Alzheimer's & Cognition

Self-reported, regular Internet use, but not overuse, in older adults is linked to a lower dementia risk, new research suggests.

Investigators followed more than 18,000 older individuals and found that regular Internet use was associated with about a 50% reduction in dementia risk, compared with their counterparts who did not use the Internet regularly.

They also found that longer duration of regular Internet use was associated with a reduced risk of dementia, although excessive daily Internet usage appeared to adversely affect dementia risk.

“Online engagement can develop and maintain cognitive reserve – resiliency against physiological damage to the brain – and increased cognitive reserve can, in turn, compensate for brain aging and reduce the risk of dementia,” study investigator Gawon Cho, a doctoral candidate at New York University School of Global Public Health, said in an interview.

The study was published online in the Journal of the American Geriatrics Society.
 

Unexamined benefits

Prior research has shown that older adult Internet users have “better overall cognitive performance, verbal reasoning, and memory,” compared with nonusers, the authors note.

However, because this body of research consists of cross-sectional analyses and longitudinal studies with brief follow-up periods, the long-term cognitive benefits of Internet usage remain “unexamined.”

In addition, despite “extensive evidence of a disproportionately high burden of dementia in people of color, individuals without higher education, and adults who experienced other socioeconomic hardships, little is known about whether the Internet has exacerbated population-level disparities in cognitive health,” the investigators add.

Another question concerns whether excessive Internet usage may actually be detrimental to neurocognitive outcomes. However, “existing evidence on the adverse effects of Internet usage is concentrated in younger populations whose brains are still undergoing maturation.”

Ms. Cho said the motivation for the study was the lack of longitudinal studies on this topic, especially those with sufficient follow-up periods. In addition, she said, there is insufficient evidence about how changes in Internet usage in older age are associated with prospective dementia risk.

For the study, investigators turned to participants in the Health and Retirement Study, an ongoing longitudinal survey of a nationally representative sample of U.S.-based older adults (aged ≥ 50 years).

All participants (n = 18,154; 47.36% male; median age, 55.17 years) were dementia-free, community-dwelling older adults who completed a 2002 baseline cognitive assessment and were asked about Internet usage every 2 years thereafter.

Participants were followed from 2002 to 2018 for a maximum of 17.1 years (median, 7.9 years), which is the longest follow-up period to date. Of the total sample, 64.76% were regular Internet users.

The study’s primary outcome was incident dementia, based on performance on the Modified Telephone Interview for Cognitive Status (TICS-M), which was administered every 2 years.

The exposure examined in the study was cumulative Internet usage in late adulthood, defined as “the number of biennial waves where participants used the Internet regularly during the first three waves.”

In addition, participants were asked how many hours they spent using the Internet during the past week for activities other than viewing television shows or movies.

The researchers also investigated whether the link between Internet usage and dementia risk varied by educational attainment, race-ethnicity, sex, and generational cohort.

Covariates included baseline TICS-M score, health, age, household income, marital status, and region of residence.
 

U-shaped curve

More than half of the sample (52.96%) showed no changes in Internet use from baseline during the study period, while one-fifth (20.54%) did show changes in use.

Investigators found a robust link between Internet usage and lower dementia risk (cause-specific hazard ratio, 0.57 [95% CI, 0.46-0.71]) – a finding that remained even after adjusting for self-selection into baseline usage (csHR, 0.54 [0.41-0.72]) and signs of cognitive decline at baseline (csHR, 0.62 [0.46-0.85]).

Each additional wave of regular Internet usage was associated with a 21% decrease in the risk of dementia (95% CI, 13%-29%), wherein additional regular periods were associated with reduced dementia risk (csHR, 0.80 [95% CI, 0.68-0.95]).

“The difference in risk between regular and nonregular users did not vary by educational attainment, race-ethnicity, sex, and generation,” the investigators note.

A U-shaped association was found between daily hours of online engagement, wherein the lowest risk was observed in those with 0.1-2 hours of usage (compared with 0 hours of usage). The risk increased in a “monotonic fashion” after 2 hours, with 6.1-8 hours of usage showing the highest risk.

This finding was not considered statistically significant, but the “consistent U-shaped trend offers a preliminary suggestion that excessive online engagement may have adverse cognitive effects on older adults,” the investigators note.

“Among older adults, regular Internet users may experience a lower risk of dementia compared to nonregular users, and longer periods of regular Internet usage in late adulthood may help reduce the risks of subsequent dementia incidence,” said Ms. Cho. “Nonetheless, using the Internet excessively daily may negatively affect the risk of dementia in older adults.”
 

Bidirectional relationship?

Commenting for this article, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, noted that some risk factors for Alzheimer’s or other dementias can’t be changed, while others are modifiable, “either at a personal or a population level.”

She called the current research “important” because it “identifies a potentially modifiable factor that may influence dementia risk.”

However, cautioned Dr. Sexton, who was not involved with the study, the findings cannot establish cause and effect. In fact, the relationship may be bidirectional.

“It may be that regular Internet usage is associated with increased cognitive stimulation, and in turn reduced risk of dementia; or it may be that individuals with lower risk of dementia are more likely to engage in regular Internet usage,” she said. Thus, “interventional studies are able to shed more light on causation.”

The Health and Retirement Study is sponsored by the National Institute on Aging and is conducted by the University of Michigan, Ann Arbor. Ms. Cho, her coauthors, and Dr. Sexton have disclosed no relevant financial relationships.

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

Self-reported, regular Internet use, but not overuse, in older adults is linked to a lower dementia risk, new research suggests.

Investigators followed more than 18,000 older individuals and found that regular Internet use was associated with about a 50% reduction in dementia risk, compared with their counterparts who did not use the Internet regularly.

They also found that longer duration of regular Internet use was associated with a reduced risk of dementia, although excessive daily Internet usage appeared to adversely affect dementia risk.

“Online engagement can develop and maintain cognitive reserve – resiliency against physiological damage to the brain – and increased cognitive reserve can, in turn, compensate for brain aging and reduce the risk of dementia,” study investigator Gawon Cho, a doctoral candidate at New York University School of Global Public Health, said in an interview.

The study was published online in the Journal of the American Geriatrics Society.
 

Unexamined benefits

Prior research has shown that older adult Internet users have “better overall cognitive performance, verbal reasoning, and memory,” compared with nonusers, the authors note.

However, because this body of research consists of cross-sectional analyses and longitudinal studies with brief follow-up periods, the long-term cognitive benefits of Internet usage remain “unexamined.”

In addition, despite “extensive evidence of a disproportionately high burden of dementia in people of color, individuals without higher education, and adults who experienced other socioeconomic hardships, little is known about whether the Internet has exacerbated population-level disparities in cognitive health,” the investigators add.

Another question concerns whether excessive Internet usage may actually be detrimental to neurocognitive outcomes. However, “existing evidence on the adverse effects of Internet usage is concentrated in younger populations whose brains are still undergoing maturation.”

Ms. Cho said the motivation for the study was the lack of longitudinal studies on this topic, especially those with sufficient follow-up periods. In addition, she said, there is insufficient evidence about how changes in Internet usage in older age are associated with prospective dementia risk.

For the study, investigators turned to participants in the Health and Retirement Study, an ongoing longitudinal survey of a nationally representative sample of U.S.-based older adults (aged ≥ 50 years).

All participants (n = 18,154; 47.36% male; median age, 55.17 years) were dementia-free, community-dwelling older adults who completed a 2002 baseline cognitive assessment and were asked about Internet usage every 2 years thereafter.

Participants were followed from 2002 to 2018 for a maximum of 17.1 years (median, 7.9 years), which is the longest follow-up period to date. Of the total sample, 64.76% were regular Internet users.

The study’s primary outcome was incident dementia, based on performance on the Modified Telephone Interview for Cognitive Status (TICS-M), which was administered every 2 years.

The exposure examined in the study was cumulative Internet usage in late adulthood, defined as “the number of biennial waves where participants used the Internet regularly during the first three waves.”

In addition, participants were asked how many hours they spent using the Internet during the past week for activities other than viewing television shows or movies.

The researchers also investigated whether the link between Internet usage and dementia risk varied by educational attainment, race-ethnicity, sex, and generational cohort.

Covariates included baseline TICS-M score, health, age, household income, marital status, and region of residence.
 

U-shaped curve

More than half of the sample (52.96%) showed no changes in Internet use from baseline during the study period, while one-fifth (20.54%) did show changes in use.

Investigators found a robust link between Internet usage and lower dementia risk (cause-specific hazard ratio, 0.57 [95% CI, 0.46-0.71]) – a finding that remained even after adjusting for self-selection into baseline usage (csHR, 0.54 [0.41-0.72]) and signs of cognitive decline at baseline (csHR, 0.62 [0.46-0.85]).

Each additional wave of regular Internet usage was associated with a 21% decrease in the risk of dementia (95% CI, 13%-29%), wherein additional regular periods were associated with reduced dementia risk (csHR, 0.80 [95% CI, 0.68-0.95]).

“The difference in risk between regular and nonregular users did not vary by educational attainment, race-ethnicity, sex, and generation,” the investigators note.

A U-shaped association was found between daily hours of online engagement, wherein the lowest risk was observed in those with 0.1-2 hours of usage (compared with 0 hours of usage). The risk increased in a “monotonic fashion” after 2 hours, with 6.1-8 hours of usage showing the highest risk.

This finding was not considered statistically significant, but the “consistent U-shaped trend offers a preliminary suggestion that excessive online engagement may have adverse cognitive effects on older adults,” the investigators note.

“Among older adults, regular Internet users may experience a lower risk of dementia compared to nonregular users, and longer periods of regular Internet usage in late adulthood may help reduce the risks of subsequent dementia incidence,” said Ms. Cho. “Nonetheless, using the Internet excessively daily may negatively affect the risk of dementia in older adults.”
 

Bidirectional relationship?

Commenting for this article, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, noted that some risk factors for Alzheimer’s or other dementias can’t be changed, while others are modifiable, “either at a personal or a population level.”

She called the current research “important” because it “identifies a potentially modifiable factor that may influence dementia risk.”

However, cautioned Dr. Sexton, who was not involved with the study, the findings cannot establish cause and effect. In fact, the relationship may be bidirectional.

“It may be that regular Internet usage is associated with increased cognitive stimulation, and in turn reduced risk of dementia; or it may be that individuals with lower risk of dementia are more likely to engage in regular Internet usage,” she said. Thus, “interventional studies are able to shed more light on causation.”

The Health and Retirement Study is sponsored by the National Institute on Aging and is conducted by the University of Michigan, Ann Arbor. Ms. Cho, her coauthors, and Dr. Sexton have disclosed no relevant financial relationships.

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

Self-reported, regular Internet use, but not overuse, in older adults is linked to a lower dementia risk, new research suggests.

Investigators followed more than 18,000 older individuals and found that regular Internet use was associated with about a 50% reduction in dementia risk, compared with their counterparts who did not use the Internet regularly.

They also found that longer duration of regular Internet use was associated with a reduced risk of dementia, although excessive daily Internet usage appeared to adversely affect dementia risk.

“Online engagement can develop and maintain cognitive reserve – resiliency against physiological damage to the brain – and increased cognitive reserve can, in turn, compensate for brain aging and reduce the risk of dementia,” study investigator Gawon Cho, a doctoral candidate at New York University School of Global Public Health, said in an interview.

The study was published online in the Journal of the American Geriatrics Society.
 

Unexamined benefits

Prior research has shown that older adult Internet users have “better overall cognitive performance, verbal reasoning, and memory,” compared with nonusers, the authors note.

However, because this body of research consists of cross-sectional analyses and longitudinal studies with brief follow-up periods, the long-term cognitive benefits of Internet usage remain “unexamined.”

In addition, despite “extensive evidence of a disproportionately high burden of dementia in people of color, individuals without higher education, and adults who experienced other socioeconomic hardships, little is known about whether the Internet has exacerbated population-level disparities in cognitive health,” the investigators add.

Another question concerns whether excessive Internet usage may actually be detrimental to neurocognitive outcomes. However, “existing evidence on the adverse effects of Internet usage is concentrated in younger populations whose brains are still undergoing maturation.”

Ms. Cho said the motivation for the study was the lack of longitudinal studies on this topic, especially those with sufficient follow-up periods. In addition, she said, there is insufficient evidence about how changes in Internet usage in older age are associated with prospective dementia risk.

For the study, investigators turned to participants in the Health and Retirement Study, an ongoing longitudinal survey of a nationally representative sample of U.S.-based older adults (aged ≥ 50 years).

All participants (n = 18,154; 47.36% male; median age, 55.17 years) were dementia-free, community-dwelling older adults who completed a 2002 baseline cognitive assessment and were asked about Internet usage every 2 years thereafter.

Participants were followed from 2002 to 2018 for a maximum of 17.1 years (median, 7.9 years), which is the longest follow-up period to date. Of the total sample, 64.76% were regular Internet users.

The study’s primary outcome was incident dementia, based on performance on the Modified Telephone Interview for Cognitive Status (TICS-M), which was administered every 2 years.

The exposure examined in the study was cumulative Internet usage in late adulthood, defined as “the number of biennial waves where participants used the Internet regularly during the first three waves.”

In addition, participants were asked how many hours they spent using the Internet during the past week for activities other than viewing television shows or movies.

The researchers also investigated whether the link between Internet usage and dementia risk varied by educational attainment, race-ethnicity, sex, and generational cohort.

Covariates included baseline TICS-M score, health, age, household income, marital status, and region of residence.
 

U-shaped curve

More than half of the sample (52.96%) showed no changes in Internet use from baseline during the study period, while one-fifth (20.54%) did show changes in use.

Investigators found a robust link between Internet usage and lower dementia risk (cause-specific hazard ratio, 0.57 [95% CI, 0.46-0.71]) – a finding that remained even after adjusting for self-selection into baseline usage (csHR, 0.54 [0.41-0.72]) and signs of cognitive decline at baseline (csHR, 0.62 [0.46-0.85]).

Each additional wave of regular Internet usage was associated with a 21% decrease in the risk of dementia (95% CI, 13%-29%), wherein additional regular periods were associated with reduced dementia risk (csHR, 0.80 [95% CI, 0.68-0.95]).

“The difference in risk between regular and nonregular users did not vary by educational attainment, race-ethnicity, sex, and generation,” the investigators note.

A U-shaped association was found between daily hours of online engagement, wherein the lowest risk was observed in those with 0.1-2 hours of usage (compared with 0 hours of usage). The risk increased in a “monotonic fashion” after 2 hours, with 6.1-8 hours of usage showing the highest risk.

This finding was not considered statistically significant, but the “consistent U-shaped trend offers a preliminary suggestion that excessive online engagement may have adverse cognitive effects on older adults,” the investigators note.

“Among older adults, regular Internet users may experience a lower risk of dementia compared to nonregular users, and longer periods of regular Internet usage in late adulthood may help reduce the risks of subsequent dementia incidence,” said Ms. Cho. “Nonetheless, using the Internet excessively daily may negatively affect the risk of dementia in older adults.”
 

Bidirectional relationship?

Commenting for this article, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, noted that some risk factors for Alzheimer’s or other dementias can’t be changed, while others are modifiable, “either at a personal or a population level.”

She called the current research “important” because it “identifies a potentially modifiable factor that may influence dementia risk.”

However, cautioned Dr. Sexton, who was not involved with the study, the findings cannot establish cause and effect. In fact, the relationship may be bidirectional.

“It may be that regular Internet usage is associated with increased cognitive stimulation, and in turn reduced risk of dementia; or it may be that individuals with lower risk of dementia are more likely to engage in regular Internet usage,” she said. Thus, “interventional studies are able to shed more light on causation.”

The Health and Retirement Study is sponsored by the National Institute on Aging and is conducted by the University of Michigan, Ann Arbor. Ms. Cho, her coauthors, and Dr. Sexton have disclosed no relevant financial relationships.

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

The history and findings in this case are suggestive of Alzheimer's disease (AD). 

AD is the most common type of dementia. It is characterized by cognitive and behavioral impairment that significantly impairs a patient's social and occupational functioning. The predominant AD pathogenesis hypothesis suggests that AD is largely caused by the accumulation of insoluble amyloid beta deposits and neurofibrillary tangles induced by highly phosphorylated tau proteins in the neocortex, hippocampus, and amygdala, as well as significant loss of neurons and synapses, which leads to brain atrophy. Estimates suggest that approximately 6.2 million people ≥ 65 years of age have AD and that by 2060, the number of Americans with AD may increase to 13.8 million, the result of an aging population and the lack of effective prevention and treatment strategies. AD is a chronic disease that confers tremendous emotional and economic burdens to individuals, families, and society. 

Insidiously progressive memory loss is commonly seen in patients presenting with AD. As the disease progresses over the course of several years, other areas of cognition are impaired. Patients may develop language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes are also observed in many individuals with AD.

Criteria for the clinical diagnosis of AD (eg, insidious onset of cognitive impairment, clear history of worsening symptoms) have been developed and are frequently employed. Among individuals who meet the core clinical criteria for probable AD dementia, biomarker evidence may help to increase the certainty that AD is the basis of the clinical dementia syndrome. Several cerebrospinal fluid and blood biomarkers have shown excellent diagnostic ability by identifying tau pathology and cerebral amyloid beta for AD. Neuroimaging is becoming increasingly important for identifying the underlying causes of cognitive impairment. Currently, MRI is considered the preferred neuroimaging modality for AD as it enables accurate measurement of the three-dimensional volume of brain structures, particularly the size of the hippocampus and related regions. CT may be used when MRI is not possible, such as in a patient with a pacemaker. 

PET is increasingly being used as a noninvasive method for depicting tau pathology deposition and distribution in patients with cognitive impairment. In 2020, the US Food and Drug Administration approved the first tau PET tracer, ¹⁸F-flortaucipir, a significant achievement in improving AD diagnosis. 

Currently, the only therapies available for AD are symptomatic therapies. Cholinesterase inhibitors and a partial N-methyl-d-aspartate antagonist are the standard medical treatment for AD. Recently approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021; and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents are often used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and/or sleep disorders, which can be problematic. Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of Alzheimer's disease (AD). 

AD is the most common type of dementia. It is characterized by cognitive and behavioral impairment that significantly impairs a patient's social and occupational functioning. The predominant AD pathogenesis hypothesis suggests that AD is largely caused by the accumulation of insoluble amyloid beta deposits and neurofibrillary tangles induced by highly phosphorylated tau proteins in the neocortex, hippocampus, and amygdala, as well as significant loss of neurons and synapses, which leads to brain atrophy. Estimates suggest that approximately 6.2 million people ≥ 65 years of age have AD and that by 2060, the number of Americans with AD may increase to 13.8 million, the result of an aging population and the lack of effective prevention and treatment strategies. AD is a chronic disease that confers tremendous emotional and economic burdens to individuals, families, and society. 

Insidiously progressive memory loss is commonly seen in patients presenting with AD. As the disease progresses over the course of several years, other areas of cognition are impaired. Patients may develop language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes are also observed in many individuals with AD.

Criteria for the clinical diagnosis of AD (eg, insidious onset of cognitive impairment, clear history of worsening symptoms) have been developed and are frequently employed. Among individuals who meet the core clinical criteria for probable AD dementia, biomarker evidence may help to increase the certainty that AD is the basis of the clinical dementia syndrome. Several cerebrospinal fluid and blood biomarkers have shown excellent diagnostic ability by identifying tau pathology and cerebral amyloid beta for AD. Neuroimaging is becoming increasingly important for identifying the underlying causes of cognitive impairment. Currently, MRI is considered the preferred neuroimaging modality for AD as it enables accurate measurement of the three-dimensional volume of brain structures, particularly the size of the hippocampus and related regions. CT may be used when MRI is not possible, such as in a patient with a pacemaker. 

PET is increasingly being used as a noninvasive method for depicting tau pathology deposition and distribution in patients with cognitive impairment. In 2020, the US Food and Drug Administration approved the first tau PET tracer, ¹⁸F-flortaucipir, a significant achievement in improving AD diagnosis. 

Currently, the only therapies available for AD are symptomatic therapies. Cholinesterase inhibitors and a partial N-methyl-d-aspartate antagonist are the standard medical treatment for AD. Recently approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021; and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents are often used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and/or sleep disorders, which can be problematic. Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of Alzheimer's disease (AD). 

AD is the most common type of dementia. It is characterized by cognitive and behavioral impairment that significantly impairs a patient's social and occupational functioning. The predominant AD pathogenesis hypothesis suggests that AD is largely caused by the accumulation of insoluble amyloid beta deposits and neurofibrillary tangles induced by highly phosphorylated tau proteins in the neocortex, hippocampus, and amygdala, as well as significant loss of neurons and synapses, which leads to brain atrophy. Estimates suggest that approximately 6.2 million people ≥ 65 years of age have AD and that by 2060, the number of Americans with AD may increase to 13.8 million, the result of an aging population and the lack of effective prevention and treatment strategies. AD is a chronic disease that confers tremendous emotional and economic burdens to individuals, families, and society. 

Insidiously progressive memory loss is commonly seen in patients presenting with AD. As the disease progresses over the course of several years, other areas of cognition are impaired. Patients may develop language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes are also observed in many individuals with AD.

Criteria for the clinical diagnosis of AD (eg, insidious onset of cognitive impairment, clear history of worsening symptoms) have been developed and are frequently employed. Among individuals who meet the core clinical criteria for probable AD dementia, biomarker evidence may help to increase the certainty that AD is the basis of the clinical dementia syndrome. Several cerebrospinal fluid and blood biomarkers have shown excellent diagnostic ability by identifying tau pathology and cerebral amyloid beta for AD. Neuroimaging is becoming increasingly important for identifying the underlying causes of cognitive impairment. Currently, MRI is considered the preferred neuroimaging modality for AD as it enables accurate measurement of the three-dimensional volume of brain structures, particularly the size of the hippocampus and related regions. CT may be used when MRI is not possible, such as in a patient with a pacemaker. 

PET is increasingly being used as a noninvasive method for depicting tau pathology deposition and distribution in patients with cognitive impairment. In 2020, the US Food and Drug Administration approved the first tau PET tracer, ¹⁸F-flortaucipir, a significant achievement in improving AD diagnosis. 

Currently, the only therapies available for AD are symptomatic therapies. Cholinesterase inhibitors and a partial N-methyl-d-aspartate antagonist are the standard medical treatment for AD. Recently approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021; and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents are often used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and/or sleep disorders, which can be problematic. Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Deep sleep may function as a buffer against cognitive decline in older adults with Alzheimer’s disease (AD) pathology by protecting cognitive reserve, new research suggests.

Investigators found that deep sleep, also known as non-REM (NREM) slow-wave sleep, can protect memory function in cognitively normal adults with a high beta-amyloid burden.

“Think of deep sleep almost like a life raft that keeps memory afloat, rather than memory getting dragged down by the weight of Alzheimer’s disease pathology,” senior investigator Matthew Walker, PhD, professor of neuroscience and psychology, University of California, Berkeley, said in a news release.

The study was published online in BMC Medicine.
 

Resilience factor

Studying resilience to existing brain pathology is “an exciting new research direction,” lead author Zsófia Zavecz, PhD, with the Center for Human Sleep Science at the University of California, Berkeley, said in an interview.

“That is, what factors explain the individual differences in cognitive function despite the same level of brain pathology, and how do some people with significant pathology have largely preserved memory?” she added.

The study included 62 cognitively normal older adults from the Berkeley Aging Cohort Study.

Sleep EEG recordings were obtained over 2 nights in a sleep lab and PET scans were used to quantify beta-amyloid. Half of the participants had high beta-amyloid burden and half were beta-amyloid negative.

After the sleep studies, all participants completed a memory task involving matching names to faces.

The results suggest that deep NREM slow-wave sleep significantly moderates the effect of beta-amyloid status on memory function.

Specifically, NREM slow-wave activity selectively supported superior memory function in adults with high beta-amyloid burden, who are most in need of cognitive reserve (B = 2.694, P = .019), the researchers report.

In contrast, adults without significant beta-amyloid pathological burden – and thus without the same need for cognitive reserve – did not similarly benefit from NREM slow-wave activity (B = –0.115, P = .876).

The findings remained significant after adjusting for age, sex, body mass index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity.

Dr. Zavecz said there are several potential reasons why deep sleep may support cognitive reserve.

One is that during deep sleep specifically, memories are replayed in the brain, and this results in a “neural reorganization” that helps stabilize the memory and make it more permanent.

“Other explanations include deep sleep’s role in maintaining homeostasis in the brain’s capacity to form new neural connections and providing an optimal brain state for the clearance of toxins interfering with healthy brain functioning,” she noted.

“The extent to which sleep could offer a protective buffer against severe cognitive impairment remains to be tested. However, this study is the first step in hopefully a series of new research that will investigate sleep as a cognitive reserve factor,” said Dr. Zavecz.
 

Encouraging data

Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said although the study sample is small, the results are “encouraging because sleep is a modifiable factor and can therefore be targeted.”

“More work is needed in a larger population before we can fully leverage this stage of sleep to reduce the risk of developing cognitive decline,” Dr. Griffin said.

Also weighing in on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said the study is “exciting on two fronts – we may have an additional marker for the development of Alzheimer’s disease to predict risk and track disease, but also targets for early intervention with sleep architecture–enhancing therapies, be they drug, device, or digital.”

“For the sake of our brain health, we all must get very familiar with the concept of cognitive or brain reserve,” said Dr. Lakhan, who was not involved in the study.

“Brain reserve refers to our ability to buttress against the threat of dementia and classically it’s been associated with ongoing brain stimulation (i.e., higher education, cognitively demanding job),” he noted.

“This line of research now opens the door that optimal sleep health – especially deep NREM slow wave sleep – correlates with greater brain reserve against Alzheimer’s disease,” Dr. Lakhan said.

The study was supported by the National Institutes of Health and the University of California, Berkeley. Dr. Walker serves as an advisor to and has equity interest in Bryte, Shuni, Oura, and StimScience. Dr. Zavecz and Dr. Lakhan report no relevant financial relationships.

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

Deep sleep may function as a buffer against cognitive decline in older adults with Alzheimer’s disease (AD) pathology by protecting cognitive reserve, new research suggests.

Investigators found that deep sleep, also known as non-REM (NREM) slow-wave sleep, can protect memory function in cognitively normal adults with a high beta-amyloid burden.

“Think of deep sleep almost like a life raft that keeps memory afloat, rather than memory getting dragged down by the weight of Alzheimer’s disease pathology,” senior investigator Matthew Walker, PhD, professor of neuroscience and psychology, University of California, Berkeley, said in a news release.

The study was published online in BMC Medicine.
 

Resilience factor

Studying resilience to existing brain pathology is “an exciting new research direction,” lead author Zsófia Zavecz, PhD, with the Center for Human Sleep Science at the University of California, Berkeley, said in an interview.

“That is, what factors explain the individual differences in cognitive function despite the same level of brain pathology, and how do some people with significant pathology have largely preserved memory?” she added.

The study included 62 cognitively normal older adults from the Berkeley Aging Cohort Study.

Sleep EEG recordings were obtained over 2 nights in a sleep lab and PET scans were used to quantify beta-amyloid. Half of the participants had high beta-amyloid burden and half were beta-amyloid negative.

After the sleep studies, all participants completed a memory task involving matching names to faces.

The results suggest that deep NREM slow-wave sleep significantly moderates the effect of beta-amyloid status on memory function.

Specifically, NREM slow-wave activity selectively supported superior memory function in adults with high beta-amyloid burden, who are most in need of cognitive reserve (B = 2.694, P = .019), the researchers report.

In contrast, adults without significant beta-amyloid pathological burden – and thus without the same need for cognitive reserve – did not similarly benefit from NREM slow-wave activity (B = –0.115, P = .876).

The findings remained significant after adjusting for age, sex, body mass index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity.

Dr. Zavecz said there are several potential reasons why deep sleep may support cognitive reserve.

One is that during deep sleep specifically, memories are replayed in the brain, and this results in a “neural reorganization” that helps stabilize the memory and make it more permanent.

“Other explanations include deep sleep’s role in maintaining homeostasis in the brain’s capacity to form new neural connections and providing an optimal brain state for the clearance of toxins interfering with healthy brain functioning,” she noted.

“The extent to which sleep could offer a protective buffer against severe cognitive impairment remains to be tested. However, this study is the first step in hopefully a series of new research that will investigate sleep as a cognitive reserve factor,” said Dr. Zavecz.
 

Encouraging data

Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said although the study sample is small, the results are “encouraging because sleep is a modifiable factor and can therefore be targeted.”

“More work is needed in a larger population before we can fully leverage this stage of sleep to reduce the risk of developing cognitive decline,” Dr. Griffin said.

Also weighing in on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said the study is “exciting on two fronts – we may have an additional marker for the development of Alzheimer’s disease to predict risk and track disease, but also targets for early intervention with sleep architecture–enhancing therapies, be they drug, device, or digital.”

“For the sake of our brain health, we all must get very familiar with the concept of cognitive or brain reserve,” said Dr. Lakhan, who was not involved in the study.

“Brain reserve refers to our ability to buttress against the threat of dementia and classically it’s been associated with ongoing brain stimulation (i.e., higher education, cognitively demanding job),” he noted.

“This line of research now opens the door that optimal sleep health – especially deep NREM slow wave sleep – correlates with greater brain reserve against Alzheimer’s disease,” Dr. Lakhan said.

The study was supported by the National Institutes of Health and the University of California, Berkeley. Dr. Walker serves as an advisor to and has equity interest in Bryte, Shuni, Oura, and StimScience. Dr. Zavecz and Dr. Lakhan report no relevant financial relationships.

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

Deep sleep may function as a buffer against cognitive decline in older adults with Alzheimer’s disease (AD) pathology by protecting cognitive reserve, new research suggests.

Investigators found that deep sleep, also known as non-REM (NREM) slow-wave sleep, can protect memory function in cognitively normal adults with a high beta-amyloid burden.

“Think of deep sleep almost like a life raft that keeps memory afloat, rather than memory getting dragged down by the weight of Alzheimer’s disease pathology,” senior investigator Matthew Walker, PhD, professor of neuroscience and psychology, University of California, Berkeley, said in a news release.

The study was published online in BMC Medicine.
 

Resilience factor

Studying resilience to existing brain pathology is “an exciting new research direction,” lead author Zsófia Zavecz, PhD, with the Center for Human Sleep Science at the University of California, Berkeley, said in an interview.

“That is, what factors explain the individual differences in cognitive function despite the same level of brain pathology, and how do some people with significant pathology have largely preserved memory?” she added.

The study included 62 cognitively normal older adults from the Berkeley Aging Cohort Study.

Sleep EEG recordings were obtained over 2 nights in a sleep lab and PET scans were used to quantify beta-amyloid. Half of the participants had high beta-amyloid burden and half were beta-amyloid negative.

After the sleep studies, all participants completed a memory task involving matching names to faces.

The results suggest that deep NREM slow-wave sleep significantly moderates the effect of beta-amyloid status on memory function.

Specifically, NREM slow-wave activity selectively supported superior memory function in adults with high beta-amyloid burden, who are most in need of cognitive reserve (B = 2.694, P = .019), the researchers report.

In contrast, adults without significant beta-amyloid pathological burden – and thus without the same need for cognitive reserve – did not similarly benefit from NREM slow-wave activity (B = –0.115, P = .876).

The findings remained significant after adjusting for age, sex, body mass index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity.

Dr. Zavecz said there are several potential reasons why deep sleep may support cognitive reserve.

One is that during deep sleep specifically, memories are replayed in the brain, and this results in a “neural reorganization” that helps stabilize the memory and make it more permanent.

“Other explanations include deep sleep’s role in maintaining homeostasis in the brain’s capacity to form new neural connections and providing an optimal brain state for the clearance of toxins interfering with healthy brain functioning,” she noted.

“The extent to which sleep could offer a protective buffer against severe cognitive impairment remains to be tested. However, this study is the first step in hopefully a series of new research that will investigate sleep as a cognitive reserve factor,” said Dr. Zavecz.
 

Encouraging data

Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said although the study sample is small, the results are “encouraging because sleep is a modifiable factor and can therefore be targeted.”

“More work is needed in a larger population before we can fully leverage this stage of sleep to reduce the risk of developing cognitive decline,” Dr. Griffin said.

Also weighing in on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said the study is “exciting on two fronts – we may have an additional marker for the development of Alzheimer’s disease to predict risk and track disease, but also targets for early intervention with sleep architecture–enhancing therapies, be they drug, device, or digital.”

“For the sake of our brain health, we all must get very familiar with the concept of cognitive or brain reserve,” said Dr. Lakhan, who was not involved in the study.

“Brain reserve refers to our ability to buttress against the threat of dementia and classically it’s been associated with ongoing brain stimulation (i.e., higher education, cognitively demanding job),” he noted.

“This line of research now opens the door that optimal sleep health – especially deep NREM slow wave sleep – correlates with greater brain reserve against Alzheimer’s disease,” Dr. Lakhan said.

The study was supported by the National Institutes of Health and the University of California, Berkeley. Dr. Walker serves as an advisor to and has equity interest in Bryte, Shuni, Oura, and StimScience. Dr. Zavecz and Dr. Lakhan report no relevant financial relationships.

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

The Food and Drug Administration has approved the antipsychotic brexpiprazole (Rexulti, Otsuka and Lundbeck) for agitation associated with Alzheimer’s disease (AD), making it the first FDA-approved drug for this indication.

“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” Tiffany Farchione, MD, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a news release.

Olivier Le Moal/Getty Images

Agitation can include symptoms that range from pacing or restlessness to verbal and physical aggression. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression,” Dr. Farchione said.

Brexpiprazole was approved by the FDA in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

Approval of the supplemental application for brexpiprazole for agitation associated with AD dementia was based on results of two randomized, double-blind, placebo-controlled studies.

In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements in agitation symptoms, as shown by total Cohen-Mansfield Agitation Inventory (CMAI) score, compared with patients who received placebo.

The recommended starting dosage for the treatment of agitation associated with AD dementia is 0.5 mg once daily on days 1-7; it was increased to 1 mg once daily on days 8-14 and then to the recommended target dose of 2 mg once daily.

The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, depending on clinical response and tolerability.

The most common side effects of brexpiprazole in patients with agitation associated with AD dementia include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances.

The drug includes a boxed warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

The supplemental application for brexpiprazole for agitation had fast-track designation.

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

The Food and Drug Administration has approved the antipsychotic brexpiprazole (Rexulti, Otsuka and Lundbeck) for agitation associated with Alzheimer’s disease (AD), making it the first FDA-approved drug for this indication.

“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” Tiffany Farchione, MD, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a news release.

Olivier Le Moal/Getty Images

Agitation can include symptoms that range from pacing or restlessness to verbal and physical aggression. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression,” Dr. Farchione said.

Brexpiprazole was approved by the FDA in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

Approval of the supplemental application for brexpiprazole for agitation associated with AD dementia was based on results of two randomized, double-blind, placebo-controlled studies.

In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements in agitation symptoms, as shown by total Cohen-Mansfield Agitation Inventory (CMAI) score, compared with patients who received placebo.

The recommended starting dosage for the treatment of agitation associated with AD dementia is 0.5 mg once daily on days 1-7; it was increased to 1 mg once daily on days 8-14 and then to the recommended target dose of 2 mg once daily.

The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, depending on clinical response and tolerability.

The most common side effects of brexpiprazole in patients with agitation associated with AD dementia include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances.

The drug includes a boxed warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

The supplemental application for brexpiprazole for agitation had fast-track designation.

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

The Food and Drug Administration has approved the antipsychotic brexpiprazole (Rexulti, Otsuka and Lundbeck) for agitation associated with Alzheimer’s disease (AD), making it the first FDA-approved drug for this indication.

“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” Tiffany Farchione, MD, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a news release.

Olivier Le Moal/Getty Images

Agitation can include symptoms that range from pacing or restlessness to verbal and physical aggression. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression,” Dr. Farchione said.

Brexpiprazole was approved by the FDA in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

Approval of the supplemental application for brexpiprazole for agitation associated with AD dementia was based on results of two randomized, double-blind, placebo-controlled studies.

In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements in agitation symptoms, as shown by total Cohen-Mansfield Agitation Inventory (CMAI) score, compared with patients who received placebo.

The recommended starting dosage for the treatment of agitation associated with AD dementia is 0.5 mg once daily on days 1-7; it was increased to 1 mg once daily on days 8-14 and then to the recommended target dose of 2 mg once daily.

The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, depending on clinical response and tolerability.

The most common side effects of brexpiprazole in patients with agitation associated with AD dementia include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances.

The drug includes a boxed warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

The supplemental application for brexpiprazole for agitation had fast-track designation.

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

Untreated hearing loss increases dementia risk in middle-aged and older adults, new research confirms. A large observational study from the United Kingdom showed a 42% increased risk for dementia in people with hearing loss compared with their peers with no hearing trouble. In addition, there was no increased risk in those with hearing loss who used hearing aids.

“The evidence is building that hearing loss may be the most impactful modifiable risk factor for dementia in mid-life, but the effectiveness of hearing aid use on reducing the risk of dementia in the real world has remained unclear,” Dongshan Zhu, PhD, with Shandong University, Jinan, China, said in a news release.

“Our study provides the best evidence to date to suggest that hearing aids could be a minimally invasive, cost-effective treatment to mitigate the potential impact of hearing loss on dementia,” Dr. Zhu said.

The study, which was published online in Lancet Public Health, comes on the heels of the 2020 Lancet Commission report on dementia, which suggested hearing loss may be linked to approximately 8% of worldwide dementia cases.
 

‘Compelling’ evidence

For the study, investigators analyzed longitudinal data on 437,704 individuals, most of whom were White, from the UK Biobank (54% female; mean age at baseline, 56 years). Roughly three quarters of the cohort had no hearing loss and one quarter had some level of hearing loss, with 12% of these individuals using hearing aids.

After the researchers controlled for relevant cofactors, compared with people without hearing loss, those with hearing loss who were not using hearing aids had an increased risk for all-cause dementia (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.29-1.56).

No increased risk was seen in people with hearing loss who were using hearing aids (HR, 1.04; 95% CI, 0.98-1.10).

The positive association of hearing aid use was observed in all-cause dementia and cause-specific dementia subtypes, including Alzheimer’s disease, vascular dementia, and non–Alzheimer’s disease nonvascular dementia.

The data also suggest that the protection against dementia conferred by hearing aid use most likely stems from direct effects from hearing aids rather than indirect mediators, such as social isolation, loneliness, and low mood.

Dr. Zhu said the findings highlight the “urgent need” for the early use of hearing aids when an individual starts having trouble hearing.

“A group effort from across society is necessary, including raising awareness of hearing loss and the potential links with dementia; increasing accessibility to hearing aids by reducing cost; and more support for primary care workers to screen for hearing impairment, raise awareness, and deliver treatment such as fitting hearing aids,” Dr. Zhu said.

Writing in a linked comment, Gill Livingston, MD, and Sergi Costafreda, MD, PhD, with University College London, noted that with addition of this study, “the evidence that hearing aids are a powerful tool to reduce the risk of dementia in people with hearing loss, is as good as possible without randomized controlled trials, which might not be practically possible or ethical because people with hearing loss should not be stopped from using effective treatments.”

“The evidence is compelling that treating hearing loss is a promising way of reducing dementia risk. This is the time to increase awareness of and detection of hearing loss, as well as the acceptability and usability of hearing aids,” Dr. Livingston and Dr. Costafreda added.
 

High-quality evidence – with caveats

Several experts offered perspective on the analysis in a statement from the U.K.-based nonprofit Science Media Centre, which was not involved with the conduct of this study. Charles Marshall, MRCP, PhD, with Queen Mary University of London, said that the study provides “high-quality evidence” that those with hearing loss who use hearing aids are at lower risk for dementia than are those with hearing loss who do not use hearing aids.

“This raises the possibility that a proportion of dementia cases could be prevented by using hearing aids to correct hearing loss. However, the observational nature of this study makes it difficult to be sure that hearing aids are actually causing the reduced risk of dementia,” Dr. Marshall added.

“Hearing aids produce slightly distorted sound, and the brain has to adapt to this in order for hearing aids to be helpful,” he said. “People who are at risk of developing dementia in the future may have early changes in their brain that impair this adaptation, and this may lead to them choosing to not use hearing aids. This would confound the association, creating the appearance that hearing aids were reducing dementia risk, when actually their use was just identifying people with relatively healthy brains,” Dr. Marshall added.

Tara Spires-Jones, PhD, with the University of Edinburgh, said this “well-conducted” study confirms previous similar studies showing an association between hearing loss and dementia risk.

Echoing Dr. Marshall, Dr. Spires-Jones noted that this type of study cannot prove conclusively that hearing loss causes dementia.

“For example,” she said, “it is possible that people who are already in the very early stages of disease are less likely to seek help for hearing loss. However, on balance, this study and the rest of the data in the field indicate that keeping your brain healthy and engaged reduces dementia risk.”

Dr. Spires-Jones said that she agrees with the investigators that it’s “important to help people with hearing loss to get effective hearing aids to help keep their brains engaged through allowing richer social interactions.”

This study was funded by the National Natural Science Foundation of China and Shandong Province, Taishan Scholars Project, China Medical Board, and China Postdoctoral Science Foundation. Dr. Zhu, Dr. Livingston, Dr. Costafreda, Dr. Marshall, and Dr. Spires-Jones have no relevant disclosures.
 

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

Untreated hearing loss increases dementia risk in middle-aged and older adults, new research confirms. A large observational study from the United Kingdom showed a 42% increased risk for dementia in people with hearing loss compared with their peers with no hearing trouble. In addition, there was no increased risk in those with hearing loss who used hearing aids.

“The evidence is building that hearing loss may be the most impactful modifiable risk factor for dementia in mid-life, but the effectiveness of hearing aid use on reducing the risk of dementia in the real world has remained unclear,” Dongshan Zhu, PhD, with Shandong University, Jinan, China, said in a news release.

“Our study provides the best evidence to date to suggest that hearing aids could be a minimally invasive, cost-effective treatment to mitigate the potential impact of hearing loss on dementia,” Dr. Zhu said.

The study, which was published online in Lancet Public Health, comes on the heels of the 2020 Lancet Commission report on dementia, which suggested hearing loss may be linked to approximately 8% of worldwide dementia cases.
 

‘Compelling’ evidence

For the study, investigators analyzed longitudinal data on 437,704 individuals, most of whom were White, from the UK Biobank (54% female; mean age at baseline, 56 years). Roughly three quarters of the cohort had no hearing loss and one quarter had some level of hearing loss, with 12% of these individuals using hearing aids.

After the researchers controlled for relevant cofactors, compared with people without hearing loss, those with hearing loss who were not using hearing aids had an increased risk for all-cause dementia (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.29-1.56).

No increased risk was seen in people with hearing loss who were using hearing aids (HR, 1.04; 95% CI, 0.98-1.10).

The positive association of hearing aid use was observed in all-cause dementia and cause-specific dementia subtypes, including Alzheimer’s disease, vascular dementia, and non–Alzheimer’s disease nonvascular dementia.

The data also suggest that the protection against dementia conferred by hearing aid use most likely stems from direct effects from hearing aids rather than indirect mediators, such as social isolation, loneliness, and low mood.

Dr. Zhu said the findings highlight the “urgent need” for the early use of hearing aids when an individual starts having trouble hearing.

“A group effort from across society is necessary, including raising awareness of hearing loss and the potential links with dementia; increasing accessibility to hearing aids by reducing cost; and more support for primary care workers to screen for hearing impairment, raise awareness, and deliver treatment such as fitting hearing aids,” Dr. Zhu said.

Writing in a linked comment, Gill Livingston, MD, and Sergi Costafreda, MD, PhD, with University College London, noted that with addition of this study, “the evidence that hearing aids are a powerful tool to reduce the risk of dementia in people with hearing loss, is as good as possible without randomized controlled trials, which might not be practically possible or ethical because people with hearing loss should not be stopped from using effective treatments.”

“The evidence is compelling that treating hearing loss is a promising way of reducing dementia risk. This is the time to increase awareness of and detection of hearing loss, as well as the acceptability and usability of hearing aids,” Dr. Livingston and Dr. Costafreda added.
 

High-quality evidence – with caveats

Several experts offered perspective on the analysis in a statement from the U.K.-based nonprofit Science Media Centre, which was not involved with the conduct of this study. Charles Marshall, MRCP, PhD, with Queen Mary University of London, said that the study provides “high-quality evidence” that those with hearing loss who use hearing aids are at lower risk for dementia than are those with hearing loss who do not use hearing aids.

“This raises the possibility that a proportion of dementia cases could be prevented by using hearing aids to correct hearing loss. However, the observational nature of this study makes it difficult to be sure that hearing aids are actually causing the reduced risk of dementia,” Dr. Marshall added.

“Hearing aids produce slightly distorted sound, and the brain has to adapt to this in order for hearing aids to be helpful,” he said. “People who are at risk of developing dementia in the future may have early changes in their brain that impair this adaptation, and this may lead to them choosing to not use hearing aids. This would confound the association, creating the appearance that hearing aids were reducing dementia risk, when actually their use was just identifying people with relatively healthy brains,” Dr. Marshall added.

Tara Spires-Jones, PhD, with the University of Edinburgh, said this “well-conducted” study confirms previous similar studies showing an association between hearing loss and dementia risk.

Echoing Dr. Marshall, Dr. Spires-Jones noted that this type of study cannot prove conclusively that hearing loss causes dementia.

“For example,” she said, “it is possible that people who are already in the very early stages of disease are less likely to seek help for hearing loss. However, on balance, this study and the rest of the data in the field indicate that keeping your brain healthy and engaged reduces dementia risk.”

Dr. Spires-Jones said that she agrees with the investigators that it’s “important to help people with hearing loss to get effective hearing aids to help keep their brains engaged through allowing richer social interactions.”

This study was funded by the National Natural Science Foundation of China and Shandong Province, Taishan Scholars Project, China Medical Board, and China Postdoctoral Science Foundation. Dr. Zhu, Dr. Livingston, Dr. Costafreda, Dr. Marshall, and Dr. Spires-Jones have no relevant disclosures.
 

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

Untreated hearing loss increases dementia risk in middle-aged and older adults, new research confirms. A large observational study from the United Kingdom showed a 42% increased risk for dementia in people with hearing loss compared with their peers with no hearing trouble. In addition, there was no increased risk in those with hearing loss who used hearing aids.

“The evidence is building that hearing loss may be the most impactful modifiable risk factor for dementia in mid-life, but the effectiveness of hearing aid use on reducing the risk of dementia in the real world has remained unclear,” Dongshan Zhu, PhD, with Shandong University, Jinan, China, said in a news release.

“Our study provides the best evidence to date to suggest that hearing aids could be a minimally invasive, cost-effective treatment to mitigate the potential impact of hearing loss on dementia,” Dr. Zhu said.

The study, which was published online in Lancet Public Health, comes on the heels of the 2020 Lancet Commission report on dementia, which suggested hearing loss may be linked to approximately 8% of worldwide dementia cases.
 

‘Compelling’ evidence

For the study, investigators analyzed longitudinal data on 437,704 individuals, most of whom were White, from the UK Biobank (54% female; mean age at baseline, 56 years). Roughly three quarters of the cohort had no hearing loss and one quarter had some level of hearing loss, with 12% of these individuals using hearing aids.

After the researchers controlled for relevant cofactors, compared with people without hearing loss, those with hearing loss who were not using hearing aids had an increased risk for all-cause dementia (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.29-1.56).

No increased risk was seen in people with hearing loss who were using hearing aids (HR, 1.04; 95% CI, 0.98-1.10).

The positive association of hearing aid use was observed in all-cause dementia and cause-specific dementia subtypes, including Alzheimer’s disease, vascular dementia, and non–Alzheimer’s disease nonvascular dementia.

The data also suggest that the protection against dementia conferred by hearing aid use most likely stems from direct effects from hearing aids rather than indirect mediators, such as social isolation, loneliness, and low mood.

Dr. Zhu said the findings highlight the “urgent need” for the early use of hearing aids when an individual starts having trouble hearing.

“A group effort from across society is necessary, including raising awareness of hearing loss and the potential links with dementia; increasing accessibility to hearing aids by reducing cost; and more support for primary care workers to screen for hearing impairment, raise awareness, and deliver treatment such as fitting hearing aids,” Dr. Zhu said.

Writing in a linked comment, Gill Livingston, MD, and Sergi Costafreda, MD, PhD, with University College London, noted that with addition of this study, “the evidence that hearing aids are a powerful tool to reduce the risk of dementia in people with hearing loss, is as good as possible without randomized controlled trials, which might not be practically possible or ethical because people with hearing loss should not be stopped from using effective treatments.”

“The evidence is compelling that treating hearing loss is a promising way of reducing dementia risk. This is the time to increase awareness of and detection of hearing loss, as well as the acceptability and usability of hearing aids,” Dr. Livingston and Dr. Costafreda added.
 

High-quality evidence – with caveats

Several experts offered perspective on the analysis in a statement from the U.K.-based nonprofit Science Media Centre, which was not involved with the conduct of this study. Charles Marshall, MRCP, PhD, with Queen Mary University of London, said that the study provides “high-quality evidence” that those with hearing loss who use hearing aids are at lower risk for dementia than are those with hearing loss who do not use hearing aids.

“This raises the possibility that a proportion of dementia cases could be prevented by using hearing aids to correct hearing loss. However, the observational nature of this study makes it difficult to be sure that hearing aids are actually causing the reduced risk of dementia,” Dr. Marshall added.

“Hearing aids produce slightly distorted sound, and the brain has to adapt to this in order for hearing aids to be helpful,” he said. “People who are at risk of developing dementia in the future may have early changes in their brain that impair this adaptation, and this may lead to them choosing to not use hearing aids. This would confound the association, creating the appearance that hearing aids were reducing dementia risk, when actually their use was just identifying people with relatively healthy brains,” Dr. Marshall added.

Tara Spires-Jones, PhD, with the University of Edinburgh, said this “well-conducted” study confirms previous similar studies showing an association between hearing loss and dementia risk.

Echoing Dr. Marshall, Dr. Spires-Jones noted that this type of study cannot prove conclusively that hearing loss causes dementia.

“For example,” she said, “it is possible that people who are already in the very early stages of disease are less likely to seek help for hearing loss. However, on balance, this study and the rest of the data in the field indicate that keeping your brain healthy and engaged reduces dementia risk.”

Dr. Spires-Jones said that she agrees with the investigators that it’s “important to help people with hearing loss to get effective hearing aids to help keep their brains engaged through allowing richer social interactions.”

This study was funded by the National Natural Science Foundation of China and Shandong Province, Taishan Scholars Project, China Medical Board, and China Postdoctoral Science Foundation. Dr. Zhu, Dr. Livingston, Dr. Costafreda, Dr. Marshall, and Dr. Spires-Jones have no relevant disclosures.
 

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

Screening for cognitive impairment should be part of multidisciplinary care for stroke survivors, the American Heart Association says in a new scientific statement.

“Cognitive impairment after stroke is very common, is associated with other post-stroke outcomes, and often has significant impact on the quality of life,” Nada El Husseini, MD, MHSc, chair of the scientific statement writing group, told this news organization.

“It is important to screen stroke survivors for cognitive impairment as well as for associated comorbidities such as mood and sleep disorders,” said Dr. El Husseini, associate professor of neurology at Duke University Medical Center in Durham, N.C.

The scientific statement was published online in Stroke. It’s the first to specifically focus on the cognitive impairment resulting from an overt stroke (ischemic or hemorrhagic).
 

‘Actionable’ considerations for care

The writing group performed a “scoping” review of the literature on the prevalence, diagnosis, and management of poststroke cognitive impairment (PSCI) to provide a framework for “actionable considerations” for clinical practice as well as to highlight gaps needing additional studies, Dr. El Husseini explained.

PSCI, ranging from mild to severe, occurs in up to 60% of stroke survivors in the first year after stroke; yet, it is often underreported and underdiagnosed, the writing group notes.

Up to 20% of stroke survivors who experience mild cognitive impairment fully recover cognitive function, and cognitive recovery is most likely within the first 6 months after a stroke.

However, improvement in cognitive impairment without return to prestroke levels is more frequent than is complete recovery. As many as one in three stroke survivors may develop dementia within 5 years of stroke.

The writing group also notes that PSCI is often associated with other conditions, including physical disability, sleep disorders, behavioral and personality changes, depression, and other neuropsychological changes – each of which may contribute to lower quality of life.

Currently, there is no “gold standard” for cognitive screening following stroke, but several brief cognitive screening tests, including the Mini–Mental State Examination and the Montreal Cognitive Assessment, are widely used to identify cognitive impairment after stroke.

The statement also highlights the importance of assessing cognitive changes over time after stroke. Stroke survivors who experience unexplained difficulties with cognitive-related activities of daily living, following care instructions, or providing a reliable health history may be candidates for additional cognitive screening.
 

Manage risk factors to prevent repeat stroke

“Anticipatory guidance regarding home and driving safety and, return to work (if applicable) along with interdisciplinary collaboration among different medical and ancillary specialists in the diagnosis and management of cognitive impairment is key for the holistic care of stroke survivors,” Dr. El Husseini told this news organization.

The multidisciplinary poststroke health care team could include neurologists, occupational therapists, speech therapists, nurses, neuropsychologists, gerontologists, and primary care providers.

“Because recurrent stroke is strongly associated with the development of cognitive impairment and dementia, prevention of recurrent strokes should be sought to decrease that risk,” Dr. El Husseini said. This includes addressing stroke risk factors, including high blood pressure, high cholesterol, type 2 diabetes, and atrial fibrillation.

The writing group says research is needed in the future to determine how cognitive impairment develops after stroke and the impact of nonbrain factors, including infection, frailty, and social factors.

Further research is also needed to determine best practices for cognitive screening after stroke, including the development and use of screening instruments that consider demographic, cultural, and linguistic factors in determining “normal” function.

“Perhaps the most pressing need, however, is the development of effective and culturally relevant treatments for poststroke cognitive impairment,” Dr. El Husseini said in a news release.

“We hope to see big enough clinical trials that assess various techniques, medications, and lifestyle changes in diverse groups of patients that may help improve cognitive function,” she added.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Stroke Council, the Council on Cardiovascular Radiology and Intervention, the Council on Hypertension, and the Council on Lifestyle and Cardiometabolic Health.
 

Screening for cognitive impairment should be part of multidisciplinary care for stroke survivors, the American Heart Association says in a new scientific statement.

“Cognitive impairment after stroke is very common, is associated with other post-stroke outcomes, and often has significant impact on the quality of life,” Nada El Husseini, MD, MHSc, chair of the scientific statement writing group, told this news organization.

“It is important to screen stroke survivors for cognitive impairment as well as for associated comorbidities such as mood and sleep disorders,” said Dr. El Husseini, associate professor of neurology at Duke University Medical Center in Durham, N.C.

The scientific statement was published online in Stroke. It’s the first to specifically focus on the cognitive impairment resulting from an overt stroke (ischemic or hemorrhagic).
 

‘Actionable’ considerations for care

The writing group performed a “scoping” review of the literature on the prevalence, diagnosis, and management of poststroke cognitive impairment (PSCI) to provide a framework for “actionable considerations” for clinical practice as well as to highlight gaps needing additional studies, Dr. El Husseini explained.

PSCI, ranging from mild to severe, occurs in up to 60% of stroke survivors in the first year after stroke; yet, it is often underreported and underdiagnosed, the writing group notes.

Up to 20% of stroke survivors who experience mild cognitive impairment fully recover cognitive function, and cognitive recovery is most likely within the first 6 months after a stroke.

However, improvement in cognitive impairment without return to prestroke levels is more frequent than is complete recovery. As many as one in three stroke survivors may develop dementia within 5 years of stroke.

The writing group also notes that PSCI is often associated with other conditions, including physical disability, sleep disorders, behavioral and personality changes, depression, and other neuropsychological changes – each of which may contribute to lower quality of life.

Currently, there is no “gold standard” for cognitive screening following stroke, but several brief cognitive screening tests, including the Mini–Mental State Examination and the Montreal Cognitive Assessment, are widely used to identify cognitive impairment after stroke.

The statement also highlights the importance of assessing cognitive changes over time after stroke. Stroke survivors who experience unexplained difficulties with cognitive-related activities of daily living, following care instructions, or providing a reliable health history may be candidates for additional cognitive screening.
 

Manage risk factors to prevent repeat stroke

“Anticipatory guidance regarding home and driving safety and, return to work (if applicable) along with interdisciplinary collaboration among different medical and ancillary specialists in the diagnosis and management of cognitive impairment is key for the holistic care of stroke survivors,” Dr. El Husseini told this news organization.

The multidisciplinary poststroke health care team could include neurologists, occupational therapists, speech therapists, nurses, neuropsychologists, gerontologists, and primary care providers.

“Because recurrent stroke is strongly associated with the development of cognitive impairment and dementia, prevention of recurrent strokes should be sought to decrease that risk,” Dr. El Husseini said. This includes addressing stroke risk factors, including high blood pressure, high cholesterol, type 2 diabetes, and atrial fibrillation.

The writing group says research is needed in the future to determine how cognitive impairment develops after stroke and the impact of nonbrain factors, including infection, frailty, and social factors.

Further research is also needed to determine best practices for cognitive screening after stroke, including the development and use of screening instruments that consider demographic, cultural, and linguistic factors in determining “normal” function.

“Perhaps the most pressing need, however, is the development of effective and culturally relevant treatments for poststroke cognitive impairment,” Dr. El Husseini said in a news release.

“We hope to see big enough clinical trials that assess various techniques, medications, and lifestyle changes in diverse groups of patients that may help improve cognitive function,” she added.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Stroke Council, the Council on Cardiovascular Radiology and Intervention, the Council on Hypertension, and the Council on Lifestyle and Cardiometabolic Health.
 

Screening for cognitive impairment should be part of multidisciplinary care for stroke survivors, the American Heart Association says in a new scientific statement.

“Cognitive impairment after stroke is very common, is associated with other post-stroke outcomes, and often has significant impact on the quality of life,” Nada El Husseini, MD, MHSc, chair of the scientific statement writing group, told this news organization.

“It is important to screen stroke survivors for cognitive impairment as well as for associated comorbidities such as mood and sleep disorders,” said Dr. El Husseini, associate professor of neurology at Duke University Medical Center in Durham, N.C.

The scientific statement was published online in Stroke. It’s the first to specifically focus on the cognitive impairment resulting from an overt stroke (ischemic or hemorrhagic).
 

‘Actionable’ considerations for care

The writing group performed a “scoping” review of the literature on the prevalence, diagnosis, and management of poststroke cognitive impairment (PSCI) to provide a framework for “actionable considerations” for clinical practice as well as to highlight gaps needing additional studies, Dr. El Husseini explained.

PSCI, ranging from mild to severe, occurs in up to 60% of stroke survivors in the first year after stroke; yet, it is often underreported and underdiagnosed, the writing group notes.

Up to 20% of stroke survivors who experience mild cognitive impairment fully recover cognitive function, and cognitive recovery is most likely within the first 6 months after a stroke.

However, improvement in cognitive impairment without return to prestroke levels is more frequent than is complete recovery. As many as one in three stroke survivors may develop dementia within 5 years of stroke.

The writing group also notes that PSCI is often associated with other conditions, including physical disability, sleep disorders, behavioral and personality changes, depression, and other neuropsychological changes – each of which may contribute to lower quality of life.

Currently, there is no “gold standard” for cognitive screening following stroke, but several brief cognitive screening tests, including the Mini–Mental State Examination and the Montreal Cognitive Assessment, are widely used to identify cognitive impairment after stroke.

The statement also highlights the importance of assessing cognitive changes over time after stroke. Stroke survivors who experience unexplained difficulties with cognitive-related activities of daily living, following care instructions, or providing a reliable health history may be candidates for additional cognitive screening.
 

Manage risk factors to prevent repeat stroke

“Anticipatory guidance regarding home and driving safety and, return to work (if applicable) along with interdisciplinary collaboration among different medical and ancillary specialists in the diagnosis and management of cognitive impairment is key for the holistic care of stroke survivors,” Dr. El Husseini told this news organization.

The multidisciplinary poststroke health care team could include neurologists, occupational therapists, speech therapists, nurses, neuropsychologists, gerontologists, and primary care providers.

“Because recurrent stroke is strongly associated with the development of cognitive impairment and dementia, prevention of recurrent strokes should be sought to decrease that risk,” Dr. El Husseini said. This includes addressing stroke risk factors, including high blood pressure, high cholesterol, type 2 diabetes, and atrial fibrillation.

The writing group says research is needed in the future to determine how cognitive impairment develops after stroke and the impact of nonbrain factors, including infection, frailty, and social factors.

Further research is also needed to determine best practices for cognitive screening after stroke, including the development and use of screening instruments that consider demographic, cultural, and linguistic factors in determining “normal” function.

“Perhaps the most pressing need, however, is the development of effective and culturally relevant treatments for poststroke cognitive impairment,” Dr. El Husseini said in a news release.

“We hope to see big enough clinical trials that assess various techniques, medications, and lifestyle changes in diverse groups of patients that may help improve cognitive function,” she added.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Stroke Council, the Council on Cardiovascular Radiology and Intervention, the Council on Hypertension, and the Council on Lifestyle and Cardiometabolic Health.
 

BOSTON – Results of a phase 2 study demonstrate potential Alzheimer’s disease–modifying effects of an investigational oral antiamyloid agent, represented by positive changes in plasma and imaging biomarkers of Alzheimer’s disease pathology.

Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau₁₈₁) , a marker of amyloid-induced neuronal injury in Alzheimer’s disease, as well as slowing of hippocampal atrophy and stabilization of cognition.

“The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade, which leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau₁₈₁,” John Hey, PhD, Alzheon’s chief scientific officer, said in a statement.

“The severalfold greater reduction on the p-tau₁₈₁ biomarker in plasma compared to plaque-clearing antiamyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer’s patients,” Dr. Hey added.

The results were presented at the 2023 annual meeting of the American Academy of Neurology.
 

ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.

The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of Alzheimer’s disease pathology for 84 adults with early Alzheimer’s disease who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of patients with Alzheimer’s disease.

The mean age of the cohort was 69 years, and 51% are women; 70% had mild cognitive impairment, and 30% had mild Alzheimer’s disease. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half were taking a cholinesterase inhibitor.

Significant plasma p-tau₁₈₁ reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005, respectively), Dr. Hey reported.

After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer’s Disease Neuroimaging Initiative.

Composite cognitive z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. “These are very promising data,” Dr. Hey told conference attendees.

He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities–edema (ARIA-E).

The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 with placebo over 78 weeks for roughly 300 adults with early Alzheimer’s disease who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.

The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The U.S. Food and Drug Administration has granted ALZ-801 fast-track designation.
 

More accessible option?

Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, noted that the “biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access.”

It’s also noteworthy that ALZ-801 was not associated with ARIA-E, “which has been reported in other antiamyloid trials and can occasionally be serious,” Dr. Griffin said.

Overall, he said the results are “encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA,” Dr. Griffin said.

The study was funded by Alzheon. Dr. Hey is an employee of Alzheon and holds stock in the company. Dr. Griffin has disclosed no relevant financial relationships.

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

BOSTON – Results of a phase 2 study demonstrate potential Alzheimer’s disease–modifying effects of an investigational oral antiamyloid agent, represented by positive changes in plasma and imaging biomarkers of Alzheimer’s disease pathology.

Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau₁₈₁) , a marker of amyloid-induced neuronal injury in Alzheimer’s disease, as well as slowing of hippocampal atrophy and stabilization of cognition.

“The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade, which leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau₁₈₁,” John Hey, PhD, Alzheon’s chief scientific officer, said in a statement.

“The severalfold greater reduction on the p-tau₁₈₁ biomarker in plasma compared to plaque-clearing antiamyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer’s patients,” Dr. Hey added.

The results were presented at the 2023 annual meeting of the American Academy of Neurology.
 

ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.

The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of Alzheimer’s disease pathology for 84 adults with early Alzheimer’s disease who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of patients with Alzheimer’s disease.

The mean age of the cohort was 69 years, and 51% are women; 70% had mild cognitive impairment, and 30% had mild Alzheimer’s disease. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half were taking a cholinesterase inhibitor.

Significant plasma p-tau₁₈₁ reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005, respectively), Dr. Hey reported.

After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer’s Disease Neuroimaging Initiative.

Composite cognitive z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. “These are very promising data,” Dr. Hey told conference attendees.

He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities–edema (ARIA-E).

The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 with placebo over 78 weeks for roughly 300 adults with early Alzheimer’s disease who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.

The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The U.S. Food and Drug Administration has granted ALZ-801 fast-track designation.
 

More accessible option?

Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, noted that the “biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access.”

It’s also noteworthy that ALZ-801 was not associated with ARIA-E, “which has been reported in other antiamyloid trials and can occasionally be serious,” Dr. Griffin said.

Overall, he said the results are “encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA,” Dr. Griffin said.

The study was funded by Alzheon. Dr. Hey is an employee of Alzheon and holds stock in the company. Dr. Griffin has disclosed no relevant financial relationships.

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

BOSTON – Results of a phase 2 study demonstrate potential Alzheimer’s disease–modifying effects of an investigational oral antiamyloid agent, represented by positive changes in plasma and imaging biomarkers of Alzheimer’s disease pathology.

Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau₁₈₁) , a marker of amyloid-induced neuronal injury in Alzheimer’s disease, as well as slowing of hippocampal atrophy and stabilization of cognition.

“The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade, which leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau₁₈₁,” John Hey, PhD, Alzheon’s chief scientific officer, said in a statement.

“The severalfold greater reduction on the p-tau₁₈₁ biomarker in plasma compared to plaque-clearing antiamyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer’s patients,” Dr. Hey added.

The results were presented at the 2023 annual meeting of the American Academy of Neurology.
 

ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.

The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of Alzheimer’s disease pathology for 84 adults with early Alzheimer’s disease who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of patients with Alzheimer’s disease.

The mean age of the cohort was 69 years, and 51% are women; 70% had mild cognitive impairment, and 30% had mild Alzheimer’s disease. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half were taking a cholinesterase inhibitor.

Significant plasma p-tau₁₈₁ reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005, respectively), Dr. Hey reported.

After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer’s Disease Neuroimaging Initiative.

Composite cognitive z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. “These are very promising data,” Dr. Hey told conference attendees.

He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities–edema (ARIA-E).

The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 with placebo over 78 weeks for roughly 300 adults with early Alzheimer’s disease who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.

The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The U.S. Food and Drug Administration has granted ALZ-801 fast-track designation.
 

More accessible option?

Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, noted that the “biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access.”

It’s also noteworthy that ALZ-801 was not associated with ARIA-E, “which has been reported in other antiamyloid trials and can occasionally be serious,” Dr. Griffin said.

Overall, he said the results are “encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA,” Dr. Griffin said.

The study was funded by Alzheon. Dr. Hey is an employee of Alzheon and holds stock in the company. Dr. Griffin has disclosed no relevant financial relationships.

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

BOSTON – The investigational drug donanemab yielded greater amyloid clearance and amyloid plaque reduction than aducanumab in early, symptomatic Alzheimer’s disease, according to the results of a head-to-head study.

Nearly 40% of patients treated with donanemab had amyloid clearance at 6 months compared with less than 2% of those who received aducanumab, which was approved in 2021 amid a great deal of controversy.

Titration for donanemab progressed more quickly, with participants receiving a maximum dose twice as early as those on aducanumab, without any increase in rates of amyloid-related imaging abnormalities (ARIA) – the most common side effect of amyloid drugs.

Early results from the randomized phase 3 TRAILBLAZER-ALZ 4 trial of donanemab come just 3 months after the Food and Drug Administration denied manufacturer Eli Lilly’s request for accelerated approval for the drug.

“This study shows that the drug with the quicker titration scheme, donanemab, produced more amyloid lowering and did it without having more ARIA,” said lead investigator Stephen P. Salloway, MD, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor of neurology at Brown University.

The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
 

Multicenter, head-to-head trial

Donanemab received breakthrough therapy designation in 2021. The drug works similarly to aducanumab and lecanemab, which was approved earlier this year. All three bind to different parts of the amyloid molecule and stimulate an immune response to help clear amyloid plaques, although they each have a distinctive binding component.

TRAILBLAZER-ALZ 4 was conducted at 31 sites across the United States, enrolling 140 patients aged 50-85 years with early and symptomatic Alzheimer’s disease. Study participants received donanemab or aducanumab at escalating doses for 18 months.

Donanemab was titrated more quickly, with participants receiving 700 mg via IV infusion once a month for 3 months before reaching the maximum dose of 1,400 mg in the fourth month of the study.

Aducanumab titration was slower, beginning at 1 mg/kg via IV monthly for 2 months, then 3 mg/kg for another 2 months, and 6 mg/kg for 2 more months before reaching the maximum dose of 10 mg/kg in the seventh month.

After 6 months of treatment, PET scan analysis revealed that 37.9% of donanemab-treated patients achieved amyloid clearance compared with just 1.6% of those who received aducanumab (P < .001).

Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with 3.8% of patients in the aducanumab group (P = .008).

Amyloid levels were 65.2% lower in donanemab patients, while levels in those receiving aducanumab were reduced by 17.0% (P < .001). Among those with intermediate tau, amyloid levels decreased with donanemab by 63.9% and 25.4% with aducanumab (P ≤ .001).

Investigators also noted a greater reduction in plasma ptau217 with donanemab.

Adverse events were similar between groups, with 62.0% of the donanemab group and 66.7% of aducanumab-treated participants reporting an adverse event.

There were no serious adverse events due to ARIA with donanemab, but one participant in the aducanumab group had a serious adverse event linked to ARIA.

“Even though the amyloid lowering was greater with donanemab, the rate of ARIA was similar, which suggests that the speed and depth of amyloid removal is not driving ARIA,” Dr. Salloway said.

There are three other Trailblazer trials of donanemab. Unlike in similar trials, participants in all three of these studies who received the trial drug could discontinue treatment once criteria for amyloid clearance were met.

That’s precisely what happened with Trailblazer 2, the study on which Lilly based its request for accelerated approval. Ironically, that trial design also contributed to the FDA’s decision to reject that request.

The FDA required data from at least 100 patients who had received donanemab for a minimum of 1 year. While the trial included more than 100 patients, many patients discontinued treatment early after achieving the targeted amount of amyloid clearance.

“They had success, and they got punished for it, in my opinion,” Dr. Salloway said.

Final data from Trailblazer 2 is due in the next month, and if results are positive, Lilly is expected to file for full approval.
 

Questions remain

“This is an interesting study that suggests donanemab may remove amyloid faster in more people than aducanumab,” said Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings.

Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, also commented on the findings. He noted that faster amyloid clearance “means less time for requiring sometimes burdensome and expensive infusions.”

Both Dr. Snyder and Dr. Fillit noted that longer-term results are needed, along with studies of whether amyloid clearance offers a protective benefit against Alzheimer’s dementia. More results from Trailblazer 4 will be reported after 12 months and again at 18 months.

“There are obviously still a lot of questions about these drugs and whether reducing amyloid plaque will actually preserve cognitive function or at least slow decline,” Dr. Fillit said.

It will also be important to understand the timing of treatment, including when anti-amyloid therapies should be administered and for how long.

“It will be important to understand how these results translate to patient care and treatment plans, should this drug receive FDA approval,” Dr. Snyder said. “Patients should have the opportunity to make a decision, alongside their physician, on a treatment path that is right for them.”

The study was funded by Eli Lilly. Dr. Salloway has been a consultant for Biogen, EISAI, Lilly, Genentech, Novo Nordisk, Prothena, and others. Dr. Snyder and Dr. Fillit have disclosed no relevant financial relationships.
 

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

BOSTON – The investigational drug donanemab yielded greater amyloid clearance and amyloid plaque reduction than aducanumab in early, symptomatic Alzheimer’s disease, according to the results of a head-to-head study.

Nearly 40% of patients treated with donanemab had amyloid clearance at 6 months compared with less than 2% of those who received aducanumab, which was approved in 2021 amid a great deal of controversy.

Titration for donanemab progressed more quickly, with participants receiving a maximum dose twice as early as those on aducanumab, without any increase in rates of amyloid-related imaging abnormalities (ARIA) – the most common side effect of amyloid drugs.

Early results from the randomized phase 3 TRAILBLAZER-ALZ 4 trial of donanemab come just 3 months after the Food and Drug Administration denied manufacturer Eli Lilly’s request for accelerated approval for the drug.

“This study shows that the drug with the quicker titration scheme, donanemab, produced more amyloid lowering and did it without having more ARIA,” said lead investigator Stephen P. Salloway, MD, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor of neurology at Brown University.

The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
 

Multicenter, head-to-head trial

Donanemab received breakthrough therapy designation in 2021. The drug works similarly to aducanumab and lecanemab, which was approved earlier this year. All three bind to different parts of the amyloid molecule and stimulate an immune response to help clear amyloid plaques, although they each have a distinctive binding component.

TRAILBLAZER-ALZ 4 was conducted at 31 sites across the United States, enrolling 140 patients aged 50-85 years with early and symptomatic Alzheimer’s disease. Study participants received donanemab or aducanumab at escalating doses for 18 months.

Donanemab was titrated more quickly, with participants receiving 700 mg via IV infusion once a month for 3 months before reaching the maximum dose of 1,400 mg in the fourth month of the study.

Aducanumab titration was slower, beginning at 1 mg/kg via IV monthly for 2 months, then 3 mg/kg for another 2 months, and 6 mg/kg for 2 more months before reaching the maximum dose of 10 mg/kg in the seventh month.

After 6 months of treatment, PET scan analysis revealed that 37.9% of donanemab-treated patients achieved amyloid clearance compared with just 1.6% of those who received aducanumab (P < .001).

Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with 3.8% of patients in the aducanumab group (P = .008).

Amyloid levels were 65.2% lower in donanemab patients, while levels in those receiving aducanumab were reduced by 17.0% (P < .001). Among those with intermediate tau, amyloid levels decreased with donanemab by 63.9% and 25.4% with aducanumab (P ≤ .001).

Investigators also noted a greater reduction in plasma ptau217 with donanemab.

Adverse events were similar between groups, with 62.0% of the donanemab group and 66.7% of aducanumab-treated participants reporting an adverse event.

There were no serious adverse events due to ARIA with donanemab, but one participant in the aducanumab group had a serious adverse event linked to ARIA.

“Even though the amyloid lowering was greater with donanemab, the rate of ARIA was similar, which suggests that the speed and depth of amyloid removal is not driving ARIA,” Dr. Salloway said.

There are three other Trailblazer trials of donanemab. Unlike in similar trials, participants in all three of these studies who received the trial drug could discontinue treatment once criteria for amyloid clearance were met.

That’s precisely what happened with Trailblazer 2, the study on which Lilly based its request for accelerated approval. Ironically, that trial design also contributed to the FDA’s decision to reject that request.

The FDA required data from at least 100 patients who had received donanemab for a minimum of 1 year. While the trial included more than 100 patients, many patients discontinued treatment early after achieving the targeted amount of amyloid clearance.

“They had success, and they got punished for it, in my opinion,” Dr. Salloway said.

Final data from Trailblazer 2 is due in the next month, and if results are positive, Lilly is expected to file for full approval.
 

Questions remain

“This is an interesting study that suggests donanemab may remove amyloid faster in more people than aducanumab,” said Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings.

Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, also commented on the findings. He noted that faster amyloid clearance “means less time for requiring sometimes burdensome and expensive infusions.”

Both Dr. Snyder and Dr. Fillit noted that longer-term results are needed, along with studies of whether amyloid clearance offers a protective benefit against Alzheimer’s dementia. More results from Trailblazer 4 will be reported after 12 months and again at 18 months.

“There are obviously still a lot of questions about these drugs and whether reducing amyloid plaque will actually preserve cognitive function or at least slow decline,” Dr. Fillit said.

It will also be important to understand the timing of treatment, including when anti-amyloid therapies should be administered and for how long.

“It will be important to understand how these results translate to patient care and treatment plans, should this drug receive FDA approval,” Dr. Snyder said. “Patients should have the opportunity to make a decision, alongside their physician, on a treatment path that is right for them.”

The study was funded by Eli Lilly. Dr. Salloway has been a consultant for Biogen, EISAI, Lilly, Genentech, Novo Nordisk, Prothena, and others. Dr. Snyder and Dr. Fillit have disclosed no relevant financial relationships.
 

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

BOSTON – The investigational drug donanemab yielded greater amyloid clearance and amyloid plaque reduction than aducanumab in early, symptomatic Alzheimer’s disease, according to the results of a head-to-head study.

Nearly 40% of patients treated with donanemab had amyloid clearance at 6 months compared with less than 2% of those who received aducanumab, which was approved in 2021 amid a great deal of controversy.

Titration for donanemab progressed more quickly, with participants receiving a maximum dose twice as early as those on aducanumab, without any increase in rates of amyloid-related imaging abnormalities (ARIA) – the most common side effect of amyloid drugs.

Early results from the randomized phase 3 TRAILBLAZER-ALZ 4 trial of donanemab come just 3 months after the Food and Drug Administration denied manufacturer Eli Lilly’s request for accelerated approval for the drug.

“This study shows that the drug with the quicker titration scheme, donanemab, produced more amyloid lowering and did it without having more ARIA,” said lead investigator Stephen P. Salloway, MD, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor of neurology at Brown University.

The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
 

Multicenter, head-to-head trial

Donanemab received breakthrough therapy designation in 2021. The drug works similarly to aducanumab and lecanemab, which was approved earlier this year. All three bind to different parts of the amyloid molecule and stimulate an immune response to help clear amyloid plaques, although they each have a distinctive binding component.

TRAILBLAZER-ALZ 4 was conducted at 31 sites across the United States, enrolling 140 patients aged 50-85 years with early and symptomatic Alzheimer’s disease. Study participants received donanemab or aducanumab at escalating doses for 18 months.

Donanemab was titrated more quickly, with participants receiving 700 mg via IV infusion once a month for 3 months before reaching the maximum dose of 1,400 mg in the fourth month of the study.

Aducanumab titration was slower, beginning at 1 mg/kg via IV monthly for 2 months, then 3 mg/kg for another 2 months, and 6 mg/kg for 2 more months before reaching the maximum dose of 10 mg/kg in the seventh month.

After 6 months of treatment, PET scan analysis revealed that 37.9% of donanemab-treated patients achieved amyloid clearance compared with just 1.6% of those who received aducanumab (P < .001).

Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with 3.8% of patients in the aducanumab group (P = .008).

Amyloid levels were 65.2% lower in donanemab patients, while levels in those receiving aducanumab were reduced by 17.0% (P < .001). Among those with intermediate tau, amyloid levels decreased with donanemab by 63.9% and 25.4% with aducanumab (P ≤ .001).

Investigators also noted a greater reduction in plasma ptau217 with donanemab.

Adverse events were similar between groups, with 62.0% of the donanemab group and 66.7% of aducanumab-treated participants reporting an adverse event.

There were no serious adverse events due to ARIA with donanemab, but one participant in the aducanumab group had a serious adverse event linked to ARIA.

“Even though the amyloid lowering was greater with donanemab, the rate of ARIA was similar, which suggests that the speed and depth of amyloid removal is not driving ARIA,” Dr. Salloway said.

There are three other Trailblazer trials of donanemab. Unlike in similar trials, participants in all three of these studies who received the trial drug could discontinue treatment once criteria for amyloid clearance were met.

That’s precisely what happened with Trailblazer 2, the study on which Lilly based its request for accelerated approval. Ironically, that trial design also contributed to the FDA’s decision to reject that request.

The FDA required data from at least 100 patients who had received donanemab for a minimum of 1 year. While the trial included more than 100 patients, many patients discontinued treatment early after achieving the targeted amount of amyloid clearance.

“They had success, and they got punished for it, in my opinion,” Dr. Salloway said.

Final data from Trailblazer 2 is due in the next month, and if results are positive, Lilly is expected to file for full approval.
 

Questions remain

“This is an interesting study that suggests donanemab may remove amyloid faster in more people than aducanumab,” said Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings.

Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, also commented on the findings. He noted that faster amyloid clearance “means less time for requiring sometimes burdensome and expensive infusions.”

Both Dr. Snyder and Dr. Fillit noted that longer-term results are needed, along with studies of whether amyloid clearance offers a protective benefit against Alzheimer’s dementia. More results from Trailblazer 4 will be reported after 12 months and again at 18 months.

“There are obviously still a lot of questions about these drugs and whether reducing amyloid plaque will actually preserve cognitive function or at least slow decline,” Dr. Fillit said.

It will also be important to understand the timing of treatment, including when anti-amyloid therapies should be administered and for how long.

“It will be important to understand how these results translate to patient care and treatment plans, should this drug receive FDA approval,” Dr. Snyder said. “Patients should have the opportunity to make a decision, alongside their physician, on a treatment path that is right for them.”

The study was funded by Eli Lilly. Dr. Salloway has been a consultant for Biogen, EISAI, Lilly, Genentech, Novo Nordisk, Prothena, and others. Dr. Snyder and Dr. Fillit have disclosed no relevant financial relationships.
 

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

SAN DIEGO – Emerging biomarkers and treatments offer more options to diagnose and manage Alzheimer’s disease (AD) and related dementias, but high costs and potentially serious complications mean using them with caution, said a presenter at the annual meeting of the American College of Physicians.

Dementia prevalence is increasing as the proportion of the U.S. population older than 65 rises, said Zaldy Tan, MD, professor of neurology at Cedars-Sinai Medical Center, Los Angeles. AD deaths more than doubled between 2000 and 2018, he noted, while deaths from HIV infection, stroke, and heart disease decreased.

Most people in the United States who have AD are White, but studies suggest that, compared with Whites, the risk of AD is two times higher in Blacks and 1.5 times higher in Hispanics . “These data suggest that both genes and social determinants of health are at play,” Dr. Tan said.
 

Diagnosis of Alzheimer’s disease

The different types of dementia make it challenging for primary care physicians to identify the cause of cognitive impairment. “Even though AD is the most common type, clinicians should keep in mind that another type of dementia may be the cause of cognitive impairment,” Dr. Tan cautioned. Other dementia diagnoses include vascular, Lewy body, and frontotemporal.

Diagnostic criteria for AD include evidence of significant cognitive decline in at least one cognitive domain that interferes with independence in everyday activities, as well as the absence of another mental disorder or delirium that would explain the cognitive deficits.

“We see many patients with depressive symptoms and mild cognitive impairment, and it is not always easy to tell which of them have dementia because of the overlap in the symptoms of depression and AD,” said internist Roderick Kim, MD, of Grand Rapids, Mich., who attended the session.

It can be challenging to convince patients to undergo the appropriate diagnostic workup, Dr. Kim said. “This can delay treatment, so it is important to explain to patients that cognitive decline can progress quickly and that there are treatment options to slow it down.”
 

Why do we need biomarkers for Alzheimer’s disease?

AD is characterized by a long preclinical phase with no specific symptoms other than the typical signs and symptoms of aging, Dr. Tan said. That means cognitive impairment progresses rapidly after diagnosis in most patients with AD.

“In most cases, an accurate history, physical and neurologic examinations, basic labs, and neuroimaging are sufficient for memory loss evaluation. However, as more disease-modifying therapies come to market, biomarkers will rise in importance in primary care,” he said.

This long asymptomatic phase of AD creates the need for diagnostic biomarkers for an earlier diagnosis, he said. Amyloid-beta and tau deposits in PET images and the levels of amyloid-beta seeds, phosphorylated tau, and neurofilament light chain in the cerebrospinal fluid can be used as diagnostic biomarkers in patients with suspected AD. Emerging blood biomarkers for earlier detection include the levels of amyloid-beta_1–42, phosphorylated tau, and neurofilament light chain.

With biomarkers and other new tools for the diagnosis of dementia in primary care, Dr. Tan said: “The greatest challenge is cost, as blood-based biomarkers are not currently covered by insurance and still rather costly. In addition, blood-based biomarkers will need to receive [Food and Drug Administration] approval in order to have more widespread availability.”


 

New and emerging therapies for Alzheimer’s disease

There are two classes of FDA-approved medications to manage cognitive symptoms of dementia: acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The selections may be trial and error for each patient, Dr. Tan said.

“The approved medications can exert subtle benefits that are clinically observable. Thus, barring any contraindications or intolerance, most patients with AD would benefit from a trial of one or both of these medication classes,” said Dr. Tan. He added that it is equally important to wean off and discontinue these medications if there is intolerance or lack of a subjective or objective beneficial response.

Other medications are available for some of the most common behavioral problems associated with dementia, such as agitation, depression, and disorientation. Dr. Tan advised not to prescribe behavioral medications until nonpharmacologic interventions prove to be ineffective or impractical. Behavioral medications have many side effects, some of which are potentially serious, he said, so the risk-benefit ratio should be considered.

In his own practice, when nonpharmacologic strategies do not improve the behavioral symptoms of dementia, Dr. Tan said that, “in cases where a person is at risk of harm to themselves or others, a discussion with the patient and their caregivers about the pros and cons of medications to treat the behavior need to be had. Careful monitoring of the response and dose escalation or deprescribing when appropriate is important to keep in mind.”

Disease-modifying agents have recently provided new hope for AD treatment. Aducanumab and lecanemab, both monoclonal antibodies that target amyloids, are the first two drugs that received accelerated FDA approval for AD.

Although these monoclonal antibodies can help clear deposited amyloid plaques and show some benefit in slowing cognitive impairment in clinical trials, the real-world benefits were unclear enough for Medicare to limit coverage to people enrolled in approved studies to gather more data. Additionally, these agents can cause potentially amyloid-related imaging abnormalities, which may indicate edema, effusion, or microhemorrhage. Therefore, clinicians need to have a clear conversation of risks and benefits with patients and caregivers about these treatments.
 

Looking ahead

When asked about the most promising emerging technologies or techniques related to dementia diagnosis and management, Dr. Tan noted that multiple technology companies and start-ups are looking for new ways to detect dementia earlier or keep persons with dementia safe at home. Some devices deliver brain waves, computerized brain games or tests, automated pill dispensers, and fall monitors.

“Some of these are potentially helpful, but not every person with dementia will benefit. In addition, most of these technologies are out-of-pocket expenses for the patients and their families. It is important to know what is out there but also be cautious about outrageous claims,” he added.

Dr. Tan reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

SAN DIEGO – Emerging biomarkers and treatments offer more options to diagnose and manage Alzheimer’s disease (AD) and related dementias, but high costs and potentially serious complications mean using them with caution, said a presenter at the annual meeting of the American College of Physicians.

Dementia prevalence is increasing as the proportion of the U.S. population older than 65 rises, said Zaldy Tan, MD, professor of neurology at Cedars-Sinai Medical Center, Los Angeles. AD deaths more than doubled between 2000 and 2018, he noted, while deaths from HIV infection, stroke, and heart disease decreased.

Most people in the United States who have AD are White, but studies suggest that, compared with Whites, the risk of AD is two times higher in Blacks and 1.5 times higher in Hispanics . “These data suggest that both genes and social determinants of health are at play,” Dr. Tan said.
 

Diagnosis of Alzheimer’s disease

The different types of dementia make it challenging for primary care physicians to identify the cause of cognitive impairment. “Even though AD is the most common type, clinicians should keep in mind that another type of dementia may be the cause of cognitive impairment,” Dr. Tan cautioned. Other dementia diagnoses include vascular, Lewy body, and frontotemporal.

Diagnostic criteria for AD include evidence of significant cognitive decline in at least one cognitive domain that interferes with independence in everyday activities, as well as the absence of another mental disorder or delirium that would explain the cognitive deficits.

“We see many patients with depressive symptoms and mild cognitive impairment, and it is not always easy to tell which of them have dementia because of the overlap in the symptoms of depression and AD,” said internist Roderick Kim, MD, of Grand Rapids, Mich., who attended the session.

It can be challenging to convince patients to undergo the appropriate diagnostic workup, Dr. Kim said. “This can delay treatment, so it is important to explain to patients that cognitive decline can progress quickly and that there are treatment options to slow it down.”
 

Why do we need biomarkers for Alzheimer’s disease?

AD is characterized by a long preclinical phase with no specific symptoms other than the typical signs and symptoms of aging, Dr. Tan said. That means cognitive impairment progresses rapidly after diagnosis in most patients with AD.

“In most cases, an accurate history, physical and neurologic examinations, basic labs, and neuroimaging are sufficient for memory loss evaluation. However, as more disease-modifying therapies come to market, biomarkers will rise in importance in primary care,” he said.

This long asymptomatic phase of AD creates the need for diagnostic biomarkers for an earlier diagnosis, he said. Amyloid-beta and tau deposits in PET images and the levels of amyloid-beta seeds, phosphorylated tau, and neurofilament light chain in the cerebrospinal fluid can be used as diagnostic biomarkers in patients with suspected AD. Emerging blood biomarkers for earlier detection include the levels of amyloid-beta_1–42, phosphorylated tau, and neurofilament light chain.

With biomarkers and other new tools for the diagnosis of dementia in primary care, Dr. Tan said: “The greatest challenge is cost, as blood-based biomarkers are not currently covered by insurance and still rather costly. In addition, blood-based biomarkers will need to receive [Food and Drug Administration] approval in order to have more widespread availability.”


 

New and emerging therapies for Alzheimer’s disease

There are two classes of FDA-approved medications to manage cognitive symptoms of dementia: acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The selections may be trial and error for each patient, Dr. Tan said.

“The approved medications can exert subtle benefits that are clinically observable. Thus, barring any contraindications or intolerance, most patients with AD would benefit from a trial of one or both of these medication classes,” said Dr. Tan. He added that it is equally important to wean off and discontinue these medications if there is intolerance or lack of a subjective or objective beneficial response.

Other medications are available for some of the most common behavioral problems associated with dementia, such as agitation, depression, and disorientation. Dr. Tan advised not to prescribe behavioral medications until nonpharmacologic interventions prove to be ineffective or impractical. Behavioral medications have many side effects, some of which are potentially serious, he said, so the risk-benefit ratio should be considered.

In his own practice, when nonpharmacologic strategies do not improve the behavioral symptoms of dementia, Dr. Tan said that, “in cases where a person is at risk of harm to themselves or others, a discussion with the patient and their caregivers about the pros and cons of medications to treat the behavior need to be had. Careful monitoring of the response and dose escalation or deprescribing when appropriate is important to keep in mind.”

Disease-modifying agents have recently provided new hope for AD treatment. Aducanumab and lecanemab, both monoclonal antibodies that target amyloids, are the first two drugs that received accelerated FDA approval for AD.

Although these monoclonal antibodies can help clear deposited amyloid plaques and show some benefit in slowing cognitive impairment in clinical trials, the real-world benefits were unclear enough for Medicare to limit coverage to people enrolled in approved studies to gather more data. Additionally, these agents can cause potentially amyloid-related imaging abnormalities, which may indicate edema, effusion, or microhemorrhage. Therefore, clinicians need to have a clear conversation of risks and benefits with patients and caregivers about these treatments.
 

Looking ahead

When asked about the most promising emerging technologies or techniques related to dementia diagnosis and management, Dr. Tan noted that multiple technology companies and start-ups are looking for new ways to detect dementia earlier or keep persons with dementia safe at home. Some devices deliver brain waves, computerized brain games or tests, automated pill dispensers, and fall monitors.

“Some of these are potentially helpful, but not every person with dementia will benefit. In addition, most of these technologies are out-of-pocket expenses for the patients and their families. It is important to know what is out there but also be cautious about outrageous claims,” he added.

Dr. Tan reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

SAN DIEGO – Emerging biomarkers and treatments offer more options to diagnose and manage Alzheimer’s disease (AD) and related dementias, but high costs and potentially serious complications mean using them with caution, said a presenter at the annual meeting of the American College of Physicians.

Dementia prevalence is increasing as the proportion of the U.S. population older than 65 rises, said Zaldy Tan, MD, professor of neurology at Cedars-Sinai Medical Center, Los Angeles. AD deaths more than doubled between 2000 and 2018, he noted, while deaths from HIV infection, stroke, and heart disease decreased.

Most people in the United States who have AD are White, but studies suggest that, compared with Whites, the risk of AD is two times higher in Blacks and 1.5 times higher in Hispanics . “These data suggest that both genes and social determinants of health are at play,” Dr. Tan said.
 

Diagnosis of Alzheimer’s disease

The different types of dementia make it challenging for primary care physicians to identify the cause of cognitive impairment. “Even though AD is the most common type, clinicians should keep in mind that another type of dementia may be the cause of cognitive impairment,” Dr. Tan cautioned. Other dementia diagnoses include vascular, Lewy body, and frontotemporal.

Diagnostic criteria for AD include evidence of significant cognitive decline in at least one cognitive domain that interferes with independence in everyday activities, as well as the absence of another mental disorder or delirium that would explain the cognitive deficits.

“We see many patients with depressive symptoms and mild cognitive impairment, and it is not always easy to tell which of them have dementia because of the overlap in the symptoms of depression and AD,” said internist Roderick Kim, MD, of Grand Rapids, Mich., who attended the session.

It can be challenging to convince patients to undergo the appropriate diagnostic workup, Dr. Kim said. “This can delay treatment, so it is important to explain to patients that cognitive decline can progress quickly and that there are treatment options to slow it down.”
 

Why do we need biomarkers for Alzheimer’s disease?

AD is characterized by a long preclinical phase with no specific symptoms other than the typical signs and symptoms of aging, Dr. Tan said. That means cognitive impairment progresses rapidly after diagnosis in most patients with AD.

“In most cases, an accurate history, physical and neurologic examinations, basic labs, and neuroimaging are sufficient for memory loss evaluation. However, as more disease-modifying therapies come to market, biomarkers will rise in importance in primary care,” he said.

This long asymptomatic phase of AD creates the need for diagnostic biomarkers for an earlier diagnosis, he said. Amyloid-beta and tau deposits in PET images and the levels of amyloid-beta seeds, phosphorylated tau, and neurofilament light chain in the cerebrospinal fluid can be used as diagnostic biomarkers in patients with suspected AD. Emerging blood biomarkers for earlier detection include the levels of amyloid-beta_1–42, phosphorylated tau, and neurofilament light chain.

With biomarkers and other new tools for the diagnosis of dementia in primary care, Dr. Tan said: “The greatest challenge is cost, as blood-based biomarkers are not currently covered by insurance and still rather costly. In addition, blood-based biomarkers will need to receive [Food and Drug Administration] approval in order to have more widespread availability.”


 

New and emerging therapies for Alzheimer’s disease

There are two classes of FDA-approved medications to manage cognitive symptoms of dementia: acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The selections may be trial and error for each patient, Dr. Tan said.

“The approved medications can exert subtle benefits that are clinically observable. Thus, barring any contraindications or intolerance, most patients with AD would benefit from a trial of one or both of these medication classes,” said Dr. Tan. He added that it is equally important to wean off and discontinue these medications if there is intolerance or lack of a subjective or objective beneficial response.

Other medications are available for some of the most common behavioral problems associated with dementia, such as agitation, depression, and disorientation. Dr. Tan advised not to prescribe behavioral medications until nonpharmacologic interventions prove to be ineffective or impractical. Behavioral medications have many side effects, some of which are potentially serious, he said, so the risk-benefit ratio should be considered.

In his own practice, when nonpharmacologic strategies do not improve the behavioral symptoms of dementia, Dr. Tan said that, “in cases where a person is at risk of harm to themselves or others, a discussion with the patient and their caregivers about the pros and cons of medications to treat the behavior need to be had. Careful monitoring of the response and dose escalation or deprescribing when appropriate is important to keep in mind.”

Disease-modifying agents have recently provided new hope for AD treatment. Aducanumab and lecanemab, both monoclonal antibodies that target amyloids, are the first two drugs that received accelerated FDA approval for AD.

Although these monoclonal antibodies can help clear deposited amyloid plaques and show some benefit in slowing cognitive impairment in clinical trials, the real-world benefits were unclear enough for Medicare to limit coverage to people enrolled in approved studies to gather more data. Additionally, these agents can cause potentially amyloid-related imaging abnormalities, which may indicate edema, effusion, or microhemorrhage. Therefore, clinicians need to have a clear conversation of risks and benefits with patients and caregivers about these treatments.
 

Looking ahead

When asked about the most promising emerging technologies or techniques related to dementia diagnosis and management, Dr. Tan noted that multiple technology companies and start-ups are looking for new ways to detect dementia earlier or keep persons with dementia safe at home. Some devices deliver brain waves, computerized brain games or tests, automated pill dispensers, and fall monitors.

“Some of these are potentially helpful, but not every person with dementia will benefit. In addition, most of these technologies are out-of-pocket expenses for the patients and their families. It is important to know what is out there but also be cautious about outrageous claims,” he added.

Dr. Tan reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon