Gupta: For many patients, there is fear, given the novel nature of the virus/pandemic, that their symptoms may persist long term. Acknowledgment of their symptoms is validating and important for us to recognize as we learn more about the virus. As we are finding, many patients are going online to find answers, after sometimes feeling rushed or dismissed initially in the clinical setting.

In my experience, the bar is fairly high for most patients to reach out to their physicians with complaints of lingering symptoms after acute infection. For the ones who do reach out, they tend to have either a greater constellation of symptoms or higher severity of one or two key symptoms. After assessing and, when appropriate, ruling out secondary infections or newly developed conditions, I shift toward symptom management. I encourage such patients to build up slowly. I suggest they work first on their activities of daily living (bathing, grooming), then their instrumental activities of daily living (cooking, cleaning, checking the mail), and then to engage, based on their tolerance of symptoms, to light purposeful exercise. There are many online resources for at-home exercise activities that I recommend to patients who are more debilitated; some larger centers are beginning to offer some forms of telepulmonary rehab.

Based on what we know about other causes of viral pneumonitis and ARDS, I ask such symptomatic patients to expect a slow, gradual, and in most cases a complete recovery, and depending on the individual case, I recommend pulmonary function tests and imaging that may be helpful to track that progress.

I remind myself, and patients, that our understanding may change as we learn more over time. Checking in at set intervals, even if not in person but through a phone call, can go a long way in a setting where we do not have a specific therapy, other than gradual exercise training, to help these patients recover faster. Reassurance and encouragement are vital for patients who are struggling with the lingering burden of disease and who may find it difficult to return to work or function as usual at home. The final point is to be mindful of our patient’s mental health and, where our reassurance is not enough, to consider appropriate mental health referrals.

Q: Can you handle this kind of problem with telemedicine or which patients with lingering symptoms need to come into the office – or failing that, the ED?

Dr. Gupta: Telemedicine in the outpatient setting provides a helpful tool to assess and manage patients, in my experience, with limited and straightforward complaints. Its scope is limited diagnostically (assessing symptoms and signs) as is its reach (ability to connect with elderly, disabled, or patients without/limited telemedicine access). In many instances, telemedicine limits our ability to connect with patients emotionally and build trust. Many patients who have gone through the acute illness that we see in pulmonary clinic on follow-up are older in age, and for many, video visits are not a practical solution. Telemedicine visits can sometimes present challenges for me as well in terms of thoroughly conveying lifestyle and symptom management strategies. Health literacy is typically easier to gauge and address in person.

For patients with any degree of enduring dyspnea, more so in the acute phase, I recommend home pulse oximetry for monitoring their oxygen saturation if it is financially and technically feasible for them to obtain one. Sending a patient to the ED is an option of last resort, but one that is necessary in some cases. I expect patients with lingering symptoms to tell me that symptoms may be persisting, hopefully gradually improving, and not getting worse. If post–COVID-19 symptoms such as fever, dyspnea, fatigue, or lightheadedness are new or worsening, particularly rapidly, the safest and best option I advise patients is to go to the ED for further assessment and testing. Postviral bacterial pneumonia is something we should consider, and there is some potential for aspergillosis as well.

Q: Do you have any concerns about patients with asthma, chronic obstructive pulmonary disease, or other pulmonary issues having lingering symptoms that may mask exacerbations or may cause exacerbation of their disease?

Dr. Gupta: So far, patients with chronic lung conditions do not appear to have not been disproportionately affected by the pandemic in terms of absolute numbers or percentage wise compared to the general public. I think that sheltering in place has been readily followed by many of these patients, and in addition, I assume better adherence to their maintenance therapies has likely helped. The very few cases of patients with underlying chronic obstructive pulmonary disease and interstitial lung disease that I have seen have fared very poorly when they were diagnosed with COVID-19 in the hospital. There are emerging data about short-term outcomes from severe COVID-19 infection in patients with interstitial lung disease in Europe (medRxiv. 2020 Jul 17. doi: 10.1101/2020.07.15.20152967), and from physicians treating pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (Ann Am Thorac Soc. 2020 Jul 29. doi: 10.1513/AnnalsATS.202005-521OC). But so far, little has been published on the outcomes of mild disease in these patients with chronic lung disease.

Q: It’s still early days to know the significance of lingering symptoms. But at what point do you begin to consider the possibility of some kind of relapse? And what is your next move if the symptoms get worse?

Dr. Gupta: COVID-19 recurrence, whether because of reinfection or relapse, is a potential concern but not one that is very commonly seen so far in my purview. Generally, symptoms of post–COVID-19 infection that are lingering trend toward getting better, even if slowly. If post–COVID-19 infection symptoms are progressing (particularly if rapidly), that would be a strong indication to evaluate that patient in the ED (less likely in clinic), reswab them for SARS-CoV-2, and obtain further testing such as blood work and imaging. A significant challenge from a research perspective will be determining if coinfection with another virus is playing a role as we move closer to the fall season.

[email protected]

For some patients, a bout of COVID-19 may not be over after hospital discharge, acute symptoms subside, or a couple of tests for SARS-CoV-2 come back negative. Those who have reached these milestones of conquering the disease may find that their recovery journey has only begun. Debilitating symptoms such as fatigue, headache, and dyspnea may linger for weeks or longer. Patients with persistent symptoms, often referred to as “long haulers” in reference to the duration of their recovery, are looking for answers about their condition and when their COVID-19 illness will finally resolve.

Long-haul patients organize

What started as an accumulation of anecdotal evidence in social media, blogs, and the mainstream press about slow recovery and long-lasting symptoms of COVID-19 is now the focus of clinical trials in the population of recovering patients. Projects such as the COVID Symptom Study, initiated by the Massachusetts General Hospital, Boston; the Harvard School of Public Health, Boston; King’s College London; and Stanford (Calif.) University, are collecting data on symptoms from millions of patients and will eventually contribute to a better understanding of prolonged recovery.

Patients looking for answers have created groups on social media such as Facebook to exchange information about their experiences (e.g., Survivor Corps, COVID-19 Support Group, COVID-19 Recovered Survivors). Recovering patients have created patient-led research organizations (Body Politic COVID-19 Support Group) to explore persistent symptoms and begin to create data for research.
 

Some data on lingering symptoms

A small study of 143 previously hospitalized, recovering patients in Italy found that 87.4% of the cohort had at least one persistent symptom 2 months or longer after initial onset and at more than a month after discharge. In this sample, only 5% had been intubated. (JAMA 2020 Jul 9. doi: 10.1001/jama.2020.12603).

One study found that even patients who have had relatively mild symptoms and were not hospitalized can have persistent symptoms. The Centers for Disease Control and Prevention conducted a survey of adults who tested positive for the positive reverse transcription–polymerase chain reaction test for SARS-CoV-2 and found that, among the 292 respondents, 35% were still feeling the impact of the disease 2-3 weeks after testing. Fatigue (71%), cough (61%), and headache (61%) were the most commonly reported symptoms. The survey found that delayed recovery was evident in nearly a quarter of 18- to 34-year-olds and in a third of 35- to 49-year-olds who were not sick enough to require hospitalization (MMWR. 2020 Jul 24. doi: 10.15585/mmwr.mm6930e1).

Sachin Gupta, MD, FCCP, ATSF, a pulmonologist and member of the CHEST Physician editorial advisory board, has treated patients with COVID-19 and shared some of his thoughts on the problem of prolonged symptoms of COVID-19.
 

Q: Should clinicians expect to see COVID-19 patients who have symptoms persisting weeks after they are diagnosed?

Dr. Gupta: I think clinicians, especially in primary care, are already seeing many patients with lingering symptoms, both respiratory and nonrespiratory related, and debility. A few patients here in the San Francisco Bay Area that I have spoken with 4-6 weeks out from their acute illness have complained of persisting, though improving, fatigue and cough. Early studies are confirming this as a topical issue. There may be other long-lasting sequelae of COVID-19 beyond the common mild lingering symptoms. It will also be important to consider (and get more data on) to what degree asymptomatic patients develop some degree of mild inflammatory and subsequent fibrotic changes in organs like the lungs and heart

Q: How does the recovery phase of COVID-19 compare with recovery from severe influenza or ARDS?

Dr. Gupta: Most prior influenza and acute respiratory distress syndrome (ARDS) studies have provided initial follow-up at 3 months and beyond, so technically speaking, it is a little difficult to compare the symptomatology patterns in the JAMA study of 2 months on follow-up. Nevertheless, the key takeaway is that, even though few patients in the study had ARDS requiring intubation (severe disease), many patients with milder disease had significant lingering symptoms (55% with three or more symptoms) at 2 months.

This fits logically with the premise, which we have some limited data on with ARDS (N Engl J Med. 2003;348:683-93. doi: 10.1056/NEJMoa022450) and severe influenza infection survivors (Nature Sci Rep. 2017;7:17275. doi: 10.1038/s41598-017-17497-6) that varying degrees of the inflammation cascade triggered by certain viruses can lead to changes in important patient-reported outcomes, and objective measures such as pulmonary function over the long term.

Q: What can you do for patients with lingering symptoms of COVID-19 or what can you tell them about their symptoms?

Dr. Gupta: For many patients, there is fear, given the novel nature of the virus/pandemic, that their symptoms may persist long term. Acknowledgment of their symptoms is validating and important for us to recognize as we learn more about the virus. As we are finding, many patients are going online to find answers, after sometimes feeling rushed or dismissed initially in the clinical setting.

In my experience, the bar is fairly high for most patients to reach out to their physicians with complaints of lingering symptoms after acute infection. For the ones who do reach out, they tend to have either a greater constellation of symptoms or higher severity of one or two key symptoms. After assessing and, when appropriate, ruling out secondary infections or newly developed conditions, I shift toward symptom management. I encourage such patients to build up slowly. I suggest they work first on their activities of daily living (bathing, grooming), then their instrumental activities of daily living (cooking, cleaning, checking the mail), and then to engage, based on their tolerance of symptoms, to light purposeful exercise. There are many online resources for at-home exercise activities that I recommend to patients who are more debilitated; some larger centers are beginning to offer some forms of telepulmonary rehab.

Based on what we know about other causes of viral pneumonitis and ARDS, I ask such symptomatic patients to expect a slow, gradual, and in most cases a complete recovery, and depending on the individual case, I recommend pulmonary function tests and imaging that may be helpful to track that progress.

I remind myself, and patients, that our understanding may change as we learn more over time. Checking in at set intervals, even if not in person but through a phone call, can go a long way in a setting where we do not have a specific therapy, other than gradual exercise training, to help these patients recover faster. Reassurance and encouragement are vital for patients who are struggling with the lingering burden of disease and who may find it difficult to return to work or function as usual at home. The final point is to be mindful of our patient’s mental health and, where our reassurance is not enough, to consider appropriate mental health referrals.

Q: Can you handle this kind of problem with telemedicine or which patients with lingering symptoms need to come into the office – or failing that, the ED?

Dr. Gupta: Telemedicine in the outpatient setting provides a helpful tool to assess and manage patients, in my experience, with limited and straightforward complaints. Its scope is limited diagnostically (assessing symptoms and signs) as is its reach (ability to connect with elderly, disabled, or patients without/limited telemedicine access). In many instances, telemedicine limits our ability to connect with patients emotionally and build trust. Many patients who have gone through the acute illness that we see in pulmonary clinic on follow-up are older in age, and for many, video visits are not a practical solution. Telemedicine visits can sometimes present challenges for me as well in terms of thoroughly conveying lifestyle and symptom management strategies. Health literacy is typically easier to gauge and address in person.

For patients with any degree of enduring dyspnea, more so in the acute phase, I recommend home pulse oximetry for monitoring their oxygen saturation if it is financially and technically feasible for them to obtain one. Sending a patient to the ED is an option of last resort, but one that is necessary in some cases. I expect patients with lingering symptoms to tell me that symptoms may be persisting, hopefully gradually improving, and not getting worse. If post–COVID-19 symptoms such as fever, dyspnea, fatigue, or lightheadedness are new or worsening, particularly rapidly, the safest and best option I advise patients is to go to the ED for further assessment and testing. Postviral bacterial pneumonia is something we should consider, and there is some potential for aspergillosis as well.

Q: Do you have any concerns about patients with asthma, chronic obstructive pulmonary disease, or other pulmonary issues having lingering symptoms that may mask exacerbations or may cause exacerbation of their disease?

Dr. Gupta: So far, patients with chronic lung conditions do not appear to have not been disproportionately affected by the pandemic in terms of absolute numbers or percentage wise compared to the general public. I think that sheltering in place has been readily followed by many of these patients, and in addition, I assume better adherence to their maintenance therapies has likely helped. The very few cases of patients with underlying chronic obstructive pulmonary disease and interstitial lung disease that I have seen have fared very poorly when they were diagnosed with COVID-19 in the hospital. There are emerging data about short-term outcomes from severe COVID-19 infection in patients with interstitial lung disease in Europe (medRxiv. 2020 Jul 17. doi: 10.1101/2020.07.15.20152967), and from physicians treating pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (Ann Am Thorac Soc. 2020 Jul 29. doi: 10.1513/AnnalsATS.202005-521OC). But so far, little has been published on the outcomes of mild disease in these patients with chronic lung disease.

Q: It’s still early days to know the significance of lingering symptoms. But at what point do you begin to consider the possibility of some kind of relapse? And what is your next move if the symptoms get worse?

Dr. Gupta: COVID-19 recurrence, whether because of reinfection or relapse, is a potential concern but not one that is very commonly seen so far in my purview. Generally, symptoms of post–COVID-19 infection that are lingering trend toward getting better, even if slowly. If post–COVID-19 infection symptoms are progressing (particularly if rapidly), that would be a strong indication to evaluate that patient in the ED (less likely in clinic), reswab them for SARS-CoV-2, and obtain further testing such as blood work and imaging. A significant challenge from a research perspective will be determining if coinfection with another virus is playing a role as we move closer to the fall season.

[email protected]

For some patients, a bout of COVID-19 may not be over after hospital discharge, acute symptoms subside, or a couple of tests for SARS-CoV-2 come back negative. Those who have reached these milestones of conquering the disease may find that their recovery journey has only begun. Debilitating symptoms such as fatigue, headache, and dyspnea may linger for weeks or longer. Patients with persistent symptoms, often referred to as “long haulers” in reference to the duration of their recovery, are looking for answers about their condition and when their COVID-19 illness will finally resolve.

Long-haul patients organize

What started as an accumulation of anecdotal evidence in social media, blogs, and the mainstream press about slow recovery and long-lasting symptoms of COVID-19 is now the focus of clinical trials in the population of recovering patients. Projects such as the COVID Symptom Study, initiated by the Massachusetts General Hospital, Boston; the Harvard School of Public Health, Boston; King’s College London; and Stanford (Calif.) University, are collecting data on symptoms from millions of patients and will eventually contribute to a better understanding of prolonged recovery.

Patients looking for answers have created groups on social media such as Facebook to exchange information about their experiences (e.g., Survivor Corps, COVID-19 Support Group, COVID-19 Recovered Survivors). Recovering patients have created patient-led research organizations (Body Politic COVID-19 Support Group) to explore persistent symptoms and begin to create data for research.
 

Some data on lingering symptoms

A small study of 143 previously hospitalized, recovering patients in Italy found that 87.4% of the cohort had at least one persistent symptom 2 months or longer after initial onset and at more than a month after discharge. In this sample, only 5% had been intubated. (JAMA 2020 Jul 9. doi: 10.1001/jama.2020.12603).

One study found that even patients who have had relatively mild symptoms and were not hospitalized can have persistent symptoms. The Centers for Disease Control and Prevention conducted a survey of adults who tested positive for the positive reverse transcription–polymerase chain reaction test for SARS-CoV-2 and found that, among the 292 respondents, 35% were still feeling the impact of the disease 2-3 weeks after testing. Fatigue (71%), cough (61%), and headache (61%) were the most commonly reported symptoms. The survey found that delayed recovery was evident in nearly a quarter of 18- to 34-year-olds and in a third of 35- to 49-year-olds who were not sick enough to require hospitalization (MMWR. 2020 Jul 24. doi: 10.15585/mmwr.mm6930e1).

Sachin Gupta, MD, FCCP, ATSF, a pulmonologist and member of the CHEST Physician editorial advisory board, has treated patients with COVID-19 and shared some of his thoughts on the problem of prolonged symptoms of COVID-19.
 

Q: Should clinicians expect to see COVID-19 patients who have symptoms persisting weeks after they are diagnosed?

Dr. Gupta: I think clinicians, especially in primary care, are already seeing many patients with lingering symptoms, both respiratory and nonrespiratory related, and debility. A few patients here in the San Francisco Bay Area that I have spoken with 4-6 weeks out from their acute illness have complained of persisting, though improving, fatigue and cough. Early studies are confirming this as a topical issue. There may be other long-lasting sequelae of COVID-19 beyond the common mild lingering symptoms. It will also be important to consider (and get more data on) to what degree asymptomatic patients develop some degree of mild inflammatory and subsequent fibrotic changes in organs like the lungs and heart

Q: How does the recovery phase of COVID-19 compare with recovery from severe influenza or ARDS?

Dr. Gupta: Most prior influenza and acute respiratory distress syndrome (ARDS) studies have provided initial follow-up at 3 months and beyond, so technically speaking, it is a little difficult to compare the symptomatology patterns in the JAMA study of 2 months on follow-up. Nevertheless, the key takeaway is that, even though few patients in the study had ARDS requiring intubation (severe disease), many patients with milder disease had significant lingering symptoms (55% with three or more symptoms) at 2 months.

This fits logically with the premise, which we have some limited data on with ARDS (N Engl J Med. 2003;348:683-93. doi: 10.1056/NEJMoa022450) and severe influenza infection survivors (Nature Sci Rep. 2017;7:17275. doi: 10.1038/s41598-017-17497-6) that varying degrees of the inflammation cascade triggered by certain viruses can lead to changes in important patient-reported outcomes, and objective measures such as pulmonary function over the long term.

Q: What can you do for patients with lingering symptoms of COVID-19 or what can you tell them about their symptoms?

Dr. Gupta: For many patients, there is fear, given the novel nature of the virus/pandemic, that their symptoms may persist long term. Acknowledgment of their symptoms is validating and important for us to recognize as we learn more about the virus. As we are finding, many patients are going online to find answers, after sometimes feeling rushed or dismissed initially in the clinical setting.

In my experience, the bar is fairly high for most patients to reach out to their physicians with complaints of lingering symptoms after acute infection. For the ones who do reach out, they tend to have either a greater constellation of symptoms or higher severity of one or two key symptoms. After assessing and, when appropriate, ruling out secondary infections or newly developed conditions, I shift toward symptom management. I encourage such patients to build up slowly. I suggest they work first on their activities of daily living (bathing, grooming), then their instrumental activities of daily living (cooking, cleaning, checking the mail), and then to engage, based on their tolerance of symptoms, to light purposeful exercise. There are many online resources for at-home exercise activities that I recommend to patients who are more debilitated; some larger centers are beginning to offer some forms of telepulmonary rehab.

Based on what we know about other causes of viral pneumonitis and ARDS, I ask such symptomatic patients to expect a slow, gradual, and in most cases a complete recovery, and depending on the individual case, I recommend pulmonary function tests and imaging that may be helpful to track that progress.

I remind myself, and patients, that our understanding may change as we learn more over time. Checking in at set intervals, even if not in person but through a phone call, can go a long way in a setting where we do not have a specific therapy, other than gradual exercise training, to help these patients recover faster. Reassurance and encouragement are vital for patients who are struggling with the lingering burden of disease and who may find it difficult to return to work or function as usual at home. The final point is to be mindful of our patient’s mental health and, where our reassurance is not enough, to consider appropriate mental health referrals.

Q: Can you handle this kind of problem with telemedicine or which patients with lingering symptoms need to come into the office – or failing that, the ED?

Dr. Gupta: Telemedicine in the outpatient setting provides a helpful tool to assess and manage patients, in my experience, with limited and straightforward complaints. Its scope is limited diagnostically (assessing symptoms and signs) as is its reach (ability to connect with elderly, disabled, or patients without/limited telemedicine access). In many instances, telemedicine limits our ability to connect with patients emotionally and build trust. Many patients who have gone through the acute illness that we see in pulmonary clinic on follow-up are older in age, and for many, video visits are not a practical solution. Telemedicine visits can sometimes present challenges for me as well in terms of thoroughly conveying lifestyle and symptom management strategies. Health literacy is typically easier to gauge and address in person.

For patients with any degree of enduring dyspnea, more so in the acute phase, I recommend home pulse oximetry for monitoring their oxygen saturation if it is financially and technically feasible for them to obtain one. Sending a patient to the ED is an option of last resort, but one that is necessary in some cases. I expect patients with lingering symptoms to tell me that symptoms may be persisting, hopefully gradually improving, and not getting worse. If post–COVID-19 symptoms such as fever, dyspnea, fatigue, or lightheadedness are new or worsening, particularly rapidly, the safest and best option I advise patients is to go to the ED for further assessment and testing. Postviral bacterial pneumonia is something we should consider, and there is some potential for aspergillosis as well.

Q: Do you have any concerns about patients with asthma, chronic obstructive pulmonary disease, or other pulmonary issues having lingering symptoms that may mask exacerbations or may cause exacerbation of their disease?

Dr. Gupta: So far, patients with chronic lung conditions do not appear to have not been disproportionately affected by the pandemic in terms of absolute numbers or percentage wise compared to the general public. I think that sheltering in place has been readily followed by many of these patients, and in addition, I assume better adherence to their maintenance therapies has likely helped. The very few cases of patients with underlying chronic obstructive pulmonary disease and interstitial lung disease that I have seen have fared very poorly when they were diagnosed with COVID-19 in the hospital. There are emerging data about short-term outcomes from severe COVID-19 infection in patients with interstitial lung disease in Europe (medRxiv. 2020 Jul 17. doi: 10.1101/2020.07.15.20152967), and from physicians treating pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (Ann Am Thorac Soc. 2020 Jul 29. doi: 10.1513/AnnalsATS.202005-521OC). But so far, little has been published on the outcomes of mild disease in these patients with chronic lung disease.

Q: It’s still early days to know the significance of lingering symptoms. But at what point do you begin to consider the possibility of some kind of relapse? And what is your next move if the symptoms get worse?

Dr. Gupta: COVID-19 recurrence, whether because of reinfection or relapse, is a potential concern but not one that is very commonly seen so far in my purview. Generally, symptoms of post–COVID-19 infection that are lingering trend toward getting better, even if slowly. If post–COVID-19 infection symptoms are progressing (particularly if rapidly), that would be a strong indication to evaluate that patient in the ED (less likely in clinic), reswab them for SARS-CoV-2, and obtain further testing such as blood work and imaging. A significant challenge from a research perspective will be determining if coinfection with another virus is playing a role as we move closer to the fall season.

[email protected]

Sleep problems in children from birth to middle childhood may lead to decreased emotional well-being and quality of life by the time a child is 10-11 years old, a recent longitudinal study has found.

The effects of these impairments increased over time and included internalizing and externalizing concerns, self-control, and quality of life, but did not appear to significantly affect cognitive or academic skills, according to Ariel A. Williamson, PhD, DBSM, of Children’s Hospital of Philadelphia, and colleagues. While children with consistent sleep problems experienced the worse outcomes, mild sleep problems also were associated with impairment, the researchers said.

“The range of impairments across academic and psychosocial domains in middle childhood indicate that it is important to screen for sleep problems consistently over the course of a child’s development, especially to target children who experience persistent sleep problems over time,” said Dr. Williamson in a press release.

The researchers examined data from 5,107 children in the Longitudinal Study of Australian Children – Birth Cohort, where sleep problems and well-being outcomes were measured at multiple time points. Behaviors such as difficulty getting off to sleep at night, not happy to sleep alone, and waking during the night were defined as sleep problems. The investigators found five main domains of sleep issues: children who had persistent sleep problems through middle childhood (7.7%), limited sleep problems as an infant or during preschool (9.0%), mild sleep problems over time (14.4%), increased sleep problems during middle childhood (17.0%), and a group that did not experience sleep problems (51.9%).

Caregivers reported sleep issues in the cohort, while well-being outcomes were reported by caregivers and teachers, and tasks were completed by the children at 10-11 years of age. Dr. Williamson and colleagues examined well-being in terms of emotional and behavioral functioning, health-related quality of life, cognitive skills, and academic achievement.
 

Different reports from teacher and caregivers

Teacher and caregivers reported different effects in children with persistent sleep problems. Teachers reported moderate internalizing (effect size, –0.65; 95% confidence interval [CI],–0.87 to –0.43; P < .001) and externalizing concerns (ES, –0.40; 95% CI, –0.58 to –0.21; P less than .001), compared with children who did not have sleep problems, whereas caregivers reported large internalizing (ES, –0.75; 95% CI, –0.92 to –0.57; P less than .001) and externalizing concerns (ES, –0.70; 95% CI, –0.86 to –0.53; P < .001). Children with persistent sleep problems had moderate impairment of self-control as reported by caregivers, compared with children with no sleep problems (ES, –0.37; 95% CI, –0.52 to –0.21; P < .001). Psychosocial and health-related quality of life reported by caregivers were worse in children with persistent sleep problems, compared with children who did not have sleep problems (ES range, –0.78 to –0.90; 95% CI, –1.06 to –0.56; P < .001).

For children who exhibited increased sleep problems in middle childhood, caregivers (ES for both, –0.61; 95% CI, –0.76 to –0.46; P < .001) and teachers (ES range, –0.29 to –0.39; 95% CI, –0.53 to –0.15; P < .001) reported greater rates of internalizing and externalizing symptoms, compared with children who had no sleep issues.

Small impairments in internalizing internal or externalizing symptoms were seen in children who had limited sleep problems as an infant or in preschool (ES, –0.12; 95% CI, –0.23 to –0.01; P < .05) as reported by teachers, and in children with mild sleep problems over time (ES, –0.19; 95% CI, –0.30 to –0.08; P < .001) as reported by caregivers. There were no significant impairments in self-control for children in either the infant or preschool impairment group or in the group of children with mild sleep problems.

Across all groups, sleep problems did not significantly impair nonverbal reasoning, and most areas of academic competencies were not significantly impaired among groups except in language and literacy, and mathematical thinking for children with persistent sleep problems (ES, –0.41 for both; 95% CI, –0.60 to –0.23; P < .001). Children with increased sleep problems during middle childhood “had few academic and cognitive impairments,” and academic impairments among children with mild sleep problems were not significant.


 

Expert opinion

Brandon M. Seay MD, FAAP, pediatric pulmonologist and sleep specialist at Children’s Healthcare of Atlanta, said in an interview that the study is one of the first to offer longitudinal data for impairment in children with sleep problems. He said the paper emphasizes the need for recognizing when children are demonstrating sleep problems. “It just shows that problems that aren’t dealt with earlier on definitely have bigger impacts on sleep as you go through life,” he said.

Although primary care physicians and pediatricians should be already asking questions about sleep through anticipatory guidance, he said, intervening earlier for sleep problems is important. He noted children who exhibit sleep problems over time are more likely to have issues in handling their emotions and eventually may develop cognitive issues. “[W]e know that if these problems continue to go through, this paper’s showing us that they have worse effects down the road,” he said.
 

Impact of the COVID-19 crisis

These problems may also be worsened by the COVID-19 pandemic. Dr. Seay noted that with many parents working from home, sleep schedules can be affected and parents may also be co-sleeping with their children, which can cause chronic insomnia and early waking. To help address sleep issues, especially ones that may have arisen during COVID-19, parents should make sure their children show up for primary care visits to report problems, and clinicians should make a sleep routine a focus of conversations around sleep problems.

Prior to the pandemic, “we already were hitting upon that in sleep clinic, making sure [they] get the same schedule every day,” said Dr. Seay. For parents with children who have “issues with insomnia or waking up during the night, having that routine in place does help to mitigate that a little bit, so if that routine is not there, it can actually exacerbate the issues.”

This study was funded by the Australian federal government. The authors report no relevant conflicts of interest. Dr. Seay reports no relevant conflicts of interest.

SOURCE: Williamson AA et al. J Child Psychol Psychiatry. 2020 Jul 26. doi:10.1111/jcpp.13303.

Sleep problems in children from birth to middle childhood may lead to decreased emotional well-being and quality of life by the time a child is 10-11 years old, a recent longitudinal study has found.

The effects of these impairments increased over time and included internalizing and externalizing concerns, self-control, and quality of life, but did not appear to significantly affect cognitive or academic skills, according to Ariel A. Williamson, PhD, DBSM, of Children’s Hospital of Philadelphia, and colleagues. While children with consistent sleep problems experienced the worse outcomes, mild sleep problems also were associated with impairment, the researchers said.

“The range of impairments across academic and psychosocial domains in middle childhood indicate that it is important to screen for sleep problems consistently over the course of a child’s development, especially to target children who experience persistent sleep problems over time,” said Dr. Williamson in a press release.

The researchers examined data from 5,107 children in the Longitudinal Study of Australian Children – Birth Cohort, where sleep problems and well-being outcomes were measured at multiple time points. Behaviors such as difficulty getting off to sleep at night, not happy to sleep alone, and waking during the night were defined as sleep problems. The investigators found five main domains of sleep issues: children who had persistent sleep problems through middle childhood (7.7%), limited sleep problems as an infant or during preschool (9.0%), mild sleep problems over time (14.4%), increased sleep problems during middle childhood (17.0%), and a group that did not experience sleep problems (51.9%).

Caregivers reported sleep issues in the cohort, while well-being outcomes were reported by caregivers and teachers, and tasks were completed by the children at 10-11 years of age. Dr. Williamson and colleagues examined well-being in terms of emotional and behavioral functioning, health-related quality of life, cognitive skills, and academic achievement.
 

Different reports from teacher and caregivers

Teacher and caregivers reported different effects in children with persistent sleep problems. Teachers reported moderate internalizing (effect size, –0.65; 95% confidence interval [CI],–0.87 to –0.43; P < .001) and externalizing concerns (ES, –0.40; 95% CI, –0.58 to –0.21; P less than .001), compared with children who did not have sleep problems, whereas caregivers reported large internalizing (ES, –0.75; 95% CI, –0.92 to –0.57; P less than .001) and externalizing concerns (ES, –0.70; 95% CI, –0.86 to –0.53; P < .001). Children with persistent sleep problems had moderate impairment of self-control as reported by caregivers, compared with children with no sleep problems (ES, –0.37; 95% CI, –0.52 to –0.21; P < .001). Psychosocial and health-related quality of life reported by caregivers were worse in children with persistent sleep problems, compared with children who did not have sleep problems (ES range, –0.78 to –0.90; 95% CI, –1.06 to –0.56; P < .001).

For children who exhibited increased sleep problems in middle childhood, caregivers (ES for both, –0.61; 95% CI, –0.76 to –0.46; P < .001) and teachers (ES range, –0.29 to –0.39; 95% CI, –0.53 to –0.15; P < .001) reported greater rates of internalizing and externalizing symptoms, compared with children who had no sleep issues.

Small impairments in internalizing internal or externalizing symptoms were seen in children who had limited sleep problems as an infant or in preschool (ES, –0.12; 95% CI, –0.23 to –0.01; P < .05) as reported by teachers, and in children with mild sleep problems over time (ES, –0.19; 95% CI, –0.30 to –0.08; P < .001) as reported by caregivers. There were no significant impairments in self-control for children in either the infant or preschool impairment group or in the group of children with mild sleep problems.

Across all groups, sleep problems did not significantly impair nonverbal reasoning, and most areas of academic competencies were not significantly impaired among groups except in language and literacy, and mathematical thinking for children with persistent sleep problems (ES, –0.41 for both; 95% CI, –0.60 to –0.23; P < .001). Children with increased sleep problems during middle childhood “had few academic and cognitive impairments,” and academic impairments among children with mild sleep problems were not significant.


 

Expert opinion

Brandon M. Seay MD, FAAP, pediatric pulmonologist and sleep specialist at Children’s Healthcare of Atlanta, said in an interview that the study is one of the first to offer longitudinal data for impairment in children with sleep problems. He said the paper emphasizes the need for recognizing when children are demonstrating sleep problems. “It just shows that problems that aren’t dealt with earlier on definitely have bigger impacts on sleep as you go through life,” he said.

Although primary care physicians and pediatricians should be already asking questions about sleep through anticipatory guidance, he said, intervening earlier for sleep problems is important. He noted children who exhibit sleep problems over time are more likely to have issues in handling their emotions and eventually may develop cognitive issues. “[W]e know that if these problems continue to go through, this paper’s showing us that they have worse effects down the road,” he said.
 

Impact of the COVID-19 crisis

These problems may also be worsened by the COVID-19 pandemic. Dr. Seay noted that with many parents working from home, sleep schedules can be affected and parents may also be co-sleeping with their children, which can cause chronic insomnia and early waking. To help address sleep issues, especially ones that may have arisen during COVID-19, parents should make sure their children show up for primary care visits to report problems, and clinicians should make a sleep routine a focus of conversations around sleep problems.

Prior to the pandemic, “we already were hitting upon that in sleep clinic, making sure [they] get the same schedule every day,” said Dr. Seay. For parents with children who have “issues with insomnia or waking up during the night, having that routine in place does help to mitigate that a little bit, so if that routine is not there, it can actually exacerbate the issues.”

This study was funded by the Australian federal government. The authors report no relevant conflicts of interest. Dr. Seay reports no relevant conflicts of interest.

SOURCE: Williamson AA et al. J Child Psychol Psychiatry. 2020 Jul 26. doi:10.1111/jcpp.13303.

Sleep problems in children from birth to middle childhood may lead to decreased emotional well-being and quality of life by the time a child is 10-11 years old, a recent longitudinal study has found.

The effects of these impairments increased over time and included internalizing and externalizing concerns, self-control, and quality of life, but did not appear to significantly affect cognitive or academic skills, according to Ariel A. Williamson, PhD, DBSM, of Children’s Hospital of Philadelphia, and colleagues. While children with consistent sleep problems experienced the worse outcomes, mild sleep problems also were associated with impairment, the researchers said.

“The range of impairments across academic and psychosocial domains in middle childhood indicate that it is important to screen for sleep problems consistently over the course of a child’s development, especially to target children who experience persistent sleep problems over time,” said Dr. Williamson in a press release.

The researchers examined data from 5,107 children in the Longitudinal Study of Australian Children – Birth Cohort, where sleep problems and well-being outcomes were measured at multiple time points. Behaviors such as difficulty getting off to sleep at night, not happy to sleep alone, and waking during the night were defined as sleep problems. The investigators found five main domains of sleep issues: children who had persistent sleep problems through middle childhood (7.7%), limited sleep problems as an infant or during preschool (9.0%), mild sleep problems over time (14.4%), increased sleep problems during middle childhood (17.0%), and a group that did not experience sleep problems (51.9%).

Caregivers reported sleep issues in the cohort, while well-being outcomes were reported by caregivers and teachers, and tasks were completed by the children at 10-11 years of age. Dr. Williamson and colleagues examined well-being in terms of emotional and behavioral functioning, health-related quality of life, cognitive skills, and academic achievement.
 

Different reports from teacher and caregivers

Teacher and caregivers reported different effects in children with persistent sleep problems. Teachers reported moderate internalizing (effect size, –0.65; 95% confidence interval [CI],–0.87 to –0.43; P < .001) and externalizing concerns (ES, –0.40; 95% CI, –0.58 to –0.21; P less than .001), compared with children who did not have sleep problems, whereas caregivers reported large internalizing (ES, –0.75; 95% CI, –0.92 to –0.57; P less than .001) and externalizing concerns (ES, –0.70; 95% CI, –0.86 to –0.53; P < .001). Children with persistent sleep problems had moderate impairment of self-control as reported by caregivers, compared with children with no sleep problems (ES, –0.37; 95% CI, –0.52 to –0.21; P < .001). Psychosocial and health-related quality of life reported by caregivers were worse in children with persistent sleep problems, compared with children who did not have sleep problems (ES range, –0.78 to –0.90; 95% CI, –1.06 to –0.56; P < .001).

For children who exhibited increased sleep problems in middle childhood, caregivers (ES for both, –0.61; 95% CI, –0.76 to –0.46; P < .001) and teachers (ES range, –0.29 to –0.39; 95% CI, –0.53 to –0.15; P < .001) reported greater rates of internalizing and externalizing symptoms, compared with children who had no sleep issues.

Small impairments in internalizing internal or externalizing symptoms were seen in children who had limited sleep problems as an infant or in preschool (ES, –0.12; 95% CI, –0.23 to –0.01; P < .05) as reported by teachers, and in children with mild sleep problems over time (ES, –0.19; 95% CI, –0.30 to –0.08; P < .001) as reported by caregivers. There were no significant impairments in self-control for children in either the infant or preschool impairment group or in the group of children with mild sleep problems.

Across all groups, sleep problems did not significantly impair nonverbal reasoning, and most areas of academic competencies were not significantly impaired among groups except in language and literacy, and mathematical thinking for children with persistent sleep problems (ES, –0.41 for both; 95% CI, –0.60 to –0.23; P < .001). Children with increased sleep problems during middle childhood “had few academic and cognitive impairments,” and academic impairments among children with mild sleep problems were not significant.


 

Expert opinion

Brandon M. Seay MD, FAAP, pediatric pulmonologist and sleep specialist at Children’s Healthcare of Atlanta, said in an interview that the study is one of the first to offer longitudinal data for impairment in children with sleep problems. He said the paper emphasizes the need for recognizing when children are demonstrating sleep problems. “It just shows that problems that aren’t dealt with earlier on definitely have bigger impacts on sleep as you go through life,” he said.

Although primary care physicians and pediatricians should be already asking questions about sleep through anticipatory guidance, he said, intervening earlier for sleep problems is important. He noted children who exhibit sleep problems over time are more likely to have issues in handling their emotions and eventually may develop cognitive issues. “[W]e know that if these problems continue to go through, this paper’s showing us that they have worse effects down the road,” he said.
 

Impact of the COVID-19 crisis

These problems may also be worsened by the COVID-19 pandemic. Dr. Seay noted that with many parents working from home, sleep schedules can be affected and parents may also be co-sleeping with their children, which can cause chronic insomnia and early waking. To help address sleep issues, especially ones that may have arisen during COVID-19, parents should make sure their children show up for primary care visits to report problems, and clinicians should make a sleep routine a focus of conversations around sleep problems.

Prior to the pandemic, “we already were hitting upon that in sleep clinic, making sure [they] get the same schedule every day,” said Dr. Seay. For parents with children who have “issues with insomnia or waking up during the night, having that routine in place does help to mitigate that a little bit, so if that routine is not there, it can actually exacerbate the issues.”

This study was funded by the Australian federal government. The authors report no relevant conflicts of interest. Dr. Seay reports no relevant conflicts of interest.

SOURCE: Williamson AA et al. J Child Psychol Psychiatry. 2020 Jul 26. doi:10.1111/jcpp.13303.

Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

“In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug,” lead author Florence Gressier, MD, PhD, CESP, Inserm, department of psychiatry, Le Kremlin Bicêtre, France, said in an interview.

“In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed,” she said.
 

Heated controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a “game changer”.

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the Food and Drug Administration revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston’s United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a “white coat summit” in front of the U.S. Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.
 

Sudden onset

For the new review, “we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed,” Dr. Gressier said.

“We think the format of the letter to the editor allows information to be provided in a concise and clear manner,” she added.

According to the FDA’s Adverse Event Reporting System database, 12% of reported adverse events (520 of 4,336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

The researchers acknowledged that the incidence of psychiatric adverse effects associated with the use of chloroquine is “unclear in the absence of high-quality, randomized placebo-controlled trials of its safety.” Nevertheless, they pointed out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria .

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis .

“In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight,” the authors wrote.

They noted that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually “sudden.”

In addition, they warn that the drug’s psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some “subtle” symptoms might persist after stopping the drug, possibly owing to its “extremely long” half-life, the authors stated.

Dr. Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine “and warn their patients about the risk induced by chloroquine.”
 

Safe but ‘not benign’

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, said she uses hydroxychloroquine “all the time” in clinical practice to treat patients with rheumatic conditions.

“I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects,” Dr. Bose said in an interview.

Because clinicians are trying all types of possible treatments for COVID-19, “if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe,” she added.

Nevertheless, the drug is “not benign, and regular side effects will be there, and of course, higher doses will cause more side effects,” said Dr. Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.
 

Be wary

James “Jimmy” Potash, MD, MPH, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, said in an interview that the “take-home message of this letter is that serious psychiatric effects, psychotic illness in particular,” can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, “these are potentially very concerning side effects that psychiatrists should be aware of,” noted Dr. Potash, department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been “completely psychiatrically healthy” took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

“If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak,” Dr. Potash said.

In an interview, Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vt., a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs; and faculty associate in the department of mental health at Johns Hopkins Bloomberg School of Public Health, said that the authors of the letter “are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions.”

He added: “I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system.”

Dr. Gressier and the other letter authors, Dr. Bose, and Dr. Potash have reported no relevant financial relationships. Dr. Nevin has been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

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

Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

“In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug,” lead author Florence Gressier, MD, PhD, CESP, Inserm, department of psychiatry, Le Kremlin Bicêtre, France, said in an interview.

“In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed,” she said.
 

Heated controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a “game changer”.

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the Food and Drug Administration revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston’s United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a “white coat summit” in front of the U.S. Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.
 

Sudden onset

For the new review, “we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed,” Dr. Gressier said.

“We think the format of the letter to the editor allows information to be provided in a concise and clear manner,” she added.

According to the FDA’s Adverse Event Reporting System database, 12% of reported adverse events (520 of 4,336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

The researchers acknowledged that the incidence of psychiatric adverse effects associated with the use of chloroquine is “unclear in the absence of high-quality, randomized placebo-controlled trials of its safety.” Nevertheless, they pointed out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria .

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis .

“In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight,” the authors wrote.

They noted that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually “sudden.”

In addition, they warn that the drug’s psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some “subtle” symptoms might persist after stopping the drug, possibly owing to its “extremely long” half-life, the authors stated.

Dr. Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine “and warn their patients about the risk induced by chloroquine.”
 

Safe but ‘not benign’

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, said she uses hydroxychloroquine “all the time” in clinical practice to treat patients with rheumatic conditions.

“I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects,” Dr. Bose said in an interview.

Because clinicians are trying all types of possible treatments for COVID-19, “if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe,” she added.

Nevertheless, the drug is “not benign, and regular side effects will be there, and of course, higher doses will cause more side effects,” said Dr. Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.
 

Be wary

James “Jimmy” Potash, MD, MPH, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, said in an interview that the “take-home message of this letter is that serious psychiatric effects, psychotic illness in particular,” can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, “these are potentially very concerning side effects that psychiatrists should be aware of,” noted Dr. Potash, department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been “completely psychiatrically healthy” took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

“If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak,” Dr. Potash said.

In an interview, Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vt., a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs; and faculty associate in the department of mental health at Johns Hopkins Bloomberg School of Public Health, said that the authors of the letter “are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions.”

He added: “I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system.”

Dr. Gressier and the other letter authors, Dr. Bose, and Dr. Potash have reported no relevant financial relationships. Dr. Nevin has been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

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

Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

“In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug,” lead author Florence Gressier, MD, PhD, CESP, Inserm, department of psychiatry, Le Kremlin Bicêtre, France, said in an interview.

“In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed,” she said.
 

Heated controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a “game changer”.

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the Food and Drug Administration revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston’s United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a “white coat summit” in front of the U.S. Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.
 

Sudden onset

For the new review, “we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed,” Dr. Gressier said.

“We think the format of the letter to the editor allows information to be provided in a concise and clear manner,” she added.

According to the FDA’s Adverse Event Reporting System database, 12% of reported adverse events (520 of 4,336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

The researchers acknowledged that the incidence of psychiatric adverse effects associated with the use of chloroquine is “unclear in the absence of high-quality, randomized placebo-controlled trials of its safety.” Nevertheless, they pointed out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria .

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis .

“In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight,” the authors wrote.

They noted that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually “sudden.”

In addition, they warn that the drug’s psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some “subtle” symptoms might persist after stopping the drug, possibly owing to its “extremely long” half-life, the authors stated.

Dr. Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine “and warn their patients about the risk induced by chloroquine.”
 

Safe but ‘not benign’

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, said she uses hydroxychloroquine “all the time” in clinical practice to treat patients with rheumatic conditions.

“I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects,” Dr. Bose said in an interview.

Because clinicians are trying all types of possible treatments for COVID-19, “if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe,” she added.

Nevertheless, the drug is “not benign, and regular side effects will be there, and of course, higher doses will cause more side effects,” said Dr. Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.
 

Be wary

James “Jimmy” Potash, MD, MPH, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, said in an interview that the “take-home message of this letter is that serious psychiatric effects, psychotic illness in particular,” can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, “these are potentially very concerning side effects that psychiatrists should be aware of,” noted Dr. Potash, department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been “completely psychiatrically healthy” took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

“If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak,” Dr. Potash said.

In an interview, Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vt., a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs; and faculty associate in the department of mental health at Johns Hopkins Bloomberg School of Public Health, said that the authors of the letter “are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions.”

He added: “I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system.”

Dr. Gressier and the other letter authors, Dr. Bose, and Dr. Potash have reported no relevant financial relationships. Dr. Nevin has been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

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

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study’s authors.

Their results show that the antidepressant effect of botulinum toxin “administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection,” according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration’s current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA’s previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also see in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study’s finding go “beyond breaking a positive feedback loop between depression and the ‘frown’ wrinkles in the glabellar region of the forehead.” The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians “expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes.”

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

“Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical,” Dr. Abagyan said. “Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression.”

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, “physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients.” Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

“Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only,” she added. “This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect.”

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

“It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects,” she said. “However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation.”

The study “certainly raises a lot of questions,” particularly about the “apparent multiple mechanisms of action of BoNT that we don’t understand yet,” Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. “I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication,” he added.

“I think what we all as clinicians need to take away from this paper is that there is a great deal we don’t understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression, said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study’s authors.

Their results show that the antidepressant effect of botulinum toxin “administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection,” according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration’s current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA’s previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also see in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study’s finding go “beyond breaking a positive feedback loop between depression and the ‘frown’ wrinkles in the glabellar region of the forehead.” The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians “expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes.”

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

“Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical,” Dr. Abagyan said. “Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression.”

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, “physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients.” Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

“Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only,” she added. “This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect.”

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

“It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects,” she said. “However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation.”

The study “certainly raises a lot of questions,” particularly about the “apparent multiple mechanisms of action of BoNT that we don’t understand yet,” Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. “I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication,” he added.

“I think what we all as clinicians need to take away from this paper is that there is a great deal we don’t understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression, said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study’s authors.

Their results show that the antidepressant effect of botulinum toxin “administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection,” according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration’s current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA’s previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also see in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study’s finding go “beyond breaking a positive feedback loop between depression and the ‘frown’ wrinkles in the glabellar region of the forehead.” The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians “expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes.”

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

“Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical,” Dr. Abagyan said. “Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression.”

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, “physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients.” Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

“Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only,” she added. “This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect.”

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

“It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects,” she said. “However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation.”

The study “certainly raises a lot of questions,” particularly about the “apparent multiple mechanisms of action of BoNT that we don’t understand yet,” Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. “I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication,” he added.

“I think what we all as clinicians need to take away from this paper is that there is a great deal we don’t understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression, said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

Dr. Ira Weintraub, a recently retired orthopedic surgeon who now works at a medical billing consultancy, saw a hip replacement bill for over $400,000 earlier this year.

“The patient stayed in the hospital 17 days, which is only 17 times normal. The bill got paid,” mused Weintraub, chief medical officer of Portland, Oregon-based WellRithms, which helps self-funded employers and workers’ compensation insurers make sense of large, complex medical bills and ensure they pay the fair amount.

Charges like that go a long way toward explaining why hospitals are eager to restore joint replacements to pre-COVID levels as quickly as possible – an eagerness tempered only by safety concerns amid a resurgence of the coronavirus in some regions of the country. Revenue losses at hospitals and outpatient surgery centers may have exceeded $5 billion from canceled knee and hip replacements alone during a roughly two-month hiatus on elective procedures earlier this year.

The cost of joint replacement surgery varies widely – though, on average, it is in the tens, not hundreds, of thousands of dollars. Still, given the high and rapidly growing volume, it’s easy to see why joint replacement operations have become a vital chunk of revenue at most U.S. hospitals.

The rate of knee and hip replacements more than doubled from 2000 to 2015, according to inpatient discharge data from the Agency for Healthcare Research and Quality. And that growth is likely to continue: Knee replacements are expected to triple between now and 2040, with hip replacements not far behind, according to projections published last year in the Journal of Rheumatology.

Joint procedures are usually not emergencies, and they were among the first to be scrubbed or delayed when hospitals froze elective surgeries in March – and again in July in some areas plagued by renewed COVID outbreaks. Loss of the revenue has hit hospitals hard, and regaining it will be crucial to their financial convalescence.

“Without orthopedic volumes returning to something near their pre-pandemic levels, it will make it difficult for health systems to get back to anywhere near break-even from a bottom-line perspective,” said Stephen Thome, a principal in health care consulting at Grant Thornton, an advisory, audit and tax firm.

It’s impossible to know exactly how much knee and hip replacements are worth to hospitals, because no definitive data on total volume or price exists.

But using published estimates of volume, extrapolating average commercial payments from published Medicare rates based on a study, and making an educated guess of patient coinsurance, Thome helped KHN arrive at an annual market value for American hospitals and surgery centers of between $15.5 billion and $21.5 billion for knee replacements alone.

That suggests a revenue loss of $1.3 billion to $1.8 billion per month for the period the surgeries were shut down. These figures include ambulatory surgery centers not owned by hospitals, which also suspended most operations in late March, all of April and into May.

If you add hip replacements, which account for about half the volume of knees and are paid at similar rates, the total annual value rises to a range of $23 billion to $32 billion, with monthly revenue losses from $1.9 billion to $2.7 billion.

The American Hospital Association projects total revenue lost at U.S. hospitals will reach $323 billion by year’s end, not counting additional losses from surgeries canceled during the current coronavirus spike. That amount is partially offset by $69 billion in federal relief dollars hospitals have received so far, according to the association. The California Hospital Association puts the net revenue loss for hospitals in that state at about $10.5 billion, said spokesperson Jan Emerson-Shea.

Hospitals resumed joint replacement surgeries in early to mid-May, with the timing and ramp-up speed varying by region and hospital. Some hospitals restored volume quickly; others took a more cautious route and continue to lose revenue. Still others have had to shut down again.

At the NYU Langone Orthopedic Hospital in New York City, “people are starting to come in and you see the operating rooms full again,” said Dr. Claudette Lajam, chief orthopedic safety officer.

At St. Jude Medical Center in Fullerton, California, where the coronavirus is raging, inpatient joint replacements resumed in the second or third week of May – cautiously at first, but volume is “very close to pre-pandemic levels at this point,” said Dr. Kevin Khajavi, chairman of the hospital’s orthopedic surgery department. However, “we are constantly monitoring the situation to determine if we have to scale back once again,” he said.

In large swaths of Texas, elective surgeries were once again suspended in July because of the COVID-19 resurgence. The same is true at many hospitals in Florida, Alabama, South Carolina and Nevada.

The Mayo Clinic in Phoenix suspended nonemergency joint replacement surgeries in early July. It resumed outpatient replacement procedures the week of July 27, but still has not resumed nonemergency inpatient procedures, said Dr. Mark Spangehl, an orthopedic surgeon there. In terms of medical urgency, joint replacements are “at the bottom of the totem pole,” Spangehl said.

In terms of cash flow, however, joint replacements are decidedly not at the bottom of the totem pole. They have become a cash cow as the number of patients undergoing them has skyrocketed in recent decades.

The volume is being driven by an aging population, an epidemic of obesity and a significant rise in the number of younger people replacing joints worn out by years of sports and exercise.

It’s also being driven by the cash. Once only done in hospitals, the operations are now increasingly performed at ambulatory surgery centers – especially on younger, healthier patients who don’t require hospitalization.

The surgery centers are often physician-owned, but private equity groups such as Bain Capital and KKR & Co. have taken an interest in them, drawn by their high growth potential, robust financial returns and ability to offer competitive prices.

“[G]enerally the savings should be very good – but I do see a lot of outlier surgery centers where they are charging exorbitant amounts of money – $100,000 wouldn’t be too much,” said WellRithm’s Weintraub, who co-owned such a surgery center in Portland.

Fear of catching the coronavirus in a hospital is reinforcing the outpatient trend. Matthew Davis, a 58-year-old resident of Washington, was scheduled for a hip replacement on March 30 but got cold feet because of COVID-19, and canceled just before all elective surgeries were halted. When it came time to reschedule in June, he overcame his reservations in large part because the surgeon planned to perform the procedure at a free-standing surgery center.

“That was key to me – avoiding an overnight hospital stay to minimize my exposure,” Davis said. “These joint replacements are almost industrial-scale. They are cranking out joint replacements 9 to 5. I went in at 6:30 a.m. and I was walking out the door at 11:30.”

Acutely aware of the financial benefits, hospitals and surgery clinics have been marketing joint replacements for years, competing for coveted rankings and running ads that show healthy aging people, all smiles, engaged in vigorous activity.

However, a 2014 study concluded that one-third of knee replacements were not warranted, mainly because the symptoms of the patients were not severe enough to justify the procedures.

“The whole marketing of health care is so manipulative to the consuming public,” said Lisa McGiffert, a longtime consumer advocate and co-founder of the Patient Safety Action Network. “People might be encouraged to get a knee replacement, when in reality something less invasive could have improved their condition.”

McGiffert recounted a conversation with an orthopedic surgeon in Washington state who told her about a patient who requested a knee replacement, even though he had not tried any lower-impact treatments to fix the problem. “I asked the surgeon, ‘You didn’t do it, did you?’ And he said, ‘Of course I did. He would just have gone to somebody else.’ ”

This Kaiser Health News story first published on California Healthline, a service of the California Health Care Foundation.

Dr. Ira Weintraub, a recently retired orthopedic surgeon who now works at a medical billing consultancy, saw a hip replacement bill for over $400,000 earlier this year.

“The patient stayed in the hospital 17 days, which is only 17 times normal. The bill got paid,” mused Weintraub, chief medical officer of Portland, Oregon-based WellRithms, which helps self-funded employers and workers’ compensation insurers make sense of large, complex medical bills and ensure they pay the fair amount.

Charges like that go a long way toward explaining why hospitals are eager to restore joint replacements to pre-COVID levels as quickly as possible – an eagerness tempered only by safety concerns amid a resurgence of the coronavirus in some regions of the country. Revenue losses at hospitals and outpatient surgery centers may have exceeded $5 billion from canceled knee and hip replacements alone during a roughly two-month hiatus on elective procedures earlier this year.

The cost of joint replacement surgery varies widely – though, on average, it is in the tens, not hundreds, of thousands of dollars. Still, given the high and rapidly growing volume, it’s easy to see why joint replacement operations have become a vital chunk of revenue at most U.S. hospitals.

The rate of knee and hip replacements more than doubled from 2000 to 2015, according to inpatient discharge data from the Agency for Healthcare Research and Quality. And that growth is likely to continue: Knee replacements are expected to triple between now and 2040, with hip replacements not far behind, according to projections published last year in the Journal of Rheumatology.

Joint procedures are usually not emergencies, and they were among the first to be scrubbed or delayed when hospitals froze elective surgeries in March – and again in July in some areas plagued by renewed COVID outbreaks. Loss of the revenue has hit hospitals hard, and regaining it will be crucial to their financial convalescence.

“Without orthopedic volumes returning to something near their pre-pandemic levels, it will make it difficult for health systems to get back to anywhere near break-even from a bottom-line perspective,” said Stephen Thome, a principal in health care consulting at Grant Thornton, an advisory, audit and tax firm.

It’s impossible to know exactly how much knee and hip replacements are worth to hospitals, because no definitive data on total volume or price exists.

But using published estimates of volume, extrapolating average commercial payments from published Medicare rates based on a study, and making an educated guess of patient coinsurance, Thome helped KHN arrive at an annual market value for American hospitals and surgery centers of between $15.5 billion and $21.5 billion for knee replacements alone.

That suggests a revenue loss of $1.3 billion to $1.8 billion per month for the period the surgeries were shut down. These figures include ambulatory surgery centers not owned by hospitals, which also suspended most operations in late March, all of April and into May.

If you add hip replacements, which account for about half the volume of knees and are paid at similar rates, the total annual value rises to a range of $23 billion to $32 billion, with monthly revenue losses from $1.9 billion to $2.7 billion.

The American Hospital Association projects total revenue lost at U.S. hospitals will reach $323 billion by year’s end, not counting additional losses from surgeries canceled during the current coronavirus spike. That amount is partially offset by $69 billion in federal relief dollars hospitals have received so far, according to the association. The California Hospital Association puts the net revenue loss for hospitals in that state at about $10.5 billion, said spokesperson Jan Emerson-Shea.

Hospitals resumed joint replacement surgeries in early to mid-May, with the timing and ramp-up speed varying by region and hospital. Some hospitals restored volume quickly; others took a more cautious route and continue to lose revenue. Still others have had to shut down again.

At the NYU Langone Orthopedic Hospital in New York City, “people are starting to come in and you see the operating rooms full again,” said Dr. Claudette Lajam, chief orthopedic safety officer.

At St. Jude Medical Center in Fullerton, California, where the coronavirus is raging, inpatient joint replacements resumed in the second or third week of May – cautiously at first, but volume is “very close to pre-pandemic levels at this point,” said Dr. Kevin Khajavi, chairman of the hospital’s orthopedic surgery department. However, “we are constantly monitoring the situation to determine if we have to scale back once again,” he said.

In large swaths of Texas, elective surgeries were once again suspended in July because of the COVID-19 resurgence. The same is true at many hospitals in Florida, Alabama, South Carolina and Nevada.

The Mayo Clinic in Phoenix suspended nonemergency joint replacement surgeries in early July. It resumed outpatient replacement procedures the week of July 27, but still has not resumed nonemergency inpatient procedures, said Dr. Mark Spangehl, an orthopedic surgeon there. In terms of medical urgency, joint replacements are “at the bottom of the totem pole,” Spangehl said.

In terms of cash flow, however, joint replacements are decidedly not at the bottom of the totem pole. They have become a cash cow as the number of patients undergoing them has skyrocketed in recent decades.

The volume is being driven by an aging population, an epidemic of obesity and a significant rise in the number of younger people replacing joints worn out by years of sports and exercise.

It’s also being driven by the cash. Once only done in hospitals, the operations are now increasingly performed at ambulatory surgery centers – especially on younger, healthier patients who don’t require hospitalization.

The surgery centers are often physician-owned, but private equity groups such as Bain Capital and KKR & Co. have taken an interest in them, drawn by their high growth potential, robust financial returns and ability to offer competitive prices.

“[G]enerally the savings should be very good – but I do see a lot of outlier surgery centers where they are charging exorbitant amounts of money – $100,000 wouldn’t be too much,” said WellRithm’s Weintraub, who co-owned such a surgery center in Portland.

Fear of catching the coronavirus in a hospital is reinforcing the outpatient trend. Matthew Davis, a 58-year-old resident of Washington, was scheduled for a hip replacement on March 30 but got cold feet because of COVID-19, and canceled just before all elective surgeries were halted. When it came time to reschedule in June, he overcame his reservations in large part because the surgeon planned to perform the procedure at a free-standing surgery center.

“That was key to me – avoiding an overnight hospital stay to minimize my exposure,” Davis said. “These joint replacements are almost industrial-scale. They are cranking out joint replacements 9 to 5. I went in at 6:30 a.m. and I was walking out the door at 11:30.”

Acutely aware of the financial benefits, hospitals and surgery clinics have been marketing joint replacements for years, competing for coveted rankings and running ads that show healthy aging people, all smiles, engaged in vigorous activity.

However, a 2014 study concluded that one-third of knee replacements were not warranted, mainly because the symptoms of the patients were not severe enough to justify the procedures.

“The whole marketing of health care is so manipulative to the consuming public,” said Lisa McGiffert, a longtime consumer advocate and co-founder of the Patient Safety Action Network. “People might be encouraged to get a knee replacement, when in reality something less invasive could have improved their condition.”

McGiffert recounted a conversation with an orthopedic surgeon in Washington state who told her about a patient who requested a knee replacement, even though he had not tried any lower-impact treatments to fix the problem. “I asked the surgeon, ‘You didn’t do it, did you?’ And he said, ‘Of course I did. He would just have gone to somebody else.’ ”

This Kaiser Health News story first published on California Healthline, a service of the California Health Care Foundation.

Dr. Ira Weintraub, a recently retired orthopedic surgeon who now works at a medical billing consultancy, saw a hip replacement bill for over $400,000 earlier this year.

“The patient stayed in the hospital 17 days, which is only 17 times normal. The bill got paid,” mused Weintraub, chief medical officer of Portland, Oregon-based WellRithms, which helps self-funded employers and workers’ compensation insurers make sense of large, complex medical bills and ensure they pay the fair amount.

Charges like that go a long way toward explaining why hospitals are eager to restore joint replacements to pre-COVID levels as quickly as possible – an eagerness tempered only by safety concerns amid a resurgence of the coronavirus in some regions of the country. Revenue losses at hospitals and outpatient surgery centers may have exceeded $5 billion from canceled knee and hip replacements alone during a roughly two-month hiatus on elective procedures earlier this year.

The cost of joint replacement surgery varies widely – though, on average, it is in the tens, not hundreds, of thousands of dollars. Still, given the high and rapidly growing volume, it’s easy to see why joint replacement operations have become a vital chunk of revenue at most U.S. hospitals.

The rate of knee and hip replacements more than doubled from 2000 to 2015, according to inpatient discharge data from the Agency for Healthcare Research and Quality. And that growth is likely to continue: Knee replacements are expected to triple between now and 2040, with hip replacements not far behind, according to projections published last year in the Journal of Rheumatology.

Joint procedures are usually not emergencies, and they were among the first to be scrubbed or delayed when hospitals froze elective surgeries in March – and again in July in some areas plagued by renewed COVID outbreaks. Loss of the revenue has hit hospitals hard, and regaining it will be crucial to their financial convalescence.

“Without orthopedic volumes returning to something near their pre-pandemic levels, it will make it difficult for health systems to get back to anywhere near break-even from a bottom-line perspective,” said Stephen Thome, a principal in health care consulting at Grant Thornton, an advisory, audit and tax firm.

It’s impossible to know exactly how much knee and hip replacements are worth to hospitals, because no definitive data on total volume or price exists.

But using published estimates of volume, extrapolating average commercial payments from published Medicare rates based on a study, and making an educated guess of patient coinsurance, Thome helped KHN arrive at an annual market value for American hospitals and surgery centers of between $15.5 billion and $21.5 billion for knee replacements alone.

That suggests a revenue loss of $1.3 billion to $1.8 billion per month for the period the surgeries were shut down. These figures include ambulatory surgery centers not owned by hospitals, which also suspended most operations in late March, all of April and into May.

If you add hip replacements, which account for about half the volume of knees and are paid at similar rates, the total annual value rises to a range of $23 billion to $32 billion, with monthly revenue losses from $1.9 billion to $2.7 billion.

The American Hospital Association projects total revenue lost at U.S. hospitals will reach $323 billion by year’s end, not counting additional losses from surgeries canceled during the current coronavirus spike. That amount is partially offset by $69 billion in federal relief dollars hospitals have received so far, according to the association. The California Hospital Association puts the net revenue loss for hospitals in that state at about $10.5 billion, said spokesperson Jan Emerson-Shea.

Hospitals resumed joint replacement surgeries in early to mid-May, with the timing and ramp-up speed varying by region and hospital. Some hospitals restored volume quickly; others took a more cautious route and continue to lose revenue. Still others have had to shut down again.

At the NYU Langone Orthopedic Hospital in New York City, “people are starting to come in and you see the operating rooms full again,” said Dr. Claudette Lajam, chief orthopedic safety officer.

At St. Jude Medical Center in Fullerton, California, where the coronavirus is raging, inpatient joint replacements resumed in the second or third week of May – cautiously at first, but volume is “very close to pre-pandemic levels at this point,” said Dr. Kevin Khajavi, chairman of the hospital’s orthopedic surgery department. However, “we are constantly monitoring the situation to determine if we have to scale back once again,” he said.

In large swaths of Texas, elective surgeries were once again suspended in July because of the COVID-19 resurgence. The same is true at many hospitals in Florida, Alabama, South Carolina and Nevada.

The Mayo Clinic in Phoenix suspended nonemergency joint replacement surgeries in early July. It resumed outpatient replacement procedures the week of July 27, but still has not resumed nonemergency inpatient procedures, said Dr. Mark Spangehl, an orthopedic surgeon there. In terms of medical urgency, joint replacements are “at the bottom of the totem pole,” Spangehl said.

In terms of cash flow, however, joint replacements are decidedly not at the bottom of the totem pole. They have become a cash cow as the number of patients undergoing them has skyrocketed in recent decades.

The volume is being driven by an aging population, an epidemic of obesity and a significant rise in the number of younger people replacing joints worn out by years of sports and exercise.

It’s also being driven by the cash. Once only done in hospitals, the operations are now increasingly performed at ambulatory surgery centers – especially on younger, healthier patients who don’t require hospitalization.

The surgery centers are often physician-owned, but private equity groups such as Bain Capital and KKR & Co. have taken an interest in them, drawn by their high growth potential, robust financial returns and ability to offer competitive prices.

“[G]enerally the savings should be very good – but I do see a lot of outlier surgery centers where they are charging exorbitant amounts of money – $100,000 wouldn’t be too much,” said WellRithm’s Weintraub, who co-owned such a surgery center in Portland.

Fear of catching the coronavirus in a hospital is reinforcing the outpatient trend. Matthew Davis, a 58-year-old resident of Washington, was scheduled for a hip replacement on March 30 but got cold feet because of COVID-19, and canceled just before all elective surgeries were halted. When it came time to reschedule in June, he overcame his reservations in large part because the surgeon planned to perform the procedure at a free-standing surgery center.

“That was key to me – avoiding an overnight hospital stay to minimize my exposure,” Davis said. “These joint replacements are almost industrial-scale. They are cranking out joint replacements 9 to 5. I went in at 6:30 a.m. and I was walking out the door at 11:30.”

Acutely aware of the financial benefits, hospitals and surgery clinics have been marketing joint replacements for years, competing for coveted rankings and running ads that show healthy aging people, all smiles, engaged in vigorous activity.

However, a 2014 study concluded that one-third of knee replacements were not warranted, mainly because the symptoms of the patients were not severe enough to justify the procedures.

“The whole marketing of health care is so manipulative to the consuming public,” said Lisa McGiffert, a longtime consumer advocate and co-founder of the Patient Safety Action Network. “People might be encouraged to get a knee replacement, when in reality something less invasive could have improved their condition.”

McGiffert recounted a conversation with an orthopedic surgeon in Washington state who told her about a patient who requested a knee replacement, even though he had not tried any lower-impact treatments to fix the problem. “I asked the surgeon, ‘You didn’t do it, did you?’ And he said, ‘Of course I did. He would just have gone to somebody else.’ ”

This Kaiser Health News story first published on California Healthline, a service of the California Health Care Foundation.

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

Findings from a large randomized, controlled trial do not support the use of vitamin D3 supplementation for adults for the sole purpose of preventing depression.

Among adults aged 50 years or older who were without clinically relevant depressive symptoms at baseline, vitamin D3 supplementation taken over 5 years did not reduce the risk for depression or make a difference in the quality of mood.

“The study is among the largest of its kind ever, and it was able to address whether vitamin D3 supplementation is useful for what we call ‘universal prevention’ of depression,” Olivia Okereke, MD, Massachusetts General Hospital, Boston, said in an interview.

“These results tell us that there is no benefit to using vitamin D3 supplements for the sole purpose of preventing depression in the general population of middle-aged and older adults,” said Dr. Okereke.

“Because of the high dose and long duration of treatment and the randomized placebo-controlled design, we can have high confidence in results,” she added.

The study was published online August 4 in JAMA.
 

The VITAL-DEP trial

The findings are based on 18,353 older adults (mean age, 67.5 years; 49% women) in the VITAL-DEP study; 16,657 were at risk for incident depression (ie, had no history of depression), and 1696 were at risk for recurrent depression (i.e., had a history of depression but had not undergone treatment for depression within the past 2 years).

Roughly half were randomly allocated to receive vitamin D3 (2000 IU/d of cholecalciferol) and half to receive matching placebo for a median of 5.3 years. The participants’ mean level of 25-hydroxyvitamin D was 31.1 ng/mL; for about 12%, levels were lower than 20 ng/mL.

The risk for depression or clinically relevant depressive symptoms (total of incident and recurrent cases) was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years). The hazard ratio was 0.97 (95% confidence interval, 0.87-1.09; P = .62).

“Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up,” the researchers report.

There was also no significant between-group difference in the other primary outcome – the mean difference in mood scores on the eight-item Patient Health Questionnaire depression scale (PHQ-8).

The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from 0 over the entire follow-up (0.01 points; 95% CI, −0.04 to 0.05 points) or at any point during follow-up.

To date, 13 randomized clinical trials have examined the effects of vitamin D3 supplementation on depression or mood during middle age or in older adults, and all except one reported null findings, Dr. Okereke and colleagues noted in their article.

The current study is the only one large enough to examine vitamin D3 supplementation for the universal prevention of depression, they point out.

Although the findings do not support vitamin D3 supplementation for depression prevention, Dr. Okereke said, “we cannot yet exclude the possibility of benefit of vitamin D3 for preventing depression among subgroups with certain health risk factors. We also know that vitamin D is essential for bone health, and this study does not tell us whether vitamin D3 is useful for prevention of other health outcomes.”

VITAL-DEP was supported by a grant from the National Institute of Mental Health. Pharmavite donated the vitamin D3, matching placebos, and packaging in the form of calendar packs. Dr. Okereke reported receiving royalties from Springer Publishing for a book on the prevention of late-life depression.

This article first appeared on Medscape.com.

Findings from a large randomized, controlled trial do not support the use of vitamin D3 supplementation for adults for the sole purpose of preventing depression.

Among adults aged 50 years or older who were without clinically relevant depressive symptoms at baseline, vitamin D3 supplementation taken over 5 years did not reduce the risk for depression or make a difference in the quality of mood.

“The study is among the largest of its kind ever, and it was able to address whether vitamin D3 supplementation is useful for what we call ‘universal prevention’ of depression,” Olivia Okereke, MD, Massachusetts General Hospital, Boston, said in an interview.

“These results tell us that there is no benefit to using vitamin D3 supplements for the sole purpose of preventing depression in the general population of middle-aged and older adults,” said Dr. Okereke.

“Because of the high dose and long duration of treatment and the randomized placebo-controlled design, we can have high confidence in results,” she added.

The study was published online August 4 in JAMA.
 

The VITAL-DEP trial

The findings are based on 18,353 older adults (mean age, 67.5 years; 49% women) in the VITAL-DEP study; 16,657 were at risk for incident depression (ie, had no history of depression), and 1696 were at risk for recurrent depression (i.e., had a history of depression but had not undergone treatment for depression within the past 2 years).

Roughly half were randomly allocated to receive vitamin D3 (2000 IU/d of cholecalciferol) and half to receive matching placebo for a median of 5.3 years. The participants’ mean level of 25-hydroxyvitamin D was 31.1 ng/mL; for about 12%, levels were lower than 20 ng/mL.

The risk for depression or clinically relevant depressive symptoms (total of incident and recurrent cases) was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years). The hazard ratio was 0.97 (95% confidence interval, 0.87-1.09; P = .62).

“Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up,” the researchers report.

There was also no significant between-group difference in the other primary outcome – the mean difference in mood scores on the eight-item Patient Health Questionnaire depression scale (PHQ-8).

The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from 0 over the entire follow-up (0.01 points; 95% CI, −0.04 to 0.05 points) or at any point during follow-up.

To date, 13 randomized clinical trials have examined the effects of vitamin D3 supplementation on depression or mood during middle age or in older adults, and all except one reported null findings, Dr. Okereke and colleagues noted in their article.

The current study is the only one large enough to examine vitamin D3 supplementation for the universal prevention of depression, they point out.

Although the findings do not support vitamin D3 supplementation for depression prevention, Dr. Okereke said, “we cannot yet exclude the possibility of benefit of vitamin D3 for preventing depression among subgroups with certain health risk factors. We also know that vitamin D is essential for bone health, and this study does not tell us whether vitamin D3 is useful for prevention of other health outcomes.”

VITAL-DEP was supported by a grant from the National Institute of Mental Health. Pharmavite donated the vitamin D3, matching placebos, and packaging in the form of calendar packs. Dr. Okereke reported receiving royalties from Springer Publishing for a book on the prevention of late-life depression.

This article first appeared on Medscape.com.

Findings from a large randomized, controlled trial do not support the use of vitamin D3 supplementation for adults for the sole purpose of preventing depression.

Among adults aged 50 years or older who were without clinically relevant depressive symptoms at baseline, vitamin D3 supplementation taken over 5 years did not reduce the risk for depression or make a difference in the quality of mood.

“The study is among the largest of its kind ever, and it was able to address whether vitamin D3 supplementation is useful for what we call ‘universal prevention’ of depression,” Olivia Okereke, MD, Massachusetts General Hospital, Boston, said in an interview.

“These results tell us that there is no benefit to using vitamin D3 supplements for the sole purpose of preventing depression in the general population of middle-aged and older adults,” said Dr. Okereke.

“Because of the high dose and long duration of treatment and the randomized placebo-controlled design, we can have high confidence in results,” she added.

The study was published online August 4 in JAMA.
 

The VITAL-DEP trial

The findings are based on 18,353 older adults (mean age, 67.5 years; 49% women) in the VITAL-DEP study; 16,657 were at risk for incident depression (ie, had no history of depression), and 1696 were at risk for recurrent depression (i.e., had a history of depression but had not undergone treatment for depression within the past 2 years).

Roughly half were randomly allocated to receive vitamin D3 (2000 IU/d of cholecalciferol) and half to receive matching placebo for a median of 5.3 years. The participants’ mean level of 25-hydroxyvitamin D was 31.1 ng/mL; for about 12%, levels were lower than 20 ng/mL.

The risk for depression or clinically relevant depressive symptoms (total of incident and recurrent cases) was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years). The hazard ratio was 0.97 (95% confidence interval, 0.87-1.09; P = .62).

“Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up,” the researchers report.

There was also no significant between-group difference in the other primary outcome – the mean difference in mood scores on the eight-item Patient Health Questionnaire depression scale (PHQ-8).

The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from 0 over the entire follow-up (0.01 points; 95% CI, −0.04 to 0.05 points) or at any point during follow-up.

To date, 13 randomized clinical trials have examined the effects of vitamin D3 supplementation on depression or mood during middle age or in older adults, and all except one reported null findings, Dr. Okereke and colleagues noted in their article.

The current study is the only one large enough to examine vitamin D3 supplementation for the universal prevention of depression, they point out.

Although the findings do not support vitamin D3 supplementation for depression prevention, Dr. Okereke said, “we cannot yet exclude the possibility of benefit of vitamin D3 for preventing depression among subgroups with certain health risk factors. We also know that vitamin D is essential for bone health, and this study does not tell us whether vitamin D3 is useful for prevention of other health outcomes.”

VITAL-DEP was supported by a grant from the National Institute of Mental Health. Pharmavite donated the vitamin D3, matching placebos, and packaging in the form of calendar packs. Dr. Okereke reported receiving royalties from Springer Publishing for a book on the prevention of late-life depression.

This article first appeared on Medscape.com.