Cannabis users had a 22% increased risk of an emergency department (ED) visit or hospitalization compared to nonusers, as determined from data from more than 30,000 individuals.

Although cannabis contains compounds similar to tobacco, “data published on the association between cannabis smoking and airways health have been contradictory,” and whether smoking cannabis increases a user’s risk of developing acute respiratory illness remains unclear, wrote Nicholas T. Vozoris, MD, of the University of Toronto, and colleagues.

Smithore/Getty Images

In a study published in BMJ Open Respiratory Research, the investigators reviewed national health records data from 35,114 individuals aged 12-65 years for the period January 2009 to December 2015. Of these persons, 4,807 of the 6,425 who reported cannabis use in the past year were matched with 10,395 never-users who served as controls. The mean age of the study population at the index date was 35 years, and 42% were women; demographics were similar between users and control persons.

Overall, the odds of respiratory-related emergency department visits or hospitalizations were not significantly different between the cannabis users and the control persons (3.6% vs. 3.9%; odds ratio, 0.91). However, cannabis users had significantly greater odds of all-cause ED visits or hospitalizations (30.0% vs. 26.0%; OR, 1.22). All-cause mortality was 0.2% for both groups.

Respiratory problems were the second-highest reason for all-cause visits, the researchers noted. The lack of a difference in respiratory-related visits between cannabis users and nonusers conflicts somewhat with previous studies on this topic, which were limited, the researchers noted in their discussion.

The negative results also might stem from factors for which the researchers could not adjust, including insufficient cannabis smoke exposure among users in the study population, noninhalational cannabis use, which is less likely to have a respiratory effect, and possible secondhand exposure among control persons.

“It is also possible that our analysis might have been insufficiently powered to detect a significant signal with respect to the primary outcome,” they noted.

However, after the researchers controlled for multiple variables, the risk of an equally important morbidity outcome, all-cause ED visits or hospitalizations, was significantly greater among cannabis users than among control individuals, and respiratory reasons were the second most common cause for ED visits and hospitalizations in the all-cause outcome, they emphasized.

The study findings were limited by several factors, including the retrospective and observational design and the inability to control for all confounding variables, the researchers noted. Other limitations include the use of self-reports and potential for bias, the inability to perform dose-response analysis, and the high number of infrequent cannabis users in the study population.

However, the results suggest that cannabis use is associated with an increased risk of serious health events and should be discouraged, although more research is needed to confirm the current study findings, they concluded.
 

Consider range of causes for cannabis emergency visits

“With growing numbers of states legalizing recreational use of cannabis, it’s important to understand whether cannabis use is associated with increased emergency department visits,” Robert D. Glatter, MD, an emergency medicine physician at Lenox Hill Hospital, New York, told this news organization.

Previous studies have shown an association between increased ED visits and cannabis use in states, especially with edibles, where cannabis is legal, and “the current study reinforces the elevated risk of ED visits along with hospitalizations,” he said.

“While the researchers found no increased risk of respiratory-related complaints among users compared to the general population, there was an associated increase in ED visits and hospitalizations, which is important to understand,” said Dr. Glatter, who was not involved in the study.

“While this observational study found that the incidence of respiratory complaints was not significantly different among frequent users of cannabis, the increased odds that cannabis users would require evaluation in the emergency room or even hospitalization was still apparent even after the investigators controlled for such factors as use of alcohol, tobacco, illicit drug use, or other mental health–related disorders,” Dr. Glatter noted.

“That said, it’s a bit surprising that with the continued popularity of vaping, especially among teens, there was still not any appreciable or significant increase in respiratory complaints observed. Beyond this finding, I was not surprised by the overall conclusions of the current study, as we continue to see an elevated number of patients presenting to the ED with adverse events related to cannabis use.”

Dr. Glatter noted that “the majority of patients we see in the ED are associated with use of edibles, since it takes longer for the person to feel the effects, leading the user to consume more of the product up front, with delayed effects lasting up to 12 hours. This is what gets people into trouble and leads to toxicity of cannabis, or ‘overdoses,’ “ he explained.

When consuming edible cannabis products, “[p]eople need to begin at low dosages and not take additional gummies up front, since it can take up to 2 or even 3 hours in some cases to feel the initial effects. With the drug’s effects lasting up to 12 hours, it’s especially important to avoid operating any motor vehicles, bicycles, or scooters, since reaction time is impaired, as well as overall judgment, balance, and fine motor skills,” Dr. Glatter said.

Cannabis can land users in the ED for a range of reasons, said Dr. Glatter. “According to the study, 15% of the emergency room visits and hospitalizations were due to acute trauma, 14% due to respiratory issues, and 13% to gastrointestinal illnesses. These effects were seen in first-time users but not those with chronic use, according to the study inclusion criteria.”

Cannabis use could result in physical injuries through “impaired judgment, coordination, combined with an altered state of consciousness or generalized drowsiness, that could contribute to an increase in motor vehicle collisions, along with an increased risk for falls leading to lacerations, fractures, contusions, or bruising,” said Dr. Glatter. “Cannabis may also lead to an altered sense of perception related to interactions with others, resulting in feelings of anxiety or restlessness culminating in physical altercations and other injuries.”

The current study indicates the need for understanding the potential physical and psychological effects of cannabis use, he said.

“Additional research is needed to better understand the relative percentage cases related to edibles vs. inhalation presenting to the ED,” he noted. “There is no question that edibles continue to present significant dangers for those who don’t read labels or remain poorly informed regarding their dosing as a result of delayed onset and longer duration,” he said. To help reduce risk of toxicity, the concept of a “high lasting 12-15 hours, as with edibles, as opposed to 3-4 hours from inhalation must be clearly stated on packaging and better communicated with users, as the toxicity with edibles is more often from lack of prior knowledge about onset of effects related to dosing.”

In addition, the “potential for psychosis to develop with more chronic cannabis use, along with cannabinoid hyperemesis syndrome should be on every clinician’s radar,” Dr. Glatter emphasized.

“The bottom line is that as more states legalize the use of cannabis, it’s vital to also implement comprehensive public education efforts to provide users with the reported risks associated with not only inhalation (vaping or flower) but also edibles, which account for an increasingly greater percentage of ED visits and associated adverse effects,” he said.

The study was supported by the Lung Association–Ontario, as well as by grants from the Ontario Ministry of Health and the Ministry of Long-Term Care. The researchers and Dr. Glatter have disclosed no relevant financial relationships.

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

Cannabis users had a 22% increased risk of an emergency department (ED) visit or hospitalization compared to nonusers, as determined from data from more than 30,000 individuals.

Although cannabis contains compounds similar to tobacco, “data published on the association between cannabis smoking and airways health have been contradictory,” and whether smoking cannabis increases a user’s risk of developing acute respiratory illness remains unclear, wrote Nicholas T. Vozoris, MD, of the University of Toronto, and colleagues.

Smithore/Getty Images

In a study published in BMJ Open Respiratory Research, the investigators reviewed national health records data from 35,114 individuals aged 12-65 years for the period January 2009 to December 2015. Of these persons, 4,807 of the 6,425 who reported cannabis use in the past year were matched with 10,395 never-users who served as controls. The mean age of the study population at the index date was 35 years, and 42% were women; demographics were similar between users and control persons.

Overall, the odds of respiratory-related emergency department visits or hospitalizations were not significantly different between the cannabis users and the control persons (3.6% vs. 3.9%; odds ratio, 0.91). However, cannabis users had significantly greater odds of all-cause ED visits or hospitalizations (30.0% vs. 26.0%; OR, 1.22). All-cause mortality was 0.2% for both groups.

Respiratory problems were the second-highest reason for all-cause visits, the researchers noted. The lack of a difference in respiratory-related visits between cannabis users and nonusers conflicts somewhat with previous studies on this topic, which were limited, the researchers noted in their discussion.

The negative results also might stem from factors for which the researchers could not adjust, including insufficient cannabis smoke exposure among users in the study population, noninhalational cannabis use, which is less likely to have a respiratory effect, and possible secondhand exposure among control persons.

“It is also possible that our analysis might have been insufficiently powered to detect a significant signal with respect to the primary outcome,” they noted.

However, after the researchers controlled for multiple variables, the risk of an equally important morbidity outcome, all-cause ED visits or hospitalizations, was significantly greater among cannabis users than among control individuals, and respiratory reasons were the second most common cause for ED visits and hospitalizations in the all-cause outcome, they emphasized.

The study findings were limited by several factors, including the retrospective and observational design and the inability to control for all confounding variables, the researchers noted. Other limitations include the use of self-reports and potential for bias, the inability to perform dose-response analysis, and the high number of infrequent cannabis users in the study population.

However, the results suggest that cannabis use is associated with an increased risk of serious health events and should be discouraged, although more research is needed to confirm the current study findings, they concluded.
 

Consider range of causes for cannabis emergency visits

“With growing numbers of states legalizing recreational use of cannabis, it’s important to understand whether cannabis use is associated with increased emergency department visits,” Robert D. Glatter, MD, an emergency medicine physician at Lenox Hill Hospital, New York, told this news organization.

Previous studies have shown an association between increased ED visits and cannabis use in states, especially with edibles, where cannabis is legal, and “the current study reinforces the elevated risk of ED visits along with hospitalizations,” he said.

“While the researchers found no increased risk of respiratory-related complaints among users compared to the general population, there was an associated increase in ED visits and hospitalizations, which is important to understand,” said Dr. Glatter, who was not involved in the study.

“While this observational study found that the incidence of respiratory complaints was not significantly different among frequent users of cannabis, the increased odds that cannabis users would require evaluation in the emergency room or even hospitalization was still apparent even after the investigators controlled for such factors as use of alcohol, tobacco, illicit drug use, or other mental health–related disorders,” Dr. Glatter noted.

“That said, it’s a bit surprising that with the continued popularity of vaping, especially among teens, there was still not any appreciable or significant increase in respiratory complaints observed. Beyond this finding, I was not surprised by the overall conclusions of the current study, as we continue to see an elevated number of patients presenting to the ED with adverse events related to cannabis use.”

Dr. Glatter noted that “the majority of patients we see in the ED are associated with use of edibles, since it takes longer for the person to feel the effects, leading the user to consume more of the product up front, with delayed effects lasting up to 12 hours. This is what gets people into trouble and leads to toxicity of cannabis, or ‘overdoses,’ “ he explained.

When consuming edible cannabis products, “[p]eople need to begin at low dosages and not take additional gummies up front, since it can take up to 2 or even 3 hours in some cases to feel the initial effects. With the drug’s effects lasting up to 12 hours, it’s especially important to avoid operating any motor vehicles, bicycles, or scooters, since reaction time is impaired, as well as overall judgment, balance, and fine motor skills,” Dr. Glatter said.

Cannabis can land users in the ED for a range of reasons, said Dr. Glatter. “According to the study, 15% of the emergency room visits and hospitalizations were due to acute trauma, 14% due to respiratory issues, and 13% to gastrointestinal illnesses. These effects were seen in first-time users but not those with chronic use, according to the study inclusion criteria.”

Cannabis use could result in physical injuries through “impaired judgment, coordination, combined with an altered state of consciousness or generalized drowsiness, that could contribute to an increase in motor vehicle collisions, along with an increased risk for falls leading to lacerations, fractures, contusions, or bruising,” said Dr. Glatter. “Cannabis may also lead to an altered sense of perception related to interactions with others, resulting in feelings of anxiety or restlessness culminating in physical altercations and other injuries.”

The current study indicates the need for understanding the potential physical and psychological effects of cannabis use, he said.

“Additional research is needed to better understand the relative percentage cases related to edibles vs. inhalation presenting to the ED,” he noted. “There is no question that edibles continue to present significant dangers for those who don’t read labels or remain poorly informed regarding their dosing as a result of delayed onset and longer duration,” he said. To help reduce risk of toxicity, the concept of a “high lasting 12-15 hours, as with edibles, as opposed to 3-4 hours from inhalation must be clearly stated on packaging and better communicated with users, as the toxicity with edibles is more often from lack of prior knowledge about onset of effects related to dosing.”

In addition, the “potential for psychosis to develop with more chronic cannabis use, along with cannabinoid hyperemesis syndrome should be on every clinician’s radar,” Dr. Glatter emphasized.

“The bottom line is that as more states legalize the use of cannabis, it’s vital to also implement comprehensive public education efforts to provide users with the reported risks associated with not only inhalation (vaping or flower) but also edibles, which account for an increasingly greater percentage of ED visits and associated adverse effects,” he said.

The study was supported by the Lung Association–Ontario, as well as by grants from the Ontario Ministry of Health and the Ministry of Long-Term Care. The researchers and Dr. Glatter have disclosed no relevant financial relationships.

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

Cannabis users had a 22% increased risk of an emergency department (ED) visit or hospitalization compared to nonusers, as determined from data from more than 30,000 individuals.

Although cannabis contains compounds similar to tobacco, “data published on the association between cannabis smoking and airways health have been contradictory,” and whether smoking cannabis increases a user’s risk of developing acute respiratory illness remains unclear, wrote Nicholas T. Vozoris, MD, of the University of Toronto, and colleagues.

Smithore/Getty Images

In a study published in BMJ Open Respiratory Research, the investigators reviewed national health records data from 35,114 individuals aged 12-65 years for the period January 2009 to December 2015. Of these persons, 4,807 of the 6,425 who reported cannabis use in the past year were matched with 10,395 never-users who served as controls. The mean age of the study population at the index date was 35 years, and 42% were women; demographics were similar between users and control persons.

Overall, the odds of respiratory-related emergency department visits or hospitalizations were not significantly different between the cannabis users and the control persons (3.6% vs. 3.9%; odds ratio, 0.91). However, cannabis users had significantly greater odds of all-cause ED visits or hospitalizations (30.0% vs. 26.0%; OR, 1.22). All-cause mortality was 0.2% for both groups.

Respiratory problems were the second-highest reason for all-cause visits, the researchers noted. The lack of a difference in respiratory-related visits between cannabis users and nonusers conflicts somewhat with previous studies on this topic, which were limited, the researchers noted in their discussion.

The negative results also might stem from factors for which the researchers could not adjust, including insufficient cannabis smoke exposure among users in the study population, noninhalational cannabis use, which is less likely to have a respiratory effect, and possible secondhand exposure among control persons.

“It is also possible that our analysis might have been insufficiently powered to detect a significant signal with respect to the primary outcome,” they noted.

However, after the researchers controlled for multiple variables, the risk of an equally important morbidity outcome, all-cause ED visits or hospitalizations, was significantly greater among cannabis users than among control individuals, and respiratory reasons were the second most common cause for ED visits and hospitalizations in the all-cause outcome, they emphasized.

The study findings were limited by several factors, including the retrospective and observational design and the inability to control for all confounding variables, the researchers noted. Other limitations include the use of self-reports and potential for bias, the inability to perform dose-response analysis, and the high number of infrequent cannabis users in the study population.

However, the results suggest that cannabis use is associated with an increased risk of serious health events and should be discouraged, although more research is needed to confirm the current study findings, they concluded.
 

Consider range of causes for cannabis emergency visits

“With growing numbers of states legalizing recreational use of cannabis, it’s important to understand whether cannabis use is associated with increased emergency department visits,” Robert D. Glatter, MD, an emergency medicine physician at Lenox Hill Hospital, New York, told this news organization.

Previous studies have shown an association between increased ED visits and cannabis use in states, especially with edibles, where cannabis is legal, and “the current study reinforces the elevated risk of ED visits along with hospitalizations,” he said.

“While the researchers found no increased risk of respiratory-related complaints among users compared to the general population, there was an associated increase in ED visits and hospitalizations, which is important to understand,” said Dr. Glatter, who was not involved in the study.

“While this observational study found that the incidence of respiratory complaints was not significantly different among frequent users of cannabis, the increased odds that cannabis users would require evaluation in the emergency room or even hospitalization was still apparent even after the investigators controlled for such factors as use of alcohol, tobacco, illicit drug use, or other mental health–related disorders,” Dr. Glatter noted.

“That said, it’s a bit surprising that with the continued popularity of vaping, especially among teens, there was still not any appreciable or significant increase in respiratory complaints observed. Beyond this finding, I was not surprised by the overall conclusions of the current study, as we continue to see an elevated number of patients presenting to the ED with adverse events related to cannabis use.”

Dr. Glatter noted that “the majority of patients we see in the ED are associated with use of edibles, since it takes longer for the person to feel the effects, leading the user to consume more of the product up front, with delayed effects lasting up to 12 hours. This is what gets people into trouble and leads to toxicity of cannabis, or ‘overdoses,’ “ he explained.

When consuming edible cannabis products, “[p]eople need to begin at low dosages and not take additional gummies up front, since it can take up to 2 or even 3 hours in some cases to feel the initial effects. With the drug’s effects lasting up to 12 hours, it’s especially important to avoid operating any motor vehicles, bicycles, or scooters, since reaction time is impaired, as well as overall judgment, balance, and fine motor skills,” Dr. Glatter said.

Cannabis can land users in the ED for a range of reasons, said Dr. Glatter. “According to the study, 15% of the emergency room visits and hospitalizations were due to acute trauma, 14% due to respiratory issues, and 13% to gastrointestinal illnesses. These effects were seen in first-time users but not those with chronic use, according to the study inclusion criteria.”

Cannabis use could result in physical injuries through “impaired judgment, coordination, combined with an altered state of consciousness or generalized drowsiness, that could contribute to an increase in motor vehicle collisions, along with an increased risk for falls leading to lacerations, fractures, contusions, or bruising,” said Dr. Glatter. “Cannabis may also lead to an altered sense of perception related to interactions with others, resulting in feelings of anxiety or restlessness culminating in physical altercations and other injuries.”

The current study indicates the need for understanding the potential physical and psychological effects of cannabis use, he said.

“Additional research is needed to better understand the relative percentage cases related to edibles vs. inhalation presenting to the ED,” he noted. “There is no question that edibles continue to present significant dangers for those who don’t read labels or remain poorly informed regarding their dosing as a result of delayed onset and longer duration,” he said. To help reduce risk of toxicity, the concept of a “high lasting 12-15 hours, as with edibles, as opposed to 3-4 hours from inhalation must be clearly stated on packaging and better communicated with users, as the toxicity with edibles is more often from lack of prior knowledge about onset of effects related to dosing.”

In addition, the “potential for psychosis to develop with more chronic cannabis use, along with cannabinoid hyperemesis syndrome should be on every clinician’s radar,” Dr. Glatter emphasized.

“The bottom line is that as more states legalize the use of cannabis, it’s vital to also implement comprehensive public education efforts to provide users with the reported risks associated with not only inhalation (vaping or flower) but also edibles, which account for an increasingly greater percentage of ED visits and associated adverse effects,” he said.

The study was supported by the Lung Association–Ontario, as well as by grants from the Ontario Ministry of Health and the Ministry of Long-Term Care. The researchers and Dr. Glatter have disclosed no relevant financial relationships.

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

Primary care providers could add more than $100,000 to their incomes by billing more often for prevention and coordination of care services using Medicare codes, a new study shows.

According to the new research, primary care physicians used these codes for a median of only 2.3% of services provided to eligible patients.

“Investing in primary care is good for the health of patients, for achieving health equity, and for improving the value of health care spending, and yet the U.S. underinvests in primary care,” lead author Sumit D. Agarwal, MD, of Brigham and Women’s Hospital, Boston, said in an interview.

“One strategy to rectify this has been to add billing codes to the physician fee schedule for PCPs to use and thus raise primary care spending; Medicare has been activating new codes for the better part of 2 decades, and we wanted to investigate how successful this strategy of adding codes to the Medicare Physician Fee Schedule (MPFS) schedule has been to inform discussions on how best to finance primary care in the United States,” he said.

In a study published in Annals of Internal Medicine, Dr. Agarwal and colleagues reviewed nationally representative claims and survey data from 2019 and 2020. They analyzed 34 distinct prevention and coordination codes in 13 categories that have been added the MPFS since 2005. Of these, four involved coordination of care (cognitive impairment, behavioral health integration, chronic care management, and transitional care management). The other nine categories in prevention were wellness visits, advance care planning, shared decision making for lung cancer screening, obesity counseling, behavioral counseling for CVD, depression screening, alcohol misuse counseling, alcohol misuse screening, and smoking cessation counseling.

Overall, 8.8%-100% of older adult patients were eligible for preventive services. A range of patients (5.0%-60.6%) had codes for receiving services in their patient information.

“However, a much smaller fraction of eligible patients was billed for having received the service, ranging from less than 1% for alcohol misuse counseling or obesity counseling to 35.8% for wellness visits, with most below 10%,” the researchers wrote.

The median use of billing codes was 2.3% for eligible patients.

A PCP who provided and billed preventive services to half of all eligible patients could potentially increase revenues of $1,269 to $45,406 per code, with an annual revenue increase of $124,435 (interquartile range $30,654 to $226,813) for prevention services. Similarly, providing and billing coordination of care service to half of all eligible patients could increase revenue by $86,082 (IQR, $18,011 to $154,152).

“Importantly, all of these prevention and coordination codes involve decomposing the comprehensive care of a patient into component parts, each with multiple steps and checklists, which may be inconsistent with how PCPs practice and document care,” the researchers wrote in their discussion. “Unlike hospitals, primary care practices are typically unable to use departments of trained coders to maximize billing and ensure that documentation matches the requirements specified in billing rules,” they added.

The study findings were limited by several factors including the focus only on the Medicare segment of PCPs’ panels, which suggests conservative estimates of reimbursement, the researchers noted. Other limitations include response bias to the use of surveys, lack of survey data on specific billing requirements, and the potential underestimation of services by PCPs who delivered some, but not all, components of a service code.

However, the results reflect previous research to show the underutilization of prevention and coordination codes in primary care, and the need for ways to increase their use, the researchers said. “The discrepancies between service eligibility, provision of services regardless of billing, and actual billing suggest that attempting to codify each distinct activity done by a PCP in the MPFS may not be an effective strategy for supporting primary care,” they concluded.
 

Barriers to code use persist for PCPs

“What surprised us was that there were many codes; we analyzed 34 in the paper in 13 distinct categories of services, and Medicare continues to add new primary care codes to the fee schedule,” Dr. Agarwal said in an interview. Also surprising, “take-up is low virtually across the board, and this isn’t for lack of eligibility,” he said. The low use of the codes “is not for lack of counseling patients on diet, drinking, exercise, smoking, or anything else for which these codes are meant to pay PCPs ... The potential revenue from these codes in aggregate is huge,” Dr. Agarwal emphasized.

“My hope is not necessarily that physicians read this study and start using some or all of these codes more frequently,” said Dr. Agarwal. “It can be tempting to think of this as money left on the table, but it’s not; there are compliance, billing, and opportunity costs from using these codes,” he said. “For individual PCPs seeing individual patients for the breadth that is primary care, I’m not sure the juice is worth the squeeze,” he added. “My coauthors and I are all primary care physicians. We know from our research and first-hand that these codes can be cumbersome to use.” These codes also don’t reflect how PCPs practice, he said. “PCPs are not in the business of slicing and dicing a visit or patient to extract as much revenue as possible. The physician-patient interaction is more complex, and richer, than these codes imply. Instead, I hope our paper encourages Medicare and policymakers to take a harder look at other strategies for investing in primary care,” Dr. Agarwal added.

As for additional research, “Primary care spending is going in the wrong direction,” said Dr. Agarwal. “We need to figure out how best to finance primary care in the United States.”

Recent studies have examined the successes and limitations of the primary care medical home model, Medicare’s Comprehensive Primary Care Initiative, and primary care spending legislation, he said. “Our study is another piece of the puzzle: at least in its current form,” and the results suggest “that one-off codes were nice in theory but not in practice,” he noted.
 

New codes are cumbersome

“It’s tempting to interpret underuse of new billing codes as a simple change management problem,” Davoren Chick, MD, chief learning officer of the American College of Physicians, wrote in an accompanying editorial. However, the underuse of codes for preventive service and coordination of care likely stems from the details of the codes, he said.

The new codes require the documentation of specific components and a minimum duration of services, he explained. “Codes that reward discrete service episodes disadvantage physicians who appropriately integrate preventive services within a continuous patient care relationship,” he added.

Dr. Chick presented an example of a primary care physician who would have to deliver intensive behavioral therapy for obesity in 15-minute episodes outside of a routine office visit to meet the billing criteria for current Medicare codes.

Dr. Chick called on clinicians to educate themselves on the coding rules for the services they provide “not only to optimize current payment but also to advocate for change.”

He concluded: “Widespread underuse of new preventive service and coordination of care codes reflects system failure, not physician failure. We must stand firm with this knowledge to demand increased payment for feasible, patient-centered primary care commensurate with its value in achieving better outcomes and lower costs.”

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Agarwal and Dr. Chick had no financial conflicts to disclose.

Primary care providers could add more than $100,000 to their incomes by billing more often for prevention and coordination of care services using Medicare codes, a new study shows.

According to the new research, primary care physicians used these codes for a median of only 2.3% of services provided to eligible patients.

“Investing in primary care is good for the health of patients, for achieving health equity, and for improving the value of health care spending, and yet the U.S. underinvests in primary care,” lead author Sumit D. Agarwal, MD, of Brigham and Women’s Hospital, Boston, said in an interview.

“One strategy to rectify this has been to add billing codes to the physician fee schedule for PCPs to use and thus raise primary care spending; Medicare has been activating new codes for the better part of 2 decades, and we wanted to investigate how successful this strategy of adding codes to the Medicare Physician Fee Schedule (MPFS) schedule has been to inform discussions on how best to finance primary care in the United States,” he said.

In a study published in Annals of Internal Medicine, Dr. Agarwal and colleagues reviewed nationally representative claims and survey data from 2019 and 2020. They analyzed 34 distinct prevention and coordination codes in 13 categories that have been added the MPFS since 2005. Of these, four involved coordination of care (cognitive impairment, behavioral health integration, chronic care management, and transitional care management). The other nine categories in prevention were wellness visits, advance care planning, shared decision making for lung cancer screening, obesity counseling, behavioral counseling for CVD, depression screening, alcohol misuse counseling, alcohol misuse screening, and smoking cessation counseling.

Overall, 8.8%-100% of older adult patients were eligible for preventive services. A range of patients (5.0%-60.6%) had codes for receiving services in their patient information.

“However, a much smaller fraction of eligible patients was billed for having received the service, ranging from less than 1% for alcohol misuse counseling or obesity counseling to 35.8% for wellness visits, with most below 10%,” the researchers wrote.

The median use of billing codes was 2.3% for eligible patients.

A PCP who provided and billed preventive services to half of all eligible patients could potentially increase revenues of $1,269 to $45,406 per code, with an annual revenue increase of $124,435 (interquartile range $30,654 to $226,813) for prevention services. Similarly, providing and billing coordination of care service to half of all eligible patients could increase revenue by $86,082 (IQR, $18,011 to $154,152).

“Importantly, all of these prevention and coordination codes involve decomposing the comprehensive care of a patient into component parts, each with multiple steps and checklists, which may be inconsistent with how PCPs practice and document care,” the researchers wrote in their discussion. “Unlike hospitals, primary care practices are typically unable to use departments of trained coders to maximize billing and ensure that documentation matches the requirements specified in billing rules,” they added.

The study findings were limited by several factors including the focus only on the Medicare segment of PCPs’ panels, which suggests conservative estimates of reimbursement, the researchers noted. Other limitations include response bias to the use of surveys, lack of survey data on specific billing requirements, and the potential underestimation of services by PCPs who delivered some, but not all, components of a service code.

However, the results reflect previous research to show the underutilization of prevention and coordination codes in primary care, and the need for ways to increase their use, the researchers said. “The discrepancies between service eligibility, provision of services regardless of billing, and actual billing suggest that attempting to codify each distinct activity done by a PCP in the MPFS may not be an effective strategy for supporting primary care,” they concluded.
 

Barriers to code use persist for PCPs

“What surprised us was that there were many codes; we analyzed 34 in the paper in 13 distinct categories of services, and Medicare continues to add new primary care codes to the fee schedule,” Dr. Agarwal said in an interview. Also surprising, “take-up is low virtually across the board, and this isn’t for lack of eligibility,” he said. The low use of the codes “is not for lack of counseling patients on diet, drinking, exercise, smoking, or anything else for which these codes are meant to pay PCPs ... The potential revenue from these codes in aggregate is huge,” Dr. Agarwal emphasized.

“My hope is not necessarily that physicians read this study and start using some or all of these codes more frequently,” said Dr. Agarwal. “It can be tempting to think of this as money left on the table, but it’s not; there are compliance, billing, and opportunity costs from using these codes,” he said. “For individual PCPs seeing individual patients for the breadth that is primary care, I’m not sure the juice is worth the squeeze,” he added. “My coauthors and I are all primary care physicians. We know from our research and first-hand that these codes can be cumbersome to use.” These codes also don’t reflect how PCPs practice, he said. “PCPs are not in the business of slicing and dicing a visit or patient to extract as much revenue as possible. The physician-patient interaction is more complex, and richer, than these codes imply. Instead, I hope our paper encourages Medicare and policymakers to take a harder look at other strategies for investing in primary care,” Dr. Agarwal added.

As for additional research, “Primary care spending is going in the wrong direction,” said Dr. Agarwal. “We need to figure out how best to finance primary care in the United States.”

Recent studies have examined the successes and limitations of the primary care medical home model, Medicare’s Comprehensive Primary Care Initiative, and primary care spending legislation, he said. “Our study is another piece of the puzzle: at least in its current form,” and the results suggest “that one-off codes were nice in theory but not in practice,” he noted.
 

New codes are cumbersome

“It’s tempting to interpret underuse of new billing codes as a simple change management problem,” Davoren Chick, MD, chief learning officer of the American College of Physicians, wrote in an accompanying editorial. However, the underuse of codes for preventive service and coordination of care likely stems from the details of the codes, he said.

The new codes require the documentation of specific components and a minimum duration of services, he explained. “Codes that reward discrete service episodes disadvantage physicians who appropriately integrate preventive services within a continuous patient care relationship,” he added.

Dr. Chick presented an example of a primary care physician who would have to deliver intensive behavioral therapy for obesity in 15-minute episodes outside of a routine office visit to meet the billing criteria for current Medicare codes.

Dr. Chick called on clinicians to educate themselves on the coding rules for the services they provide “not only to optimize current payment but also to advocate for change.”

He concluded: “Widespread underuse of new preventive service and coordination of care codes reflects system failure, not physician failure. We must stand firm with this knowledge to demand increased payment for feasible, patient-centered primary care commensurate with its value in achieving better outcomes and lower costs.”

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Agarwal and Dr. Chick had no financial conflicts to disclose.

Primary care providers could add more than $100,000 to their incomes by billing more often for prevention and coordination of care services using Medicare codes, a new study shows.

According to the new research, primary care physicians used these codes for a median of only 2.3% of services provided to eligible patients.

“Investing in primary care is good for the health of patients, for achieving health equity, and for improving the value of health care spending, and yet the U.S. underinvests in primary care,” lead author Sumit D. Agarwal, MD, of Brigham and Women’s Hospital, Boston, said in an interview.

“One strategy to rectify this has been to add billing codes to the physician fee schedule for PCPs to use and thus raise primary care spending; Medicare has been activating new codes for the better part of 2 decades, and we wanted to investigate how successful this strategy of adding codes to the Medicare Physician Fee Schedule (MPFS) schedule has been to inform discussions on how best to finance primary care in the United States,” he said.

In a study published in Annals of Internal Medicine, Dr. Agarwal and colleagues reviewed nationally representative claims and survey data from 2019 and 2020. They analyzed 34 distinct prevention and coordination codes in 13 categories that have been added the MPFS since 2005. Of these, four involved coordination of care (cognitive impairment, behavioral health integration, chronic care management, and transitional care management). The other nine categories in prevention were wellness visits, advance care planning, shared decision making for lung cancer screening, obesity counseling, behavioral counseling for CVD, depression screening, alcohol misuse counseling, alcohol misuse screening, and smoking cessation counseling.

Overall, 8.8%-100% of older adult patients were eligible for preventive services. A range of patients (5.0%-60.6%) had codes for receiving services in their patient information.

“However, a much smaller fraction of eligible patients was billed for having received the service, ranging from less than 1% for alcohol misuse counseling or obesity counseling to 35.8% for wellness visits, with most below 10%,” the researchers wrote.

The median use of billing codes was 2.3% for eligible patients.

A PCP who provided and billed preventive services to half of all eligible patients could potentially increase revenues of $1,269 to $45,406 per code, with an annual revenue increase of $124,435 (interquartile range $30,654 to $226,813) for prevention services. Similarly, providing and billing coordination of care service to half of all eligible patients could increase revenue by $86,082 (IQR, $18,011 to $154,152).

“Importantly, all of these prevention and coordination codes involve decomposing the comprehensive care of a patient into component parts, each with multiple steps and checklists, which may be inconsistent with how PCPs practice and document care,” the researchers wrote in their discussion. “Unlike hospitals, primary care practices are typically unable to use departments of trained coders to maximize billing and ensure that documentation matches the requirements specified in billing rules,” they added.

The study findings were limited by several factors including the focus only on the Medicare segment of PCPs’ panels, which suggests conservative estimates of reimbursement, the researchers noted. Other limitations include response bias to the use of surveys, lack of survey data on specific billing requirements, and the potential underestimation of services by PCPs who delivered some, but not all, components of a service code.

However, the results reflect previous research to show the underutilization of prevention and coordination codes in primary care, and the need for ways to increase their use, the researchers said. “The discrepancies between service eligibility, provision of services regardless of billing, and actual billing suggest that attempting to codify each distinct activity done by a PCP in the MPFS may not be an effective strategy for supporting primary care,” they concluded.
 

Barriers to code use persist for PCPs

“What surprised us was that there were many codes; we analyzed 34 in the paper in 13 distinct categories of services, and Medicare continues to add new primary care codes to the fee schedule,” Dr. Agarwal said in an interview. Also surprising, “take-up is low virtually across the board, and this isn’t for lack of eligibility,” he said. The low use of the codes “is not for lack of counseling patients on diet, drinking, exercise, smoking, or anything else for which these codes are meant to pay PCPs ... The potential revenue from these codes in aggregate is huge,” Dr. Agarwal emphasized.

“My hope is not necessarily that physicians read this study and start using some or all of these codes more frequently,” said Dr. Agarwal. “It can be tempting to think of this as money left on the table, but it’s not; there are compliance, billing, and opportunity costs from using these codes,” he said. “For individual PCPs seeing individual patients for the breadth that is primary care, I’m not sure the juice is worth the squeeze,” he added. “My coauthors and I are all primary care physicians. We know from our research and first-hand that these codes can be cumbersome to use.” These codes also don’t reflect how PCPs practice, he said. “PCPs are not in the business of slicing and dicing a visit or patient to extract as much revenue as possible. The physician-patient interaction is more complex, and richer, than these codes imply. Instead, I hope our paper encourages Medicare and policymakers to take a harder look at other strategies for investing in primary care,” Dr. Agarwal added.

As for additional research, “Primary care spending is going in the wrong direction,” said Dr. Agarwal. “We need to figure out how best to finance primary care in the United States.”

Recent studies have examined the successes and limitations of the primary care medical home model, Medicare’s Comprehensive Primary Care Initiative, and primary care spending legislation, he said. “Our study is another piece of the puzzle: at least in its current form,” and the results suggest “that one-off codes were nice in theory but not in practice,” he noted.
 

New codes are cumbersome

“It’s tempting to interpret underuse of new billing codes as a simple change management problem,” Davoren Chick, MD, chief learning officer of the American College of Physicians, wrote in an accompanying editorial. However, the underuse of codes for preventive service and coordination of care likely stems from the details of the codes, he said.

The new codes require the documentation of specific components and a minimum duration of services, he explained. “Codes that reward discrete service episodes disadvantage physicians who appropriately integrate preventive services within a continuous patient care relationship,” he added.

Dr. Chick presented an example of a primary care physician who would have to deliver intensive behavioral therapy for obesity in 15-minute episodes outside of a routine office visit to meet the billing criteria for current Medicare codes.

Dr. Chick called on clinicians to educate themselves on the coding rules for the services they provide “not only to optimize current payment but also to advocate for change.”

He concluded: “Widespread underuse of new preventive service and coordination of care codes reflects system failure, not physician failure. We must stand firm with this knowledge to demand increased payment for feasible, patient-centered primary care commensurate with its value in achieving better outcomes and lower costs.”

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Agarwal and Dr. Chick had no financial conflicts to disclose.

This week, we celebrate our nation’s birth in a national and individual display of our patriotic attachment to this country. To understand how that patriotic attachment arises, we need to step back and look at the ways in which our brains change and define how each of us develops a sense of Self — which includes our self-definition as Americans.

For each of us, personhood is an almost miraculous product of our brain’s plasticity — the brain’s ability to change chemically, structurally, and functionally, based on our life experiences — arising from near countless moments of change in the wiring of our brain.

The incredibly complex remodeling that created “you” is a product, of course, of your very complicated, unique passage in life. You have a repertoire of skills and ability; you have stories and understanding and a history of sensing and acting and thinking in the world that is, in detail, unique only to you and your experiences.

As your brain created its model of your world by recording “what goes with what” at each brief moment of time, your brain — that most complicated and wonderful of “machines” on planet Earth — also associated billions of moments of feeling and action and thought with their source, your Self.

Because we primarily construct our model of the world through our eyes and ears, it’s not surprising that the emergent Self that is located somewhere in the center of your head behind your eyes and between your ears. Through billions of contacts with the surfaces of your hide and sensory organs, you have embodied yourself.
 

Your sense of ‘us’

These same neurologic processes extend beyond our physical beings to incorporate other contributors to our well-being into our personhoods. Loving parents, siblings, friends — and others in your clans and tribes and nations — literally grow into your personhood by these same self-associating processes. These relationships are supported in mutual identity by all of the tokens and icons and charms and customs that collectively define you and enable a sense of “us.”

Put another way, Mother Nature (or, in another cultural perspective, our Creator) has designed our brains to incorporate all of those who are close to us — and more broadly, other individuals in our clan or tribe or nation — to be a part of each of us.

Humans are highly social creatures. When we rise up and risk our lives to defend our friends, family, or cultural “in-groups,” we are literally fighting to defend ourselves — because those other individuals have grown into our very being. In defending them, we are literally defending a part of ourselves.

From one human perspective, this attachment to family and clan and tribe and nation is obviously key for our survival. We are an individually vulnerable but collectively powerful species, and attachment and mutual support are a key to our personal and collective successes in life.

From another perspective, there is also a dark side to this “gift of nature.”

We draw lines in substantially arbitrary locations across the surface of planet Earth, or we may define our self as belonging to a group in a political or social or religious context, or sect. Our tribalism can support a generally strong level of support and succor for fellow humans on our side of that line, while we regard those just across the line as undeserving of our support. If they offend us, they may become targets of our capacity for cruelty.

Our allegiances can be both wonderful and harmful.
 

The individuality of us

As we celebrate this holiday — a favorite day on my personal calendar — I am compelled to reflect on the fact that America was designed to be fractious. We Americans are not required to all operate like “peas in the pod.”

While we, as a nation, often fail to live up to our ideals, when we pursue the highest standards of liberty, we celebrate diversity, difference, and the ability of each member of our tribe to find their own path.

In a very real sense, the great American “invention” was to create a nation in which we could all find a wonderful place of our own, with the sympathy and protection of fellow citizens, and with liberty and justice for all.

Happy Independence Day to my American tribe!



Michael Merzenich, PhD, is often credited with discovering lifelong plasticity, with being the first to harness plasticity for human benefit (in his co-invention of the cochlear implant), and for pioneering the field of plasticity-based computerized brain exercise. He is professor emeritus at UCSF and a Kavli Laureate in Neuroscience, and he has been honored by each of the US National Academies of Sciences, Engineering, and Medicine. He may be most widely known for a series of specials on the brain on public television. His current focus is BrainHQ, a brain exercise app. He has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Posit Science Corporation; Stronger Brains Inc. Serve(d) as a speaker or a member of a speakers bureau for: Posit Science Corporation; Stronger Brains Inc. Received research grant from: National Institutes of Health Have a 5% or greater equity interest in: Posit Science Corporation; Stronger Brains Inc. Received income in an amount equal to or greater than $250 from: Posit Science Corporation; Stronger Brains Inc.; National Institutes of Health.

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

This week, we celebrate our nation’s birth in a national and individual display of our patriotic attachment to this country. To understand how that patriotic attachment arises, we need to step back and look at the ways in which our brains change and define how each of us develops a sense of Self — which includes our self-definition as Americans.

For each of us, personhood is an almost miraculous product of our brain’s plasticity — the brain’s ability to change chemically, structurally, and functionally, based on our life experiences — arising from near countless moments of change in the wiring of our brain.

The incredibly complex remodeling that created “you” is a product, of course, of your very complicated, unique passage in life. You have a repertoire of skills and ability; you have stories and understanding and a history of sensing and acting and thinking in the world that is, in detail, unique only to you and your experiences.

As your brain created its model of your world by recording “what goes with what” at each brief moment of time, your brain — that most complicated and wonderful of “machines” on planet Earth — also associated billions of moments of feeling and action and thought with their source, your Self.

Because we primarily construct our model of the world through our eyes and ears, it’s not surprising that the emergent Self that is located somewhere in the center of your head behind your eyes and between your ears. Through billions of contacts with the surfaces of your hide and sensory organs, you have embodied yourself.
 

Your sense of ‘us’

These same neurologic processes extend beyond our physical beings to incorporate other contributors to our well-being into our personhoods. Loving parents, siblings, friends — and others in your clans and tribes and nations — literally grow into your personhood by these same self-associating processes. These relationships are supported in mutual identity by all of the tokens and icons and charms and customs that collectively define you and enable a sense of “us.”

Put another way, Mother Nature (or, in another cultural perspective, our Creator) has designed our brains to incorporate all of those who are close to us — and more broadly, other individuals in our clan or tribe or nation — to be a part of each of us.

Humans are highly social creatures. When we rise up and risk our lives to defend our friends, family, or cultural “in-groups,” we are literally fighting to defend ourselves — because those other individuals have grown into our very being. In defending them, we are literally defending a part of ourselves.

From one human perspective, this attachment to family and clan and tribe and nation is obviously key for our survival. We are an individually vulnerable but collectively powerful species, and attachment and mutual support are a key to our personal and collective successes in life.

From another perspective, there is also a dark side to this “gift of nature.”

We draw lines in substantially arbitrary locations across the surface of planet Earth, or we may define our self as belonging to a group in a political or social or religious context, or sect. Our tribalism can support a generally strong level of support and succor for fellow humans on our side of that line, while we regard those just across the line as undeserving of our support. If they offend us, they may become targets of our capacity for cruelty.

Our allegiances can be both wonderful and harmful.
 

The individuality of us

As we celebrate this holiday — a favorite day on my personal calendar — I am compelled to reflect on the fact that America was designed to be fractious. We Americans are not required to all operate like “peas in the pod.”

While we, as a nation, often fail to live up to our ideals, when we pursue the highest standards of liberty, we celebrate diversity, difference, and the ability of each member of our tribe to find their own path.

In a very real sense, the great American “invention” was to create a nation in which we could all find a wonderful place of our own, with the sympathy and protection of fellow citizens, and with liberty and justice for all.

Happy Independence Day to my American tribe!



Michael Merzenich, PhD, is often credited with discovering lifelong plasticity, with being the first to harness plasticity for human benefit (in his co-invention of the cochlear implant), and for pioneering the field of plasticity-based computerized brain exercise. He is professor emeritus at UCSF and a Kavli Laureate in Neuroscience, and he has been honored by each of the US National Academies of Sciences, Engineering, and Medicine. He may be most widely known for a series of specials on the brain on public television. His current focus is BrainHQ, a brain exercise app. He has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Posit Science Corporation; Stronger Brains Inc. Serve(d) as a speaker or a member of a speakers bureau for: Posit Science Corporation; Stronger Brains Inc. Received research grant from: National Institutes of Health Have a 5% or greater equity interest in: Posit Science Corporation; Stronger Brains Inc. Received income in an amount equal to or greater than $250 from: Posit Science Corporation; Stronger Brains Inc.; National Institutes of Health.

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

This week, we celebrate our nation’s birth in a national and individual display of our patriotic attachment to this country. To understand how that patriotic attachment arises, we need to step back and look at the ways in which our brains change and define how each of us develops a sense of Self — which includes our self-definition as Americans.

For each of us, personhood is an almost miraculous product of our brain’s plasticity — the brain’s ability to change chemically, structurally, and functionally, based on our life experiences — arising from near countless moments of change in the wiring of our brain.

The incredibly complex remodeling that created “you” is a product, of course, of your very complicated, unique passage in life. You have a repertoire of skills and ability; you have stories and understanding and a history of sensing and acting and thinking in the world that is, in detail, unique only to you and your experiences.

As your brain created its model of your world by recording “what goes with what” at each brief moment of time, your brain — that most complicated and wonderful of “machines” on planet Earth — also associated billions of moments of feeling and action and thought with their source, your Self.

Because we primarily construct our model of the world through our eyes and ears, it’s not surprising that the emergent Self that is located somewhere in the center of your head behind your eyes and between your ears. Through billions of contacts with the surfaces of your hide and sensory organs, you have embodied yourself.
 

Your sense of ‘us’

These same neurologic processes extend beyond our physical beings to incorporate other contributors to our well-being into our personhoods. Loving parents, siblings, friends — and others in your clans and tribes and nations — literally grow into your personhood by these same self-associating processes. These relationships are supported in mutual identity by all of the tokens and icons and charms and customs that collectively define you and enable a sense of “us.”

Put another way, Mother Nature (or, in another cultural perspective, our Creator) has designed our brains to incorporate all of those who are close to us — and more broadly, other individuals in our clan or tribe or nation — to be a part of each of us.

Humans are highly social creatures. When we rise up and risk our lives to defend our friends, family, or cultural “in-groups,” we are literally fighting to defend ourselves — because those other individuals have grown into our very being. In defending them, we are literally defending a part of ourselves.

From one human perspective, this attachment to family and clan and tribe and nation is obviously key for our survival. We are an individually vulnerable but collectively powerful species, and attachment and mutual support are a key to our personal and collective successes in life.

From another perspective, there is also a dark side to this “gift of nature.”

We draw lines in substantially arbitrary locations across the surface of planet Earth, or we may define our self as belonging to a group in a political or social or religious context, or sect. Our tribalism can support a generally strong level of support and succor for fellow humans on our side of that line, while we regard those just across the line as undeserving of our support. If they offend us, they may become targets of our capacity for cruelty.

Our allegiances can be both wonderful and harmful.
 

The individuality of us

As we celebrate this holiday — a favorite day on my personal calendar — I am compelled to reflect on the fact that America was designed to be fractious. We Americans are not required to all operate like “peas in the pod.”

While we, as a nation, often fail to live up to our ideals, when we pursue the highest standards of liberty, we celebrate diversity, difference, and the ability of each member of our tribe to find their own path.

In a very real sense, the great American “invention” was to create a nation in which we could all find a wonderful place of our own, with the sympathy and protection of fellow citizens, and with liberty and justice for all.

Happy Independence Day to my American tribe!



Michael Merzenich, PhD, is often credited with discovering lifelong plasticity, with being the first to harness plasticity for human benefit (in his co-invention of the cochlear implant), and for pioneering the field of plasticity-based computerized brain exercise. He is professor emeritus at UCSF and a Kavli Laureate in Neuroscience, and he has been honored by each of the US National Academies of Sciences, Engineering, and Medicine. He may be most widely known for a series of specials on the brain on public television. His current focus is BrainHQ, a brain exercise app. He has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Posit Science Corporation; Stronger Brains Inc. Serve(d) as a speaker or a member of a speakers bureau for: Posit Science Corporation; Stronger Brains Inc. Received research grant from: National Institutes of Health Have a 5% or greater equity interest in: Posit Science Corporation; Stronger Brains Inc. Received income in an amount equal to or greater than $250 from: Posit Science Corporation; Stronger Brains Inc.; National Institutes of Health.

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

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

Research continues to demonstrate the benefits of glucagon-like peptide-1 receptor (GLP-1R) agonists or co-agonists for type 2 diabetes (T2D). Arslanian and the AWARD-PEDS investigators have published the results of a randomized controlled trial comparing once-weekly dulaglutide vs.placebo in youths between 10 and17 years of age with T2D. A1c was reduced by 1.2% with 0.75 mg dulaglutide and by 1.5% with a 1.5 mg dose, compared with placebo. Of note, there was no significant weight difference between dulaglutide and placebo, similar to what has been found with liraglutide and extended-release exenatide in similar populations. This is also contrary to the weight loss that is found with GLP-1R agonists in adult studies. While the GLP-1R agonist class provides a nice glycemic benefit in youth with T2D, it remains perplexing as to why weight loss has not been demonstrated in clinical trials.

In the SURPASS trials of the GLP-1/gastric inhibitory polypeptide (GIP) receptor co-agonist tirzepatide, there was robust A1c lowering and weight loss among individuals with T2D. A meta-analysis published by Karagiannis and colleagues of seven tirzepatide trials has shown dose-dependent superiority for A1c and weight compared withplacebo, GLP-1R agonists, and basal insulin. Gastrointestinal side effects were similar to what we have come to expect with GLP-1R agonist–based therapies. Tirzepatide, recently approved by the US Food and Drug Administration (FDA) for the treatment of T2D, is a welcome addition to the pharmacotherapy toolkit.

In the SURPASS-2 study, all doses of tirzepatide were superior to 1 mg semaglutide for both A1c and body weight reduction. Following the recent approval of 2 mg semaglutide by the FDA for the management of T2D, Vadher and colleagues explored how tirzepatide compares with 2 mg semaglutide via an indirect treatment comparison. Using data from the SUSTAIN-FORTE and SURPASS-2 trials, these authors found that A1c and weight reductions were significantly greater for 10 and 15 mg tirzepatide vs 2 mg semaglutide and similar for 5 mg tirzepatide vs 2 mg semaglutide. In the absence of a head-to-head trial, this analysis suggests greater efficacy with tirzepatide compared with high-dose semaglutide in T2D.

Continuous glucose monitoring (CGM) provides information about glycemia that is not available with A1c and capillary glucose monitoring. The coefficient of variation (CV) calculated from CGM is a good measure of glycemic variability, with a goal of ≤36%. There are inconsistent data for the association of CV with microvascular or macrovascular complications and very little study of the relationship between CV and long-term mortality. Mo and colleagues investigated the association between short-term glycemic variability measured by CV and all-cause mortality in a prospective study of 1839 individuals with T2D and a well-controlled glucose profile monitored by CGM. After about 7 years of follow-up, a greater baseline CV was associated with an increased risk for all-cause mortality, with a greater than twofold risk fo rmortality with a baseline CV of >35% compared witha baseline CV of ≤20%. This study suggests that clinicians should pay attention when CV is high, even with otherwise good glycemic control. With the expanding use of CGM, long-term intervention studies are needed to determine the role of glycemic variability(CV) in the development of complications and hard outcomes.

Research continues to demonstrate the benefits of glucagon-like peptide-1 receptor (GLP-1R) agonists or co-agonists for type 2 diabetes (T2D). Arslanian and the AWARD-PEDS investigators have published the results of a randomized controlled trial comparing once-weekly dulaglutide vs.placebo in youths between 10 and17 years of age with T2D. A1c was reduced by 1.2% with 0.75 mg dulaglutide and by 1.5% with a 1.5 mg dose, compared with placebo. Of note, there was no significant weight difference between dulaglutide and placebo, similar to what has been found with liraglutide and extended-release exenatide in similar populations. This is also contrary to the weight loss that is found with GLP-1R agonists in adult studies. While the GLP-1R agonist class provides a nice glycemic benefit in youth with T2D, it remains perplexing as to why weight loss has not been demonstrated in clinical trials.

In the SURPASS trials of the GLP-1/gastric inhibitory polypeptide (GIP) receptor co-agonist tirzepatide, there was robust A1c lowering and weight loss among individuals with T2D. A meta-analysis published by Karagiannis and colleagues of seven tirzepatide trials has shown dose-dependent superiority for A1c and weight compared withplacebo, GLP-1R agonists, and basal insulin. Gastrointestinal side effects were similar to what we have come to expect with GLP-1R agonist–based therapies. Tirzepatide, recently approved by the US Food and Drug Administration (FDA) for the treatment of T2D, is a welcome addition to the pharmacotherapy toolkit.

In the SURPASS-2 study, all doses of tirzepatide were superior to 1 mg semaglutide for both A1c and body weight reduction. Following the recent approval of 2 mg semaglutide by the FDA for the management of T2D, Vadher and colleagues explored how tirzepatide compares with 2 mg semaglutide via an indirect treatment comparison. Using data from the SUSTAIN-FORTE and SURPASS-2 trials, these authors found that A1c and weight reductions were significantly greater for 10 and 15 mg tirzepatide vs 2 mg semaglutide and similar for 5 mg tirzepatide vs 2 mg semaglutide. In the absence of a head-to-head trial, this analysis suggests greater efficacy with tirzepatide compared with high-dose semaglutide in T2D.

Continuous glucose monitoring (CGM) provides information about glycemia that is not available with A1c and capillary glucose monitoring. The coefficient of variation (CV) calculated from CGM is a good measure of glycemic variability, with a goal of ≤36%. There are inconsistent data for the association of CV with microvascular or macrovascular complications and very little study of the relationship between CV and long-term mortality. Mo and colleagues investigated the association between short-term glycemic variability measured by CV and all-cause mortality in a prospective study of 1839 individuals with T2D and a well-controlled glucose profile monitored by CGM. After about 7 years of follow-up, a greater baseline CV was associated with an increased risk for all-cause mortality, with a greater than twofold risk fo rmortality with a baseline CV of >35% compared witha baseline CV of ≤20%. This study suggests that clinicians should pay attention when CV is high, even with otherwise good glycemic control. With the expanding use of CGM, long-term intervention studies are needed to determine the role of glycemic variability(CV) in the development of complications and hard outcomes.

Research continues to demonstrate the benefits of glucagon-like peptide-1 receptor (GLP-1R) agonists or co-agonists for type 2 diabetes (T2D). Arslanian and the AWARD-PEDS investigators have published the results of a randomized controlled trial comparing once-weekly dulaglutide vs.placebo in youths between 10 and17 years of age with T2D. A1c was reduced by 1.2% with 0.75 mg dulaglutide and by 1.5% with a 1.5 mg dose, compared with placebo. Of note, there was no significant weight difference between dulaglutide and placebo, similar to what has been found with liraglutide and extended-release exenatide in similar populations. This is also contrary to the weight loss that is found with GLP-1R agonists in adult studies. While the GLP-1R agonist class provides a nice glycemic benefit in youth with T2D, it remains perplexing as to why weight loss has not been demonstrated in clinical trials.

In the SURPASS trials of the GLP-1/gastric inhibitory polypeptide (GIP) receptor co-agonist tirzepatide, there was robust A1c lowering and weight loss among individuals with T2D. A meta-analysis published by Karagiannis and colleagues of seven tirzepatide trials has shown dose-dependent superiority for A1c and weight compared withplacebo, GLP-1R agonists, and basal insulin. Gastrointestinal side effects were similar to what we have come to expect with GLP-1R agonist–based therapies. Tirzepatide, recently approved by the US Food and Drug Administration (FDA) for the treatment of T2D, is a welcome addition to the pharmacotherapy toolkit.

In the SURPASS-2 study, all doses of tirzepatide were superior to 1 mg semaglutide for both A1c and body weight reduction. Following the recent approval of 2 mg semaglutide by the FDA for the management of T2D, Vadher and colleagues explored how tirzepatide compares with 2 mg semaglutide via an indirect treatment comparison. Using data from the SUSTAIN-FORTE and SURPASS-2 trials, these authors found that A1c and weight reductions were significantly greater for 10 and 15 mg tirzepatide vs 2 mg semaglutide and similar for 5 mg tirzepatide vs 2 mg semaglutide. In the absence of a head-to-head trial, this analysis suggests greater efficacy with tirzepatide compared with high-dose semaglutide in T2D.

Continuous glucose monitoring (CGM) provides information about glycemia that is not available with A1c and capillary glucose monitoring. The coefficient of variation (CV) calculated from CGM is a good measure of glycemic variability, with a goal of ≤36%. There are inconsistent data for the association of CV with microvascular or macrovascular complications and very little study of the relationship between CV and long-term mortality. Mo and colleagues investigated the association between short-term glycemic variability measured by CV and all-cause mortality in a prospective study of 1839 individuals with T2D and a well-controlled glucose profile monitored by CGM. After about 7 years of follow-up, a greater baseline CV was associated with an increased risk for all-cause mortality, with a greater than twofold risk fo rmortality with a baseline CV of >35% compared witha baseline CV of ≤20%. This study suggests that clinicians should pay attention when CV is high, even with otherwise good glycemic control. With the expanding use of CGM, long-term intervention studies are needed to determine the role of glycemic variability(CV) in the development of complications and hard outcomes.

Addicted to cookies? Can’t stand broccoli? You may be able to blame Mom and Dad.

That’s because our taste preferences are influenced by our genes. And this may play an important role in determining our food choices and, in turn, our health, according to early study findings presented at this year’s annual meeting of the American Society for Nutrition.

“Our genetic predispositions to perceive certain tastes might be one of many reasons why some of us struggle to make healthy food choices,” says the study’s lead researcher, Julie Gervis, a doctoral degree candidate at the Tufts Jean Mayer USDA Human Nutrition Research Center on Aging.

As the field of personalized nutrition – a branch of science that uses technology to help people figure out what to eat for good health – advances, the findings could bring us closer to more effective personalized nutrition advice, better diets, and less risk for things like obesity, type 2 diabetes, and heart disease.
 

What’s your ‘polygenic taste score’?

We know genes influence our taste, but little is known about how taste-related genes impact diet quality and health. To investigate this, the researchers used data from “genome-wide association studies,” which scientists use to find gene variations associated with a trait, to create something called a polygenic taste score.

Your polygenic taste score shows how your genes impact your unique perception of taste – be it bitter, salty, sweet, sour, or savory (umami). If you have a high score for, say, sweet, that means you may be more sensitive to sweetness than someone with a moderate or low sweet score.

In the study sample of more than 6,000 adults, those with a high “bitter” score tended to eat fewer whole grains (two fewer servings a week), while those scoring high for savory ate fewer vegetables, especially orange and red types like carrots and bell peppers. That matters because whole grains have been shown to reduce heart disease risk, while a higher veggie intake is linked to lower risk of type 2 diabetes.

Meanwhile, genes related to sweet seemed key for health related to your heart and metabolism, as a higher sweet score was linked with lower triglycerides, a type of fat found in the blood.
 

From lab to shopping list

While we have a long way to go before dietitians and consumers can use polygenic taste scores, the tool could one day help us use – or minimize – the influence our genes has on our food choices, Ms. Gervis says. That may help us improve personalized nutrition advice aimed at reducing disease risk.

But first, other research needs to repeat the findings, Ms. Gervis says. And more large-scale, genome-wide studies on taste perception should be done.

“I hope these preliminary data convey the potential benefit of incorporating taste-related genes, and taste perception, into personalized nutrition,” she says. “After all, while we don’t always choose what foods are good for us, we do always choose what foods taste good to us.”

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

Addicted to cookies? Can’t stand broccoli? You may be able to blame Mom and Dad.

That’s because our taste preferences are influenced by our genes. And this may play an important role in determining our food choices and, in turn, our health, according to early study findings presented at this year’s annual meeting of the American Society for Nutrition.

“Our genetic predispositions to perceive certain tastes might be one of many reasons why some of us struggle to make healthy food choices,” says the study’s lead researcher, Julie Gervis, a doctoral degree candidate at the Tufts Jean Mayer USDA Human Nutrition Research Center on Aging.

As the field of personalized nutrition – a branch of science that uses technology to help people figure out what to eat for good health – advances, the findings could bring us closer to more effective personalized nutrition advice, better diets, and less risk for things like obesity, type 2 diabetes, and heart disease.
 

What’s your ‘polygenic taste score’?

We know genes influence our taste, but little is known about how taste-related genes impact diet quality and health. To investigate this, the researchers used data from “genome-wide association studies,” which scientists use to find gene variations associated with a trait, to create something called a polygenic taste score.

Your polygenic taste score shows how your genes impact your unique perception of taste – be it bitter, salty, sweet, sour, or savory (umami). If you have a high score for, say, sweet, that means you may be more sensitive to sweetness than someone with a moderate or low sweet score.

In the study sample of more than 6,000 adults, those with a high “bitter” score tended to eat fewer whole grains (two fewer servings a week), while those scoring high for savory ate fewer vegetables, especially orange and red types like carrots and bell peppers. That matters because whole grains have been shown to reduce heart disease risk, while a higher veggie intake is linked to lower risk of type 2 diabetes.

Meanwhile, genes related to sweet seemed key for health related to your heart and metabolism, as a higher sweet score was linked with lower triglycerides, a type of fat found in the blood.
 

From lab to shopping list

While we have a long way to go before dietitians and consumers can use polygenic taste scores, the tool could one day help us use – or minimize – the influence our genes has on our food choices, Ms. Gervis says. That may help us improve personalized nutrition advice aimed at reducing disease risk.

But first, other research needs to repeat the findings, Ms. Gervis says. And more large-scale, genome-wide studies on taste perception should be done.

“I hope these preliminary data convey the potential benefit of incorporating taste-related genes, and taste perception, into personalized nutrition,” she says. “After all, while we don’t always choose what foods are good for us, we do always choose what foods taste good to us.”

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

Addicted to cookies? Can’t stand broccoli? You may be able to blame Mom and Dad.

That’s because our taste preferences are influenced by our genes. And this may play an important role in determining our food choices and, in turn, our health, according to early study findings presented at this year’s annual meeting of the American Society for Nutrition.

“Our genetic predispositions to perceive certain tastes might be one of many reasons why some of us struggle to make healthy food choices,” says the study’s lead researcher, Julie Gervis, a doctoral degree candidate at the Tufts Jean Mayer USDA Human Nutrition Research Center on Aging.

As the field of personalized nutrition – a branch of science that uses technology to help people figure out what to eat for good health – advances, the findings could bring us closer to more effective personalized nutrition advice, better diets, and less risk for things like obesity, type 2 diabetes, and heart disease.
 

What’s your ‘polygenic taste score’?

We know genes influence our taste, but little is known about how taste-related genes impact diet quality and health. To investigate this, the researchers used data from “genome-wide association studies,” which scientists use to find gene variations associated with a trait, to create something called a polygenic taste score.

Your polygenic taste score shows how your genes impact your unique perception of taste – be it bitter, salty, sweet, sour, or savory (umami). If you have a high score for, say, sweet, that means you may be more sensitive to sweetness than someone with a moderate or low sweet score.

In the study sample of more than 6,000 adults, those with a high “bitter” score tended to eat fewer whole grains (two fewer servings a week), while those scoring high for savory ate fewer vegetables, especially orange and red types like carrots and bell peppers. That matters because whole grains have been shown to reduce heart disease risk, while a higher veggie intake is linked to lower risk of type 2 diabetes.

Meanwhile, genes related to sweet seemed key for health related to your heart and metabolism, as a higher sweet score was linked with lower triglycerides, a type of fat found in the blood.
 

From lab to shopping list

While we have a long way to go before dietitians and consumers can use polygenic taste scores, the tool could one day help us use – or minimize – the influence our genes has on our food choices, Ms. Gervis says. That may help us improve personalized nutrition advice aimed at reducing disease risk.

But first, other research needs to repeat the findings, Ms. Gervis says. And more large-scale, genome-wide studies on taste perception should be done.

“I hope these preliminary data convey the potential benefit of incorporating taste-related genes, and taste perception, into personalized nutrition,” she says. “After all, while we don’t always choose what foods are good for us, we do always choose what foods taste good to us.”

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

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

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

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

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

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

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

After the Supreme Court overturned Roe v. Wade last week, requests for vasectomies began spiking.

Urologists told The Washington Post that more men are seeking the procedure to prevent pregnancies and avoid abortion-related concerns.

“It was very, very noticeable [June 24], and then the number that came in over the weekend was huge, and the number that is still coming in far exceeds what we have experienced in the past,” Doug Stein, MD, a Florida urologist known as the “Vasectomy King” for his advocacy of the procedure, told the newspaper.

Before June 24, Dr. Stein received four or five vasectomy requests per day. But since then, that number has increased to 12 to 18 requests per day.

“Many of the guys are saying that they have been thinking about a vasectomy for a while, and the Roe v. Wade decision was just that final factor that tipped them over the edge and made them submit the online registration,” he said.

Urologists in California, Iowa, and New York also told the Post that they’ve seen a massive increase in the number of vasectomy consultations, as well as an increase in website traffic on their pages that offer information about vasectomies.

About 2 decades ago, Americans said the main reason they relied on a vasectomy as a form of birth control was that they or their partners had all the children they wanted. In the past decade, other reasons became more common, such as medical issues and problems with other types of birth control, the newspaper reported.

In anticipation of Roe v. Wade being overturned and anti-abortion legislation taking effect in states, advocates for vasectomies have encouraged people to get the procedure.

Dr. Stein said his practice is now booked through the end of August with vasectomy appointments, so he’s opening more days in his schedule to accommodate patients who submitted recent requests. He and his associate, John Curington, MD, said men under age 30 without children are requesting the procedure in greater numbers than before, with some citing the concurring opinion by Justice Clarence Thomas, which said the Supreme Court should reconsider other landmark cases that protect rights under the 14th Amendment, such as access to contraceptives.

“I’d say at least 60 or 70% are mentioning the Supreme Court decision,” Dr. Curington said, according to the Post. “And a few of them have such sophistication as young men that they actually are thinking about Justice Thomas and his opinion that contraception may fall next. And that’s shocking. That’s something that doesn’t enter into our conversations ever, until this week.”

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

After the Supreme Court overturned Roe v. Wade last week, requests for vasectomies began spiking.

Urologists told The Washington Post that more men are seeking the procedure to prevent pregnancies and avoid abortion-related concerns.

“It was very, very noticeable [June 24], and then the number that came in over the weekend was huge, and the number that is still coming in far exceeds what we have experienced in the past,” Doug Stein, MD, a Florida urologist known as the “Vasectomy King” for his advocacy of the procedure, told the newspaper.

Before June 24, Dr. Stein received four or five vasectomy requests per day. But since then, that number has increased to 12 to 18 requests per day.

“Many of the guys are saying that they have been thinking about a vasectomy for a while, and the Roe v. Wade decision was just that final factor that tipped them over the edge and made them submit the online registration,” he said.

Urologists in California, Iowa, and New York also told the Post that they’ve seen a massive increase in the number of vasectomy consultations, as well as an increase in website traffic on their pages that offer information about vasectomies.

About 2 decades ago, Americans said the main reason they relied on a vasectomy as a form of birth control was that they or their partners had all the children they wanted. In the past decade, other reasons became more common, such as medical issues and problems with other types of birth control, the newspaper reported.

In anticipation of Roe v. Wade being overturned and anti-abortion legislation taking effect in states, advocates for vasectomies have encouraged people to get the procedure.

Dr. Stein said his practice is now booked through the end of August with vasectomy appointments, so he’s opening more days in his schedule to accommodate patients who submitted recent requests. He and his associate, John Curington, MD, said men under age 30 without children are requesting the procedure in greater numbers than before, with some citing the concurring opinion by Justice Clarence Thomas, which said the Supreme Court should reconsider other landmark cases that protect rights under the 14th Amendment, such as access to contraceptives.

“I’d say at least 60 or 70% are mentioning the Supreme Court decision,” Dr. Curington said, according to the Post. “And a few of them have such sophistication as young men that they actually are thinking about Justice Thomas and his opinion that contraception may fall next. And that’s shocking. That’s something that doesn’t enter into our conversations ever, until this week.”

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

After the Supreme Court overturned Roe v. Wade last week, requests for vasectomies began spiking.

Urologists told The Washington Post that more men are seeking the procedure to prevent pregnancies and avoid abortion-related concerns.

“It was very, very noticeable [June 24], and then the number that came in over the weekend was huge, and the number that is still coming in far exceeds what we have experienced in the past,” Doug Stein, MD, a Florida urologist known as the “Vasectomy King” for his advocacy of the procedure, told the newspaper.

Before June 24, Dr. Stein received four or five vasectomy requests per day. But since then, that number has increased to 12 to 18 requests per day.

“Many of the guys are saying that they have been thinking about a vasectomy for a while, and the Roe v. Wade decision was just that final factor that tipped them over the edge and made them submit the online registration,” he said.

Urologists in California, Iowa, and New York also told the Post that they’ve seen a massive increase in the number of vasectomy consultations, as well as an increase in website traffic on their pages that offer information about vasectomies.

About 2 decades ago, Americans said the main reason they relied on a vasectomy as a form of birth control was that they or their partners had all the children they wanted. In the past decade, other reasons became more common, such as medical issues and problems with other types of birth control, the newspaper reported.

In anticipation of Roe v. Wade being overturned and anti-abortion legislation taking effect in states, advocates for vasectomies have encouraged people to get the procedure.

Dr. Stein said his practice is now booked through the end of August with vasectomy appointments, so he’s opening more days in his schedule to accommodate patients who submitted recent requests. He and his associate, John Curington, MD, said men under age 30 without children are requesting the procedure in greater numbers than before, with some citing the concurring opinion by Justice Clarence Thomas, which said the Supreme Court should reconsider other landmark cases that protect rights under the 14th Amendment, such as access to contraceptives.

“I’d say at least 60 or 70% are mentioning the Supreme Court decision,” Dr. Curington said, according to the Post. “And a few of them have such sophistication as young men that they actually are thinking about Justice Thomas and his opinion that contraception may fall next. And that’s shocking. That’s something that doesn’t enter into our conversations ever, until this week.”

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

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

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

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

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

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

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

Generalized anxiety disorder (GAD) typically begins in early adulthood and persists throughout life. Many individuals with GAD report they have felt anxious their entire lives. The essential symptom of GAD is excessive anxiety and worry about numerous events or activities. The intensity, duration, and/or frequency of the anxiety and worry are out of proportion to the actual likelihood or impact of the anticipated event. The individual finds it difficult to control their worry and prevent worrisome thoughts from interfering with attention to everyday tasks.¹

Treatment of GAD typically consists of psychotherapy and pharma­cotherapy. Several studies have suggested that concurrent psychotherapy amplifies the benefits of pharmacotherapy.^2-5 Additionally, combined treatment may differentially target specific symptoms (eg, cognitive vs somatic). The addition of psychotherapy may also increase treatment adherence and decrease potential adverse effects of pharmacotherapy.

Multiple classes of medications are available for treating GAD. Current guidelines and evidence suggest that selective serotonin reuptake inhibitors (SSRIs) should be considered a first-line intervention, followed by serotonin-norepinephrine reuptake inhibitors.^6-11 While the evidence supporting pharmacotherapy for GAD continues to expand, many patients with GAD do not respond to first-line treatment. There is limited data regarding second-line or augmentation strategies for treating these patients. Because current treatment options for GAD are commonly associated with suboptimal treatment outcomes, researchers are investigating the use of nonpharma­cologic biological interventions, such as repetitive transcranial magnetic stimulation (rTMS), which was first cleared by the FDA to treat major depressive disorder (MDD) in 2008.

In Part 1 of this 2-part article, we review 8 randomized controlled trials (RCTs) of biological interventions for GAD that have been published within the last 5 years (Table^12-19).

1. Strawn JR, Mills JA, Schroeder H, et al. Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychiatry. 2020;81(5):20m13396. doi:10.4088/JCP.20m13396

GAD is highly prevalent in adolescents, and SSRIs are often used as first-line agents. However, treatment response is often variable, and clinicians often use trial-and-error to identify an appropriate medication and dose that will result in meaningful improvement. Understanding an individual’s pharmacokinetic response may help predict response and guide therapy. Adult studies have shown cytochrome P450 (CYP) 2C19 metabolizes several SSRIs, including escitalopram, with faster CYP2C19 metabolism leading to decreased plasma concentrations. Strawn et al¹² studied the effects of escitalopram in adolescents with GAD as well as the effects of CYP2C19 metabolism.

Study design

• A double-blind, placebo-controlled trial evaluated 51 adolescents (age 12 to 17) who met DSM-IV-TR criteria for GAD. They had a baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 and a Clinical Global Impressions–Severity (CGI-S) Scale score ≥4.
• Participants were randomized to escitalo­pram (n = 26; scheduled titration to 15 mg/d, then flexible to 20 mg/d), or placebo (n = 25) and monitored for 8 weeks.
• Patients with panic disorder, agoraphobia, or social anxiety disorder were also enrolled, but GAD was the primary diagnosis.
• The primary outcome was change in PARS score and change from baseline in CGI-S and Clinical Global Impressions–Improvement (CGI-I) scale scores, with assessments completed at Week 1, Week 2, Week 4, Week 6, and Week 8, or at early termination.
• Genomic DNA was obtained via buccal swab to assess 9 alleles of CYP2C19. Plasma concentrations of escitalopram and its major metabolite, desmethylescitalopram, were collected to assess plasma escitalopram and desmethylescitalopram area under the curve for 24 hours (AUC_0-24) and maximum plasma concentration (C_MAX).

Outcomes

• Escitalopram was superior to placebo, evident by statistically significantly greater changes in PARS and CGI scores.
• Greater improvement over time on PARS was correlated with intermediate CYP2C19 metabolizers, and greater response as measured by CGI-I was associated with having at least 1 long allele of SLC6A4 and being an intermediate CYP2C19 metabolizer.
• While plasma escitalopram exposure (AUC_0-24) significantly decreased and desmethylcitalopram-to-escitalopram ratios increased with faster CYP2C19 metabolism at 15 mg/d, escitalopram exposure at the 15 mg/d dose and escitalopram-to-desmethyl­citalopram ratios did not differ at Week 8 between responders and nonresponders. Patients with activation symptoms had higher C_MAX and AUC_0-24.
• Changes in vital signs, corrected QT interval, and adverse events were similar in both groups.

Conclusions/limitations

• For adolescents with GAD, escitalopram showed a benefit compared to placebo.
• Allelic differences in CYP2C19 metabolism may lead to variations in pharmacokinetics, and understanding a patient’s CYP2C19 phenotype may help guide dosing escitalopram and predicting adverse effects.
• This study enrolled a small, predominantly female, White, treatment-naïve sample, which may limit conclusions on allelic differences. Additionally, the sample included adolescents with severe anxiety and comorbid anxiety conditions, which may limit generalizability.

Continue to: #2

Vortioxetine, an FDA-approved antidepressant, has been shown to improve anxiety symptoms in patients with GAD. Additionally, vortioxetine has shown positive effects in patients with MDD, with greater improvement seen in the working and professional population. Due to the overlap between MDD and GAD, Christensen et al¹³ assessed the effectiveness of vortioxetine on anxiety symptoms in individuals who were working.

Study design

• Researchers conducted a post-hoc analysis of a previously completed randomized, placebo-controlled trial of 301 patients as well as a previously completed randomized, placebo-controlled relapse prevention study of 687 patients. Patients in both groups met DSM-IV-TR criteria for GAD.
• Inclusion criteria included a Hamilton Anxiety Rating Scale (HAM-A) score ≥20 with HAM-A scores ≥2 on items 1 (anxious mood), and 2 (tension), and a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤16 at screening and baseline.
• Researchers compared participants who were working or pursuing an education vs the full study sample.

Outcomes

• Vortioxetine was significantly associated with benefits in anxiety symptoms, functioning, and quality of life in both working participants and the total population, with the greatest effects seen in professional (ie, managers, administrators) and associate professional (ie, technical, nursing, clerical workers, or secretarial) positions. Working participants who received placebo were more likely to relapse compared to those receiving vortioxetine.
• There did not appear to be a statistically significant benefit or increase in relapse among the skilled labor group (ie, building, electrical/factory worker, or services/sales) while receiving vortioxetine.

Conclusions/limitations

• Vortioxetine may have a more pronounced effect in patients who are working or pursuing an education vs the full GAD population, which suggests that targeting this medication at particular patient demographics may be beneficial.
• Working patients with GAD may also differ from nonworking patients by factors other than work, such as education, support system, motivation, and other personal factors.
• This study was a post-hoc analysis, which limits definitive conclusions but may help guide future studies.

Continue to: #3

3. Xie ZJ, Han N, Law S, et al. The efficacy of group cognitive-behavioural therapy plus duloxetine for generalised anxiety disorder versus duloxetine alone. Acta Neuropsychiatr. 2019;31(6):316-324. doi:10.1017/neu.2019.32

Treatment of GAD should include nonmedication options such as psychotherapy to help enhance efficacy. Few studies have evaluated whether combined cognitive-behavioral therapy (CBT) plus medication has more benefit than medication monotherapy, specifically in patients with GAD. In this randomized trial, Xie et al¹⁴ examined how a study population undergoing CBT and receiving duloxetine differed from those receiving duloxetine monotherapy for GAD.

Study design

• In this randomized, open-label trial, adults who met DSM-IV criteria for GAD and had a HAM-A score >14 were randomized to group CBT plus duloxetine (n = 89) or duloxetine only (n = 81), with follow-up at Week 4, Week 8, and Month 3.
• The primary outcomes included response and remission rates based on HAM-A score. Secondary outcomes included HAM-A total score reductions, psychic anxiety (HAMA-PA) and somatic anxiety (HAMA-SA) subscale score reductions, Hamilton Depression Rating Scale score reductions, and reductions in overall illness severity as measured by CGI-S, the Global Assessment of Functioning Scale, and the 12-item Short-Form Health Survey.

Outcomes

• At Week 4, combined therapy was superior to duloxetine alone as evident by the primary and most secondary outcomes, with continued benefits but smaller effect size at Week 8.
• At Month 3, combined therapy was significantly better only in HAM-A total score and HAMA-PA score reductions.

Conclusions/limitations

• Patients who received group CBT plus duloxetine treatment experienced faster improvement of GAD symptoms compared to patients who received duloxetine monotherapy, though the difference reduced over time.
• The most benefit appeared to be for psychic anxiety symptoms, which suggests that group CBT can help change cognition style.
• This study had a short follow-up period, high dropout rates, and recruited patients from only 1 institution.

4. Huang Z, Li Y, Bianchi MT, et al. Repetitive transcranial magnetic stimulation of the right parietal cortex for comorbid generalized anxiety disorder and insomnia: a randomized, double-blind, sham-controlled pilot study. Brain Stimul. 2018;11(5):1103-1109. doi:10.1016/j.brs.2018.05.016

Insomnia and anxiety often present together. rTMS has demonstrated efficacy in various psychiatric illnesses, but there is limited research regarding its effectiveness in GAD. Additionally, little is known regarding the benefits of rTMS for patients with comorbid insomnia and GAD. Huang et al¹⁵ examined the therapeutic effects of rTMS in patients with comorbid insomnia and GAD.

Continue to: Study design

• Adults who met DSM-IV criteria for GAD and insomnia were randomized to receive 10 days of low-intensity rTMS on the right parietal lobe (n = 18) or a sham procedure (n = 18). Inclusion criteria also included a score ≥14 on HAM-A, ≥7 on the Pittsburgh Sleep Quality Index (PSQI), and <20 on the 24-item Hamilton Depression Rating Scale (HAM-D).
• rTMS settings included a frequency of 1 Hz, 90% intensity of the resting motor threshold, 3 trains of 500 pulses, and an intertrain interval of 10 minutes.
• Study measurements included HAM-A, PSQI, and HAM-D at baseline, posttreatment at Day 10, Week 2 follow-up, and Month 1 follow-up.

Outcomes

• Significantly more patients in the rTMS group had a meaningful response as measured by change in HAM-A score at posttreatment and both follow-up sessions.
• The rTMS group had significant remission compared to the sham group at posttreatment and Week 2 follow-up, but showed no significant difference at Month 1.
• There were significant improvements in insomnia symptoms in the rTMS group at the posttreatment and follow-up time points.

Conclusions/limitations

• Low-frequency rTMS over the right parietal cortex is an effective treatment option for patients with comorbid GAD and insomnia.
• This study had a small sample size consisting of participants from only 1 institution.

5. Amsterdam JD, Li QS, Xie SX, et al. Putative antidepressant effect of chamomile (Matricaria chamomilla L.) oral extract in subjects with comorbid generalized anxiety disorder and depression. J Altern Complement Med. 2020;26(9):813-819. doi:10.1089/acm.2019.0252

GAD often presents with comorbid depression. While antidepressants are the standard approach to treatment of both conditions, patients may seek alternative therapies. In previous studies,²⁰Matricaria chamomilla L. (chamomile) has been shown to reduce GAD symptoms, and post-hoc analyses²¹ have shown its benefits in treating depression. Amsterdam et al¹⁶ assessed the effects of chamomile on patients with GAD with and without comorbid depression.

Study design

• As part of an RCT, 179 adults who met DSM-IV-TR criteria for GAD underwent an 8-week open-label phase of chamomile extract therapy (1,500 mg/d). Participants who responded were enrolled in a randomized, double-blind, placebo-control trial. Amsterdam et al¹⁶ specifically analyzed the 8-week open label portion of the study.
• Participants were divided into 2 groups: GAD without comorbid depression (n = 100), and GAD with comorbid depression (n = 79).
• Outcome measures included the 7-item generalized anxiety disorder scale (GAD-7), HAM-A, Beck Anxiety Inventory, 17-item HAM-D, 6-item HAM-D, and the Beck Depression Inventory (BDI).

Continue to: Outcomes

• Patients with comorbid depression experienced a greater, statistically significant reduction in HAM-D core symptom scores (depressed mood, guilt, suicide ideation, work and interest, retardation, and somatic symptoms general).
• The comorbid depression group experienced a trend (but not significant) reduction in total HAM-D and BDI scores.

Conclusions/limitations

• Chamomile extract may help reduce depressive symptoms in patients with GAD who also have depression.
• This study was not powered to detect significant differences in depression outcome ratings between groups, was exploratory, and was not a controlled trial.

6. Dilkov D, Hawken ER, Kaludiev E, et al. Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety dis­order: a randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:61-65. doi:10.1016/j.pnpbp.2017.05.018

Nonpharmacologic modalities, including rTMS, may be effective alternatives for treating GAD. Dilkov et al¹⁷ examined whether excitatory rTMS is an effective treatment option for GAD.

Study design

• In this double-blind, sham-controlled trial, adults who met DSM-IV criteria for GAD were randomized to excitatory rTMS of the right dorsolateral prefrontal cortex therapy (n = 15) or a sham procedure (n = 25).
• rTMS settings included a frequency of 20 Hz, 110% intensity of resting motor threshold, 20 trains, 9 seconds/train, and 51-second intertrain intervals.
• Outcomes were measured by HAM-A, CGI, and 21-item HAM-D.

Outcomes

• At the conclusion of 25 treatments, the rTMS group experienced a statistically significant reduction in GAD symptoms as measured by HAM-A.
• Improvements were also noted in the CGI and HAM-D scores in the rTMS group compared to the sham group.
• The benefits continued at the Week 4 follow-up visit.

Conclusions/limitations

• Participants in the rTMS group experienced a significant decrease in anxiety symptoms, which suggests that rTMS may be an effective treatment for GAD.
• The benefits appear sustainable even after the conclusion of the rTMS sessions.
• This study had a small sample size and excluded patients with comorbid psychiatric conditions.

Continue to: #7

Dysregulated stress response has been proposed as a mechanism for anxiety.^22,23 Patients with GAD have been reported to have alterations in cortisol levels, specifically lower morning cortisol levels and a less steep diurnal cortisol slope; however, it is not clear how treatment affects these levels. Keefe et al¹⁸ examined whether chamomile therapy in patients with GAD affects cortisol levels.

Study design

• In an 8-week, open-label study, 45 adults who met DSM-IV criteria for GAD received chamomile extract capsules 1,500 mg/d.
• Participants used at-home kits to collect their saliva so cortisol levels could be assessed at 8 am, 12 pm, 4 pm, and 8 pm.
• The GAD-7 was used to assess anxiety symptoms.

Outcomes

• Participants who experienced greater improvements in GAD symptoms had relative increases in morning cortisol levels compared to their baseline levels.
• Participants who experienced greater improvements in GAD symptoms had a greater decrease in cortisol levels throughout the day (ie, greater diurnal slope).

Conclusions/limitations

• Greater improvement in GAD symptoms after treatment with chamomile extract appeared to be correlated with increased morning cortisol levels and a steeper diurnal cortisol slope after awakening, which suggests that treatment of GAD may help improve dysregulated stress biology.
• This study had a small sample size and was not placebo-controlled.

Continue to: #8

Compared to the medications that are FDA-approved for GAD, agomelatine has a different mechanism of action, and has shown to be efficacious and tolerable in previous studies.^24-26 In this study, Stein et al¹⁹ compared agomelatine vs escitalopram for patients with severe GAD.

Study design

• In a 12-week, double-blind study, adults who met DSM-IV-TR criteria for GAD were randomized to agomelatine 25 to 50 mg/d (n = 261) or escitalopram 10 to 20 mg/d (n = 262).
• Participants had to meet specific criteria for severe anxiety, including a HAM-A total score ≥25.
• The primary outcome measure was the change in HAM-A score from baseline to Week 12. Secondary outcome measures included the rate of response as determined by change in scores on the HAM-PA, HAM-SA, CGI, Toronto Hospital Alertness Test, Snaith-Hamilton Pleasure Scale, and Leeds Sleep Evaluation Questionnaire.

Outcomes

• Participants in both the agomelatine and escitalopram groups reported similar, clinically significant mean reductions in HAM-A scores at Week 12.
• There were no significant differences in secondary measures between the 2 groups, and both groups experienced improvement in psychic and somatic symptoms, alertness, and sleep.
• Overall, the agomelatine group experienced fewer adverse events compared to the escitalopram group.

Conclusions/limitations

• Agomelatine may be an efficacious and well-tolerated treatment option for severe GAD.
• This study excluded individuals with comorbid conditions.

Bottom Line

Recent research suggests that escitalopram; vortioxetine; agomelatine; duloxetine plus group cognitive-behavioral therapy; repetitive transcranial magnetic stimulation; and chamomile extract can improve symptoms in patients with generalized anxiety disorder.

Related Resources

• Abell SR, El-Mallakh RS. Serotonin-mediated anxiety: how to recognize and treat it. Current Psychiatry. 2021;20(11):37-40. doi:10.12788/cp.0168

Drug Brand Names

Duloxetine • Cymbalta
Escitalopram • Lexapro
Vortioxetine • Trintellix

Generalized anxiety disorder (GAD) typically begins in early adulthood and persists throughout life. Many individuals with GAD report they have felt anxious their entire lives. The essential symptom of GAD is excessive anxiety and worry about numerous events or activities. The intensity, duration, and/or frequency of the anxiety and worry are out of proportion to the actual likelihood or impact of the anticipated event. The individual finds it difficult to control their worry and prevent worrisome thoughts from interfering with attention to everyday tasks.¹

Treatment of GAD typically consists of psychotherapy and pharma­cotherapy. Several studies have suggested that concurrent psychotherapy amplifies the benefits of pharmacotherapy.^2-5 Additionally, combined treatment may differentially target specific symptoms (eg, cognitive vs somatic). The addition of psychotherapy may also increase treatment adherence and decrease potential adverse effects of pharmacotherapy.

Multiple classes of medications are available for treating GAD. Current guidelines and evidence suggest that selective serotonin reuptake inhibitors (SSRIs) should be considered a first-line intervention, followed by serotonin-norepinephrine reuptake inhibitors.^6-11 While the evidence supporting pharmacotherapy for GAD continues to expand, many patients with GAD do not respond to first-line treatment. There is limited data regarding second-line or augmentation strategies for treating these patients. Because current treatment options for GAD are commonly associated with suboptimal treatment outcomes, researchers are investigating the use of nonpharma­cologic biological interventions, such as repetitive transcranial magnetic stimulation (rTMS), which was first cleared by the FDA to treat major depressive disorder (MDD) in 2008.

In Part 1 of this 2-part article, we review 8 randomized controlled trials (RCTs) of biological interventions for GAD that have been published within the last 5 years (Table^12-19).

1. Strawn JR, Mills JA, Schroeder H, et al. Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychiatry. 2020;81(5):20m13396. doi:10.4088/JCP.20m13396

GAD is highly prevalent in adolescents, and SSRIs are often used as first-line agents. However, treatment response is often variable, and clinicians often use trial-and-error to identify an appropriate medication and dose that will result in meaningful improvement. Understanding an individual’s pharmacokinetic response may help predict response and guide therapy. Adult studies have shown cytochrome P450 (CYP) 2C19 metabolizes several SSRIs, including escitalopram, with faster CYP2C19 metabolism leading to decreased plasma concentrations. Strawn et al¹² studied the effects of escitalopram in adolescents with GAD as well as the effects of CYP2C19 metabolism.

Study design

• A double-blind, placebo-controlled trial evaluated 51 adolescents (age 12 to 17) who met DSM-IV-TR criteria for GAD. They had a baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 and a Clinical Global Impressions–Severity (CGI-S) Scale score ≥4.
• Participants were randomized to escitalo­pram (n = 26; scheduled titration to 15 mg/d, then flexible to 20 mg/d), or placebo (n = 25) and monitored for 8 weeks.
• Patients with panic disorder, agoraphobia, or social anxiety disorder were also enrolled, but GAD was the primary diagnosis.
• The primary outcome was change in PARS score and change from baseline in CGI-S and Clinical Global Impressions–Improvement (CGI-I) scale scores, with assessments completed at Week 1, Week 2, Week 4, Week 6, and Week 8, or at early termination.
• Genomic DNA was obtained via buccal swab to assess 9 alleles of CYP2C19. Plasma concentrations of escitalopram and its major metabolite, desmethylescitalopram, were collected to assess plasma escitalopram and desmethylescitalopram area under the curve for 24 hours (AUC_0-24) and maximum plasma concentration (C_MAX).

Outcomes

• Escitalopram was superior to placebo, evident by statistically significantly greater changes in PARS and CGI scores.
• Greater improvement over time on PARS was correlated with intermediate CYP2C19 metabolizers, and greater response as measured by CGI-I was associated with having at least 1 long allele of SLC6A4 and being an intermediate CYP2C19 metabolizer.
• While plasma escitalopram exposure (AUC_0-24) significantly decreased and desmethylcitalopram-to-escitalopram ratios increased with faster CYP2C19 metabolism at 15 mg/d, escitalopram exposure at the 15 mg/d dose and escitalopram-to-desmethyl­citalopram ratios did not differ at Week 8 between responders and nonresponders. Patients with activation symptoms had higher C_MAX and AUC_0-24.
• Changes in vital signs, corrected QT interval, and adverse events were similar in both groups.

Conclusions/limitations

• For adolescents with GAD, escitalopram showed a benefit compared to placebo.
• Allelic differences in CYP2C19 metabolism may lead to variations in pharmacokinetics, and understanding a patient’s CYP2C19 phenotype may help guide dosing escitalopram and predicting adverse effects.
• This study enrolled a small, predominantly female, White, treatment-naïve sample, which may limit conclusions on allelic differences. Additionally, the sample included adolescents with severe anxiety and comorbid anxiety conditions, which may limit generalizability.

Continue to: #2

Vortioxetine, an FDA-approved antidepressant, has been shown to improve anxiety symptoms in patients with GAD. Additionally, vortioxetine has shown positive effects in patients with MDD, with greater improvement seen in the working and professional population. Due to the overlap between MDD and GAD, Christensen et al¹³ assessed the effectiveness of vortioxetine on anxiety symptoms in individuals who were working.

Study design

• Researchers conducted a post-hoc analysis of a previously completed randomized, placebo-controlled trial of 301 patients as well as a previously completed randomized, placebo-controlled relapse prevention study of 687 patients. Patients in both groups met DSM-IV-TR criteria for GAD.
• Inclusion criteria included a Hamilton Anxiety Rating Scale (HAM-A) score ≥20 with HAM-A scores ≥2 on items 1 (anxious mood), and 2 (tension), and a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤16 at screening and baseline.
• Researchers compared participants who were working or pursuing an education vs the full study sample.

Outcomes

• Vortioxetine was significantly associated with benefits in anxiety symptoms, functioning, and quality of life in both working participants and the total population, with the greatest effects seen in professional (ie, managers, administrators) and associate professional (ie, technical, nursing, clerical workers, or secretarial) positions. Working participants who received placebo were more likely to relapse compared to those receiving vortioxetine.
• There did not appear to be a statistically significant benefit or increase in relapse among the skilled labor group (ie, building, electrical/factory worker, or services/sales) while receiving vortioxetine.

Conclusions/limitations

• Vortioxetine may have a more pronounced effect in patients who are working or pursuing an education vs the full GAD population, which suggests that targeting this medication at particular patient demographics may be beneficial.
• Working patients with GAD may also differ from nonworking patients by factors other than work, such as education, support system, motivation, and other personal factors.
• This study was a post-hoc analysis, which limits definitive conclusions but may help guide future studies.

Continue to: #3

3. Xie ZJ, Han N, Law S, et al. The efficacy of group cognitive-behavioural therapy plus duloxetine for generalised anxiety disorder versus duloxetine alone. Acta Neuropsychiatr. 2019;31(6):316-324. doi:10.1017/neu.2019.32

Treatment of GAD should include nonmedication options such as psychotherapy to help enhance efficacy. Few studies have evaluated whether combined cognitive-behavioral therapy (CBT) plus medication has more benefit than medication monotherapy, specifically in patients with GAD. In this randomized trial, Xie et al¹⁴ examined how a study population undergoing CBT and receiving duloxetine differed from those receiving duloxetine monotherapy for GAD.

Study design

• In this randomized, open-label trial, adults who met DSM-IV criteria for GAD and had a HAM-A score >14 were randomized to group CBT plus duloxetine (n = 89) or duloxetine only (n = 81), with follow-up at Week 4, Week 8, and Month 3.
• The primary outcomes included response and remission rates based on HAM-A score. Secondary outcomes included HAM-A total score reductions, psychic anxiety (HAMA-PA) and somatic anxiety (HAMA-SA) subscale score reductions, Hamilton Depression Rating Scale score reductions, and reductions in overall illness severity as measured by CGI-S, the Global Assessment of Functioning Scale, and the 12-item Short-Form Health Survey.

Outcomes

• At Week 4, combined therapy was superior to duloxetine alone as evident by the primary and most secondary outcomes, with continued benefits but smaller effect size at Week 8.
• At Month 3, combined therapy was significantly better only in HAM-A total score and HAMA-PA score reductions.

Conclusions/limitations

• Patients who received group CBT plus duloxetine treatment experienced faster improvement of GAD symptoms compared to patients who received duloxetine monotherapy, though the difference reduced over time.
• The most benefit appeared to be for psychic anxiety symptoms, which suggests that group CBT can help change cognition style.
• This study had a short follow-up period, high dropout rates, and recruited patients from only 1 institution.

4. Huang Z, Li Y, Bianchi MT, et al. Repetitive transcranial magnetic stimulation of the right parietal cortex for comorbid generalized anxiety disorder and insomnia: a randomized, double-blind, sham-controlled pilot study. Brain Stimul. 2018;11(5):1103-1109. doi:10.1016/j.brs.2018.05.016

Insomnia and anxiety often present together. rTMS has demonstrated efficacy in various psychiatric illnesses, but there is limited research regarding its effectiveness in GAD. Additionally, little is known regarding the benefits of rTMS for patients with comorbid insomnia and GAD. Huang et al¹⁵ examined the therapeutic effects of rTMS in patients with comorbid insomnia and GAD.

Continue to: Study design

• Adults who met DSM-IV criteria for GAD and insomnia were randomized to receive 10 days of low-intensity rTMS on the right parietal lobe (n = 18) or a sham procedure (n = 18). Inclusion criteria also included a score ≥14 on HAM-A, ≥7 on the Pittsburgh Sleep Quality Index (PSQI), and <20 on the 24-item Hamilton Depression Rating Scale (HAM-D).
• rTMS settings included a frequency of 1 Hz, 90% intensity of the resting motor threshold, 3 trains of 500 pulses, and an intertrain interval of 10 minutes.
• Study measurements included HAM-A, PSQI, and HAM-D at baseline, posttreatment at Day 10, Week 2 follow-up, and Month 1 follow-up.

Outcomes

• Significantly more patients in the rTMS group had a meaningful response as measured by change in HAM-A score at posttreatment and both follow-up sessions.
• The rTMS group had significant remission compared to the sham group at posttreatment and Week 2 follow-up, but showed no significant difference at Month 1.
• There were significant improvements in insomnia symptoms in the rTMS group at the posttreatment and follow-up time points.

Conclusions/limitations

• Low-frequency rTMS over the right parietal cortex is an effective treatment option for patients with comorbid GAD and insomnia.
• This study had a small sample size consisting of participants from only 1 institution.

5. Amsterdam JD, Li QS, Xie SX, et al. Putative antidepressant effect of chamomile (Matricaria chamomilla L.) oral extract in subjects with comorbid generalized anxiety disorder and depression. J Altern Complement Med. 2020;26(9):813-819. doi:10.1089/acm.2019.0252

GAD often presents with comorbid depression. While antidepressants are the standard approach to treatment of both conditions, patients may seek alternative therapies. In previous studies,²⁰Matricaria chamomilla L. (chamomile) has been shown to reduce GAD symptoms, and post-hoc analyses²¹ have shown its benefits in treating depression. Amsterdam et al¹⁶ assessed the effects of chamomile on patients with GAD with and without comorbid depression.

Study design

• As part of an RCT, 179 adults who met DSM-IV-TR criteria for GAD underwent an 8-week open-label phase of chamomile extract therapy (1,500 mg/d). Participants who responded were enrolled in a randomized, double-blind, placebo-control trial. Amsterdam et al¹⁶ specifically analyzed the 8-week open label portion of the study.
• Participants were divided into 2 groups: GAD without comorbid depression (n = 100), and GAD with comorbid depression (n = 79).
• Outcome measures included the 7-item generalized anxiety disorder scale (GAD-7), HAM-A, Beck Anxiety Inventory, 17-item HAM-D, 6-item HAM-D, and the Beck Depression Inventory (BDI).

Continue to: Outcomes

• Patients with comorbid depression experienced a greater, statistically significant reduction in HAM-D core symptom scores (depressed mood, guilt, suicide ideation, work and interest, retardation, and somatic symptoms general).
• The comorbid depression group experienced a trend (but not significant) reduction in total HAM-D and BDI scores.

Conclusions/limitations

• Chamomile extract may help reduce depressive symptoms in patients with GAD who also have depression.
• This study was not powered to detect significant differences in depression outcome ratings between groups, was exploratory, and was not a controlled trial.

6. Dilkov D, Hawken ER, Kaludiev E, et al. Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety dis­order: a randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:61-65. doi:10.1016/j.pnpbp.2017.05.018

Nonpharmacologic modalities, including rTMS, may be effective alternatives for treating GAD. Dilkov et al¹⁷ examined whether excitatory rTMS is an effective treatment option for GAD.

Study design

• In this double-blind, sham-controlled trial, adults who met DSM-IV criteria for GAD were randomized to excitatory rTMS of the right dorsolateral prefrontal cortex therapy (n = 15) or a sham procedure (n = 25).
• rTMS settings included a frequency of 20 Hz, 110% intensity of resting motor threshold, 20 trains, 9 seconds/train, and 51-second intertrain intervals.
• Outcomes were measured by HAM-A, CGI, and 21-item HAM-D.

Outcomes

• At the conclusion of 25 treatments, the rTMS group experienced a statistically significant reduction in GAD symptoms as measured by HAM-A.
• Improvements were also noted in the CGI and HAM-D scores in the rTMS group compared to the sham group.
• The benefits continued at the Week 4 follow-up visit.

Conclusions/limitations

• Participants in the rTMS group experienced a significant decrease in anxiety symptoms, which suggests that rTMS may be an effective treatment for GAD.
• The benefits appear sustainable even after the conclusion of the rTMS sessions.
• This study had a small sample size and excluded patients with comorbid psychiatric conditions.

Continue to: #7

Dysregulated stress response has been proposed as a mechanism for anxiety.^22,23 Patients with GAD have been reported to have alterations in cortisol levels, specifically lower morning cortisol levels and a less steep diurnal cortisol slope; however, it is not clear how treatment affects these levels. Keefe et al¹⁸ examined whether chamomile therapy in patients with GAD affects cortisol levels.

Study design

• In an 8-week, open-label study, 45 adults who met DSM-IV criteria for GAD received chamomile extract capsules 1,500 mg/d.
• Participants used at-home kits to collect their saliva so cortisol levels could be assessed at 8 am, 12 pm, 4 pm, and 8 pm.
• The GAD-7 was used to assess anxiety symptoms.

Outcomes

• Participants who experienced greater improvements in GAD symptoms had relative increases in morning cortisol levels compared to their baseline levels.
• Participants who experienced greater improvements in GAD symptoms had a greater decrease in cortisol levels throughout the day (ie, greater diurnal slope).

Conclusions/limitations

• Greater improvement in GAD symptoms after treatment with chamomile extract appeared to be correlated with increased morning cortisol levels and a steeper diurnal cortisol slope after awakening, which suggests that treatment of GAD may help improve dysregulated stress biology.
• This study had a small sample size and was not placebo-controlled.

Continue to: #8

Compared to the medications that are FDA-approved for GAD, agomelatine has a different mechanism of action, and has shown to be efficacious and tolerable in previous studies.^24-26 In this study, Stein et al¹⁹ compared agomelatine vs escitalopram for patients with severe GAD.

Study design

• In a 12-week, double-blind study, adults who met DSM-IV-TR criteria for GAD were randomized to agomelatine 25 to 50 mg/d (n = 261) or escitalopram 10 to 20 mg/d (n = 262).
• Participants had to meet specific criteria for severe anxiety, including a HAM-A total score ≥25.
• The primary outcome measure was the change in HAM-A score from baseline to Week 12. Secondary outcome measures included the rate of response as determined by change in scores on the HAM-PA, HAM-SA, CGI, Toronto Hospital Alertness Test, Snaith-Hamilton Pleasure Scale, and Leeds Sleep Evaluation Questionnaire.

Outcomes

• Participants in both the agomelatine and escitalopram groups reported similar, clinically significant mean reductions in HAM-A scores at Week 12.
• There were no significant differences in secondary measures between the 2 groups, and both groups experienced improvement in psychic and somatic symptoms, alertness, and sleep.
• Overall, the agomelatine group experienced fewer adverse events compared to the escitalopram group.

Conclusions/limitations

• Agomelatine may be an efficacious and well-tolerated treatment option for severe GAD.
• This study excluded individuals with comorbid conditions.

Bottom Line

Recent research suggests that escitalopram; vortioxetine; agomelatine; duloxetine plus group cognitive-behavioral therapy; repetitive transcranial magnetic stimulation; and chamomile extract can improve symptoms in patients with generalized anxiety disorder.

Related Resources

• Abell SR, El-Mallakh RS. Serotonin-mediated anxiety: how to recognize and treat it. Current Psychiatry. 2021;20(11):37-40. doi:10.12788/cp.0168

Drug Brand Names

Duloxetine • Cymbalta
Escitalopram • Lexapro
Vortioxetine • Trintellix

Generalized anxiety disorder (GAD) typically begins in early adulthood and persists throughout life. Many individuals with GAD report they have felt anxious their entire lives. The essential symptom of GAD is excessive anxiety and worry about numerous events or activities. The intensity, duration, and/or frequency of the anxiety and worry are out of proportion to the actual likelihood or impact of the anticipated event. The individual finds it difficult to control their worry and prevent worrisome thoughts from interfering with attention to everyday tasks.¹

Treatment of GAD typically consists of psychotherapy and pharma­cotherapy. Several studies have suggested that concurrent psychotherapy amplifies the benefits of pharmacotherapy.^2-5 Additionally, combined treatment may differentially target specific symptoms (eg, cognitive vs somatic). The addition of psychotherapy may also increase treatment adherence and decrease potential adverse effects of pharmacotherapy.

Multiple classes of medications are available for treating GAD. Current guidelines and evidence suggest that selective serotonin reuptake inhibitors (SSRIs) should be considered a first-line intervention, followed by serotonin-norepinephrine reuptake inhibitors.^6-11 While the evidence supporting pharmacotherapy for GAD continues to expand, many patients with GAD do not respond to first-line treatment. There is limited data regarding second-line or augmentation strategies for treating these patients. Because current treatment options for GAD are commonly associated with suboptimal treatment outcomes, researchers are investigating the use of nonpharma­cologic biological interventions, such as repetitive transcranial magnetic stimulation (rTMS), which was first cleared by the FDA to treat major depressive disorder (MDD) in 2008.

In Part 1 of this 2-part article, we review 8 randomized controlled trials (RCTs) of biological interventions for GAD that have been published within the last 5 years (Table^12-19).

1. Strawn JR, Mills JA, Schroeder H, et al. Escitalopram in adolescents with generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychiatry. 2020;81(5):20m13396. doi:10.4088/JCP.20m13396

GAD is highly prevalent in adolescents, and SSRIs are often used as first-line agents. However, treatment response is often variable, and clinicians often use trial-and-error to identify an appropriate medication and dose that will result in meaningful improvement. Understanding an individual’s pharmacokinetic response may help predict response and guide therapy. Adult studies have shown cytochrome P450 (CYP) 2C19 metabolizes several SSRIs, including escitalopram, with faster CYP2C19 metabolism leading to decreased plasma concentrations. Strawn et al¹² studied the effects of escitalopram in adolescents with GAD as well as the effects of CYP2C19 metabolism.

Study design

• A double-blind, placebo-controlled trial evaluated 51 adolescents (age 12 to 17) who met DSM-IV-TR criteria for GAD. They had a baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 and a Clinical Global Impressions–Severity (CGI-S) Scale score ≥4.
• Participants were randomized to escitalo­pram (n = 26; scheduled titration to 15 mg/d, then flexible to 20 mg/d), or placebo (n = 25) and monitored for 8 weeks.
• Patients with panic disorder, agoraphobia, or social anxiety disorder were also enrolled, but GAD was the primary diagnosis.
• The primary outcome was change in PARS score and change from baseline in CGI-S and Clinical Global Impressions–Improvement (CGI-I) scale scores, with assessments completed at Week 1, Week 2, Week 4, Week 6, and Week 8, or at early termination.
• Genomic DNA was obtained via buccal swab to assess 9 alleles of CYP2C19. Plasma concentrations of escitalopram and its major metabolite, desmethylescitalopram, were collected to assess plasma escitalopram and desmethylescitalopram area under the curve for 24 hours (AUC_0-24) and maximum plasma concentration (C_MAX).

Outcomes

• Escitalopram was superior to placebo, evident by statistically significantly greater changes in PARS and CGI scores.
• Greater improvement over time on PARS was correlated with intermediate CYP2C19 metabolizers, and greater response as measured by CGI-I was associated with having at least 1 long allele of SLC6A4 and being an intermediate CYP2C19 metabolizer.
• While plasma escitalopram exposure (AUC_0-24) significantly decreased and desmethylcitalopram-to-escitalopram ratios increased with faster CYP2C19 metabolism at 15 mg/d, escitalopram exposure at the 15 mg/d dose and escitalopram-to-desmethyl­citalopram ratios did not differ at Week 8 between responders and nonresponders. Patients with activation symptoms had higher C_MAX and AUC_0-24.
• Changes in vital signs, corrected QT interval, and adverse events were similar in both groups.

Conclusions/limitations

• For adolescents with GAD, escitalopram showed a benefit compared to placebo.
• Allelic differences in CYP2C19 metabolism may lead to variations in pharmacokinetics, and understanding a patient’s CYP2C19 phenotype may help guide dosing escitalopram and predicting adverse effects.
• This study enrolled a small, predominantly female, White, treatment-naïve sample, which may limit conclusions on allelic differences. Additionally, the sample included adolescents with severe anxiety and comorbid anxiety conditions, which may limit generalizability.

Continue to: #2

Vortioxetine, an FDA-approved antidepressant, has been shown to improve anxiety symptoms in patients with GAD. Additionally, vortioxetine has shown positive effects in patients with MDD, with greater improvement seen in the working and professional population. Due to the overlap between MDD and GAD, Christensen et al¹³ assessed the effectiveness of vortioxetine on anxiety symptoms in individuals who were working.

Study design

• Researchers conducted a post-hoc analysis of a previously completed randomized, placebo-controlled trial of 301 patients as well as a previously completed randomized, placebo-controlled relapse prevention study of 687 patients. Patients in both groups met DSM-IV-TR criteria for GAD.
• Inclusion criteria included a Hamilton Anxiety Rating Scale (HAM-A) score ≥20 with HAM-A scores ≥2 on items 1 (anxious mood), and 2 (tension), and a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤16 at screening and baseline.
• Researchers compared participants who were working or pursuing an education vs the full study sample.

Outcomes

• Vortioxetine was significantly associated with benefits in anxiety symptoms, functioning, and quality of life in both working participants and the total population, with the greatest effects seen in professional (ie, managers, administrators) and associate professional (ie, technical, nursing, clerical workers, or secretarial) positions. Working participants who received placebo were more likely to relapse compared to those receiving vortioxetine.
• There did not appear to be a statistically significant benefit or increase in relapse among the skilled labor group (ie, building, electrical/factory worker, or services/sales) while receiving vortioxetine.

Conclusions/limitations

• Vortioxetine may have a more pronounced effect in patients who are working or pursuing an education vs the full GAD population, which suggests that targeting this medication at particular patient demographics may be beneficial.
• Working patients with GAD may also differ from nonworking patients by factors other than work, such as education, support system, motivation, and other personal factors.
• This study was a post-hoc analysis, which limits definitive conclusions but may help guide future studies.

Continue to: #3

3. Xie ZJ, Han N, Law S, et al. The efficacy of group cognitive-behavioural therapy plus duloxetine for generalised anxiety disorder versus duloxetine alone. Acta Neuropsychiatr. 2019;31(6):316-324. doi:10.1017/neu.2019.32

Treatment of GAD should include nonmedication options such as psychotherapy to help enhance efficacy. Few studies have evaluated whether combined cognitive-behavioral therapy (CBT) plus medication has more benefit than medication monotherapy, specifically in patients with GAD. In this randomized trial, Xie et al¹⁴ examined how a study population undergoing CBT and receiving duloxetine differed from those receiving duloxetine monotherapy for GAD.

Study design

• In this randomized, open-label trial, adults who met DSM-IV criteria for GAD and had a HAM-A score >14 were randomized to group CBT plus duloxetine (n = 89) or duloxetine only (n = 81), with follow-up at Week 4, Week 8, and Month 3.
• The primary outcomes included response and remission rates based on HAM-A score. Secondary outcomes included HAM-A total score reductions, psychic anxiety (HAMA-PA) and somatic anxiety (HAMA-SA) subscale score reductions, Hamilton Depression Rating Scale score reductions, and reductions in overall illness severity as measured by CGI-S, the Global Assessment of Functioning Scale, and the 12-item Short-Form Health Survey.

Outcomes

• At Week 4, combined therapy was superior to duloxetine alone as evident by the primary and most secondary outcomes, with continued benefits but smaller effect size at Week 8.
• At Month 3, combined therapy was significantly better only in HAM-A total score and HAMA-PA score reductions.

Conclusions/limitations

• Patients who received group CBT plus duloxetine treatment experienced faster improvement of GAD symptoms compared to patients who received duloxetine monotherapy, though the difference reduced over time.
• The most benefit appeared to be for psychic anxiety symptoms, which suggests that group CBT can help change cognition style.
• This study had a short follow-up period, high dropout rates, and recruited patients from only 1 institution.

4. Huang Z, Li Y, Bianchi MT, et al. Repetitive transcranial magnetic stimulation of the right parietal cortex for comorbid generalized anxiety disorder and insomnia: a randomized, double-blind, sham-controlled pilot study. Brain Stimul. 2018;11(5):1103-1109. doi:10.1016/j.brs.2018.05.016

Insomnia and anxiety often present together. rTMS has demonstrated efficacy in various psychiatric illnesses, but there is limited research regarding its effectiveness in GAD. Additionally, little is known regarding the benefits of rTMS for patients with comorbid insomnia and GAD. Huang et al¹⁵ examined the therapeutic effects of rTMS in patients with comorbid insomnia and GAD.

Continue to: Study design

• Adults who met DSM-IV criteria for GAD and insomnia were randomized to receive 10 days of low-intensity rTMS on the right parietal lobe (n = 18) or a sham procedure (n = 18). Inclusion criteria also included a score ≥14 on HAM-A, ≥7 on the Pittsburgh Sleep Quality Index (PSQI), and <20 on the 24-item Hamilton Depression Rating Scale (HAM-D).
• rTMS settings included a frequency of 1 Hz, 90% intensity of the resting motor threshold, 3 trains of 500 pulses, and an intertrain interval of 10 minutes.
• Study measurements included HAM-A, PSQI, and HAM-D at baseline, posttreatment at Day 10, Week 2 follow-up, and Month 1 follow-up.

Outcomes

• Significantly more patients in the rTMS group had a meaningful response as measured by change in HAM-A score at posttreatment and both follow-up sessions.
• The rTMS group had significant remission compared to the sham group at posttreatment and Week 2 follow-up, but showed no significant difference at Month 1.
• There were significant improvements in insomnia symptoms in the rTMS group at the posttreatment and follow-up time points.

Conclusions/limitations

• Low-frequency rTMS over the right parietal cortex is an effective treatment option for patients with comorbid GAD and insomnia.
• This study had a small sample size consisting of participants from only 1 institution.

5. Amsterdam JD, Li QS, Xie SX, et al. Putative antidepressant effect of chamomile (Matricaria chamomilla L.) oral extract in subjects with comorbid generalized anxiety disorder and depression. J Altern Complement Med. 2020;26(9):813-819. doi:10.1089/acm.2019.0252

GAD often presents with comorbid depression. While antidepressants are the standard approach to treatment of both conditions, patients may seek alternative therapies. In previous studies,²⁰Matricaria chamomilla L. (chamomile) has been shown to reduce GAD symptoms, and post-hoc analyses²¹ have shown its benefits in treating depression. Amsterdam et al¹⁶ assessed the effects of chamomile on patients with GAD with and without comorbid depression.

Study design

• As part of an RCT, 179 adults who met DSM-IV-TR criteria for GAD underwent an 8-week open-label phase of chamomile extract therapy (1,500 mg/d). Participants who responded were enrolled in a randomized, double-blind, placebo-control trial. Amsterdam et al¹⁶ specifically analyzed the 8-week open label portion of the study.
• Participants were divided into 2 groups: GAD without comorbid depression (n = 100), and GAD with comorbid depression (n = 79).
• Outcome measures included the 7-item generalized anxiety disorder scale (GAD-7), HAM-A, Beck Anxiety Inventory, 17-item HAM-D, 6-item HAM-D, and the Beck Depression Inventory (BDI).

Continue to: Outcomes

• Patients with comorbid depression experienced a greater, statistically significant reduction in HAM-D core symptom scores (depressed mood, guilt, suicide ideation, work and interest, retardation, and somatic symptoms general).
• The comorbid depression group experienced a trend (but not significant) reduction in total HAM-D and BDI scores.

Conclusions/limitations

• Chamomile extract may help reduce depressive symptoms in patients with GAD who also have depression.
• This study was not powered to detect significant differences in depression outcome ratings between groups, was exploratory, and was not a controlled trial.

6. Dilkov D, Hawken ER, Kaludiev E, et al. Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety dis­order: a randomized, double-blind sham controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:61-65. doi:10.1016/j.pnpbp.2017.05.018

Nonpharmacologic modalities, including rTMS, may be effective alternatives for treating GAD. Dilkov et al¹⁷ examined whether excitatory rTMS is an effective treatment option for GAD.

Study design

• In this double-blind, sham-controlled trial, adults who met DSM-IV criteria for GAD were randomized to excitatory rTMS of the right dorsolateral prefrontal cortex therapy (n = 15) or a sham procedure (n = 25).
• rTMS settings included a frequency of 20 Hz, 110% intensity of resting motor threshold, 20 trains, 9 seconds/train, and 51-second intertrain intervals.
• Outcomes were measured by HAM-A, CGI, and 21-item HAM-D.

Outcomes

• At the conclusion of 25 treatments, the rTMS group experienced a statistically significant reduction in GAD symptoms as measured by HAM-A.
• Improvements were also noted in the CGI and HAM-D scores in the rTMS group compared to the sham group.
• The benefits continued at the Week 4 follow-up visit.

Conclusions/limitations

• Participants in the rTMS group experienced a significant decrease in anxiety symptoms, which suggests that rTMS may be an effective treatment for GAD.
• The benefits appear sustainable even after the conclusion of the rTMS sessions.
• This study had a small sample size and excluded patients with comorbid psychiatric conditions.

Continue to: #7

Dysregulated stress response has been proposed as a mechanism for anxiety.^22,23 Patients with GAD have been reported to have alterations in cortisol levels, specifically lower morning cortisol levels and a less steep diurnal cortisol slope; however, it is not clear how treatment affects these levels. Keefe et al¹⁸ examined whether chamomile therapy in patients with GAD affects cortisol levels.

Study design

• In an 8-week, open-label study, 45 adults who met DSM-IV criteria for GAD received chamomile extract capsules 1,500 mg/d.
• Participants used at-home kits to collect their saliva so cortisol levels could be assessed at 8 am, 12 pm, 4 pm, and 8 pm.
• The GAD-7 was used to assess anxiety symptoms.

Outcomes

• Participants who experienced greater improvements in GAD symptoms had relative increases in morning cortisol levels compared to their baseline levels.
• Participants who experienced greater improvements in GAD symptoms had a greater decrease in cortisol levels throughout the day (ie, greater diurnal slope).

Conclusions/limitations

• Greater improvement in GAD symptoms after treatment with chamomile extract appeared to be correlated with increased morning cortisol levels and a steeper diurnal cortisol slope after awakening, which suggests that treatment of GAD may help improve dysregulated stress biology.
• This study had a small sample size and was not placebo-controlled.

Continue to: #8

Compared to the medications that are FDA-approved for GAD, agomelatine has a different mechanism of action, and has shown to be efficacious and tolerable in previous studies.^24-26 In this study, Stein et al¹⁹ compared agomelatine vs escitalopram for patients with severe GAD.

Study design

• In a 12-week, double-blind study, adults who met DSM-IV-TR criteria for GAD were randomized to agomelatine 25 to 50 mg/d (n = 261) or escitalopram 10 to 20 mg/d (n = 262).
• Participants had to meet specific criteria for severe anxiety, including a HAM-A total score ≥25.
• The primary outcome measure was the change in HAM-A score from baseline to Week 12. Secondary outcome measures included the rate of response as determined by change in scores on the HAM-PA, HAM-SA, CGI, Toronto Hospital Alertness Test, Snaith-Hamilton Pleasure Scale, and Leeds Sleep Evaluation Questionnaire.

Outcomes

• Participants in both the agomelatine and escitalopram groups reported similar, clinically significant mean reductions in HAM-A scores at Week 12.
• There were no significant differences in secondary measures between the 2 groups, and both groups experienced improvement in psychic and somatic symptoms, alertness, and sleep.
• Overall, the agomelatine group experienced fewer adverse events compared to the escitalopram group.

Conclusions/limitations

• Agomelatine may be an efficacious and well-tolerated treatment option for severe GAD.
• This study excluded individuals with comorbid conditions.

Bottom Line

Recent research suggests that escitalopram; vortioxetine; agomelatine; duloxetine plus group cognitive-behavioral therapy; repetitive transcranial magnetic stimulation; and chamomile extract can improve symptoms in patients with generalized anxiety disorder.

Related Resources

• Abell SR, El-Mallakh RS. Serotonin-mediated anxiety: how to recognize and treat it. Current Psychiatry. 2021;20(11):37-40. doi:10.12788/cp.0168

Drug Brand Names

Duloxetine • Cymbalta
Escitalopram • Lexapro
Vortioxetine • Trintellix