Neurology Reviews

Having two copies of the APOE4 gene may be the genetic cause of up to one fifth of all Alzheimer’s disease cases, a new study suggests.

More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.

Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease. 

“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.

Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
 

High AD Penetrance

Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. 

Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers. 

Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.

Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.

Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death. 

Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans. 

Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%. 

Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).

When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.
 

More Than a Risk Factor

Overall, study findings provide evidence that APOE4 homozygotes represent another form of genetically determined Alzheimer’s disease, similar to autosomal-dominant Alzheimer’s disease and down syndrome-associated Alzheimer’s disease, investigators said.

“Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined Alzheimer’s disease, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes,” they wrote. 

Based on the results, investigators recommend that future clinical trials avoid combining single and double APOE4 carriers into one study group. 

Because the global average proportion of APOE4 homozygotes is estimated to be approximately 2%, APOE4-homozygous Alzheimer’s disease may represent one of the most frequently occurring Mendelian diseases worldwide. This could have implications for genetic counseling and genetic screening recommendations, they said. 

“We may need to start treating these homozygotes as a separate group in our research so we can really understand the relation between amyloid and tau and symptoms in E4 homozygotes in a way that we have not been able to because of our practice in the field of thinking that APOE4 is this unitary risk effect,” co-investigator Sterling Johnson, PhD, professor of geriatrics and dementia, University of Wisconsin-Madison, said at a press briefing.

The findings may also have implications for Alzheimer’s disease prevention, investigators added.

“What’s particularly important is the promise that perhaps we could treat people before symptoms, particularly in people who already have the disease in their brain such as APOE4 homozygotes, which reliably predicts that they will have impairment and try to treat them beforehand,” co-investigator Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women›s Hospital and Massachusetts General Hospital, Boston, said at a press briefing. 

“This is important for preventing Alzheimer’s-related dementia and a real movement forward in defining the disease on the basis of genetics and biomarkers,” she added. 
 

Experts Offer Mixed Reactions

Commenting on the findings, Paul Mathews, MD, DPhil, group leader of the UK Dementia Research Institute Centre at Imperial College, said that the data point to a need to look at APOE4 differently. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically, when late middle-aged people present to their doctors with symptoms of dementia,” Dr. Mathews, who was not part of the study, said in a statement. 

In an accompany editorial, Yadong Huang, MD, PhD, Departments of Neurology and Pathology, University of California, San Francisco, and co-authors noted that the findings also have implications for clinical drug trials.

“So far, APOE4 homozygotes have not been treated as a separate predefined treatment group in clinical trials,” they wrote. “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

Other experts urge caution when interpreting the findings. 

“It is clear that APOE4 homozygosity is tightly linked to the appearance of Alzheimer’s-related pathology, but even at age 80, 12% of people with APOE4/E4 did not have amyloid/tau biomarkers,” said Yuko Hara, PhD, director of aging and Alzheimer’s disease prevention at the Alzheimer’s Drug Discovery Foundation. “Also, having two copies of APOE4 does not mean you will definitely develop symptoms of Alzheimer’s disease in your lifetime,” Dr. Hara added. 

Researchers have long known that APOE4 is a strong risk factor for Alzheimer’s disease and that people with two copies of the gene are at especially high risk, David Curtis, MD, PhD, Genetics Institute at University of College London, England, said in a statement.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” Dr. Curtis said. “No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed would have broad applicability.” 

Study funders included Fondo de Investigaciones Sanitario, Carlos III Health Institute, Fondo Europeo de Desarrollo Regional, Unión Europea, National Institutes of Health, the Department de Salut de la Generalitat de Catalunya, Horizon 2020–Research and Innovation Framework Programme from the European Union, La Caixa Foundation, EIT Digital, and the Alzheimer Association. Dr. Fortea reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, and outside the submitted work. Dr. Johnson has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. Dr. Sperling has received personal consulting fees from AbbVie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. Dr. Huang is a co-founder and scientific advisory board member of GABAeron, Inc. Dr. Mathews reports consultancies with Sudo Biosciences, Nimbus, Redburn. Dr. Hara and Dr. Curtis reported no conflicts. Complete funding sources and disclosures are included in the original articles. 

A version of this article appeared on Medscape.com.

Having two copies of the APOE4 gene may be the genetic cause of up to one fifth of all Alzheimer’s disease cases, a new study suggests.

More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.

Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease. 

“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.

Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
 

High AD Penetrance

Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. 

Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers. 

Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.

Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.

Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death. 

Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans. 

Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%. 

Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).

When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.
 

More Than a Risk Factor

Overall, study findings provide evidence that APOE4 homozygotes represent another form of genetically determined Alzheimer’s disease, similar to autosomal-dominant Alzheimer’s disease and down syndrome-associated Alzheimer’s disease, investigators said.

“Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined Alzheimer’s disease, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes,” they wrote. 

Based on the results, investigators recommend that future clinical trials avoid combining single and double APOE4 carriers into one study group. 

Because the global average proportion of APOE4 homozygotes is estimated to be approximately 2%, APOE4-homozygous Alzheimer’s disease may represent one of the most frequently occurring Mendelian diseases worldwide. This could have implications for genetic counseling and genetic screening recommendations, they said. 

“We may need to start treating these homozygotes as a separate group in our research so we can really understand the relation between amyloid and tau and symptoms in E4 homozygotes in a way that we have not been able to because of our practice in the field of thinking that APOE4 is this unitary risk effect,” co-investigator Sterling Johnson, PhD, professor of geriatrics and dementia, University of Wisconsin-Madison, said at a press briefing.

The findings may also have implications for Alzheimer’s disease prevention, investigators added.

“What’s particularly important is the promise that perhaps we could treat people before symptoms, particularly in people who already have the disease in their brain such as APOE4 homozygotes, which reliably predicts that they will have impairment and try to treat them beforehand,” co-investigator Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women›s Hospital and Massachusetts General Hospital, Boston, said at a press briefing. 

“This is important for preventing Alzheimer’s-related dementia and a real movement forward in defining the disease on the basis of genetics and biomarkers,” she added. 
 

Experts Offer Mixed Reactions

Commenting on the findings, Paul Mathews, MD, DPhil, group leader of the UK Dementia Research Institute Centre at Imperial College, said that the data point to a need to look at APOE4 differently. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically, when late middle-aged people present to their doctors with symptoms of dementia,” Dr. Mathews, who was not part of the study, said in a statement. 

In an accompany editorial, Yadong Huang, MD, PhD, Departments of Neurology and Pathology, University of California, San Francisco, and co-authors noted that the findings also have implications for clinical drug trials.

“So far, APOE4 homozygotes have not been treated as a separate predefined treatment group in clinical trials,” they wrote. “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

Other experts urge caution when interpreting the findings. 

“It is clear that APOE4 homozygosity is tightly linked to the appearance of Alzheimer’s-related pathology, but even at age 80, 12% of people with APOE4/E4 did not have amyloid/tau biomarkers,” said Yuko Hara, PhD, director of aging and Alzheimer’s disease prevention at the Alzheimer’s Drug Discovery Foundation. “Also, having two copies of APOE4 does not mean you will definitely develop symptoms of Alzheimer’s disease in your lifetime,” Dr. Hara added. 

Researchers have long known that APOE4 is a strong risk factor for Alzheimer’s disease and that people with two copies of the gene are at especially high risk, David Curtis, MD, PhD, Genetics Institute at University of College London, England, said in a statement.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” Dr. Curtis said. “No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed would have broad applicability.” 

Study funders included Fondo de Investigaciones Sanitario, Carlos III Health Institute, Fondo Europeo de Desarrollo Regional, Unión Europea, National Institutes of Health, the Department de Salut de la Generalitat de Catalunya, Horizon 2020–Research and Innovation Framework Programme from the European Union, La Caixa Foundation, EIT Digital, and the Alzheimer Association. Dr. Fortea reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, and outside the submitted work. Dr. Johnson has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. Dr. Sperling has received personal consulting fees from AbbVie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. Dr. Huang is a co-founder and scientific advisory board member of GABAeron, Inc. Dr. Mathews reports consultancies with Sudo Biosciences, Nimbus, Redburn. Dr. Hara and Dr. Curtis reported no conflicts. Complete funding sources and disclosures are included in the original articles. 

A version of this article appeared on Medscape.com.

Having two copies of the APOE4 gene may be the genetic cause of up to one fifth of all Alzheimer’s disease cases, a new study suggests.

More than 95% of those with two copies of the gene (APOE4 homozygotes) in a large multicohort study had higher levels of Alzheimer’s disease biomarkers by age 55 years than did those with other APOE gene variants. By age 65 years, most had developed Alzheimer’s disease symptoms and showed abnormal amyloid levels in cerebrospinal fluid and on PET.

Investigators said that such a high penetrance of Alzheimer’s disease pathology in this group suggests that APOE4 may not be just a risk factor for Alzheimer’s disease but also a distinct genetic form of the disease. 

“Sometimes, we say we don’t know the cause of Alzheimer’s disease, but this would be behind 15%-20% of the population of people with Alzheimer’s disease,” lead investigator Juan Fortea, MD, PhD, director of the Memory Unit of the Neurology Department at the Hospital of Sant Pau, Barcelona, Spain, said at a press briefing.

Although some experts urge caution in interpreting these results, investigators and others say the findings, published online in Nature Medicine, could lead to calls for more widespread testing for APOE4 and may spur drug development.
 

High AD Penetrance

Mutations in the APP, PSEN1, and PSEN2 genes are linked to risk for early-onset autosomal-dominant Alzheimer’s disease, and dozens of other genes are associated with greater odds of late-onset disease. Among all these genes, APOE is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. 

Prior studies found that APOE4 homozygotes have a 60% lifetime risk for Alzheimer’s disease by age 85 years, a risk higher than that found with other gene variants or in single APOE carriers or noncarriers. 

Despite that, no previous study had examined the predictability of symptom onset in APOE4 homozygotes, which make up about 2%-3% of the general population and 15-20% of those with Alzheimer’s disease. And because most biomarker studies have combined single- and double-carrier APOE4 carriers into one group, very little was known about the penetrance or disease progression in APOE4 homozygotes.

Investigators analyzed data from 3200 brain donors from the National Alzheimer’s Coordinating Center and more than 10,000 people with Alzheimer’s disease biomarkers from five multicenter cohorts in the United States and Europe.

Nearly all APOE4 homozygotes had either high or intermediate Alzheimer’s disease neuropathologic change scores compared with about 50% among APOE3 homozygotes and was the same regardless of age at time of death. 

Beginning at age 55 years, APOE4 homozygotes exhibited higher levels of abnormal Alzheimer’s disease biomarkers than did APOE3 homozygotes. By age 65 years, nearly everyone with two copies of APOE4 showed abnormal levels of amyloid in cerebrospinal fluid and 75% had positive amyloid scans. 

Other biomarkers showed a biologic penetrance of Alzheimer’s disease that increased with age. By age 80 years, penetrance for all amyloid and tau biomarkers reached 88%. 

Postmortem analysis revealed Alzheimer’s disease and dementia symptoms were evident in APOE4 homozygotes 7-10 years before APOE3 homozygotes, with Alzheimer’s disease symptoms present at age 65 years, minor cognitive impairment at 72 years, dementia at 74 years, and death at 77 years (P <.05 differences).

When they limited analysis to only those who developed Alzheimer’s disease dementia, investigators found no difference in amyloid or tau accumulation between APOE3 and APOE4 homozygotes. That was surprising given the much earlier presentation of clinical symptoms and biomarkers in those who carried two copies of APOE4.
 

More Than a Risk Factor

Overall, study findings provide evidence that APOE4 homozygotes represent another form of genetically determined Alzheimer’s disease, similar to autosomal-dominant Alzheimer’s disease and down syndrome-associated Alzheimer’s disease, investigators said.

“Our work showed that APOE4 homozygotes meet the three main characteristics of genetically determined Alzheimer’s disease, namely near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes,” they wrote. 

Based on the results, investigators recommend that future clinical trials avoid combining single and double APOE4 carriers into one study group. 

Because the global average proportion of APOE4 homozygotes is estimated to be approximately 2%, APOE4-homozygous Alzheimer’s disease may represent one of the most frequently occurring Mendelian diseases worldwide. This could have implications for genetic counseling and genetic screening recommendations, they said. 

“We may need to start treating these homozygotes as a separate group in our research so we can really understand the relation between amyloid and tau and symptoms in E4 homozygotes in a way that we have not been able to because of our practice in the field of thinking that APOE4 is this unitary risk effect,” co-investigator Sterling Johnson, PhD, professor of geriatrics and dementia, University of Wisconsin-Madison, said at a press briefing.

The findings may also have implications for Alzheimer’s disease prevention, investigators added.

“What’s particularly important is the promise that perhaps we could treat people before symptoms, particularly in people who already have the disease in their brain such as APOE4 homozygotes, which reliably predicts that they will have impairment and try to treat them beforehand,” co-investigator Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women›s Hospital and Massachusetts General Hospital, Boston, said at a press briefing. 

“This is important for preventing Alzheimer’s-related dementia and a real movement forward in defining the disease on the basis of genetics and biomarkers,” she added. 
 

Experts Offer Mixed Reactions

Commenting on the findings, Paul Mathews, MD, DPhil, group leader of the UK Dementia Research Institute Centre at Imperial College, said that the data point to a need to look at APOE4 differently. 

“One implication of this work is that testing for APOE4 gene homozygosity should be assessed for use clinically, when late middle-aged people present to their doctors with symptoms of dementia,” Dr. Mathews, who was not part of the study, said in a statement. 

In an accompany editorial, Yadong Huang, MD, PhD, Departments of Neurology and Pathology, University of California, San Francisco, and co-authors noted that the findings also have implications for clinical drug trials.

“So far, APOE4 homozygotes have not been treated as a separate predefined treatment group in clinical trials,” they wrote. “Following this study, APOE4 status must be recognized as a crucial parameter in trial design, patient recruitment and data analysis, with APOE4 homozygotes and heterozygotes being clearly separated. Such an approach may enhance the treatment efficacy and help tailor therapeutic interventions more effectively towards genetically defined patient populations.”

Other experts urge caution when interpreting the findings. 

“It is clear that APOE4 homozygosity is tightly linked to the appearance of Alzheimer’s-related pathology, but even at age 80, 12% of people with APOE4/E4 did not have amyloid/tau biomarkers,” said Yuko Hara, PhD, director of aging and Alzheimer’s disease prevention at the Alzheimer’s Drug Discovery Foundation. “Also, having two copies of APOE4 does not mean you will definitely develop symptoms of Alzheimer’s disease in your lifetime,” Dr. Hara added. 

Researchers have long known that APOE4 is a strong risk factor for Alzheimer’s disease and that people with two copies of the gene are at especially high risk, David Curtis, MD, PhD, Genetics Institute at University of College London, England, said in a statement.

“I do not see anything in this paper to justify the claim that carrying two copies of APOE4 represents some ‘distinct genetic form’ of Alzheimer’s disease,” Dr. Curtis said. “No matter how many alleles of APOE4 one carries, the underlying disease processes seem similar across cases of Alzheimer’s disease, suggesting that any effective treatment and prevention strategies, which have yet to be developed would have broad applicability.” 

Study funders included Fondo de Investigaciones Sanitario, Carlos III Health Institute, Fondo Europeo de Desarrollo Regional, Unión Europea, National Institutes of Health, the Department de Salut de la Generalitat de Catalunya, Horizon 2020–Research and Innovation Framework Programme from the European Union, La Caixa Foundation, EIT Digital, and the Alzheimer Association. Dr. Fortea reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, and outside the submitted work. Dr. Johnson has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. Dr. Sperling has received personal consulting fees from AbbVie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. Dr. Huang is a co-founder and scientific advisory board member of GABAeron, Inc. Dr. Mathews reports consultancies with Sudo Biosciences, Nimbus, Redburn. Dr. Hara and Dr. Curtis reported no conflicts. Complete funding sources and disclosures are included in the original articles. 

A version of this article appeared on Medscape.com.

High olive oil consumption is associated with a significant decreased risk for dementia-related mortality, regardless of overall diet quality, a new study suggested.

Data from a prospective study of more than 92,000 people showed consuming at least 7 g of olive oil a day — about half a tablespoon — was associated with a 28% lower risk for dementia-related death.

Replacing one teaspoon of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia-related mortality.

“Opting for olive oil, a natural product, instead of more processed fats such as margarine and mayonnaise, is a safe choice and may reduce risk of fatal dementia,” said lead investigator Anne-Julie Tessier, RD, PhD, research associate, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston.

However, “intervention studies are needed to confirm causal effect and optimal quantity of olive oil intake,” she added.

The study was published online in JAMA Network Open.
 

A Spoonful of Olive Oil

A growing body of evidence has shown a link between the Mediterranean diet and preserved cognitive function and lower risk for cardiovascular disease (CVD). But its association with dementia mortality was unknown.

Investigators analyzed data on over 92,000 participants (66% women; mean age, 56 years) in the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of CVD and cancer at baseline.

Both studies were conducted between 1990 and 2018, with olive oil intake assessed every 4 years using a food frequency questionnaire. Dementia-related mortality was ascertained from death records.

The researchers also evaluated the joint association of diet quality (particularly adherence to the Mediterranean diet and Alternative Healthy Eating Index score) and olive oil consumption with the risk for dementia-related mortality. And they estimated the difference in the risk for dementia-related mortality when other dietary fats were substituted with an equivalent amount of olive oil.

There were 4751 dementia-related deaths during the 28-year follow-up period. People with two copies of the apolipoprotein epsilon-4 (APOE epsilon-4) allele — a known risk factor for Alzheimer’s disease — had a fivefold to ninefold greater likelihood of dementia-related death.

Compared with no or rare olive oil intake, consumption of 7 g of olive oil or more per day was associated with a 28% lower risk for dementia-related mortality (adjusted hazard ratio [HR], 0.72; P < .001), after adjusting for lifestyle and socioeconomic factors. The finding remained consistent even with further adjustment for the APOE epsilon-4 allele.

Each 5-g increment in olive oil consumption had an inverse association with dementia-related death in women (HR, 0.88; 95% CI, 0.84-0.93) but not in men (HR, 0.96; 95% CI, 0.88-1.04).

No interaction by diet quality scores was found.
 

No Link With Diet Quality

“Typically, people who use olive oil for cooking or as a dressing have an overall better quality of their diet, but interestingly, we found the association between more olive oil and reduced risk of dementia-related death to be regardless of this factor,” Dr. Tessier said.

Replacing 5 g per day of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia mortality. Substitutions for other vegetable oils or butter were not significant.

“Some antioxidant compounds in olive oil can cross the blood-brain barrier, potentially having a direct effect on the brain,” Dr. Tessier said. “It is also possible that olive oil has an indirect effect on brain health by benefiting cardiovascular health.”

The authors noted several study limitations, including the possibility of reverse causation, due to the observational nature of the study.

It is also plausible that higher olive oil intake could be indicative of a healthier diet and higher socioeconomic status, although the results remained consistent after accounting these factors, the authors noted.

The study population included only healthcare professionals and was primarily non-Hispanic White people, which could limit generalizability.
 

Causality Versus Connection

Commenting on the findings, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, cautioned that the study was designed to show correlation, not causation.

Other notable limitations include measuring prevalence or incidence of dementia from death records because dementia and Alzheimer’s disease are often underreported as a cause of death.

Moreover, people in the highest olive oil consumption group also had better diet quality, higher alcohol intake, were more physically active, and less likely to smoke, Dr. Edelmayer said.

“All of these factors may have an impact on risk of cognitive decline and dementia, separately from or in addition to olive oil consumption,” said Dr. Edelmayer, who was not involved with the study.

She echoed the authors’ concerns that the study was conducted in predominantly non-Hispanic White people and noted that the protective benefits of olive oil were no longer statistically significant for men after adjusting for potential confounders.

It “would be wonderful if a particular food could delay or prevent Alzheimer’s disease, but we do not have scientific evidence that these claims are true,” Dr. Edelmayer said. “We need randomized controlled clinical trials to evaluate whether any foods have a scientifically proven beneficial effect.”

This study is supported by a research grant from the National Institutes of Health to the senior author. The NHS, NHSII, and HPFS are supported by grants from the National Institutes of Health. Tessier is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship Award. Senior author Guasch-Ferré is supported by a Novo Nordisk Foundation grant. Dr. Tessier reported no other relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Edelmayer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

High olive oil consumption is associated with a significant decreased risk for dementia-related mortality, regardless of overall diet quality, a new study suggested.

Data from a prospective study of more than 92,000 people showed consuming at least 7 g of olive oil a day — about half a tablespoon — was associated with a 28% lower risk for dementia-related death.

Replacing one teaspoon of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia-related mortality.

“Opting for olive oil, a natural product, instead of more processed fats such as margarine and mayonnaise, is a safe choice and may reduce risk of fatal dementia,” said lead investigator Anne-Julie Tessier, RD, PhD, research associate, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston.

However, “intervention studies are needed to confirm causal effect and optimal quantity of olive oil intake,” she added.

The study was published online in JAMA Network Open.
 

A Spoonful of Olive Oil

A growing body of evidence has shown a link between the Mediterranean diet and preserved cognitive function and lower risk for cardiovascular disease (CVD). But its association with dementia mortality was unknown.

Investigators analyzed data on over 92,000 participants (66% women; mean age, 56 years) in the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of CVD and cancer at baseline.

Both studies were conducted between 1990 and 2018, with olive oil intake assessed every 4 years using a food frequency questionnaire. Dementia-related mortality was ascertained from death records.

The researchers also evaluated the joint association of diet quality (particularly adherence to the Mediterranean diet and Alternative Healthy Eating Index score) and olive oil consumption with the risk for dementia-related mortality. And they estimated the difference in the risk for dementia-related mortality when other dietary fats were substituted with an equivalent amount of olive oil.

There were 4751 dementia-related deaths during the 28-year follow-up period. People with two copies of the apolipoprotein epsilon-4 (APOE epsilon-4) allele — a known risk factor for Alzheimer’s disease — had a fivefold to ninefold greater likelihood of dementia-related death.

Compared with no or rare olive oil intake, consumption of 7 g of olive oil or more per day was associated with a 28% lower risk for dementia-related mortality (adjusted hazard ratio [HR], 0.72; P < .001), after adjusting for lifestyle and socioeconomic factors. The finding remained consistent even with further adjustment for the APOE epsilon-4 allele.

Each 5-g increment in olive oil consumption had an inverse association with dementia-related death in women (HR, 0.88; 95% CI, 0.84-0.93) but not in men (HR, 0.96; 95% CI, 0.88-1.04).

No interaction by diet quality scores was found.
 

No Link With Diet Quality

“Typically, people who use olive oil for cooking or as a dressing have an overall better quality of their diet, but interestingly, we found the association between more olive oil and reduced risk of dementia-related death to be regardless of this factor,” Dr. Tessier said.

Replacing 5 g per day of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia mortality. Substitutions for other vegetable oils or butter were not significant.

“Some antioxidant compounds in olive oil can cross the blood-brain barrier, potentially having a direct effect on the brain,” Dr. Tessier said. “It is also possible that olive oil has an indirect effect on brain health by benefiting cardiovascular health.”

The authors noted several study limitations, including the possibility of reverse causation, due to the observational nature of the study.

It is also plausible that higher olive oil intake could be indicative of a healthier diet and higher socioeconomic status, although the results remained consistent after accounting these factors, the authors noted.

The study population included only healthcare professionals and was primarily non-Hispanic White people, which could limit generalizability.
 

Causality Versus Connection

Commenting on the findings, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, cautioned that the study was designed to show correlation, not causation.

Other notable limitations include measuring prevalence or incidence of dementia from death records because dementia and Alzheimer’s disease are often underreported as a cause of death.

Moreover, people in the highest olive oil consumption group also had better diet quality, higher alcohol intake, were more physically active, and less likely to smoke, Dr. Edelmayer said.

“All of these factors may have an impact on risk of cognitive decline and dementia, separately from or in addition to olive oil consumption,” said Dr. Edelmayer, who was not involved with the study.

She echoed the authors’ concerns that the study was conducted in predominantly non-Hispanic White people and noted that the protective benefits of olive oil were no longer statistically significant for men after adjusting for potential confounders.

It “would be wonderful if a particular food could delay or prevent Alzheimer’s disease, but we do not have scientific evidence that these claims are true,” Dr. Edelmayer said. “We need randomized controlled clinical trials to evaluate whether any foods have a scientifically proven beneficial effect.”

This study is supported by a research grant from the National Institutes of Health to the senior author. The NHS, NHSII, and HPFS are supported by grants from the National Institutes of Health. Tessier is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship Award. Senior author Guasch-Ferré is supported by a Novo Nordisk Foundation grant. Dr. Tessier reported no other relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Edelmayer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

High olive oil consumption is associated with a significant decreased risk for dementia-related mortality, regardless of overall diet quality, a new study suggested.

Data from a prospective study of more than 92,000 people showed consuming at least 7 g of olive oil a day — about half a tablespoon — was associated with a 28% lower risk for dementia-related death.

Replacing one teaspoon of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia-related mortality.

“Opting for olive oil, a natural product, instead of more processed fats such as margarine and mayonnaise, is a safe choice and may reduce risk of fatal dementia,” said lead investigator Anne-Julie Tessier, RD, PhD, research associate, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston.

However, “intervention studies are needed to confirm causal effect and optimal quantity of olive oil intake,” she added.

The study was published online in JAMA Network Open.
 

A Spoonful of Olive Oil

A growing body of evidence has shown a link between the Mediterranean diet and preserved cognitive function and lower risk for cardiovascular disease (CVD). But its association with dementia mortality was unknown.

Investigators analyzed data on over 92,000 participants (66% women; mean age, 56 years) in the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) who were free of CVD and cancer at baseline.

Both studies were conducted between 1990 and 2018, with olive oil intake assessed every 4 years using a food frequency questionnaire. Dementia-related mortality was ascertained from death records.

The researchers also evaluated the joint association of diet quality (particularly adherence to the Mediterranean diet and Alternative Healthy Eating Index score) and olive oil consumption with the risk for dementia-related mortality. And they estimated the difference in the risk for dementia-related mortality when other dietary fats were substituted with an equivalent amount of olive oil.

There were 4751 dementia-related deaths during the 28-year follow-up period. People with two copies of the apolipoprotein epsilon-4 (APOE epsilon-4) allele — a known risk factor for Alzheimer’s disease — had a fivefold to ninefold greater likelihood of dementia-related death.

Compared with no or rare olive oil intake, consumption of 7 g of olive oil or more per day was associated with a 28% lower risk for dementia-related mortality (adjusted hazard ratio [HR], 0.72; P < .001), after adjusting for lifestyle and socioeconomic factors. The finding remained consistent even with further adjustment for the APOE epsilon-4 allele.

Each 5-g increment in olive oil consumption had an inverse association with dementia-related death in women (HR, 0.88; 95% CI, 0.84-0.93) but not in men (HR, 0.96; 95% CI, 0.88-1.04).

No interaction by diet quality scores was found.
 

No Link With Diet Quality

“Typically, people who use olive oil for cooking or as a dressing have an overall better quality of their diet, but interestingly, we found the association between more olive oil and reduced risk of dementia-related death to be regardless of this factor,” Dr. Tessier said.

Replacing 5 g per day of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8%-14% lower risk for dementia mortality. Substitutions for other vegetable oils or butter were not significant.

“Some antioxidant compounds in olive oil can cross the blood-brain barrier, potentially having a direct effect on the brain,” Dr. Tessier said. “It is also possible that olive oil has an indirect effect on brain health by benefiting cardiovascular health.”

The authors noted several study limitations, including the possibility of reverse causation, due to the observational nature of the study.

It is also plausible that higher olive oil intake could be indicative of a healthier diet and higher socioeconomic status, although the results remained consistent after accounting these factors, the authors noted.

The study population included only healthcare professionals and was primarily non-Hispanic White people, which could limit generalizability.
 

Causality Versus Connection

Commenting on the findings, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, cautioned that the study was designed to show correlation, not causation.

Other notable limitations include measuring prevalence or incidence of dementia from death records because dementia and Alzheimer’s disease are often underreported as a cause of death.

Moreover, people in the highest olive oil consumption group also had better diet quality, higher alcohol intake, were more physically active, and less likely to smoke, Dr. Edelmayer said.

“All of these factors may have an impact on risk of cognitive decline and dementia, separately from or in addition to olive oil consumption,” said Dr. Edelmayer, who was not involved with the study.

She echoed the authors’ concerns that the study was conducted in predominantly non-Hispanic White people and noted that the protective benefits of olive oil were no longer statistically significant for men after adjusting for potential confounders.

It “would be wonderful if a particular food could delay or prevent Alzheimer’s disease, but we do not have scientific evidence that these claims are true,” Dr. Edelmayer said. “We need randomized controlled clinical trials to evaluate whether any foods have a scientifically proven beneficial effect.”

This study is supported by a research grant from the National Institutes of Health to the senior author. The NHS, NHSII, and HPFS are supported by grants from the National Institutes of Health. Tessier is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship Award. Senior author Guasch-Ferré is supported by a Novo Nordisk Foundation grant. Dr. Tessier reported no other relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Edelmayer reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Attention-deficit/hyperactivity disorder (ADHD) in adults is independently associated with an increased risk for dementia with Lewy bodies (DLB), dementia, and nonamnestic mild cognitive impairment (naMCI), results of a new study showed.

“Determining whether there is an association between ADHD and subsequent conversion to a specific type of dementia is important. This information could generate opportunities for prevention and early treatment, as well as initiate research into the pathophysiological processes involved in understanding the process of cognitive decline,” the researchers, led by Ángel Golimstok, MD, of Hospital Italiano, Buenos Aires, Argentina, wrote.

The findings were published online in The American Journal of Geriatric Psychiatry.
 

Seeking Confirmation

The researchers first identified a link between DLB and ADHD in 2011. Since then, there have been eight additional studies from other groups also showing a possible link between ADHD and DLB.

To confirm the relationship, the researchers recruited 270 individuals between the ages of 45 and 70 years between 2007 and 2012. Of these, 161 had ADHD, and 109 were healthy controls.

Participants with ADHD met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision criteria for a diagnosis in the past and had a chronic course of ADHD symptoms from adolescence to adulthood that caused mild to severe impairment.

Investigators excluded participants who had been taking ADHD medications for 6 months or more, those with MCI at study initiation, and those with other comorbid psychiatric disorders.

At baseline, all participants received a physical exam, an MRI, and a neuropsychological exam to test for any type of dementia-related impairment.

Study participants were followed for an average of 12 years. A total of 27 individuals with ADHD developed dementia versus four patients in the control group (17% vs 4%, respectively), and 19 of those also had DLB (P = .002 for both).

Of those who developed any type of dementia, 87% were from the ADHD group. The most frequent type of dementia was DLB, 95% of which occurred in the ADHD group. Overall, DLB represented 70% of the dementia cases among participants with ADHD.

A total of 108 participants with ADHD were subsequently diagnosed with naMCI versus 19 healthy controls (67% vs 17%; P < .001).

“Although this pattern of deficits is reasonably expected in early DLB, these results should be interpreted with caution because they may be related to the overlap of symptoms and cognitive deficits between ADHD and naMCI, which may lead to an overestimation of the degenerative phenomenon. Thus, our cases of naMCI could correspond to the natural aging of ADHD patients and not to pathological deterioration,” the authors wrote.

The researchers pointed out that the sample of patients with ADHD originally sought evaluation because of a cognitive complaint or their own motivation. Therefore, the study results are not generalizable to all patients with ADHD. Another limitation was the relatively small number of patients included in the sample.

There was no reported source of funding, and there were no relevant disclosures reported.

A version of this article appeared on Medscape.com.

Attention-deficit/hyperactivity disorder (ADHD) in adults is independently associated with an increased risk for dementia with Lewy bodies (DLB), dementia, and nonamnestic mild cognitive impairment (naMCI), results of a new study showed.

“Determining whether there is an association between ADHD and subsequent conversion to a specific type of dementia is important. This information could generate opportunities for prevention and early treatment, as well as initiate research into the pathophysiological processes involved in understanding the process of cognitive decline,” the researchers, led by Ángel Golimstok, MD, of Hospital Italiano, Buenos Aires, Argentina, wrote.

The findings were published online in The American Journal of Geriatric Psychiatry.
 

Seeking Confirmation

The researchers first identified a link between DLB and ADHD in 2011. Since then, there have been eight additional studies from other groups also showing a possible link between ADHD and DLB.

To confirm the relationship, the researchers recruited 270 individuals between the ages of 45 and 70 years between 2007 and 2012. Of these, 161 had ADHD, and 109 were healthy controls.

Participants with ADHD met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision criteria for a diagnosis in the past and had a chronic course of ADHD symptoms from adolescence to adulthood that caused mild to severe impairment.

Investigators excluded participants who had been taking ADHD medications for 6 months or more, those with MCI at study initiation, and those with other comorbid psychiatric disorders.

At baseline, all participants received a physical exam, an MRI, and a neuropsychological exam to test for any type of dementia-related impairment.

Study participants were followed for an average of 12 years. A total of 27 individuals with ADHD developed dementia versus four patients in the control group (17% vs 4%, respectively), and 19 of those also had DLB (P = .002 for both).

Of those who developed any type of dementia, 87% were from the ADHD group. The most frequent type of dementia was DLB, 95% of which occurred in the ADHD group. Overall, DLB represented 70% of the dementia cases among participants with ADHD.

A total of 108 participants with ADHD were subsequently diagnosed with naMCI versus 19 healthy controls (67% vs 17%; P < .001).

“Although this pattern of deficits is reasonably expected in early DLB, these results should be interpreted with caution because they may be related to the overlap of symptoms and cognitive deficits between ADHD and naMCI, which may lead to an overestimation of the degenerative phenomenon. Thus, our cases of naMCI could correspond to the natural aging of ADHD patients and not to pathological deterioration,” the authors wrote.

The researchers pointed out that the sample of patients with ADHD originally sought evaluation because of a cognitive complaint or their own motivation. Therefore, the study results are not generalizable to all patients with ADHD. Another limitation was the relatively small number of patients included in the sample.

There was no reported source of funding, and there were no relevant disclosures reported.

A version of this article appeared on Medscape.com.

Attention-deficit/hyperactivity disorder (ADHD) in adults is independently associated with an increased risk for dementia with Lewy bodies (DLB), dementia, and nonamnestic mild cognitive impairment (naMCI), results of a new study showed.

“Determining whether there is an association between ADHD and subsequent conversion to a specific type of dementia is important. This information could generate opportunities for prevention and early treatment, as well as initiate research into the pathophysiological processes involved in understanding the process of cognitive decline,” the researchers, led by Ángel Golimstok, MD, of Hospital Italiano, Buenos Aires, Argentina, wrote.

The findings were published online in The American Journal of Geriatric Psychiatry.
 

Seeking Confirmation

The researchers first identified a link between DLB and ADHD in 2011. Since then, there have been eight additional studies from other groups also showing a possible link between ADHD and DLB.

To confirm the relationship, the researchers recruited 270 individuals between the ages of 45 and 70 years between 2007 and 2012. Of these, 161 had ADHD, and 109 were healthy controls.

Participants with ADHD met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision criteria for a diagnosis in the past and had a chronic course of ADHD symptoms from adolescence to adulthood that caused mild to severe impairment.

Investigators excluded participants who had been taking ADHD medications for 6 months or more, those with MCI at study initiation, and those with other comorbid psychiatric disorders.

At baseline, all participants received a physical exam, an MRI, and a neuropsychological exam to test for any type of dementia-related impairment.

Study participants were followed for an average of 12 years. A total of 27 individuals with ADHD developed dementia versus four patients in the control group (17% vs 4%, respectively), and 19 of those also had DLB (P = .002 for both).

Of those who developed any type of dementia, 87% were from the ADHD group. The most frequent type of dementia was DLB, 95% of which occurred in the ADHD group. Overall, DLB represented 70% of the dementia cases among participants with ADHD.

A total of 108 participants with ADHD were subsequently diagnosed with naMCI versus 19 healthy controls (67% vs 17%; P < .001).

“Although this pattern of deficits is reasonably expected in early DLB, these results should be interpreted with caution because they may be related to the overlap of symptoms and cognitive deficits between ADHD and naMCI, which may lead to an overestimation of the degenerative phenomenon. Thus, our cases of naMCI could correspond to the natural aging of ADHD patients and not to pathological deterioration,” the authors wrote.

The researchers pointed out that the sample of patients with ADHD originally sought evaluation because of a cognitive complaint or their own motivation. Therefore, the study results are not generalizable to all patients with ADHD. Another limitation was the relatively small number of patients included in the sample.

There was no reported source of funding, and there were no relevant disclosures reported.

A version of this article appeared on Medscape.com.

Proton pump inhibitors (PPIs), which are used to control acid reflux, are associated with an increased risk for migraine and other severe headache types, new research showed. 

Using data from the National Health and Nutrition Examination Survey (NHANES), investigators conducted a cross-sectional analysis and found all types of acid-suppression therapy were associated with an increased risk for severe headache including migraine but that PPIs conferred the greatest risk.

“It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” lead author Margaret Slavin, PhD, of the University of Maryland in College Park, said in a press release. 

The findings were published online  in Neurology Clinical Practice. 
 

New Look at Old Data

Previous research has shown that headache is listed among the most common adverse reactions in adults taking PPIs and histamine receptor agonists (H2RAs), which include cimetidine, famotidine, and nizatidine.

Other large studies of health databases have shown increased headache risk within a week of PPI exposure.

To compare the risk from PPIs versus H2RAs and other generics, researchers analyzed data from the NHANES for those who used PPIs, H2RAs, and generic antacids to learn more about the potential link between acid-suppression therapy and headache.

They used survey data from 1999 to 2004, the only years the NHANES included a question about migraine and other headache during the past 3 months. 

Investigators analyzed data for 11,800 participants aged 20 years or older who used prescription drugs, over-the-counter medications, and nutritional supplements during the past month. 

Participants who used acid-suppressing medications had an increased risk for migraine or severe headache versus those who did not use these agents. Investigators found PPIs were tied to a 70% increased risk, while H2RAs and antacids were associated with 40% and 30% higher risks, respectively. Use of any type of acid-suppression therapy was tied to a 47% increased risk for severe headache.
 

Magnesium a Risk Factor?

While magnesium supplements are sometimes prescribed as a “natural” headache prevention therapy to prevent migraine and other headache types, the investigators noted they were surprised to find individuals taking H2RAs who met the dietary reference intake for magnesium had a nearly threefold increased risk for migraine or severe headache (odds ratio, 2.80; 95% CI, 1.02-1.45; P = .025).

However, there was no association between magnesium and the other acid-reducing medications. 

The study’s limitations included the use of a single question to identify migraine or severe headache, which may have resulted in some misclassification of the outcome. The authors also pointed out that dietary and drug-intake data may be subject to recall bias. 

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors wrote. 

There was no targeted funding. Disclosures are noted in the original article.

A version of this article appeared on Medscape.com.

Proton pump inhibitors (PPIs), which are used to control acid reflux, are associated with an increased risk for migraine and other severe headache types, new research showed. 

Using data from the National Health and Nutrition Examination Survey (NHANES), investigators conducted a cross-sectional analysis and found all types of acid-suppression therapy were associated with an increased risk for severe headache including migraine but that PPIs conferred the greatest risk.

“It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” lead author Margaret Slavin, PhD, of the University of Maryland in College Park, said in a press release. 

The findings were published online  in Neurology Clinical Practice. 
 

New Look at Old Data

Previous research has shown that headache is listed among the most common adverse reactions in adults taking PPIs and histamine receptor agonists (H2RAs), which include cimetidine, famotidine, and nizatidine.

Other large studies of health databases have shown increased headache risk within a week of PPI exposure.

To compare the risk from PPIs versus H2RAs and other generics, researchers analyzed data from the NHANES for those who used PPIs, H2RAs, and generic antacids to learn more about the potential link between acid-suppression therapy and headache.

They used survey data from 1999 to 2004, the only years the NHANES included a question about migraine and other headache during the past 3 months. 

Investigators analyzed data for 11,800 participants aged 20 years or older who used prescription drugs, over-the-counter medications, and nutritional supplements during the past month. 

Participants who used acid-suppressing medications had an increased risk for migraine or severe headache versus those who did not use these agents. Investigators found PPIs were tied to a 70% increased risk, while H2RAs and antacids were associated with 40% and 30% higher risks, respectively. Use of any type of acid-suppression therapy was tied to a 47% increased risk for severe headache.
 

Magnesium a Risk Factor?

While magnesium supplements are sometimes prescribed as a “natural” headache prevention therapy to prevent migraine and other headache types, the investigators noted they were surprised to find individuals taking H2RAs who met the dietary reference intake for magnesium had a nearly threefold increased risk for migraine or severe headache (odds ratio, 2.80; 95% CI, 1.02-1.45; P = .025).

However, there was no association between magnesium and the other acid-reducing medications. 

The study’s limitations included the use of a single question to identify migraine or severe headache, which may have resulted in some misclassification of the outcome. The authors also pointed out that dietary and drug-intake data may be subject to recall bias. 

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors wrote. 

There was no targeted funding. Disclosures are noted in the original article.

A version of this article appeared on Medscape.com.

Proton pump inhibitors (PPIs), which are used to control acid reflux, are associated with an increased risk for migraine and other severe headache types, new research showed. 

Using data from the National Health and Nutrition Examination Survey (NHANES), investigators conducted a cross-sectional analysis and found all types of acid-suppression therapy were associated with an increased risk for severe headache including migraine but that PPIs conferred the greatest risk.

“It’s important to note that many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue,” lead author Margaret Slavin, PhD, of the University of Maryland in College Park, said in a press release. 

The findings were published online  in Neurology Clinical Practice. 
 

New Look at Old Data

Previous research has shown that headache is listed among the most common adverse reactions in adults taking PPIs and histamine receptor agonists (H2RAs), which include cimetidine, famotidine, and nizatidine.

Other large studies of health databases have shown increased headache risk within a week of PPI exposure.

To compare the risk from PPIs versus H2RAs and other generics, researchers analyzed data from the NHANES for those who used PPIs, H2RAs, and generic antacids to learn more about the potential link between acid-suppression therapy and headache.

They used survey data from 1999 to 2004, the only years the NHANES included a question about migraine and other headache during the past 3 months. 

Investigators analyzed data for 11,800 participants aged 20 years or older who used prescription drugs, over-the-counter medications, and nutritional supplements during the past month. 

Participants who used acid-suppressing medications had an increased risk for migraine or severe headache versus those who did not use these agents. Investigators found PPIs were tied to a 70% increased risk, while H2RAs and antacids were associated with 40% and 30% higher risks, respectively. Use of any type of acid-suppression therapy was tied to a 47% increased risk for severe headache.
 

Magnesium a Risk Factor?

While magnesium supplements are sometimes prescribed as a “natural” headache prevention therapy to prevent migraine and other headache types, the investigators noted they were surprised to find individuals taking H2RAs who met the dietary reference intake for magnesium had a nearly threefold increased risk for migraine or severe headache (odds ratio, 2.80; 95% CI, 1.02-1.45; P = .025).

However, there was no association between magnesium and the other acid-reducing medications. 

The study’s limitations included the use of a single question to identify migraine or severe headache, which may have resulted in some misclassification of the outcome. The authors also pointed out that dietary and drug-intake data may be subject to recall bias. 

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors wrote. 

There was no targeted funding. Disclosures are noted in the original article.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.