An increase of patients presenting with the complex combination of hypermobile Ehlers-Danlos syndrome (hEDS) with co-existing gastrointestinal (GI) symptoms, postural orthostatic tachycardia syndrome (POTS), and/or mast cell activation syndrome (MCAS), has prompted the issuance of clinical practice guidance from AGA to help clinicians comprehend such cases.

“Recognizing and treating GI symptoms in patients with hEDS or hypermobility spectrum disorders and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs,” AGA reported in the update, published in Clinical Gastroenterology and Hepatology.

Importantly, “the poor understanding of these overlapping syndromes can lead to nonstandardized approaches to diagnostic evaluation and management,” the authors noted.

“Gastroenterology providers should be aware of the features of [these syndromes] to recognize the full complexity of patients presenting with multisystemic symptoms.”

Hypermobility spectrum disorders, which include hEDS, are typically genetic, and patients experience pain along with joint hypermobility, or extreme flexibility of joints beyond the normal range of motion.

With research showing that most of those patients — up to 98% — also experience GI symptoms, gastroenterologists may be encountering them more commonly than realized, Lucinda A. Harris, MD, AGAF, of the Mayo Clinic School of Medicine, in Scottsdale, Arizona, explained to GI & Hepatology News.

“As our knowledge in gastroenterology has progressed, we realize that hypermobility itself predisposes individuals to disorders of brain-gut interaction,” she said. “We may only be seeing the tip of the iceberg when it comes to diagnosing patients with hypermobility.”

Additionally, “many of these patients have POTS, which has also been increasingly diagnosed,” Harris added. “The strong overlap of these conditions prompted us to present this data.”

With a lack of evidence-based understanding of the overlapping syndromes, AGA’s guidance does not carry formal ratings but is drawn from a review of the published literature and expert opinion.

In addition to the key recommendation of being aware of the observed combination of syndromes, their recommendations include:

• Regarding testing: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of the disorders, but universal testing for POTS/MCAS in all patients with hEDS or hypermobility spectrum disorders is not currently supported by the evidence, the guidance advises.
• Gastroenterologists seeing patients with disorders of gut-brain interaction should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS or offer appropriate referral to a specialist where resources are available, the AGA recommends.
• Medical management: Management of GI symptoms in hEDS or hypermobility spectrum disorders and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results.
• In addition to general disorders of gut-brain interactions and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.

Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.

In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS or hypermobility spectrum disorders and disorders of gut-brain interaction with episodic symptoms that suggest a more generalized mast cell disorder involving two or more physiological systems. However, current data does not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS or hypermobility spectrum disorders without clinical or laboratory evidence of a primary or secondary mast cell disorder, the authors noted.

Harris explained that patients presenting with gut-brain disorders are often mistakenly classified as having irritable bowel syndrome or dyspepsia, whereas these conditions may be affecting the GI disorders they have.

“For example, a patient with Ehlers-Danlos syndrome might have problems with constipation, which is impacted by pelvic floor dysfunction,” she said. “Due to their hypermobility, they may experience more pelvic floor descent than usual.”

“If we do not recognize this, the patient risks developing rectal prolapse or not effectively addressing their constipation.”

Regarding patient characteristics, Harris said that those with hEDS and POTS appear to more likely be women and tend to present in younger patients, aged 18-50 years. Of note, there is no genetic test for hEDS.

“The take-home point for clinicians should be to consider POTS and Ehlers-Danlos syndrome when encountering young female patients with symptoms of palpitations, hypermobility, and orthostatic intolerance,” she said.

“Recognizing hypermobility is crucial, not only for GI symptoms but also to prevent joint dislocations, tendon ruptures, and other connective tissue issues.”

Clinicians are further urged to “offer informed counseling, and guide patients away from unreliable sources or fragmented care to foster therapeutic relationships and evidence-based care,” the authors added.

 

Deciphering Gut-Brain Disorder Challenges

Commenting to GI & Hepatology News, Clair Francomano, MD, a professor of medical and molecular genetics at the Indiana University School of Medicine, in Indianapolis, said the new guidance sheds important light on the syndromes.

“I’m delighted to see this guidance offered through the AGA as it will encourage gastroenterologists to think of EDS, POTS and MCAS when they are evaluating patients with disorders of gut-brain interaction,” Francomano said.

“This should allow patients to receive more accurate and timely diagnoses and appropriate management.”

Francomano noted that the Ehlers-Danlos Society, which provides information for clinicians and patients alike on the syndromes, and where she serves on the medical scientific board, has also been active in raising awareness.

“While co-occurrence of POTS and MCAS with EDS has in fact been recognized for many years, I do think awareness is increasing, in large part due to the advocacy and educational efforts of the Ehlers-Danlos Society,” she said.

The take-home message? “When clinicians see disorders of the gut-brain axis, POTS or MCAS, they should be thinking, ‘Could this be related to joint hypermobility or Ehlers-Danlos syndrome?’” Francomano said.

Harris reported serving as a consultant for AbbVie, Ardelyx, Salix, and Gemelli Biotech and reported receiving research support from Takeda and Anyx. Francomano did not report any relevant disclosures.

A version of this article appeared on Medscape.com.

An increase of patients presenting with the complex combination of hypermobile Ehlers-Danlos syndrome (hEDS) with co-existing gastrointestinal (GI) symptoms, postural orthostatic tachycardia syndrome (POTS), and/or mast cell activation syndrome (MCAS), has prompted the issuance of clinical practice guidance from AGA to help clinicians comprehend such cases.

“Recognizing and treating GI symptoms in patients with hEDS or hypermobility spectrum disorders and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs,” AGA reported in the update, published in Clinical Gastroenterology and Hepatology.

Importantly, “the poor understanding of these overlapping syndromes can lead to nonstandardized approaches to diagnostic evaluation and management,” the authors noted.

“Gastroenterology providers should be aware of the features of [these syndromes] to recognize the full complexity of patients presenting with multisystemic symptoms.”

Hypermobility spectrum disorders, which include hEDS, are typically genetic, and patients experience pain along with joint hypermobility, or extreme flexibility of joints beyond the normal range of motion.

With research showing that most of those patients — up to 98% — also experience GI symptoms, gastroenterologists may be encountering them more commonly than realized, Lucinda A. Harris, MD, AGAF, of the Mayo Clinic School of Medicine, in Scottsdale, Arizona, explained to GI & Hepatology News.

“As our knowledge in gastroenterology has progressed, we realize that hypermobility itself predisposes individuals to disorders of brain-gut interaction,” she said. “We may only be seeing the tip of the iceberg when it comes to diagnosing patients with hypermobility.”

Additionally, “many of these patients have POTS, which has also been increasingly diagnosed,” Harris added. “The strong overlap of these conditions prompted us to present this data.”

With a lack of evidence-based understanding of the overlapping syndromes, AGA’s guidance does not carry formal ratings but is drawn from a review of the published literature and expert opinion.

In addition to the key recommendation of being aware of the observed combination of syndromes, their recommendations include:

• Regarding testing: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of the disorders, but universal testing for POTS/MCAS in all patients with hEDS or hypermobility spectrum disorders is not currently supported by the evidence, the guidance advises.
• Gastroenterologists seeing patients with disorders of gut-brain interaction should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS or offer appropriate referral to a specialist where resources are available, the AGA recommends.
• Medical management: Management of GI symptoms in hEDS or hypermobility spectrum disorders and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results.
• In addition to general disorders of gut-brain interactions and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.

Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.

In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS or hypermobility spectrum disorders and disorders of gut-brain interaction with episodic symptoms that suggest a more generalized mast cell disorder involving two or more physiological systems. However, current data does not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS or hypermobility spectrum disorders without clinical or laboratory evidence of a primary or secondary mast cell disorder, the authors noted.

Harris explained that patients presenting with gut-brain disorders are often mistakenly classified as having irritable bowel syndrome or dyspepsia, whereas these conditions may be affecting the GI disorders they have.

“For example, a patient with Ehlers-Danlos syndrome might have problems with constipation, which is impacted by pelvic floor dysfunction,” she said. “Due to their hypermobility, they may experience more pelvic floor descent than usual.”

“If we do not recognize this, the patient risks developing rectal prolapse or not effectively addressing their constipation.”

Regarding patient characteristics, Harris said that those with hEDS and POTS appear to more likely be women and tend to present in younger patients, aged 18-50 years. Of note, there is no genetic test for hEDS.

“The take-home point for clinicians should be to consider POTS and Ehlers-Danlos syndrome when encountering young female patients with symptoms of palpitations, hypermobility, and orthostatic intolerance,” she said.

“Recognizing hypermobility is crucial, not only for GI symptoms but also to prevent joint dislocations, tendon ruptures, and other connective tissue issues.”

Clinicians are further urged to “offer informed counseling, and guide patients away from unreliable sources or fragmented care to foster therapeutic relationships and evidence-based care,” the authors added.

 

Deciphering Gut-Brain Disorder Challenges

Commenting to GI & Hepatology News, Clair Francomano, MD, a professor of medical and molecular genetics at the Indiana University School of Medicine, in Indianapolis, said the new guidance sheds important light on the syndromes.

“I’m delighted to see this guidance offered through the AGA as it will encourage gastroenterologists to think of EDS, POTS and MCAS when they are evaluating patients with disorders of gut-brain interaction,” Francomano said.

“This should allow patients to receive more accurate and timely diagnoses and appropriate management.”

Francomano noted that the Ehlers-Danlos Society, which provides information for clinicians and patients alike on the syndromes, and where she serves on the medical scientific board, has also been active in raising awareness.

“While co-occurrence of POTS and MCAS with EDS has in fact been recognized for many years, I do think awareness is increasing, in large part due to the advocacy and educational efforts of the Ehlers-Danlos Society,” she said.

The take-home message? “When clinicians see disorders of the gut-brain axis, POTS or MCAS, they should be thinking, ‘Could this be related to joint hypermobility or Ehlers-Danlos syndrome?’” Francomano said.

Harris reported serving as a consultant for AbbVie, Ardelyx, Salix, and Gemelli Biotech and reported receiving research support from Takeda and Anyx. Francomano did not report any relevant disclosures.

A version of this article appeared on Medscape.com.

An increase of patients presenting with the complex combination of hypermobile Ehlers-Danlos syndrome (hEDS) with co-existing gastrointestinal (GI) symptoms, postural orthostatic tachycardia syndrome (POTS), and/or mast cell activation syndrome (MCAS), has prompted the issuance of clinical practice guidance from AGA to help clinicians comprehend such cases.

“Recognizing and treating GI symptoms in patients with hEDS or hypermobility spectrum disorders and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs,” AGA reported in the update, published in Clinical Gastroenterology and Hepatology.

Importantly, “the poor understanding of these overlapping syndromes can lead to nonstandardized approaches to diagnostic evaluation and management,” the authors noted.

“Gastroenterology providers should be aware of the features of [these syndromes] to recognize the full complexity of patients presenting with multisystemic symptoms.”

Hypermobility spectrum disorders, which include hEDS, are typically genetic, and patients experience pain along with joint hypermobility, or extreme flexibility of joints beyond the normal range of motion.

With research showing that most of those patients — up to 98% — also experience GI symptoms, gastroenterologists may be encountering them more commonly than realized, Lucinda A. Harris, MD, AGAF, of the Mayo Clinic School of Medicine, in Scottsdale, Arizona, explained to GI & Hepatology News.

“As our knowledge in gastroenterology has progressed, we realize that hypermobility itself predisposes individuals to disorders of brain-gut interaction,” she said. “We may only be seeing the tip of the iceberg when it comes to diagnosing patients with hypermobility.”

Additionally, “many of these patients have POTS, which has also been increasingly diagnosed,” Harris added. “The strong overlap of these conditions prompted us to present this data.”

With a lack of evidence-based understanding of the overlapping syndromes, AGA’s guidance does not carry formal ratings but is drawn from a review of the published literature and expert opinion.

In addition to the key recommendation of being aware of the observed combination of syndromes, their recommendations include:

• Regarding testing: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of the disorders, but universal testing for POTS/MCAS in all patients with hEDS or hypermobility spectrum disorders is not currently supported by the evidence, the guidance advises.
• Gastroenterologists seeing patients with disorders of gut-brain interaction should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS or offer appropriate referral to a specialist where resources are available, the AGA recommends.
• Medical management: Management of GI symptoms in hEDS or hypermobility spectrum disorders and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results.
• In addition to general disorders of gut-brain interactions and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.

Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.

In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS or hypermobility spectrum disorders and disorders of gut-brain interaction with episodic symptoms that suggest a more generalized mast cell disorder involving two or more physiological systems. However, current data does not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS or hypermobility spectrum disorders without clinical or laboratory evidence of a primary or secondary mast cell disorder, the authors noted.

Harris explained that patients presenting with gut-brain disorders are often mistakenly classified as having irritable bowel syndrome or dyspepsia, whereas these conditions may be affecting the GI disorders they have.

“For example, a patient with Ehlers-Danlos syndrome might have problems with constipation, which is impacted by pelvic floor dysfunction,” she said. “Due to their hypermobility, they may experience more pelvic floor descent than usual.”

“If we do not recognize this, the patient risks developing rectal prolapse or not effectively addressing their constipation.”

Regarding patient characteristics, Harris said that those with hEDS and POTS appear to more likely be women and tend to present in younger patients, aged 18-50 years. Of note, there is no genetic test for hEDS.

“The take-home point for clinicians should be to consider POTS and Ehlers-Danlos syndrome when encountering young female patients with symptoms of palpitations, hypermobility, and orthostatic intolerance,” she said.

“Recognizing hypermobility is crucial, not only for GI symptoms but also to prevent joint dislocations, tendon ruptures, and other connective tissue issues.”

Clinicians are further urged to “offer informed counseling, and guide patients away from unreliable sources or fragmented care to foster therapeutic relationships and evidence-based care,” the authors added.

 

Deciphering Gut-Brain Disorder Challenges

Commenting to GI & Hepatology News, Clair Francomano, MD, a professor of medical and molecular genetics at the Indiana University School of Medicine, in Indianapolis, said the new guidance sheds important light on the syndromes.

“I’m delighted to see this guidance offered through the AGA as it will encourage gastroenterologists to think of EDS, POTS and MCAS when they are evaluating patients with disorders of gut-brain interaction,” Francomano said.

“This should allow patients to receive more accurate and timely diagnoses and appropriate management.”

Francomano noted that the Ehlers-Danlos Society, which provides information for clinicians and patients alike on the syndromes, and where she serves on the medical scientific board, has also been active in raising awareness.

“While co-occurrence of POTS and MCAS with EDS has in fact been recognized for many years, I do think awareness is increasing, in large part due to the advocacy and educational efforts of the Ehlers-Danlos Society,” she said.

The take-home message? “When clinicians see disorders of the gut-brain axis, POTS or MCAS, they should be thinking, ‘Could this be related to joint hypermobility or Ehlers-Danlos syndrome?’” Francomano said.

Harris reported serving as a consultant for AbbVie, Ardelyx, Salix, and Gemelli Biotech and reported receiving research support from Takeda and Anyx. Francomano did not report any relevant disclosures.

A version of this article appeared on Medscape.com.

Out-of-pocket costs for bowel preparation are deterring people, especially vulnerable and underserved groups, from colonoscopy for colorectal cancer (CRC) screening, a large insurance-claims analysis in Gastroenterology reported.

Moreover, this cost-sharing contravenes the preventive-care provisions for bowel preparation mandated by the Affordable Care Act (ACA).

Led by Gastroenterologist Eric D. Shah, MD, MBA, a clinical associate professor at the University of Michigan in Ann Arbor, Michigan, the study found a significant proportion of prescribed bowel preparation claims — 53% for commercial plans and 83% for Medicare — still involve patient cost-sharing, indicating noncompliance with ACA guidelines. Although expense-sharing was less prevalent among Medicaid claims (just 27%), it was not eliminated, suggesting room for improvement in coverage enforcement across the board.

“Colon cancer is unique in that it can be prevented with colonoscopy, but where are the patients? Bowel prep is a major reason that patients defer screening,” Shah told GI & Hepatology News. He said his group was quite surprised that the majority in the study cohort were paying something out of pocket when these costs should have been covered. “Primary care doctors may not think to ask about bowel prep costs when they order screening colonoscopies.”

The findings emerged from an analysis of 2,593,079 prescription drug claims: 52.9% from commercial plans, 35% from Medicare Part D plans, and 8.3% from Medicaid plans.

“These patient costs of $30 or $50 are a real not a theoretical deterrent,” said Whitney Jones, MD, a gastroenterologist, adjunct clinical professor at the University of Louisville in Louisville, Kentucky, and founder of the nonprofit Colon Cancer Prevention Project. Jones was not involved in the analysis. “Some insurers require prior patient authorization for the low-dose preps, but gastroenterologists are doing so many colonoscopies they don’t always have time to get a PA [prior authorization] on everyone.” 

With the increasing use of blood and stool-based CRC testing, he added, “when you get a positive result, it’s really important to have the procedure quickly.” And appropriate bowel preparation is a small, cost-effective portion of the total costs of colonoscopy, a procedure that ultimately saves insurers significant money in treatment costs.

The authors noted that while CRC is the second-leading cause of cancer-related deaths in the US, screening rates remain low, with only 59% of adults aged 45 years or older up to date with screening. Screening rates are particularly low among racial and ethnic minority groups as compared with White individuals, a disparity that highlights the need to address existing barriers and enhance screening efforts.

In the current study, shared costs by bowel preparation volume also varied. Low-volume formulations had consistently higher out-of-pocket costs: a median of $60 for low-volume vs $10 for high-volume in commercial plans. In Medicare, 75% of high-volume claims had shared costs compared with 90% for their low-volume counterparts. The cost-sharing difference was slightly narrower with Medicaid: 27% of high-volume claims vs 30% of low-volume claims.

This is concerning, as low-volume options, which are preferred by patients for their better tolerability, can enhance uptake and adherence and improve colonoscopy outcomes. Shah advises physicians to consider prescribing low-volume preparations. “Let patients know about the potential out-of-pocket cost and about copay cards and assistance programs and use high-volume preps as an alternative rather than a go-to,” he said.

As to costs across insurance types, among commercial plans, the median nonzero out-of-pocket cost was $10 for high-volume and $60 for low-volume product claims. For Medicare, the median nonzero out-of-pocket cost was $8 for high-volume and $55.99 for low-volume products.

Under the ACA, CRC screening is classified as a recommended preventive service, requiring health plans to cover it without cost-sharing. Although the Centers for Medicare & Medicaid Services previously tried to enforce this mandate in 2015 and 2016, stating that colonoscopy preparation medications should be covered at no cost, many health plans are still not compliant.

At the nonfederal level, Jones noted, Kentucky, which has a significant high-risk population, recently became the first state to pass legislation requiring health benefit plans to cover all guideline-recommended CRC exams and lab tests.

For its part, AGA has also called on payers to eliminate all cost-sharing barriers across the CRC screening continuum.

Of note, the study authors said, the higher compliance with the ACA mandate in commercial and Medicaid plans than in Medicare highlights disparities that may disproportionately affect vulnerable older adults. While nearly half of commercial patients and nearly three quarters of Medicaid patients incurred zero out-of-pocket costs, fewer than 17% of Medicare beneficiaries, or 1 in 6, did so.

Although these costs may be low relative to the colonoscopy, they nevertheless can deter uptake of preventive screenings, potentially leading to higher CRC incidence and mortality. “While some patients may be willing to pay modest out-of-pocket costs, any required payment, however small, can serve as a barrier to preventative care, particularly in underserved populations,” they wrote. “These financial barriers will continue to contribute to widening disparities and hinder progress toward equitable screening outcomes.”

In the meantime, said Shah, “Physicians should advocate now to their representatives in Congress that bowel prep costs should already be covered as part of the ACA.”

This study was funded by Sebela Pharmaceuticals, maker of SUFLAVE preparation. The authors had no conflicts of interest to declare. Jones is a speaker and consultant for Grail LLC.

A version of this article appeared on Medscape.com.

Out-of-pocket costs for bowel preparation are deterring people, especially vulnerable and underserved groups, from colonoscopy for colorectal cancer (CRC) screening, a large insurance-claims analysis in Gastroenterology reported.

Moreover, this cost-sharing contravenes the preventive-care provisions for bowel preparation mandated by the Affordable Care Act (ACA).

Led by Gastroenterologist Eric D. Shah, MD, MBA, a clinical associate professor at the University of Michigan in Ann Arbor, Michigan, the study found a significant proportion of prescribed bowel preparation claims — 53% for commercial plans and 83% for Medicare — still involve patient cost-sharing, indicating noncompliance with ACA guidelines. Although expense-sharing was less prevalent among Medicaid claims (just 27%), it was not eliminated, suggesting room for improvement in coverage enforcement across the board.

“Colon cancer is unique in that it can be prevented with colonoscopy, but where are the patients? Bowel prep is a major reason that patients defer screening,” Shah told GI & Hepatology News. He said his group was quite surprised that the majority in the study cohort were paying something out of pocket when these costs should have been covered. “Primary care doctors may not think to ask about bowel prep costs when they order screening colonoscopies.”

The findings emerged from an analysis of 2,593,079 prescription drug claims: 52.9% from commercial plans, 35% from Medicare Part D plans, and 8.3% from Medicaid plans.

“These patient costs of $30 or $50 are a real not a theoretical deterrent,” said Whitney Jones, MD, a gastroenterologist, adjunct clinical professor at the University of Louisville in Louisville, Kentucky, and founder of the nonprofit Colon Cancer Prevention Project. Jones was not involved in the analysis. “Some insurers require prior patient authorization for the low-dose preps, but gastroenterologists are doing so many colonoscopies they don’t always have time to get a PA [prior authorization] on everyone.” 

With the increasing use of blood and stool-based CRC testing, he added, “when you get a positive result, it’s really important to have the procedure quickly.” And appropriate bowel preparation is a small, cost-effective portion of the total costs of colonoscopy, a procedure that ultimately saves insurers significant money in treatment costs.

The authors noted that while CRC is the second-leading cause of cancer-related deaths in the US, screening rates remain low, with only 59% of adults aged 45 years or older up to date with screening. Screening rates are particularly low among racial and ethnic minority groups as compared with White individuals, a disparity that highlights the need to address existing barriers and enhance screening efforts.

In the current study, shared costs by bowel preparation volume also varied. Low-volume formulations had consistently higher out-of-pocket costs: a median of $60 for low-volume vs $10 for high-volume in commercial plans. In Medicare, 75% of high-volume claims had shared costs compared with 90% for their low-volume counterparts. The cost-sharing difference was slightly narrower with Medicaid: 27% of high-volume claims vs 30% of low-volume claims.

This is concerning, as low-volume options, which are preferred by patients for their better tolerability, can enhance uptake and adherence and improve colonoscopy outcomes. Shah advises physicians to consider prescribing low-volume preparations. “Let patients know about the potential out-of-pocket cost and about copay cards and assistance programs and use high-volume preps as an alternative rather than a go-to,” he said.

As to costs across insurance types, among commercial plans, the median nonzero out-of-pocket cost was $10 for high-volume and $60 for low-volume product claims. For Medicare, the median nonzero out-of-pocket cost was $8 for high-volume and $55.99 for low-volume products.

Under the ACA, CRC screening is classified as a recommended preventive service, requiring health plans to cover it without cost-sharing. Although the Centers for Medicare & Medicaid Services previously tried to enforce this mandate in 2015 and 2016, stating that colonoscopy preparation medications should be covered at no cost, many health plans are still not compliant.

At the nonfederal level, Jones noted, Kentucky, which has a significant high-risk population, recently became the first state to pass legislation requiring health benefit plans to cover all guideline-recommended CRC exams and lab tests.

For its part, AGA has also called on payers to eliminate all cost-sharing barriers across the CRC screening continuum.

Of note, the study authors said, the higher compliance with the ACA mandate in commercial and Medicaid plans than in Medicare highlights disparities that may disproportionately affect vulnerable older adults. While nearly half of commercial patients and nearly three quarters of Medicaid patients incurred zero out-of-pocket costs, fewer than 17% of Medicare beneficiaries, or 1 in 6, did so.

Although these costs may be low relative to the colonoscopy, they nevertheless can deter uptake of preventive screenings, potentially leading to higher CRC incidence and mortality. “While some patients may be willing to pay modest out-of-pocket costs, any required payment, however small, can serve as a barrier to preventative care, particularly in underserved populations,” they wrote. “These financial barriers will continue to contribute to widening disparities and hinder progress toward equitable screening outcomes.”

In the meantime, said Shah, “Physicians should advocate now to their representatives in Congress that bowel prep costs should already be covered as part of the ACA.”

This study was funded by Sebela Pharmaceuticals, maker of SUFLAVE preparation. The authors had no conflicts of interest to declare. Jones is a speaker and consultant for Grail LLC.

A version of this article appeared on Medscape.com.

Out-of-pocket costs for bowel preparation are deterring people, especially vulnerable and underserved groups, from colonoscopy for colorectal cancer (CRC) screening, a large insurance-claims analysis in Gastroenterology reported.

Moreover, this cost-sharing contravenes the preventive-care provisions for bowel preparation mandated by the Affordable Care Act (ACA).

Led by Gastroenterologist Eric D. Shah, MD, MBA, a clinical associate professor at the University of Michigan in Ann Arbor, Michigan, the study found a significant proportion of prescribed bowel preparation claims — 53% for commercial plans and 83% for Medicare — still involve patient cost-sharing, indicating noncompliance with ACA guidelines. Although expense-sharing was less prevalent among Medicaid claims (just 27%), it was not eliminated, suggesting room for improvement in coverage enforcement across the board.

“Colon cancer is unique in that it can be prevented with colonoscopy, but where are the patients? Bowel prep is a major reason that patients defer screening,” Shah told GI & Hepatology News. He said his group was quite surprised that the majority in the study cohort were paying something out of pocket when these costs should have been covered. “Primary care doctors may not think to ask about bowel prep costs when they order screening colonoscopies.”

The findings emerged from an analysis of 2,593,079 prescription drug claims: 52.9% from commercial plans, 35% from Medicare Part D plans, and 8.3% from Medicaid plans.

“These patient costs of $30 or $50 are a real not a theoretical deterrent,” said Whitney Jones, MD, a gastroenterologist, adjunct clinical professor at the University of Louisville in Louisville, Kentucky, and founder of the nonprofit Colon Cancer Prevention Project. Jones was not involved in the analysis. “Some insurers require prior patient authorization for the low-dose preps, but gastroenterologists are doing so many colonoscopies they don’t always have time to get a PA [prior authorization] on everyone.” 

With the increasing use of blood and stool-based CRC testing, he added, “when you get a positive result, it’s really important to have the procedure quickly.” And appropriate bowel preparation is a small, cost-effective portion of the total costs of colonoscopy, a procedure that ultimately saves insurers significant money in treatment costs.

The authors noted that while CRC is the second-leading cause of cancer-related deaths in the US, screening rates remain low, with only 59% of adults aged 45 years or older up to date with screening. Screening rates are particularly low among racial and ethnic minority groups as compared with White individuals, a disparity that highlights the need to address existing barriers and enhance screening efforts.

In the current study, shared costs by bowel preparation volume also varied. Low-volume formulations had consistently higher out-of-pocket costs: a median of $60 for low-volume vs $10 for high-volume in commercial plans. In Medicare, 75% of high-volume claims had shared costs compared with 90% for their low-volume counterparts. The cost-sharing difference was slightly narrower with Medicaid: 27% of high-volume claims vs 30% of low-volume claims.

This is concerning, as low-volume options, which are preferred by patients for their better tolerability, can enhance uptake and adherence and improve colonoscopy outcomes. Shah advises physicians to consider prescribing low-volume preparations. “Let patients know about the potential out-of-pocket cost and about copay cards and assistance programs and use high-volume preps as an alternative rather than a go-to,” he said.

As to costs across insurance types, among commercial plans, the median nonzero out-of-pocket cost was $10 for high-volume and $60 for low-volume product claims. For Medicare, the median nonzero out-of-pocket cost was $8 for high-volume and $55.99 for low-volume products.

Under the ACA, CRC screening is classified as a recommended preventive service, requiring health plans to cover it without cost-sharing. Although the Centers for Medicare & Medicaid Services previously tried to enforce this mandate in 2015 and 2016, stating that colonoscopy preparation medications should be covered at no cost, many health plans are still not compliant.

At the nonfederal level, Jones noted, Kentucky, which has a significant high-risk population, recently became the first state to pass legislation requiring health benefit plans to cover all guideline-recommended CRC exams and lab tests.

For its part, AGA has also called on payers to eliminate all cost-sharing barriers across the CRC screening continuum.

Of note, the study authors said, the higher compliance with the ACA mandate in commercial and Medicaid plans than in Medicare highlights disparities that may disproportionately affect vulnerable older adults. While nearly half of commercial patients and nearly three quarters of Medicaid patients incurred zero out-of-pocket costs, fewer than 17% of Medicare beneficiaries, or 1 in 6, did so.

Although these costs may be low relative to the colonoscopy, they nevertheless can deter uptake of preventive screenings, potentially leading to higher CRC incidence and mortality. “While some patients may be willing to pay modest out-of-pocket costs, any required payment, however small, can serve as a barrier to preventative care, particularly in underserved populations,” they wrote. “These financial barriers will continue to contribute to widening disparities and hinder progress toward equitable screening outcomes.”

In the meantime, said Shah, “Physicians should advocate now to their representatives in Congress that bowel prep costs should already be covered as part of the ACA.”

This study was funded by Sebela Pharmaceuticals, maker of SUFLAVE preparation. The authors had no conflicts of interest to declare. Jones is a speaker and consultant for Grail LLC.

A version of this article appeared on Medscape.com.

Diets high in packaged breads, cookies, and other highly processed grain products may raise the risk for inflammatory bowel disease (IBD), while minimally processed grain products may offer some protection, a large study has found.

The sweeping analysis of 124,590 adults from 21 countries found that those eating at least 19 g of ultraprocessed grains a day were about twice as likely to be diagnosed with IBD as peers eating less than 9 g daily.

“Our study adds robust evidence from a large, diverse global cohort that frequent consumption of ultraprocessed grains is associated with an increased risk of developing inflammatory bowel disease,” Neeraj Narula, MD, MPH, gastroenterologist and associate professor of medicine, McMaster University, Hamilton, Ontario, Canada, told GI & Hepatology News.

The study also “further clarifies that not all grains carry risk — minimally processed grains like fresh bread and rice were associated with lower risk even. These results build on and specify previous findings linking ultraprocessed foods more broadly to IBD,” Narula said.

The study was published in The American Journal of Gastroenterology.

 

Diet Matters to IBD Risk

According to the latest US data (2021-2023), ultraprocessed foods made up 62% of daily calories for young people and 53% for adults in 2021-2023.

The Prospective Urban Rural Epidemiology (PURE) study has followed participants aged 35-70 years for a median of nearly 13 years. At enrollment, volunteers completed country-specific food-frequency questionnaires, enabling researchers to quantify usual intake of more than 130 food items and track new cases of IBD reported at biennial follow-ups.

The researchers classified packaged breads, sweet breakfast cereals, crackers, pastries and ready-to-heat pizza or pasta as ultraprocessed grains because they are refined and typically contain additives such as emulsifiers and preservatives. Fresh bakery bread and plain rice were analyzed separately as minimally processed grain references.

During a median of 12.9 years, 605 participants developed IBD; 497 developed ulcerative colitis (UC) and 108 developed Crohn’s disease. 

Increased intake of ultraprocessed grains was associated with a higher risk for IBD, with hazard ratios (HR) of 2.08 for intake of ≥ 50 g/d and 1.37 for 19-50 g/d compared to intake of < 19 g/d. The increased risk was largely driven by a significantly increased risk for UC (HR, 2.46) and not Crohn’s disease (HR, 0.98).

Among the different ultraprocessed grain products, packaged bread stood out: Consuming ≥ 30 g/d of packaged bread (a little more than one slice) was associated with a greater than twofold increased risk for IBD (HR, 2.11) compared to no intake of packaged bread.

In contrast, greater consumption of fresh bread was associated with a reduced risk of developing IBD (HR, 0.61 for ≥ 65 g/d and 0.45 for 16-65 g/d compared to < 16 g/d).

Increased intake of rice was also associated with a lower risk of developing IBD (HR, 0.63 for ≥ 1 serving/d and 0.99 for < 1 serving/d).

When the researchers widened the lens to all ultraprocessed foods — from sodas to salty snacks — the risk for IBD climbed further.

Participants eating at least five servings a day had nearly a fourfold greater odds of IBD than those eating fewer than one serving (HR, 3.95) — a finding consistent with other data from the PURE study cohort.

 

What to Tell Patients?

The authors acknowledged in their paper that it’s difficult — if not impossible — to completely avoid ultraprocessed food in the Western diet.

They said their findings support “public health strategies to promote consumption of whole and minimally processed foods while reducing the consumption of highly processed alternatives.”

“I tell my patients that emerging literature shows an association between ultraprocessed food intake and IBD risk, but it’s not yet clear whether simply cutting out those foods will improve disease activity once IBD is established,” Narula told GI & Hepatology News.

“However, I still encourage patients to reduce ultraprocessed foods and to follow a Mediterranean-style diet — focusing on minimally processed grains, fruits, vegetables, healthy fats, and lean proteins — to support overall gut and general health,” Narula said.

Reached for comment, Ashwin Ananthakrishnan, MD, MPH, AGAF, associate professor of medicine, Massachusetts General Hospital, Boston, who wasn’t part of the study, said it “adds incrementally to the growing data on how ultraprocessed foods may affect the risk of IBD.”

“They (and others) have previously shown a link between general ultraprocessed food consumption and risk of IBD. Others have shown that some of this is mediated through refined grains. This study more specifically studies that question and demonstrates an association,” said Ananthkrishnan.

“This should not be used, however, to counsel patients. It does not study the impact of grain intake on patients with IBD. It may help inform population level preventive strategies (or in high-risk individuals) but requires more confirmation since there is significant heterogeneity between the various countries in this cohort. Countries that have high refined grain intake are also enriched in several other IBD risk factors (including genetics),” Ananthkrishnan told GI & Hepatology News.

The PURE study is an investigator-initiated study funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Ontario. It received support from Canadian Institutes of Health Research’s Strategy for Patient Oriented Research, Ontario SPOR Support Unit, and Ontario Ministry of Health and Long-Term Care and unrestricted grants from several pharmaceutical companies. Narula declared receiving honoraria from Janssen, Abbvie, Takeda, Pfizer, Sandoz, Novartis, Iterative Health, Innomar Strategies, Fresinius Kabi, Amgen, Organon, Eli Lilly, and Ferring. Ananthkrishnan declared having no relevant disclosures.

A version of this article appeared on Medscape.com.

Diets high in packaged breads, cookies, and other highly processed grain products may raise the risk for inflammatory bowel disease (IBD), while minimally processed grain products may offer some protection, a large study has found.

The sweeping analysis of 124,590 adults from 21 countries found that those eating at least 19 g of ultraprocessed grains a day were about twice as likely to be diagnosed with IBD as peers eating less than 9 g daily.

“Our study adds robust evidence from a large, diverse global cohort that frequent consumption of ultraprocessed grains is associated with an increased risk of developing inflammatory bowel disease,” Neeraj Narula, MD, MPH, gastroenterologist and associate professor of medicine, McMaster University, Hamilton, Ontario, Canada, told GI & Hepatology News.

The study also “further clarifies that not all grains carry risk — minimally processed grains like fresh bread and rice were associated with lower risk even. These results build on and specify previous findings linking ultraprocessed foods more broadly to IBD,” Narula said.

The study was published in The American Journal of Gastroenterology.

 

Diet Matters to IBD Risk

According to the latest US data (2021-2023), ultraprocessed foods made up 62% of daily calories for young people and 53% for adults in 2021-2023.

The Prospective Urban Rural Epidemiology (PURE) study has followed participants aged 35-70 years for a median of nearly 13 years. At enrollment, volunteers completed country-specific food-frequency questionnaires, enabling researchers to quantify usual intake of more than 130 food items and track new cases of IBD reported at biennial follow-ups.

The researchers classified packaged breads, sweet breakfast cereals, crackers, pastries and ready-to-heat pizza or pasta as ultraprocessed grains because they are refined and typically contain additives such as emulsifiers and preservatives. Fresh bakery bread and plain rice were analyzed separately as minimally processed grain references.

During a median of 12.9 years, 605 participants developed IBD; 497 developed ulcerative colitis (UC) and 108 developed Crohn’s disease. 

Increased intake of ultraprocessed grains was associated with a higher risk for IBD, with hazard ratios (HR) of 2.08 for intake of ≥ 50 g/d and 1.37 for 19-50 g/d compared to intake of < 19 g/d. The increased risk was largely driven by a significantly increased risk for UC (HR, 2.46) and not Crohn’s disease (HR, 0.98).

Among the different ultraprocessed grain products, packaged bread stood out: Consuming ≥ 30 g/d of packaged bread (a little more than one slice) was associated with a greater than twofold increased risk for IBD (HR, 2.11) compared to no intake of packaged bread.

In contrast, greater consumption of fresh bread was associated with a reduced risk of developing IBD (HR, 0.61 for ≥ 65 g/d and 0.45 for 16-65 g/d compared to < 16 g/d).

Increased intake of rice was also associated with a lower risk of developing IBD (HR, 0.63 for ≥ 1 serving/d and 0.99 for < 1 serving/d).

When the researchers widened the lens to all ultraprocessed foods — from sodas to salty snacks — the risk for IBD climbed further.

Participants eating at least five servings a day had nearly a fourfold greater odds of IBD than those eating fewer than one serving (HR, 3.95) — a finding consistent with other data from the PURE study cohort.

 

What to Tell Patients?

The authors acknowledged in their paper that it’s difficult — if not impossible — to completely avoid ultraprocessed food in the Western diet.

They said their findings support “public health strategies to promote consumption of whole and minimally processed foods while reducing the consumption of highly processed alternatives.”

“I tell my patients that emerging literature shows an association between ultraprocessed food intake and IBD risk, but it’s not yet clear whether simply cutting out those foods will improve disease activity once IBD is established,” Narula told GI & Hepatology News.

“However, I still encourage patients to reduce ultraprocessed foods and to follow a Mediterranean-style diet — focusing on minimally processed grains, fruits, vegetables, healthy fats, and lean proteins — to support overall gut and general health,” Narula said.

Reached for comment, Ashwin Ananthakrishnan, MD, MPH, AGAF, associate professor of medicine, Massachusetts General Hospital, Boston, who wasn’t part of the study, said it “adds incrementally to the growing data on how ultraprocessed foods may affect the risk of IBD.”

“They (and others) have previously shown a link between general ultraprocessed food consumption and risk of IBD. Others have shown that some of this is mediated through refined grains. This study more specifically studies that question and demonstrates an association,” said Ananthkrishnan.

“This should not be used, however, to counsel patients. It does not study the impact of grain intake on patients with IBD. It may help inform population level preventive strategies (or in high-risk individuals) but requires more confirmation since there is significant heterogeneity between the various countries in this cohort. Countries that have high refined grain intake are also enriched in several other IBD risk factors (including genetics),” Ananthkrishnan told GI & Hepatology News.

The PURE study is an investigator-initiated study funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Ontario. It received support from Canadian Institutes of Health Research’s Strategy for Patient Oriented Research, Ontario SPOR Support Unit, and Ontario Ministry of Health and Long-Term Care and unrestricted grants from several pharmaceutical companies. Narula declared receiving honoraria from Janssen, Abbvie, Takeda, Pfizer, Sandoz, Novartis, Iterative Health, Innomar Strategies, Fresinius Kabi, Amgen, Organon, Eli Lilly, and Ferring. Ananthkrishnan declared having no relevant disclosures.

A version of this article appeared on Medscape.com.

Diets high in packaged breads, cookies, and other highly processed grain products may raise the risk for inflammatory bowel disease (IBD), while minimally processed grain products may offer some protection, a large study has found.

The sweeping analysis of 124,590 adults from 21 countries found that those eating at least 19 g of ultraprocessed grains a day were about twice as likely to be diagnosed with IBD as peers eating less than 9 g daily.

“Our study adds robust evidence from a large, diverse global cohort that frequent consumption of ultraprocessed grains is associated with an increased risk of developing inflammatory bowel disease,” Neeraj Narula, MD, MPH, gastroenterologist and associate professor of medicine, McMaster University, Hamilton, Ontario, Canada, told GI & Hepatology News.

The study also “further clarifies that not all grains carry risk — minimally processed grains like fresh bread and rice were associated with lower risk even. These results build on and specify previous findings linking ultraprocessed foods more broadly to IBD,” Narula said.

The study was published in The American Journal of Gastroenterology.

 

Diet Matters to IBD Risk

According to the latest US data (2021-2023), ultraprocessed foods made up 62% of daily calories for young people and 53% for adults in 2021-2023.

The Prospective Urban Rural Epidemiology (PURE) study has followed participants aged 35-70 years for a median of nearly 13 years. At enrollment, volunteers completed country-specific food-frequency questionnaires, enabling researchers to quantify usual intake of more than 130 food items and track new cases of IBD reported at biennial follow-ups.

The researchers classified packaged breads, sweet breakfast cereals, crackers, pastries and ready-to-heat pizza or pasta as ultraprocessed grains because they are refined and typically contain additives such as emulsifiers and preservatives. Fresh bakery bread and plain rice were analyzed separately as minimally processed grain references.

During a median of 12.9 years, 605 participants developed IBD; 497 developed ulcerative colitis (UC) and 108 developed Crohn’s disease. 

Increased intake of ultraprocessed grains was associated with a higher risk for IBD, with hazard ratios (HR) of 2.08 for intake of ≥ 50 g/d and 1.37 for 19-50 g/d compared to intake of < 19 g/d. The increased risk was largely driven by a significantly increased risk for UC (HR, 2.46) and not Crohn’s disease (HR, 0.98).

Among the different ultraprocessed grain products, packaged bread stood out: Consuming ≥ 30 g/d of packaged bread (a little more than one slice) was associated with a greater than twofold increased risk for IBD (HR, 2.11) compared to no intake of packaged bread.

In contrast, greater consumption of fresh bread was associated with a reduced risk of developing IBD (HR, 0.61 for ≥ 65 g/d and 0.45 for 16-65 g/d compared to < 16 g/d).

Increased intake of rice was also associated with a lower risk of developing IBD (HR, 0.63 for ≥ 1 serving/d and 0.99 for < 1 serving/d).

When the researchers widened the lens to all ultraprocessed foods — from sodas to salty snacks — the risk for IBD climbed further.

Participants eating at least five servings a day had nearly a fourfold greater odds of IBD than those eating fewer than one serving (HR, 3.95) — a finding consistent with other data from the PURE study cohort.

 

What to Tell Patients?

The authors acknowledged in their paper that it’s difficult — if not impossible — to completely avoid ultraprocessed food in the Western diet.

They said their findings support “public health strategies to promote consumption of whole and minimally processed foods while reducing the consumption of highly processed alternatives.”

“I tell my patients that emerging literature shows an association between ultraprocessed food intake and IBD risk, but it’s not yet clear whether simply cutting out those foods will improve disease activity once IBD is established,” Narula told GI & Hepatology News.

“However, I still encourage patients to reduce ultraprocessed foods and to follow a Mediterranean-style diet — focusing on minimally processed grains, fruits, vegetables, healthy fats, and lean proteins — to support overall gut and general health,” Narula said.

Reached for comment, Ashwin Ananthakrishnan, MD, MPH, AGAF, associate professor of medicine, Massachusetts General Hospital, Boston, who wasn’t part of the study, said it “adds incrementally to the growing data on how ultraprocessed foods may affect the risk of IBD.”

“They (and others) have previously shown a link between general ultraprocessed food consumption and risk of IBD. Others have shown that some of this is mediated through refined grains. This study more specifically studies that question and demonstrates an association,” said Ananthkrishnan.

“This should not be used, however, to counsel patients. It does not study the impact of grain intake on patients with IBD. It may help inform population level preventive strategies (or in high-risk individuals) but requires more confirmation since there is significant heterogeneity between the various countries in this cohort. Countries that have high refined grain intake are also enriched in several other IBD risk factors (including genetics),” Ananthkrishnan told GI & Hepatology News.

The PURE study is an investigator-initiated study funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Ontario. It received support from Canadian Institutes of Health Research’s Strategy for Patient Oriented Research, Ontario SPOR Support Unit, and Ontario Ministry of Health and Long-Term Care and unrestricted grants from several pharmaceutical companies. Narula declared receiving honoraria from Janssen, Abbvie, Takeda, Pfizer, Sandoz, Novartis, Iterative Health, Innomar Strategies, Fresinius Kabi, Amgen, Organon, Eli Lilly, and Ferring. Ananthkrishnan declared having no relevant disclosures.

A version of this article appeared on Medscape.com.

Most GI service chiefs in the U.S. Veterans Affairs (VA) healthcare system support point-of-care ultrasound (POCUS) training, but fewer than half have the technology in their facility, according to a national survey.

Low POCUS uptake may be explained by substantial barriers to implementation, including lack of trained instructors, necessary equipment, and support staff, lead author Keerthi Thallapureddy, MD, of the University of Texas Health San Antonio, and colleagues, reported.

“POCUS is being increasingly used by gastroenterologists due to its portability and real-time diagnostic ability,” the investigators wrote in Gastro Hep Advances, but “there is limited understanding of how gastroenterologists use POCUS.”

To learn more, the investigators conducted a nationwide survey of the VA healthcare system. Separate questionnaires were sent to chiefs of staff (n = 130) and GI service chiefs (n = 117), yielding response rates of 100% and 79%, respectively.

Respondents represented a wide distribution of geographic regions and institutional complexity levels, with 80% of GI groups based at high-complexity centers and 92% in urban locations. A minority (8%) reported the presence of a liver transplant program.

Data collection focused on the prevalence of POCUS use, types of clinical applications, institutional policies and training processes, and perceived or actual barriers to wider adoption. Barriers were sorted into three categories: training, equipment, and infrastructure.

Of the 93 GI service chiefs who participated in the survey, 44% reported that at least 1 gastroenterologist at their facility currently uses POCUS. Most common procedural uses were paracentesis (23%) and liver biopsy (13%), while ascites assessment (19%) and biliary visualization (7%) were the most common diagnostic uses.

Among the same respondents, 69% said they would support sending clinicians to a POCUS training course, and 37% said their teams had expressed an active interest in pursuing such training. Only 17% of facilities had a formal process in place to obtain POCUS training, and an equal proportion had implemented a facility-wide policy to guide its use.

Barriers to implementation were widespread and often multifactorial. 

Most challenges related to training: 48% of sites reported a lack of trained providers, 28% cited insufficient funding for training, 24% noted a lack of training opportunities, and 14% reported difficulty securing travel funds. 

Equipment limitations were also common, with 41% of sites lacking ultrasound machines and 27% lacking funding to purchase them. 

Institutional infrastructure posed further hurdles. Nearly a quarter of GI chiefs (23%) reported lacking a clinician champion to lead implementation, while others cited a lack of support staff, simulation space, privileging criteria, image archiving capabilities, or standardized reporting forms.

“Our findings on current POCUS use, training, barriers, and infrastructure can guide expansion of POCUS use and training among GI groups,” Dr. Thallapureddy and colleagues wrote, noting that early efforts to expand access to GI-specific POCUS training are already underway. 

They cited growing interest from national organizations such as the American Gastroenterological Association and the American Association for the Study of Liver Diseases, the latter of which piloted training workshops at the 2024 Liver Meeting. Similarly, the International Bowel Ultrasound Group now offers a 3-part certification program in intestinal ultrasound and is developing additional online and interactive modules to improve training accessibility.

The study was supported by the US Department of Veterans Affairs, Quality Enhancement Research Initiative Partnered Evaluation Initiative Grant, and the VA National Center for Patient Safety. The investigators reported no conflicts of interest.
 

Most GI service chiefs in the U.S. Veterans Affairs (VA) healthcare system support point-of-care ultrasound (POCUS) training, but fewer than half have the technology in their facility, according to a national survey.

Low POCUS uptake may be explained by substantial barriers to implementation, including lack of trained instructors, necessary equipment, and support staff, lead author Keerthi Thallapureddy, MD, of the University of Texas Health San Antonio, and colleagues, reported.

“POCUS is being increasingly used by gastroenterologists due to its portability and real-time diagnostic ability,” the investigators wrote in Gastro Hep Advances, but “there is limited understanding of how gastroenterologists use POCUS.”

To learn more, the investigators conducted a nationwide survey of the VA healthcare system. Separate questionnaires were sent to chiefs of staff (n = 130) and GI service chiefs (n = 117), yielding response rates of 100% and 79%, respectively.

Respondents represented a wide distribution of geographic regions and institutional complexity levels, with 80% of GI groups based at high-complexity centers and 92% in urban locations. A minority (8%) reported the presence of a liver transplant program.

Data collection focused on the prevalence of POCUS use, types of clinical applications, institutional policies and training processes, and perceived or actual barriers to wider adoption. Barriers were sorted into three categories: training, equipment, and infrastructure.

Of the 93 GI service chiefs who participated in the survey, 44% reported that at least 1 gastroenterologist at their facility currently uses POCUS. Most common procedural uses were paracentesis (23%) and liver biopsy (13%), while ascites assessment (19%) and biliary visualization (7%) were the most common diagnostic uses.

Among the same respondents, 69% said they would support sending clinicians to a POCUS training course, and 37% said their teams had expressed an active interest in pursuing such training. Only 17% of facilities had a formal process in place to obtain POCUS training, and an equal proportion had implemented a facility-wide policy to guide its use.

Barriers to implementation were widespread and often multifactorial. 

Most challenges related to training: 48% of sites reported a lack of trained providers, 28% cited insufficient funding for training, 24% noted a lack of training opportunities, and 14% reported difficulty securing travel funds. 

Equipment limitations were also common, with 41% of sites lacking ultrasound machines and 27% lacking funding to purchase them. 

Institutional infrastructure posed further hurdles. Nearly a quarter of GI chiefs (23%) reported lacking a clinician champion to lead implementation, while others cited a lack of support staff, simulation space, privileging criteria, image archiving capabilities, or standardized reporting forms.

“Our findings on current POCUS use, training, barriers, and infrastructure can guide expansion of POCUS use and training among GI groups,” Dr. Thallapureddy and colleagues wrote, noting that early efforts to expand access to GI-specific POCUS training are already underway. 

They cited growing interest from national organizations such as the American Gastroenterological Association and the American Association for the Study of Liver Diseases, the latter of which piloted training workshops at the 2024 Liver Meeting. Similarly, the International Bowel Ultrasound Group now offers a 3-part certification program in intestinal ultrasound and is developing additional online and interactive modules to improve training accessibility.

The study was supported by the US Department of Veterans Affairs, Quality Enhancement Research Initiative Partnered Evaluation Initiative Grant, and the VA National Center for Patient Safety. The investigators reported no conflicts of interest.
 

Most GI service chiefs in the U.S. Veterans Affairs (VA) healthcare system support point-of-care ultrasound (POCUS) training, but fewer than half have the technology in their facility, according to a national survey.

Low POCUS uptake may be explained by substantial barriers to implementation, including lack of trained instructors, necessary equipment, and support staff, lead author Keerthi Thallapureddy, MD, of the University of Texas Health San Antonio, and colleagues, reported.

“POCUS is being increasingly used by gastroenterologists due to its portability and real-time diagnostic ability,” the investigators wrote in Gastro Hep Advances, but “there is limited understanding of how gastroenterologists use POCUS.”

To learn more, the investigators conducted a nationwide survey of the VA healthcare system. Separate questionnaires were sent to chiefs of staff (n = 130) and GI service chiefs (n = 117), yielding response rates of 100% and 79%, respectively.

Respondents represented a wide distribution of geographic regions and institutional complexity levels, with 80% of GI groups based at high-complexity centers and 92% in urban locations. A minority (8%) reported the presence of a liver transplant program.

Data collection focused on the prevalence of POCUS use, types of clinical applications, institutional policies and training processes, and perceived or actual barriers to wider adoption. Barriers were sorted into three categories: training, equipment, and infrastructure.

Of the 93 GI service chiefs who participated in the survey, 44% reported that at least 1 gastroenterologist at their facility currently uses POCUS. Most common procedural uses were paracentesis (23%) and liver biopsy (13%), while ascites assessment (19%) and biliary visualization (7%) were the most common diagnostic uses.

Among the same respondents, 69% said they would support sending clinicians to a POCUS training course, and 37% said their teams had expressed an active interest in pursuing such training. Only 17% of facilities had a formal process in place to obtain POCUS training, and an equal proportion had implemented a facility-wide policy to guide its use.

Barriers to implementation were widespread and often multifactorial. 

Most challenges related to training: 48% of sites reported a lack of trained providers, 28% cited insufficient funding for training, 24% noted a lack of training opportunities, and 14% reported difficulty securing travel funds. 

Equipment limitations were also common, with 41% of sites lacking ultrasound machines and 27% lacking funding to purchase them. 

Institutional infrastructure posed further hurdles. Nearly a quarter of GI chiefs (23%) reported lacking a clinician champion to lead implementation, while others cited a lack of support staff, simulation space, privileging criteria, image archiving capabilities, or standardized reporting forms.

“Our findings on current POCUS use, training, barriers, and infrastructure can guide expansion of POCUS use and training among GI groups,” Dr. Thallapureddy and colleagues wrote, noting that early efforts to expand access to GI-specific POCUS training are already underway. 

They cited growing interest from national organizations such as the American Gastroenterological Association and the American Association for the Study of Liver Diseases, the latter of which piloted training workshops at the 2024 Liver Meeting. Similarly, the International Bowel Ultrasound Group now offers a 3-part certification program in intestinal ultrasound and is developing additional online and interactive modules to improve training accessibility.

The study was supported by the US Department of Veterans Affairs, Quality Enhancement Research Initiative Partnered Evaluation Initiative Grant, and the VA National Center for Patient Safety. The investigators reported no conflicts of interest.
 

Medications for inflammatory bowel disease (IBD) appear to have no impact on risk of incident malignancies among patients with a history of breast cancer, according to investigators.

These findings diminish concerns that IBD therapy could theoretically reactivate dormant micrometastases, lead author Guillaume Le Cosquer, MD, of Toulouse University Hospital, Toulouse, France, and colleagues, reported.

“In patients with IBD, medical management of subjects with a history of breast cancer is a frequent and unresolved problem for clinicians,” the investigators wrote in Clinical Gastroenterology and Hepatology (2024 Nov. doi: 10.1016/j.cgh.2024.09.034).

Previous studies have reported that conventional immunosuppressants and biologics do not increase risk of incident cancer among IBD patients with a prior nondigestive malignancy; however, recent guidelines from the European Crohn’s and Colitis Organisation (ECCO) suggest that data are insufficient to make associated recommendations, prompting the present study.

“[T]he major strength of our work is that it is the first to focus on the most frequent cancer (breast cancer) in patients with IBD only, with the longest follow-up after breast cancer in patients with IBD ever published,” Dr. Le Cosquer and colleagues noted.

The dataset included 207 patients with IBD and a history of breast cancer, drawn from 7 tertiary centers across France. 

The index date was the time of breast cancer diagnosis, and patients were followed for a median of 71 months. The median time from cancer diagnosis to initiation of IBD treatment was 28 months. 

First-line post-cancer treatments included conventional immunosuppressants (19.3%), anti–tumor necrosis factor (anti-TNF) agents (19.8%), vedolizumab (7.2%), and ustekinumab (1.9%). Approximately half (51.6%) received no immunosuppressive therapy during follow-up.

Over the study period, 42 incident cancers were recorded (20.3%), among which 34 were breast cancer recurrences. Adjusted incidence rates per 1000 person-years were 10.2 (95% CI, 6.0–16.4) in the untreated group and 28.9 (95% CI, 11.6–59.6) in patients exposed to immunosuppressive or biologic therapies (P = .0519). Incident cancer–free survival did not differ significantly between treated and untreated groups (P = .4796).

On multivariable analysis, independent predictors of incident cancer included T4d stage (P = .036), triple-negative status (P = .016), and follow-up duration shorter than 71 months (P = .005).

“[I]mmunosuppressant and biologic use in selected patients with IBD with prior breast cancer does not seem to increase the risk of incident cancer,” the investigators wrote, noting that the main predictors of cancer recurrence were known poor prognostic features of breast cancer.

Dr. Le Cosquer and colleagues acknowledged a lack of prospective safety data for biologic therapies among patients with prior malignancy, as these individuals are often excluded from clinical trials. Still, they underscored alignment between their findings and earlier retrospective studies, including analyses from the SAPPHIRE registry and Medicare data, which also found no significant increase in breast cancer recurrence with anti-TNF agents or newer biologics such as vedolizumab and ustekinumab. 

“Our findings will help clinicians to make decisions in multidisciplinary meetings to start immunosuppressants or biologics in case of IBD flare-up in these patients,” they concluded.

The investigators disclosed relationships with AbbVie, Janssen, Takeda, and others.

Medications for inflammatory bowel disease (IBD) appear to have no impact on risk of incident malignancies among patients with a history of breast cancer, according to investigators.

These findings diminish concerns that IBD therapy could theoretically reactivate dormant micrometastases, lead author Guillaume Le Cosquer, MD, of Toulouse University Hospital, Toulouse, France, and colleagues, reported.

“In patients with IBD, medical management of subjects with a history of breast cancer is a frequent and unresolved problem for clinicians,” the investigators wrote in Clinical Gastroenterology and Hepatology (2024 Nov. doi: 10.1016/j.cgh.2024.09.034).

Previous studies have reported that conventional immunosuppressants and biologics do not increase risk of incident cancer among IBD patients with a prior nondigestive malignancy; however, recent guidelines from the European Crohn’s and Colitis Organisation (ECCO) suggest that data are insufficient to make associated recommendations, prompting the present study.

“[T]he major strength of our work is that it is the first to focus on the most frequent cancer (breast cancer) in patients with IBD only, with the longest follow-up after breast cancer in patients with IBD ever published,” Dr. Le Cosquer and colleagues noted.

The dataset included 207 patients with IBD and a history of breast cancer, drawn from 7 tertiary centers across France. 

The index date was the time of breast cancer diagnosis, and patients were followed for a median of 71 months. The median time from cancer diagnosis to initiation of IBD treatment was 28 months. 

First-line post-cancer treatments included conventional immunosuppressants (19.3%), anti–tumor necrosis factor (anti-TNF) agents (19.8%), vedolizumab (7.2%), and ustekinumab (1.9%). Approximately half (51.6%) received no immunosuppressive therapy during follow-up.

Over the study period, 42 incident cancers were recorded (20.3%), among which 34 were breast cancer recurrences. Adjusted incidence rates per 1000 person-years were 10.2 (95% CI, 6.0–16.4) in the untreated group and 28.9 (95% CI, 11.6–59.6) in patients exposed to immunosuppressive or biologic therapies (P = .0519). Incident cancer–free survival did not differ significantly between treated and untreated groups (P = .4796).

On multivariable analysis, independent predictors of incident cancer included T4d stage (P = .036), triple-negative status (P = .016), and follow-up duration shorter than 71 months (P = .005).

“[I]mmunosuppressant and biologic use in selected patients with IBD with prior breast cancer does not seem to increase the risk of incident cancer,” the investigators wrote, noting that the main predictors of cancer recurrence were known poor prognostic features of breast cancer.

Dr. Le Cosquer and colleagues acknowledged a lack of prospective safety data for biologic therapies among patients with prior malignancy, as these individuals are often excluded from clinical trials. Still, they underscored alignment between their findings and earlier retrospective studies, including analyses from the SAPPHIRE registry and Medicare data, which also found no significant increase in breast cancer recurrence with anti-TNF agents or newer biologics such as vedolizumab and ustekinumab. 

“Our findings will help clinicians to make decisions in multidisciplinary meetings to start immunosuppressants or biologics in case of IBD flare-up in these patients,” they concluded.

The investigators disclosed relationships with AbbVie, Janssen, Takeda, and others.

Medications for inflammatory bowel disease (IBD) appear to have no impact on risk of incident malignancies among patients with a history of breast cancer, according to investigators.

These findings diminish concerns that IBD therapy could theoretically reactivate dormant micrometastases, lead author Guillaume Le Cosquer, MD, of Toulouse University Hospital, Toulouse, France, and colleagues, reported.

“In patients with IBD, medical management of subjects with a history of breast cancer is a frequent and unresolved problem for clinicians,” the investigators wrote in Clinical Gastroenterology and Hepatology (2024 Nov. doi: 10.1016/j.cgh.2024.09.034).

Previous studies have reported that conventional immunosuppressants and biologics do not increase risk of incident cancer among IBD patients with a prior nondigestive malignancy; however, recent guidelines from the European Crohn’s and Colitis Organisation (ECCO) suggest that data are insufficient to make associated recommendations, prompting the present study.

“[T]he major strength of our work is that it is the first to focus on the most frequent cancer (breast cancer) in patients with IBD only, with the longest follow-up after breast cancer in patients with IBD ever published,” Dr. Le Cosquer and colleagues noted.

The dataset included 207 patients with IBD and a history of breast cancer, drawn from 7 tertiary centers across France. 

The index date was the time of breast cancer diagnosis, and patients were followed for a median of 71 months. The median time from cancer diagnosis to initiation of IBD treatment was 28 months. 

First-line post-cancer treatments included conventional immunosuppressants (19.3%), anti–tumor necrosis factor (anti-TNF) agents (19.8%), vedolizumab (7.2%), and ustekinumab (1.9%). Approximately half (51.6%) received no immunosuppressive therapy during follow-up.

Over the study period, 42 incident cancers were recorded (20.3%), among which 34 were breast cancer recurrences. Adjusted incidence rates per 1000 person-years were 10.2 (95% CI, 6.0–16.4) in the untreated group and 28.9 (95% CI, 11.6–59.6) in patients exposed to immunosuppressive or biologic therapies (P = .0519). Incident cancer–free survival did not differ significantly between treated and untreated groups (P = .4796).

On multivariable analysis, independent predictors of incident cancer included T4d stage (P = .036), triple-negative status (P = .016), and follow-up duration shorter than 71 months (P = .005).

“[I]mmunosuppressant and biologic use in selected patients with IBD with prior breast cancer does not seem to increase the risk of incident cancer,” the investigators wrote, noting that the main predictors of cancer recurrence were known poor prognostic features of breast cancer.

Dr. Le Cosquer and colleagues acknowledged a lack of prospective safety data for biologic therapies among patients with prior malignancy, as these individuals are often excluded from clinical trials. Still, they underscored alignment between their findings and earlier retrospective studies, including analyses from the SAPPHIRE registry and Medicare data, which also found no significant increase in breast cancer recurrence with anti-TNF agents or newer biologics such as vedolizumab and ustekinumab. 

“Our findings will help clinicians to make decisions in multidisciplinary meetings to start immunosuppressants or biologics in case of IBD flare-up in these patients,” they concluded.

The investigators disclosed relationships with AbbVie, Janssen, Takeda, and others.

Gastroenterology (GI) subspecialty training is carefully designed to develop expertise in digestive diseases and gastrointestinal endoscopy, while facilitating the transition from generalist to subspecialty consultant. The concept of effective consultation extends far beyond clinical expertise and has been explored repeatedly, beginning with Goldman’s “Ten Commandments” in 1983.^1,2 How should these best practices be specifically applied to GI? More importantly, what kind of experience would you want if you were the referring provider or the patient themselves?

Below are five essential tips to guide your development as a high-impact GI consultant with a reputation for excellence. 
 

1. Be Kind

Survey studies of medical/surgical residents and attending hospitalists have demonstrated that willingness to accept consultation requests was the single factor consistently rated as most important in determining the quality of the consultation interaction.^3,4 Unfortunately, nearly 65% of respondents reported encountering pushback when requesting subspecialty consultation. It is critical to recognize that when you receive a GI consult request, the requester has already decided that it is needed. Whether that request comports with our individual notion of “necessary” or “important,” this is a colleague’s request for help. There are myriad reasons why a request may be made, but they are unified in this principle.

Effective teamwork in healthcare settings enhances clinical performance and patient safety. Positive relationships with colleagues and healthcare team members also mitigate the emotional basis for physician burnout.⁵ Be kind and courteous to those who seek your assistance. Move beyond the notion of the “bad” or “soft” consult and seek instead to understand how you can help.

A requesting physician may phrase the consult question vaguely or may know that the patient is having a GI-related issue, but simply lack the specific knowledge to know what is needed. In these instances, it is our role to listen and help guide them to the correct thought process to ensure the best care of the patient. These important interactions establish our reputation, create our referral bases, and directly affect our sense of personal satisfaction.

 

2. Be Timely

GI presents an appealing breadth of pathology, but this also corresponds to a wide variety of indications for consultation and, therefore, urgency of need. In a busy clinical practice, not all requests can be urgently prioritized. However, it is the consultant’s responsibility to identify patients that require urgent evaluation and intervention to avert a potential adverse outcome.

We are well-trained in the medical triage of consultations. There are explicit guidelines for assessing urgency for GI bleeding, foreign body ingestion, choledocholithiasis, and many other indications. However, there are often special contextual circumstances that will elevate the urgency of a seemingly non-urgent consult request. Does the patient have an upcoming surgery or treatment that will depend on your input? Are they facing an imminent loss of insurance coverage? Is their non-severe GI disease leading to more severe impact on non-GI organ systems? The referring provider knows the patient better than you – seek to understand the context of the consult request.
 

Timeliness also applies to our communication. Communicate recommendations directly to the consulting service as soon as the patient is seen. When a colleague reaches out with a concern about a patient, make sure to take that request seriously. If you are unable to address the concern immediately, at least provide acknowledgment and an estimated timeline for response. As the maxim states, the effectiveness of a consultant is just as dependent on availability as it is on ability.

 

3. Be Specific

The same survey studies indicate that the second most critical aspect of successful subspecialty consultation is delivering clear recommendations. Accordingly, I always urge my trainees to challenge me when we leave a consult interaction if they feel that our plan is vague or imprecise.

Specificity in consult recommendations is an essential way to demonstrate your expertise and provide value. Clear and definitive recommendations enhance others’ perception of your skill, reduce the need for additional clarifying communication, and lead to more efficient, higher quality care. Avoid vague language, such as asking the requester to “consider” a test or intervention. When recommending medication, specify the dose, frequency, duration, and expected timeline of effect. Rather than recommending “cross-sectional imaging,” specify what modality and protocol. Instead of recommending “adequate resuscitation,” specify your target endpoints. If you engage in multidisciplinary discussion, ensure you strive for a specific group consensus plan and communicate this to all members of the team.

Specificity also applies to the quality of your documentation. Ensure that your clinical notes outline your rationale for your recommended plan, specific contingencies based on results of recommended testing, and a plan for follow-up care. When referring for open-access endoscopy, specifically outline what to look for and which specimens or endoscopic interventions are needed. Be precise in your procedure documentation – avoid vague terms such as small/medium/large and instead quantify in terms of millimeter/centimeter measurement. If you do not adopt specific classification schemes (e.g. Prague classification, Paris classification, Eosinophilic Esophagitis Endoscopic Reference Score, etc.), ensure you provide enough descriptive language to convey an adequate understanding of the findings.

 

4. Be Helpful

A consultant’s primary directive is to be of service to the consulting provider and the patient. As an educational leader, I am often asked what attributes separate a high-performing trainee from an average one. My feeling is that the most critical attribute is a sense of ownership over patient care.

As a consultant, when others feel we are exhibiting engagement and ownership in a patient’s care, they perceive that we are working together as an effective healthcare team. Interestingly, survey studies of inpatient care show that primary services do not necessarily value assistance with orders or care coordination – they consider these as core aspects of their daily work. What they did value was ongoing daily progress notes/communication, regardless of patient acuity or consulting specialty. This is a potent signal that our continued engagement (both inpatient and outpatient) is perceived as helpful.

Helpfulness is further aided by ensuring mutual understanding. While survey data indicate that sharing specific literature citations may not always be perceived positively, explaining the consultant’s rationale for their recommendations is highly valued. Take the time to tactfully explain your assessment of the patient and why you arrived at your specific recommendations. If your recommendations differ from what the requester expected (e.g. a procedure was expected but is not offered), ensure you explain why and answer questions they may have. This fosters mutual respect and proactively averts conflict or discontent from misunderstanding.

Multidisciplinary collaboration is another important avenue for aiding our patients and colleagues. Studies across a wide range of disease processes (including GI bleeding, IBD, etc.) and medical settings have demonstrated that multidisciplinary collaboration unequivocally improves patient outcomes.⁶ The success of these collaborations relies on our willingness to fully engage in these conversations, despite the fact that they may often be logistically challenging. 

We all know how difficult it can be to locate and organize multiple medical specialists with complex varying clinical schedules and busy personal lives. Choosing to do so demonstrates a dedication to providing the highest level of care and elevates both patient and physician satisfaction. Having chosen to cultivate several ongoing multidisciplinary conferences/collaborations, I can attest to the notion that the outcome is well worth the effort.

 

5. Be Honest

While we always strive to provide the answers for our patients and colleagues, we must also acknowledge our limitations. Be honest with yourself when you encounter a scenario that pushes beyond the boundaries of your knowledge and comfort. Be willing to admit when you yourself need to consult others or seek an outside referral to provide the care a patient needs. Aspiring physicians often espouse that a devotion to lifelong learning is a key driver of their desire to pursue a career in medicine. These scenarios provide a key opportunity to expand our knowledge while doing what is right for our patients.

Be equally honest about your comfort with “curbside” consultations. Studies show that subspecialists receive on average of 3-4 such requests per week.⁷ The perception of these interactions is starkly discrepant between the requester and recipient. While over 80% of surveyed primary nonsurgical services felt that curbside consultations were helpful in patient care, a similar proportion of subspecialists expressed concern that insufficient clinical information was provided, even leading to a fear of litigation. While straightforward, informal conversations on narrow, well-defined questions can be helpful and efficient, the consultant should always feel comfortable seeking an opportunity for formal consultation when the details are unclear or the case/question is complex.

 

Closing Thoughts

Being an effective GI consultant isn’t just about what you know—it’s about how you apply it, how you communicate it, and how you make others feel in the process.

The attributes outlined above are not ancillary traits—they are essential components of high-quality consultation. When consistently applied, they enhance collaboration, improve patient outcomes, and reinforce trust within the healthcare system. By committing to them, you establish your reputation of excellence and play a role in elevating the field of gastroenterology more broadly.

Dr. Kahn is based in the Division of Gastroenterology and Hepatology at Mayo Clinic, Scottsdale, Arizona. He reports no conflicts of interest in regard to this article.

References

1. Goldman L, et al. Ten commandments for effective consultations. Arch Intern Med. 1983 Sep.

2. Salerno SM, et al. Principles of effective consultation: an update for the 21st-century consultant. Arch Intern Med. 2007 Feb. doi: 10.1001/archinte.167.3.271.

3. Adams TN, et al. Hospitalist Perspective of Interactions with Medicine Subspecialty Consult Services. J Hosp Med. 2018 May. doi: 10.12788/jhm.2882.

4. Matsuo T, et al. Essential consultants’ skills and attitudes (Willing CONSULT): a cross-sectional survey. BMC Med Educ. 2021 Jul. doi: 10.1186/s12909-021-02810-9.

5. Welp A, Manser T. Integrating teamwork, clinician occupational well-being and patient safety - development of a conceptual framework based on a systematic review. BMC Health Serv Res. 2016 Jul. doi: 10.1186/s12913-016-1535-y.

6. Webster CS, et al. Interprofessional Learning in Multidisciplinary Healthcare Teams Is Associated With Reduced Patient Mortality: A Quantitative Systematic Review and Meta-analysis. J Patient Saf. 2024 Jan. doi: 10.1097/PTS.0000000000001170.

7. Lin M, et al. Curbside Consultations: The Good, the Bad, and the Ugly. Clin Gastroenterol Hepatol. 2016 Jan. doi: 10.1016/j.cgh.2015.09.026.

Gastroenterology (GI) subspecialty training is carefully designed to develop expertise in digestive diseases and gastrointestinal endoscopy, while facilitating the transition from generalist to subspecialty consultant. The concept of effective consultation extends far beyond clinical expertise and has been explored repeatedly, beginning with Goldman’s “Ten Commandments” in 1983.^1,2 How should these best practices be specifically applied to GI? More importantly, what kind of experience would you want if you were the referring provider or the patient themselves?

Below are five essential tips to guide your development as a high-impact GI consultant with a reputation for excellence. 
 

1. Be Kind

Survey studies of medical/surgical residents and attending hospitalists have demonstrated that willingness to accept consultation requests was the single factor consistently rated as most important in determining the quality of the consultation interaction.^3,4 Unfortunately, nearly 65% of respondents reported encountering pushback when requesting subspecialty consultation. It is critical to recognize that when you receive a GI consult request, the requester has already decided that it is needed. Whether that request comports with our individual notion of “necessary” or “important,” this is a colleague’s request for help. There are myriad reasons why a request may be made, but they are unified in this principle.

Effective teamwork in healthcare settings enhances clinical performance and patient safety. Positive relationships with colleagues and healthcare team members also mitigate the emotional basis for physician burnout.⁵ Be kind and courteous to those who seek your assistance. Move beyond the notion of the “bad” or “soft” consult and seek instead to understand how you can help.

A requesting physician may phrase the consult question vaguely or may know that the patient is having a GI-related issue, but simply lack the specific knowledge to know what is needed. In these instances, it is our role to listen and help guide them to the correct thought process to ensure the best care of the patient. These important interactions establish our reputation, create our referral bases, and directly affect our sense of personal satisfaction.

 

2. Be Timely

GI presents an appealing breadth of pathology, but this also corresponds to a wide variety of indications for consultation and, therefore, urgency of need. In a busy clinical practice, not all requests can be urgently prioritized. However, it is the consultant’s responsibility to identify patients that require urgent evaluation and intervention to avert a potential adverse outcome.

We are well-trained in the medical triage of consultations. There are explicit guidelines for assessing urgency for GI bleeding, foreign body ingestion, choledocholithiasis, and many other indications. However, there are often special contextual circumstances that will elevate the urgency of a seemingly non-urgent consult request. Does the patient have an upcoming surgery or treatment that will depend on your input? Are they facing an imminent loss of insurance coverage? Is their non-severe GI disease leading to more severe impact on non-GI organ systems? The referring provider knows the patient better than you – seek to understand the context of the consult request.
 

Timeliness also applies to our communication. Communicate recommendations directly to the consulting service as soon as the patient is seen. When a colleague reaches out with a concern about a patient, make sure to take that request seriously. If you are unable to address the concern immediately, at least provide acknowledgment and an estimated timeline for response. As the maxim states, the effectiveness of a consultant is just as dependent on availability as it is on ability.

 

3. Be Specific

The same survey studies indicate that the second most critical aspect of successful subspecialty consultation is delivering clear recommendations. Accordingly, I always urge my trainees to challenge me when we leave a consult interaction if they feel that our plan is vague or imprecise.

Specificity in consult recommendations is an essential way to demonstrate your expertise and provide value. Clear and definitive recommendations enhance others’ perception of your skill, reduce the need for additional clarifying communication, and lead to more efficient, higher quality care. Avoid vague language, such as asking the requester to “consider” a test or intervention. When recommending medication, specify the dose, frequency, duration, and expected timeline of effect. Rather than recommending “cross-sectional imaging,” specify what modality and protocol. Instead of recommending “adequate resuscitation,” specify your target endpoints. If you engage in multidisciplinary discussion, ensure you strive for a specific group consensus plan and communicate this to all members of the team.

Specificity also applies to the quality of your documentation. Ensure that your clinical notes outline your rationale for your recommended plan, specific contingencies based on results of recommended testing, and a plan for follow-up care. When referring for open-access endoscopy, specifically outline what to look for and which specimens or endoscopic interventions are needed. Be precise in your procedure documentation – avoid vague terms such as small/medium/large and instead quantify in terms of millimeter/centimeter measurement. If you do not adopt specific classification schemes (e.g. Prague classification, Paris classification, Eosinophilic Esophagitis Endoscopic Reference Score, etc.), ensure you provide enough descriptive language to convey an adequate understanding of the findings.

 

4. Be Helpful

A consultant’s primary directive is to be of service to the consulting provider and the patient. As an educational leader, I am often asked what attributes separate a high-performing trainee from an average one. My feeling is that the most critical attribute is a sense of ownership over patient care.

As a consultant, when others feel we are exhibiting engagement and ownership in a patient’s care, they perceive that we are working together as an effective healthcare team. Interestingly, survey studies of inpatient care show that primary services do not necessarily value assistance with orders or care coordination – they consider these as core aspects of their daily work. What they did value was ongoing daily progress notes/communication, regardless of patient acuity or consulting specialty. This is a potent signal that our continued engagement (both inpatient and outpatient) is perceived as helpful.

Helpfulness is further aided by ensuring mutual understanding. While survey data indicate that sharing specific literature citations may not always be perceived positively, explaining the consultant’s rationale for their recommendations is highly valued. Take the time to tactfully explain your assessment of the patient and why you arrived at your specific recommendations. If your recommendations differ from what the requester expected (e.g. a procedure was expected but is not offered), ensure you explain why and answer questions they may have. This fosters mutual respect and proactively averts conflict or discontent from misunderstanding.

Multidisciplinary collaboration is another important avenue for aiding our patients and colleagues. Studies across a wide range of disease processes (including GI bleeding, IBD, etc.) and medical settings have demonstrated that multidisciplinary collaboration unequivocally improves patient outcomes.⁶ The success of these collaborations relies on our willingness to fully engage in these conversations, despite the fact that they may often be logistically challenging. 

We all know how difficult it can be to locate and organize multiple medical specialists with complex varying clinical schedules and busy personal lives. Choosing to do so demonstrates a dedication to providing the highest level of care and elevates both patient and physician satisfaction. Having chosen to cultivate several ongoing multidisciplinary conferences/collaborations, I can attest to the notion that the outcome is well worth the effort.

 

5. Be Honest

While we always strive to provide the answers for our patients and colleagues, we must also acknowledge our limitations. Be honest with yourself when you encounter a scenario that pushes beyond the boundaries of your knowledge and comfort. Be willing to admit when you yourself need to consult others or seek an outside referral to provide the care a patient needs. Aspiring physicians often espouse that a devotion to lifelong learning is a key driver of their desire to pursue a career in medicine. These scenarios provide a key opportunity to expand our knowledge while doing what is right for our patients.

Be equally honest about your comfort with “curbside” consultations. Studies show that subspecialists receive on average of 3-4 such requests per week.⁷ The perception of these interactions is starkly discrepant between the requester and recipient. While over 80% of surveyed primary nonsurgical services felt that curbside consultations were helpful in patient care, a similar proportion of subspecialists expressed concern that insufficient clinical information was provided, even leading to a fear of litigation. While straightforward, informal conversations on narrow, well-defined questions can be helpful and efficient, the consultant should always feel comfortable seeking an opportunity for formal consultation when the details are unclear or the case/question is complex.

 

Closing Thoughts

Being an effective GI consultant isn’t just about what you know—it’s about how you apply it, how you communicate it, and how you make others feel in the process.

The attributes outlined above are not ancillary traits—they are essential components of high-quality consultation. When consistently applied, they enhance collaboration, improve patient outcomes, and reinforce trust within the healthcare system. By committing to them, you establish your reputation of excellence and play a role in elevating the field of gastroenterology more broadly.

Dr. Kahn is based in the Division of Gastroenterology and Hepatology at Mayo Clinic, Scottsdale, Arizona. He reports no conflicts of interest in regard to this article.

References

1. Goldman L, et al. Ten commandments for effective consultations. Arch Intern Med. 1983 Sep.

2. Salerno SM, et al. Principles of effective consultation: an update for the 21st-century consultant. Arch Intern Med. 2007 Feb. doi: 10.1001/archinte.167.3.271.

3. Adams TN, et al. Hospitalist Perspective of Interactions with Medicine Subspecialty Consult Services. J Hosp Med. 2018 May. doi: 10.12788/jhm.2882.

4. Matsuo T, et al. Essential consultants’ skills and attitudes (Willing CONSULT): a cross-sectional survey. BMC Med Educ. 2021 Jul. doi: 10.1186/s12909-021-02810-9.

5. Welp A, Manser T. Integrating teamwork, clinician occupational well-being and patient safety - development of a conceptual framework based on a systematic review. BMC Health Serv Res. 2016 Jul. doi: 10.1186/s12913-016-1535-y.

6. Webster CS, et al. Interprofessional Learning in Multidisciplinary Healthcare Teams Is Associated With Reduced Patient Mortality: A Quantitative Systematic Review and Meta-analysis. J Patient Saf. 2024 Jan. doi: 10.1097/PTS.0000000000001170.

7. Lin M, et al. Curbside Consultations: The Good, the Bad, and the Ugly. Clin Gastroenterol Hepatol. 2016 Jan. doi: 10.1016/j.cgh.2015.09.026.

Gastroenterology (GI) subspecialty training is carefully designed to develop expertise in digestive diseases and gastrointestinal endoscopy, while facilitating the transition from generalist to subspecialty consultant. The concept of effective consultation extends far beyond clinical expertise and has been explored repeatedly, beginning with Goldman’s “Ten Commandments” in 1983.^1,2 How should these best practices be specifically applied to GI? More importantly, what kind of experience would you want if you were the referring provider or the patient themselves?

Below are five essential tips to guide your development as a high-impact GI consultant with a reputation for excellence. 
 

1. Be Kind

Survey studies of medical/surgical residents and attending hospitalists have demonstrated that willingness to accept consultation requests was the single factor consistently rated as most important in determining the quality of the consultation interaction.^3,4 Unfortunately, nearly 65% of respondents reported encountering pushback when requesting subspecialty consultation. It is critical to recognize that when you receive a GI consult request, the requester has already decided that it is needed. Whether that request comports with our individual notion of “necessary” or “important,” this is a colleague’s request for help. There are myriad reasons why a request may be made, but they are unified in this principle.

Effective teamwork in healthcare settings enhances clinical performance and patient safety. Positive relationships with colleagues and healthcare team members also mitigate the emotional basis for physician burnout.⁵ Be kind and courteous to those who seek your assistance. Move beyond the notion of the “bad” or “soft” consult and seek instead to understand how you can help.

A requesting physician may phrase the consult question vaguely or may know that the patient is having a GI-related issue, but simply lack the specific knowledge to know what is needed. In these instances, it is our role to listen and help guide them to the correct thought process to ensure the best care of the patient. These important interactions establish our reputation, create our referral bases, and directly affect our sense of personal satisfaction.

 

2. Be Timely

GI presents an appealing breadth of pathology, but this also corresponds to a wide variety of indications for consultation and, therefore, urgency of need. In a busy clinical practice, not all requests can be urgently prioritized. However, it is the consultant’s responsibility to identify patients that require urgent evaluation and intervention to avert a potential adverse outcome.

We are well-trained in the medical triage of consultations. There are explicit guidelines for assessing urgency for GI bleeding, foreign body ingestion, choledocholithiasis, and many other indications. However, there are often special contextual circumstances that will elevate the urgency of a seemingly non-urgent consult request. Does the patient have an upcoming surgery or treatment that will depend on your input? Are they facing an imminent loss of insurance coverage? Is their non-severe GI disease leading to more severe impact on non-GI organ systems? The referring provider knows the patient better than you – seek to understand the context of the consult request.
 

Timeliness also applies to our communication. Communicate recommendations directly to the consulting service as soon as the patient is seen. When a colleague reaches out with a concern about a patient, make sure to take that request seriously. If you are unable to address the concern immediately, at least provide acknowledgment and an estimated timeline for response. As the maxim states, the effectiveness of a consultant is just as dependent on availability as it is on ability.

 

3. Be Specific

The same survey studies indicate that the second most critical aspect of successful subspecialty consultation is delivering clear recommendations. Accordingly, I always urge my trainees to challenge me when we leave a consult interaction if they feel that our plan is vague or imprecise.

Specificity in consult recommendations is an essential way to demonstrate your expertise and provide value. Clear and definitive recommendations enhance others’ perception of your skill, reduce the need for additional clarifying communication, and lead to more efficient, higher quality care. Avoid vague language, such as asking the requester to “consider” a test or intervention. When recommending medication, specify the dose, frequency, duration, and expected timeline of effect. Rather than recommending “cross-sectional imaging,” specify what modality and protocol. Instead of recommending “adequate resuscitation,” specify your target endpoints. If you engage in multidisciplinary discussion, ensure you strive for a specific group consensus plan and communicate this to all members of the team.

Specificity also applies to the quality of your documentation. Ensure that your clinical notes outline your rationale for your recommended plan, specific contingencies based on results of recommended testing, and a plan for follow-up care. When referring for open-access endoscopy, specifically outline what to look for and which specimens or endoscopic interventions are needed. Be precise in your procedure documentation – avoid vague terms such as small/medium/large and instead quantify in terms of millimeter/centimeter measurement. If you do not adopt specific classification schemes (e.g. Prague classification, Paris classification, Eosinophilic Esophagitis Endoscopic Reference Score, etc.), ensure you provide enough descriptive language to convey an adequate understanding of the findings.

 

4. Be Helpful

A consultant’s primary directive is to be of service to the consulting provider and the patient. As an educational leader, I am often asked what attributes separate a high-performing trainee from an average one. My feeling is that the most critical attribute is a sense of ownership over patient care.

As a consultant, when others feel we are exhibiting engagement and ownership in a patient’s care, they perceive that we are working together as an effective healthcare team. Interestingly, survey studies of inpatient care show that primary services do not necessarily value assistance with orders or care coordination – they consider these as core aspects of their daily work. What they did value was ongoing daily progress notes/communication, regardless of patient acuity or consulting specialty. This is a potent signal that our continued engagement (both inpatient and outpatient) is perceived as helpful.

Helpfulness is further aided by ensuring mutual understanding. While survey data indicate that sharing specific literature citations may not always be perceived positively, explaining the consultant’s rationale for their recommendations is highly valued. Take the time to tactfully explain your assessment of the patient and why you arrived at your specific recommendations. If your recommendations differ from what the requester expected (e.g. a procedure was expected but is not offered), ensure you explain why and answer questions they may have. This fosters mutual respect and proactively averts conflict or discontent from misunderstanding.

Multidisciplinary collaboration is another important avenue for aiding our patients and colleagues. Studies across a wide range of disease processes (including GI bleeding, IBD, etc.) and medical settings have demonstrated that multidisciplinary collaboration unequivocally improves patient outcomes.⁶ The success of these collaborations relies on our willingness to fully engage in these conversations, despite the fact that they may often be logistically challenging. 

We all know how difficult it can be to locate and organize multiple medical specialists with complex varying clinical schedules and busy personal lives. Choosing to do so demonstrates a dedication to providing the highest level of care and elevates both patient and physician satisfaction. Having chosen to cultivate several ongoing multidisciplinary conferences/collaborations, I can attest to the notion that the outcome is well worth the effort.

 

5. Be Honest

While we always strive to provide the answers for our patients and colleagues, we must also acknowledge our limitations. Be honest with yourself when you encounter a scenario that pushes beyond the boundaries of your knowledge and comfort. Be willing to admit when you yourself need to consult others or seek an outside referral to provide the care a patient needs. Aspiring physicians often espouse that a devotion to lifelong learning is a key driver of their desire to pursue a career in medicine. These scenarios provide a key opportunity to expand our knowledge while doing what is right for our patients.

Be equally honest about your comfort with “curbside” consultations. Studies show that subspecialists receive on average of 3-4 such requests per week.⁷ The perception of these interactions is starkly discrepant between the requester and recipient. While over 80% of surveyed primary nonsurgical services felt that curbside consultations were helpful in patient care, a similar proportion of subspecialists expressed concern that insufficient clinical information was provided, even leading to a fear of litigation. While straightforward, informal conversations on narrow, well-defined questions can be helpful and efficient, the consultant should always feel comfortable seeking an opportunity for formal consultation when the details are unclear or the case/question is complex.

 

Closing Thoughts

Being an effective GI consultant isn’t just about what you know—it’s about how you apply it, how you communicate it, and how you make others feel in the process.

The attributes outlined above are not ancillary traits—they are essential components of high-quality consultation. When consistently applied, they enhance collaboration, improve patient outcomes, and reinforce trust within the healthcare system. By committing to them, you establish your reputation of excellence and play a role in elevating the field of gastroenterology more broadly.

Dr. Kahn is based in the Division of Gastroenterology and Hepatology at Mayo Clinic, Scottsdale, Arizona. He reports no conflicts of interest in regard to this article.

References

1. Goldman L, et al. Ten commandments for effective consultations. Arch Intern Med. 1983 Sep.

2. Salerno SM, et al. Principles of effective consultation: an update for the 21st-century consultant. Arch Intern Med. 2007 Feb. doi: 10.1001/archinte.167.3.271.

3. Adams TN, et al. Hospitalist Perspective of Interactions with Medicine Subspecialty Consult Services. J Hosp Med. 2018 May. doi: 10.12788/jhm.2882.

4. Matsuo T, et al. Essential consultants’ skills and attitudes (Willing CONSULT): a cross-sectional survey. BMC Med Educ. 2021 Jul. doi: 10.1186/s12909-021-02810-9.

5. Welp A, Manser T. Integrating teamwork, clinician occupational well-being and patient safety - development of a conceptual framework based on a systematic review. BMC Health Serv Res. 2016 Jul. doi: 10.1186/s12913-016-1535-y.

6. Webster CS, et al. Interprofessional Learning in Multidisciplinary Healthcare Teams Is Associated With Reduced Patient Mortality: A Quantitative Systematic Review and Meta-analysis. J Patient Saf. 2024 Jan. doi: 10.1097/PTS.0000000000001170.

7. Lin M, et al. Curbside Consultations: The Good, the Bad, and the Ugly. Clin Gastroenterol Hepatol. 2016 Jan. doi: 10.1016/j.cgh.2015.09.026.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Cancer patients experience depression at rates > 5 times that of the general population.^1-11 Despite an increase in palliative care use, depression rates continued to rise.^2-4 Between 5% to 16% of outpatients, 4% to 14% of inpatients, and up to 49% of patients receiving palliative care experience depression.⁵ This issue also impacts families and caregivers.¹ A 2021 meta-analysis found that 23% of active military personnel and 20% of veterans experience depression.¹¹

Antidepressants approved by the US Food and Drug Administration (FDA) target the serotonin, norepinephrine, or dopamine systems and include boxed warnings about an increased risk of suicidal thoughts in adults aged 18 to 24 years.^12,13 These medications are categorized into several classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor modulators (SRMs), serotonin-melatonin receptor antagonists (SMRAs), and N—methyl-D-aspartate receptor antagonists (NMDARAs).^14,15 The first FDA-approved antidepressants, iproniazid (an MAOI) and imipramine (a TCA) laid the foundation for the development of newer classes like SSRIs and SNRIs.^15-17

Older antidepressants such as MAOIs and TCAs are used less due to their adverse effects (AEs) and drug interactions. MAOIs, such as iproniazid, selegiline, moclobemide, tranylcypromine, isocarboxazid, and phenelzine, have numerous AEs and drug interactions, making them unsuitable for first- or second-line treatment of depression.^14,18-21 TCAs such as doxepin, amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, maprotiline, and amoxapine have a narrow therapeutic index requiring careful monitoring for signs of toxicity such as QRS widening, tremors, or confusion. Despite the issues, TCAs are generally classified as second-line agents for major depressive disorder (MDD). TCAs have off-label uses for migraine prophylaxis, treatment of obsessive-compulsive disorder (OCD), insomnia, and chronic pain management first-line.^14,22-29

Newer antidepressants, including TeCAs and NDRIs, are typically more effective, but also come with safety concerns. TeCAs like mirtazapine interact with several medications, including MAOIs, serotonin-increasing drugs, alcohol, cannabidiol, and marijuana. Mirtazapine is FDA-approved for the treatment of moderate to severe depression in adults. It is also used off-label to treat insomnia, panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), headaches, and migraines. Compared to other antidepressants, mirtazapine is effective for all stages of depression and addresses a broad range of related symptoms.^14,30-34 NDRIs, such as bupropion, also interact with various medications, including MAOIs, other antidepressants, stimulants, and alcohol. Bupropion is FDA-approved for smoking cessation and to treat depression and SAD. It is also used off-label for depression- related bipolar disorder or sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), and obesity.^14,35-42

SSRIs, SNRIs, and SRMs should be used with caution. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, paroxetine, and fluvoxamine are first-line treatments for depression and various psychiatric disorders due to their safety and efficacy. Common AEs of SSRIs include sexual dysfunction, sleep disturbances, weight changes, and gastrointestinal (GI) issues. SSRIs can prolong the QT interval, posing a risk of life-threatening arrhythmia, and may interact with other medications, necessitating treatment adjustments. The FDA approved SSRIs for MDD, GAD, bulimia nervosa, bipolar depression, OCD, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, PTSD, and SAD. Off-label uses include binge eating disorder, body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause. Among SSRIs, sertraline and escitalopram are noted for their effectiveness and tolerability.^14,43-53

SNRIs, including duloxetine, venlafaxine, desvenlafaxine, milnacipran, and levomilnacipran, may increase bleeding risk, especially when taken with blood thinners. They can also elevate blood pressure, which may worsen if combined with stimulants. SNRIs may interact with other medications that affect serotonin levels, increasing the risk of serotonin syndrome when taken with triptans, pain medications, or other antidepressants.¹⁴ Desvenlafaxine has been approved by the FDA (but not by the European Medicines Agency).^54-56 Duloxetine is FDA-approved for the treatment of depression, neuropathic pain, anxiety disorders, fibromyalgia, and musculoskeletal disorders. It is used off-label to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence.^57-61 Venlafaxine is FDA-approved for depression, SAD, and panic disorder, and is prescribed off-label to treat ADHD, neuropathy, fibromyalgia, cataplexy, and PTSD, either alone or in combination with other medications.^62,63 Milnacipran is not approved for MDD; levomilnacipran received approval in 2013.⁶⁴

SRMs such as trazodone, nefazodone, vilazodone, and vortioxetine also function as serotonin reuptake inhibitors.^14,15 Trazodone is FDA-approved for MDD. It has been used off-label to treat anxiety, Alzheimer disease, substance misuse, bulimia nervosa, insomnia, fibromyalgia, and PTSD when first-line SSRIs are ineffective. A notable AE of trazodone is orthostatic hypotension, which can lead to dizziness and increase the risk of falls, especially in geriatric patients.^65-70 Nefazodone was discontinued in Europe in 2003 due to rare cases of liver toxicity but remains available in the US.^71-74 Vilazodone and vortioxetine are FDA-approved.

The latest classes of antidepressants include SMRAs and NMDARAs.¹⁴ Agomelatine, an SMRA, was approved in Europe in 2009 but rejected by the FDA in 2011 due to liver toxicity.⁷⁵ NMDARAs like esketamine and a combination of dextromethorphan and bupropion received FDA approval in 2019 and 2022, respectively.^76,77

This retrospective study analyzes noncancer drugs used during systemic chemotherapy based on a dataset of 14 antineoplastic agents. It sought to identify the most dispensed noncancer drug groups, discuss findings, compare patients with and without antidepressant prescriptions, and examine trends in antidepressant use from 2002 to 2023. This analysis expands on prior research.^78-81

Methods

The Walter Reed National Military Medical Center Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and Military Health System (MHS) data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Data Sources

The JPC DoD Cancer Registry Program contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in CAPER represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2024. PDTS records are available from 2002 to 2004. Each observation in PDTS represents a prescription filled for an MHS beneficiary, excluding those filled at international civilian pharmacies and inpatient pharmacy prescriptions.

This cross-sectional analysis requested data extraction for specific cancer drugs from the DoD Cancer Registry, focusing on treatment details, diagnosis dates, patient demographics, and physicians’ comments on AEs. After identifying patients, CAPER was used to identify additional health conditions. PDTS was used to compile a list of prescription medications filled during systemic cancer treatment or < 2 years postdiagnosis.

The 2016 Surveillance, Epidemiology, and End Results Program Coding and Staging Manual and International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^82,83 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the subgroup divided by the total number of patients or data variables. To compare the mean number of dispensed antidepressants to those without antidepressants, a 2-tailed, 2-sample z test was used to calculate the P value and determine statistical significance (P < .05) using socscistatistics.com.

Data were extracted 3 times between 2021 and 2023. The initial 2021 protocol focused on erlotinib and gefitinib. A modified protocol in 2022 added paclitaxel, cisplatin, docetaxel, pemetrexed, and crizotinib; further modification in 2023 included 8 new antineoplastic agents and 2 anticoagulants. Sotorasib has not been prescribed in the MHS, and JPC lacks records for noncancer drugs. The 2023 dataset comprised 2210 patients with cancer treated with 14 antineoplastic agents; 2104 had documented diagnoses and 2113 had recorded prescriptions. Data for erlotinib, gefitinib, and paclitaxel have been published previously.^78,79

Results

Of 2113 patients with recorded prescriptions, 1297 patients (61.4%) received 109 cancer drugs, including 96 antineoplastics, 7 disease-modifying antirheumatic agents, 4 biologic response modifiers, and 2 calcitonin gene-related peptides. Fourteen antineoplastic agents had complete data from JPC, while others were noted for combination therapies or treatment switches from the PDTS (Table 1). Seventy-six cancer drugs were prescribed with antidepressants in 489 patients (eAppendix).

The JPC provided 2242 entries for 2210 patients, ranging in age from 2 months to 88 years (mean, 56 years), documenting treatment from September 1988 to January 2023. Thirty-two patients had duplicate entries due to multiple cancer locations or occurrences. Of the 2242 patients, 1541 (68.7%) were aged > 50 years, 975 patients (43.5%) had cancers that were stage III or IV, and 1267 (56.5%) had cancers that were stage 0, I, II, or not applicable/unknown. There were 51 different types of cancer: breast, lung, testicular, endometrial, and ovarian were most common (n ≥ 100 patients). Forty-two cancer types were documented among 750 patients prescribed antidepressants (Table 2).

The CAPER database recorded 8882 unique diagnoses for 2104 patients, while PDTS noted 1089 unique prescriptions within 273 therapeutic codes for 2113 patients. Nine therapeutic codes (opiate agonists, adrenals, cathartics-laxatives, nonsteroidal anti-inflammatory agents, antihistamines for GI conditions, 5-HT3 receptor antagonists, analgesics and antipyretic miscellanea, antineoplastic agents, and proton-pump inhibitors) and 8 drugs (dexamethasone, prochlorperazine, ondansetron, docusate, acetaminophen, ibuprofen, oxycodone, and polyethylene glycol 3350) were associated with > 1000 patients (≥ 50%). Patients had between 1 and 275 unique health conditions and filled 1 to 108 prescriptions. The mean (SD) number of diagnoses and prescriptions was 50 (28) and 29 (12), respectively. Of the 273 therapeutic codes, 30 groups were analyzed, with others categorized into miscellaneous groups such as lotions, vaccines, and devices. Significant differences in mean number of prescriptions were found for patients taking antidepressants compared to those not (P < .05), except for anticonvulsants and antipsychotics (P = .12 and .09, respectively) (Table 3).

Antidepressants

Of the 2113 patients with recorded prescriptions, 750 (35.5%) were dispensed 17 different antidepressants. Among these 17 antidepressants, 183 (8.7%) patients received duloxetine, 158 (7.5%) received venlafaxine, 118 (5.6%) received trazodone, and 107 (5.1%) received sertraline (Figure 1, Table 4). Of the 750 patients, 509 (67.9%) received 1 antidepressant, 168 (22.4%) received 2, 60 (8.0%) received 3, and 13 (1.7%) received > 3. Combinations varied, but only duloxetine and trazodone were prescribed to > 10 patients.

Antidepressants were prescribed annually at an overall mean (SD) rate of 23% (5%) from 2003 to 2022 (Figure 2). Patients on antidepressants during systemic therapy had a greater number of diagnosed medical conditions and received more prescription medications compared to those not taking antidepressants (P < .001) (Figure 3). The 745 patients taking antidepressants in CAPER data had between 1 and 275 diagnosed medical issues, with a mean (SD) of 55 (31) vs a range of 1 to 209 and a mean (SD) of 46 (26) for the 1359 patients not taking antidepressants. The 750 patients on antidepressants in PDTS data had between 8 and 108 prescriptions dispensed, with a mean (SD) of 32 (12), vs a range of 1 to 65 prescriptions and a mean (SD) of 29 (12) for 1363 patients not taking antidepressants.

Discussion

The JPC DoD Cancer Registry includes information on cancer types, stages, treatment regimens, and physicians’ notes, while noncancer drugs are sourced from the PDTS database. The pharmacy uses a different documentation system, leading to varied classifications.

Database reliance has its drawbacks. For example, megestrol is coded as a cancer drug, although it’s primarily used for endometrial or gynecologic cancers. Many drugs have multiple therapeutic codes assigned to them, including 10 antineoplastic agents: diclofenac, Bacillus Calmette-Guérin (BCG), megestrol acetate, tamoxifen, anastrozole, letrozole, leuprolide, goserelin, degarelix, and fluorouracil. Diclofenac, BCG, and mitomycin have been repurposed for cancer treatment.^84-87 From 2003 to 2023, diclofenac was prescribed to 350 patients for mild-to-moderate pain, with only 2 patients receiving it for cancer in 2018. FDA-approved for bladder cancer in 1990, BCG was prescribed for cancer treatment for 1 patient in 2021 after being used for vaccines between 2003 and 2018. Tamoxifen, used for hormone receptor-positive breast cancer from 2004 to 2017 with 53 patients, switched to estrogen agonist-antagonists from 2017 to 2023 with 123 patients. Only a few of the 168 patients were prescribed tamoxifen using both codes.^88-91 Anastrozole and letrozole were coded as antiestrogens for 7 and 18 patients, respectively, while leuprolide and goserelin were coded as gonadotropins for 59 and 18 patients. Degarelix was coded as antigonadotropins, fluorouracil as skin and mucous membrane agents miscellaneous, and megestrol acetate as progestins for 7, 6, and 3 patients, respectively. Duloxetine was given to 186 patients, primarily for depression from 2005 to 2023, with 7 patients treated for fibromyalgia from 2022 to 2023.

Antidepressants Observed

Tables 1 and 5 provide insight into the FDA approval of 14 antineoplastics and antidepressants and their CYP metabolic pathways.^92-122 In Table 4, the most prescribed antidepressant classes are SNRIs, SRMs, SSRIs, TeCAs, NDRIs, and TCAs. This trend highlights a preference for newer medications with weak CYP inhibition. A total of 349 patients were prescribed SSRIs, 343 SNRIs, 119 SRMs, 109 TCAs, 83 TeCAs, and 79 NDRIs. MAOIs, SMRAs, and NMDARAs were not observed in this dataset. While there are instances of dextromethorphan-bupropion and sertraline-escitalopram being dispensed together, it remains unclear whether these were NMDARA combinations.

Among the 14 specific antineoplastic agents, 10 are metabolized by CYP isoenzymes, primarily CYP3A4. Duloxetine neither inhibits nor is metabolized by CYP3A4, a reason it is often recommended, following venlafaxine.

Both duloxetine and venlafaxine are used off-label for chemotherapy-induced peripheral neuropathy related to paclitaxel and docetaxel. According to the CYP metabolized pathway, duloxetine tends to have more favorable DDIs than venlafaxine. In PDTS data, 371 patients were treated with paclitaxel and 180 with docetaxel, with respective antidepressant prescriptions of 156 and 70. Of the 156 patients dispensed paclitaxel, 62 (40%) were dispensed with duloxetine compared to 43 (28%) with venlafaxine. Of the 70 patients dispensed docetaxel, 23 (33%) received duloxetine vs 24 (34%) with venlafaxine.

Of 85 patients prescribed duloxetine, 75 received it with either paclitaxel or docetaxel (5 received both). Five patients had documented AEs (1 neuropathy related). Of 67 patients prescribed venlafaxine, 66 received it with either paclitaxel or docetaxel. Two patients had documented AEs (1 was neuropathy related, the same patient who received duloxetine). Of the 687 patients treated with paclitaxel and 337 with docetaxel in all databases, 4 experienced neuropathic AEs from both medications.⁷⁹

Antidepressants can increase the risk of bleeding, especially when combined with blood thinners, and may elevate blood pressure, particularly alongside stimulants. Of the 554 patients prescribed 9 different anticoagulants, enoxaparin, apixaban, and rivaroxaban were the most common (each > 100 patients). Among these, 201 patients (36%) received both anticoagulants and antidepressants: duloxetine for 64 patients, venlafaxine for 30, trazodone for 35, and sertraline for 26. There were no data available to assess bleeding rates related to the evaluation of DDIs between these medication classes.

Antidepressants can be prescribed for erectile dysfunction. Of the 148 patients prescribed an antidepressant for erectile dysfunction, duloxetine, trazodone, and mirtazapine were the most common. Antidepressant preferences varied by cancer type. Duloxetine was the only antidepressant used for all types of cancer. Venlafaxine, duloxetine, trazodone, sertraline, and escitalopram were the most prescribed antidepressants for breast cancer, while duloxetine, mirtazapine, citalopram, sertraline, and trazodone were the most prescribed for lung cancer. Sertraline, duloxetine, trazodone, amitriptyline, and escitalopram were most common for testicular cancer. Duloxetine, venlafaxine, trazodone, amitriptyline, and sertraline were the most prescribed for endometrial cancer, while duloxetine, venlafaxine, amitriptyline, citalopram, and sertraline were most prescribed for ovarian cancer.

The broadness of International Statistical Classification of Diseases, Tenth Revision codes made it challenging to identify nondepression diagnoses in the analyzed population. However, if all antidepressants were prescribed to treat depression, service members with cancer exhibited a higher depression rate (35%) than the general population (25%). Of 2104 patients, 191 (9.1%) had mood disorders, and 706 (33.6%) had mental disorders: 346 (49.0%) had 1 diagnosis, and 360 (51.0%) had multiple diagnoses. The percentage of diagnoses varied yearly, with notable drops in 2003, 2007, 2011, 2014, and 2018, and peaks in 2006, 2008, 2013, 2017, and 2022. This fluctuation was influenced by events like the establishment of PDTS in 2002, the 2008 economic recession, a hospital relocation in 2011, the 2014 Ebola outbreak, and the COVID-19 pandemic. Although the number of patients receiving antidepressants increased from 2019 to 2022, the overall percentage of patients receiving them did not significantly change from 2003 to 2022, aligning with previous research.^5,125

Many medications have potential uses beyond what is detailed in the prescribing information. Antidepressants can relieve pain, while pain medications may help with depression. Opioids were once thought to effectively treat depression, but this perspective has changed with a greater understanding of their risks, including misuse.^126-131 Pain is a severe and often unbearable AE of cancer. Of 2113 patients, 92% received opioids; 34% received both opioids and antidepressants; 2% received only antidepressants; and 7% received neither. This study didn’t clarify whether those on opioids alone recognized their depression or if those on both were aware of their dependence. While SSRIs are generally not addictive, they can lead to physical dependence, and any medication can be abused if not managed properly.^132-134

Conclusions

This retrospective study analyzes data from antineoplastic agents used in systemic cancer treatment between 1988 and 2023, with a particular focus on the use of antidepressants. Data on antidepressant prescriptions are incomplete and specific to these agents, which means the findings cannot be generalized to all antidepressants. Hence, the results indicate that patients taking antidepressants had more diagnosed health issues and received more medications compared to patients who were not on these drugs.

This study underscores the need for further research into the effects of antidepressants on cancer treatment, utilizing all data from the DoD Cancer Registry. Future research should explore DDIs between antidepressants and other cancer and noncancer medications, as this study did not assess AE documentation, unlike in studies involving erlotinib, gefitinib, and paclitaxel.^78,79 Further investigation is needed to evaluate the impact of discontinuing antidepressant use during cancer treatment. This comprehensive overview provides insights for clinicians to help them make informed decisions regarding the prescription of antidepressants in the context of cancer treatment.

Cancer patients experience depression at rates > 5 times that of the general population.^1-11 Despite an increase in palliative care use, depression rates continued to rise.^2-4 Between 5% to 16% of outpatients, 4% to 14% of inpatients, and up to 49% of patients receiving palliative care experience depression.⁵ This issue also impacts families and caregivers.¹ A 2021 meta-analysis found that 23% of active military personnel and 20% of veterans experience depression.¹¹

Antidepressants approved by the US Food and Drug Administration (FDA) target the serotonin, norepinephrine, or dopamine systems and include boxed warnings about an increased risk of suicidal thoughts in adults aged 18 to 24 years.^12,13 These medications are categorized into several classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor modulators (SRMs), serotonin-melatonin receptor antagonists (SMRAs), and N—methyl-D-aspartate receptor antagonists (NMDARAs).^14,15 The first FDA-approved antidepressants, iproniazid (an MAOI) and imipramine (a TCA) laid the foundation for the development of newer classes like SSRIs and SNRIs.^15-17

Older antidepressants such as MAOIs and TCAs are used less due to their adverse effects (AEs) and drug interactions. MAOIs, such as iproniazid, selegiline, moclobemide, tranylcypromine, isocarboxazid, and phenelzine, have numerous AEs and drug interactions, making them unsuitable for first- or second-line treatment of depression.^14,18-21 TCAs such as doxepin, amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, maprotiline, and amoxapine have a narrow therapeutic index requiring careful monitoring for signs of toxicity such as QRS widening, tremors, or confusion. Despite the issues, TCAs are generally classified as second-line agents for major depressive disorder (MDD). TCAs have off-label uses for migraine prophylaxis, treatment of obsessive-compulsive disorder (OCD), insomnia, and chronic pain management first-line.^14,22-29

Newer antidepressants, including TeCAs and NDRIs, are typically more effective, but also come with safety concerns. TeCAs like mirtazapine interact with several medications, including MAOIs, serotonin-increasing drugs, alcohol, cannabidiol, and marijuana. Mirtazapine is FDA-approved for the treatment of moderate to severe depression in adults. It is also used off-label to treat insomnia, panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), headaches, and migraines. Compared to other antidepressants, mirtazapine is effective for all stages of depression and addresses a broad range of related symptoms.^14,30-34 NDRIs, such as bupropion, also interact with various medications, including MAOIs, other antidepressants, stimulants, and alcohol. Bupropion is FDA-approved for smoking cessation and to treat depression and SAD. It is also used off-label for depression- related bipolar disorder or sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), and obesity.^14,35-42

SSRIs, SNRIs, and SRMs should be used with caution. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, paroxetine, and fluvoxamine are first-line treatments for depression and various psychiatric disorders due to their safety and efficacy. Common AEs of SSRIs include sexual dysfunction, sleep disturbances, weight changes, and gastrointestinal (GI) issues. SSRIs can prolong the QT interval, posing a risk of life-threatening arrhythmia, and may interact with other medications, necessitating treatment adjustments. The FDA approved SSRIs for MDD, GAD, bulimia nervosa, bipolar depression, OCD, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, PTSD, and SAD. Off-label uses include binge eating disorder, body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause. Among SSRIs, sertraline and escitalopram are noted for their effectiveness and tolerability.^14,43-53

SNRIs, including duloxetine, venlafaxine, desvenlafaxine, milnacipran, and levomilnacipran, may increase bleeding risk, especially when taken with blood thinners. They can also elevate blood pressure, which may worsen if combined with stimulants. SNRIs may interact with other medications that affect serotonin levels, increasing the risk of serotonin syndrome when taken with triptans, pain medications, or other antidepressants.¹⁴ Desvenlafaxine has been approved by the FDA (but not by the European Medicines Agency).^54-56 Duloxetine is FDA-approved for the treatment of depression, neuropathic pain, anxiety disorders, fibromyalgia, and musculoskeletal disorders. It is used off-label to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence.^57-61 Venlafaxine is FDA-approved for depression, SAD, and panic disorder, and is prescribed off-label to treat ADHD, neuropathy, fibromyalgia, cataplexy, and PTSD, either alone or in combination with other medications.^62,63 Milnacipran is not approved for MDD; levomilnacipran received approval in 2013.⁶⁴

SRMs such as trazodone, nefazodone, vilazodone, and vortioxetine also function as serotonin reuptake inhibitors.^14,15 Trazodone is FDA-approved for MDD. It has been used off-label to treat anxiety, Alzheimer disease, substance misuse, bulimia nervosa, insomnia, fibromyalgia, and PTSD when first-line SSRIs are ineffective. A notable AE of trazodone is orthostatic hypotension, which can lead to dizziness and increase the risk of falls, especially in geriatric patients.^65-70 Nefazodone was discontinued in Europe in 2003 due to rare cases of liver toxicity but remains available in the US.^71-74 Vilazodone and vortioxetine are FDA-approved.

The latest classes of antidepressants include SMRAs and NMDARAs.¹⁴ Agomelatine, an SMRA, was approved in Europe in 2009 but rejected by the FDA in 2011 due to liver toxicity.⁷⁵ NMDARAs like esketamine and a combination of dextromethorphan and bupropion received FDA approval in 2019 and 2022, respectively.^76,77

This retrospective study analyzes noncancer drugs used during systemic chemotherapy based on a dataset of 14 antineoplastic agents. It sought to identify the most dispensed noncancer drug groups, discuss findings, compare patients with and without antidepressant prescriptions, and examine trends in antidepressant use from 2002 to 2023. This analysis expands on prior research.^78-81

Methods

The Walter Reed National Military Medical Center Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and Military Health System (MHS) data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Data Sources

The JPC DoD Cancer Registry Program contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in CAPER represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2024. PDTS records are available from 2002 to 2004. Each observation in PDTS represents a prescription filled for an MHS beneficiary, excluding those filled at international civilian pharmacies and inpatient pharmacy prescriptions.

This cross-sectional analysis requested data extraction for specific cancer drugs from the DoD Cancer Registry, focusing on treatment details, diagnosis dates, patient demographics, and physicians’ comments on AEs. After identifying patients, CAPER was used to identify additional health conditions. PDTS was used to compile a list of prescription medications filled during systemic cancer treatment or < 2 years postdiagnosis.

The 2016 Surveillance, Epidemiology, and End Results Program Coding and Staging Manual and International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^82,83 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the subgroup divided by the total number of patients or data variables. To compare the mean number of dispensed antidepressants to those without antidepressants, a 2-tailed, 2-sample z test was used to calculate the P value and determine statistical significance (P < .05) using socscistatistics.com.

Data were extracted 3 times between 2021 and 2023. The initial 2021 protocol focused on erlotinib and gefitinib. A modified protocol in 2022 added paclitaxel, cisplatin, docetaxel, pemetrexed, and crizotinib; further modification in 2023 included 8 new antineoplastic agents and 2 anticoagulants. Sotorasib has not been prescribed in the MHS, and JPC lacks records for noncancer drugs. The 2023 dataset comprised 2210 patients with cancer treated with 14 antineoplastic agents; 2104 had documented diagnoses and 2113 had recorded prescriptions. Data for erlotinib, gefitinib, and paclitaxel have been published previously.^78,79

Results

Of 2113 patients with recorded prescriptions, 1297 patients (61.4%) received 109 cancer drugs, including 96 antineoplastics, 7 disease-modifying antirheumatic agents, 4 biologic response modifiers, and 2 calcitonin gene-related peptides. Fourteen antineoplastic agents had complete data from JPC, while others were noted for combination therapies or treatment switches from the PDTS (Table 1). Seventy-six cancer drugs were prescribed with antidepressants in 489 patients (eAppendix).

The JPC provided 2242 entries for 2210 patients, ranging in age from 2 months to 88 years (mean, 56 years), documenting treatment from September 1988 to January 2023. Thirty-two patients had duplicate entries due to multiple cancer locations or occurrences. Of the 2242 patients, 1541 (68.7%) were aged > 50 years, 975 patients (43.5%) had cancers that were stage III or IV, and 1267 (56.5%) had cancers that were stage 0, I, II, or not applicable/unknown. There were 51 different types of cancer: breast, lung, testicular, endometrial, and ovarian were most common (n ≥ 100 patients). Forty-two cancer types were documented among 750 patients prescribed antidepressants (Table 2).

The CAPER database recorded 8882 unique diagnoses for 2104 patients, while PDTS noted 1089 unique prescriptions within 273 therapeutic codes for 2113 patients. Nine therapeutic codes (opiate agonists, adrenals, cathartics-laxatives, nonsteroidal anti-inflammatory agents, antihistamines for GI conditions, 5-HT3 receptor antagonists, analgesics and antipyretic miscellanea, antineoplastic agents, and proton-pump inhibitors) and 8 drugs (dexamethasone, prochlorperazine, ondansetron, docusate, acetaminophen, ibuprofen, oxycodone, and polyethylene glycol 3350) were associated with > 1000 patients (≥ 50%). Patients had between 1 and 275 unique health conditions and filled 1 to 108 prescriptions. The mean (SD) number of diagnoses and prescriptions was 50 (28) and 29 (12), respectively. Of the 273 therapeutic codes, 30 groups were analyzed, with others categorized into miscellaneous groups such as lotions, vaccines, and devices. Significant differences in mean number of prescriptions were found for patients taking antidepressants compared to those not (P < .05), except for anticonvulsants and antipsychotics (P = .12 and .09, respectively) (Table 3).

Antidepressants

Of the 2113 patients with recorded prescriptions, 750 (35.5%) were dispensed 17 different antidepressants. Among these 17 antidepressants, 183 (8.7%) patients received duloxetine, 158 (7.5%) received venlafaxine, 118 (5.6%) received trazodone, and 107 (5.1%) received sertraline (Figure 1, Table 4). Of the 750 patients, 509 (67.9%) received 1 antidepressant, 168 (22.4%) received 2, 60 (8.0%) received 3, and 13 (1.7%) received > 3. Combinations varied, but only duloxetine and trazodone were prescribed to > 10 patients.

Antidepressants were prescribed annually at an overall mean (SD) rate of 23% (5%) from 2003 to 2022 (Figure 2). Patients on antidepressants during systemic therapy had a greater number of diagnosed medical conditions and received more prescription medications compared to those not taking antidepressants (P < .001) (Figure 3). The 745 patients taking antidepressants in CAPER data had between 1 and 275 diagnosed medical issues, with a mean (SD) of 55 (31) vs a range of 1 to 209 and a mean (SD) of 46 (26) for the 1359 patients not taking antidepressants. The 750 patients on antidepressants in PDTS data had between 8 and 108 prescriptions dispensed, with a mean (SD) of 32 (12), vs a range of 1 to 65 prescriptions and a mean (SD) of 29 (12) for 1363 patients not taking antidepressants.

Discussion

The JPC DoD Cancer Registry includes information on cancer types, stages, treatment regimens, and physicians’ notes, while noncancer drugs are sourced from the PDTS database. The pharmacy uses a different documentation system, leading to varied classifications.

Database reliance has its drawbacks. For example, megestrol is coded as a cancer drug, although it’s primarily used for endometrial or gynecologic cancers. Many drugs have multiple therapeutic codes assigned to them, including 10 antineoplastic agents: diclofenac, Bacillus Calmette-Guérin (BCG), megestrol acetate, tamoxifen, anastrozole, letrozole, leuprolide, goserelin, degarelix, and fluorouracil. Diclofenac, BCG, and mitomycin have been repurposed for cancer treatment.^84-87 From 2003 to 2023, diclofenac was prescribed to 350 patients for mild-to-moderate pain, with only 2 patients receiving it for cancer in 2018. FDA-approved for bladder cancer in 1990, BCG was prescribed for cancer treatment for 1 patient in 2021 after being used for vaccines between 2003 and 2018. Tamoxifen, used for hormone receptor-positive breast cancer from 2004 to 2017 with 53 patients, switched to estrogen agonist-antagonists from 2017 to 2023 with 123 patients. Only a few of the 168 patients were prescribed tamoxifen using both codes.^88-91 Anastrozole and letrozole were coded as antiestrogens for 7 and 18 patients, respectively, while leuprolide and goserelin were coded as gonadotropins for 59 and 18 patients. Degarelix was coded as antigonadotropins, fluorouracil as skin and mucous membrane agents miscellaneous, and megestrol acetate as progestins for 7, 6, and 3 patients, respectively. Duloxetine was given to 186 patients, primarily for depression from 2005 to 2023, with 7 patients treated for fibromyalgia from 2022 to 2023.

Antidepressants Observed

Tables 1 and 5 provide insight into the FDA approval of 14 antineoplastics and antidepressants and their CYP metabolic pathways.^92-122 In Table 4, the most prescribed antidepressant classes are SNRIs, SRMs, SSRIs, TeCAs, NDRIs, and TCAs. This trend highlights a preference for newer medications with weak CYP inhibition. A total of 349 patients were prescribed SSRIs, 343 SNRIs, 119 SRMs, 109 TCAs, 83 TeCAs, and 79 NDRIs. MAOIs, SMRAs, and NMDARAs were not observed in this dataset. While there are instances of dextromethorphan-bupropion and sertraline-escitalopram being dispensed together, it remains unclear whether these were NMDARA combinations.

Among the 14 specific antineoplastic agents, 10 are metabolized by CYP isoenzymes, primarily CYP3A4. Duloxetine neither inhibits nor is metabolized by CYP3A4, a reason it is often recommended, following venlafaxine.

Both duloxetine and venlafaxine are used off-label for chemotherapy-induced peripheral neuropathy related to paclitaxel and docetaxel. According to the CYP metabolized pathway, duloxetine tends to have more favorable DDIs than venlafaxine. In PDTS data, 371 patients were treated with paclitaxel and 180 with docetaxel, with respective antidepressant prescriptions of 156 and 70. Of the 156 patients dispensed paclitaxel, 62 (40%) were dispensed with duloxetine compared to 43 (28%) with venlafaxine. Of the 70 patients dispensed docetaxel, 23 (33%) received duloxetine vs 24 (34%) with venlafaxine.

Of 85 patients prescribed duloxetine, 75 received it with either paclitaxel or docetaxel (5 received both). Five patients had documented AEs (1 neuropathy related). Of 67 patients prescribed venlafaxine, 66 received it with either paclitaxel or docetaxel. Two patients had documented AEs (1 was neuropathy related, the same patient who received duloxetine). Of the 687 patients treated with paclitaxel and 337 with docetaxel in all databases, 4 experienced neuropathic AEs from both medications.⁷⁹

Antidepressants can increase the risk of bleeding, especially when combined with blood thinners, and may elevate blood pressure, particularly alongside stimulants. Of the 554 patients prescribed 9 different anticoagulants, enoxaparin, apixaban, and rivaroxaban were the most common (each > 100 patients). Among these, 201 patients (36%) received both anticoagulants and antidepressants: duloxetine for 64 patients, venlafaxine for 30, trazodone for 35, and sertraline for 26. There were no data available to assess bleeding rates related to the evaluation of DDIs between these medication classes.

Antidepressants can be prescribed for erectile dysfunction. Of the 148 patients prescribed an antidepressant for erectile dysfunction, duloxetine, trazodone, and mirtazapine were the most common. Antidepressant preferences varied by cancer type. Duloxetine was the only antidepressant used for all types of cancer. Venlafaxine, duloxetine, trazodone, sertraline, and escitalopram were the most prescribed antidepressants for breast cancer, while duloxetine, mirtazapine, citalopram, sertraline, and trazodone were the most prescribed for lung cancer. Sertraline, duloxetine, trazodone, amitriptyline, and escitalopram were most common for testicular cancer. Duloxetine, venlafaxine, trazodone, amitriptyline, and sertraline were the most prescribed for endometrial cancer, while duloxetine, venlafaxine, amitriptyline, citalopram, and sertraline were most prescribed for ovarian cancer.

The broadness of International Statistical Classification of Diseases, Tenth Revision codes made it challenging to identify nondepression diagnoses in the analyzed population. However, if all antidepressants were prescribed to treat depression, service members with cancer exhibited a higher depression rate (35%) than the general population (25%). Of 2104 patients, 191 (9.1%) had mood disorders, and 706 (33.6%) had mental disorders: 346 (49.0%) had 1 diagnosis, and 360 (51.0%) had multiple diagnoses. The percentage of diagnoses varied yearly, with notable drops in 2003, 2007, 2011, 2014, and 2018, and peaks in 2006, 2008, 2013, 2017, and 2022. This fluctuation was influenced by events like the establishment of PDTS in 2002, the 2008 economic recession, a hospital relocation in 2011, the 2014 Ebola outbreak, and the COVID-19 pandemic. Although the number of patients receiving antidepressants increased from 2019 to 2022, the overall percentage of patients receiving them did not significantly change from 2003 to 2022, aligning with previous research.^5,125

Many medications have potential uses beyond what is detailed in the prescribing information. Antidepressants can relieve pain, while pain medications may help with depression. Opioids were once thought to effectively treat depression, but this perspective has changed with a greater understanding of their risks, including misuse.^126-131 Pain is a severe and often unbearable AE of cancer. Of 2113 patients, 92% received opioids; 34% received both opioids and antidepressants; 2% received only antidepressants; and 7% received neither. This study didn’t clarify whether those on opioids alone recognized their depression or if those on both were aware of their dependence. While SSRIs are generally not addictive, they can lead to physical dependence, and any medication can be abused if not managed properly.^132-134

Conclusions

This retrospective study analyzes data from antineoplastic agents used in systemic cancer treatment between 1988 and 2023, with a particular focus on the use of antidepressants. Data on antidepressant prescriptions are incomplete and specific to these agents, which means the findings cannot be generalized to all antidepressants. Hence, the results indicate that patients taking antidepressants had more diagnosed health issues and received more medications compared to patients who were not on these drugs.

This study underscores the need for further research into the effects of antidepressants on cancer treatment, utilizing all data from the DoD Cancer Registry. Future research should explore DDIs between antidepressants and other cancer and noncancer medications, as this study did not assess AE documentation, unlike in studies involving erlotinib, gefitinib, and paclitaxel.^78,79 Further investigation is needed to evaluate the impact of discontinuing antidepressant use during cancer treatment. This comprehensive overview provides insights for clinicians to help them make informed decisions regarding the prescription of antidepressants in the context of cancer treatment.

Cancer patients experience depression at rates > 5 times that of the general population.^1-11 Despite an increase in palliative care use, depression rates continued to rise.^2-4 Between 5% to 16% of outpatients, 4% to 14% of inpatients, and up to 49% of patients receiving palliative care experience depression.⁵ This issue also impacts families and caregivers.¹ A 2021 meta-analysis found that 23% of active military personnel and 20% of veterans experience depression.¹¹

Antidepressants approved by the US Food and Drug Administration (FDA) target the serotonin, norepinephrine, or dopamine systems and include boxed warnings about an increased risk of suicidal thoughts in adults aged 18 to 24 years.^12,13 These medications are categorized into several classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor modulators (SRMs), serotonin-melatonin receptor antagonists (SMRAs), and N—methyl-D-aspartate receptor antagonists (NMDARAs).^14,15 The first FDA-approved antidepressants, iproniazid (an MAOI) and imipramine (a TCA) laid the foundation for the development of newer classes like SSRIs and SNRIs.^15-17

Older antidepressants such as MAOIs and TCAs are used less due to their adverse effects (AEs) and drug interactions. MAOIs, such as iproniazid, selegiline, moclobemide, tranylcypromine, isocarboxazid, and phenelzine, have numerous AEs and drug interactions, making them unsuitable for first- or second-line treatment of depression.^14,18-21 TCAs such as doxepin, amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, maprotiline, and amoxapine have a narrow therapeutic index requiring careful monitoring for signs of toxicity such as QRS widening, tremors, or confusion. Despite the issues, TCAs are generally classified as second-line agents for major depressive disorder (MDD). TCAs have off-label uses for migraine prophylaxis, treatment of obsessive-compulsive disorder (OCD), insomnia, and chronic pain management first-line.^14,22-29

Newer antidepressants, including TeCAs and NDRIs, are typically more effective, but also come with safety concerns. TeCAs like mirtazapine interact with several medications, including MAOIs, serotonin-increasing drugs, alcohol, cannabidiol, and marijuana. Mirtazapine is FDA-approved for the treatment of moderate to severe depression in adults. It is also used off-label to treat insomnia, panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), headaches, and migraines. Compared to other antidepressants, mirtazapine is effective for all stages of depression and addresses a broad range of related symptoms.^14,30-34 NDRIs, such as bupropion, also interact with various medications, including MAOIs, other antidepressants, stimulants, and alcohol. Bupropion is FDA-approved for smoking cessation and to treat depression and SAD. It is also used off-label for depression- related bipolar disorder or sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), and obesity.^14,35-42

SSRIs, SNRIs, and SRMs should be used with caution. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, paroxetine, and fluvoxamine are first-line treatments for depression and various psychiatric disorders due to their safety and efficacy. Common AEs of SSRIs include sexual dysfunction, sleep disturbances, weight changes, and gastrointestinal (GI) issues. SSRIs can prolong the QT interval, posing a risk of life-threatening arrhythmia, and may interact with other medications, necessitating treatment adjustments. The FDA approved SSRIs for MDD, GAD, bulimia nervosa, bipolar depression, OCD, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, PTSD, and SAD. Off-label uses include binge eating disorder, body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause. Among SSRIs, sertraline and escitalopram are noted for their effectiveness and tolerability.^14,43-53

SNRIs, including duloxetine, venlafaxine, desvenlafaxine, milnacipran, and levomilnacipran, may increase bleeding risk, especially when taken with blood thinners. They can also elevate blood pressure, which may worsen if combined with stimulants. SNRIs may interact with other medications that affect serotonin levels, increasing the risk of serotonin syndrome when taken with triptans, pain medications, or other antidepressants.¹⁴ Desvenlafaxine has been approved by the FDA (but not by the European Medicines Agency).^54-56 Duloxetine is FDA-approved for the treatment of depression, neuropathic pain, anxiety disorders, fibromyalgia, and musculoskeletal disorders. It is used off-label to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence.^57-61 Venlafaxine is FDA-approved for depression, SAD, and panic disorder, and is prescribed off-label to treat ADHD, neuropathy, fibromyalgia, cataplexy, and PTSD, either alone or in combination with other medications.^62,63 Milnacipran is not approved for MDD; levomilnacipran received approval in 2013.⁶⁴

SRMs such as trazodone, nefazodone, vilazodone, and vortioxetine also function as serotonin reuptake inhibitors.^14,15 Trazodone is FDA-approved for MDD. It has been used off-label to treat anxiety, Alzheimer disease, substance misuse, bulimia nervosa, insomnia, fibromyalgia, and PTSD when first-line SSRIs are ineffective. A notable AE of trazodone is orthostatic hypotension, which can lead to dizziness and increase the risk of falls, especially in geriatric patients.^65-70 Nefazodone was discontinued in Europe in 2003 due to rare cases of liver toxicity but remains available in the US.^71-74 Vilazodone and vortioxetine are FDA-approved.

The latest classes of antidepressants include SMRAs and NMDARAs.¹⁴ Agomelatine, an SMRA, was approved in Europe in 2009 but rejected by the FDA in 2011 due to liver toxicity.⁷⁵ NMDARAs like esketamine and a combination of dextromethorphan and bupropion received FDA approval in 2019 and 2022, respectively.^76,77

This retrospective study analyzes noncancer drugs used during systemic chemotherapy based on a dataset of 14 antineoplastic agents. It sought to identify the most dispensed noncancer drug groups, discuss findings, compare patients with and without antidepressant prescriptions, and examine trends in antidepressant use from 2002 to 2023. This analysis expands on prior research.^78-81

Methods

The Walter Reed National Military Medical Center Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and Military Health System (MHS) data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Data Sources

The JPC DoD Cancer Registry Program contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in CAPER represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2024. PDTS records are available from 2002 to 2004. Each observation in PDTS represents a prescription filled for an MHS beneficiary, excluding those filled at international civilian pharmacies and inpatient pharmacy prescriptions.

This cross-sectional analysis requested data extraction for specific cancer drugs from the DoD Cancer Registry, focusing on treatment details, diagnosis dates, patient demographics, and physicians’ comments on AEs. After identifying patients, CAPER was used to identify additional health conditions. PDTS was used to compile a list of prescription medications filled during systemic cancer treatment or < 2 years postdiagnosis.

The 2016 Surveillance, Epidemiology, and End Results Program Coding and Staging Manual and International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^82,83 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the subgroup divided by the total number of patients or data variables. To compare the mean number of dispensed antidepressants to those without antidepressants, a 2-tailed, 2-sample z test was used to calculate the P value and determine statistical significance (P < .05) using socscistatistics.com.

Data were extracted 3 times between 2021 and 2023. The initial 2021 protocol focused on erlotinib and gefitinib. A modified protocol in 2022 added paclitaxel, cisplatin, docetaxel, pemetrexed, and crizotinib; further modification in 2023 included 8 new antineoplastic agents and 2 anticoagulants. Sotorasib has not been prescribed in the MHS, and JPC lacks records for noncancer drugs. The 2023 dataset comprised 2210 patients with cancer treated with 14 antineoplastic agents; 2104 had documented diagnoses and 2113 had recorded prescriptions. Data for erlotinib, gefitinib, and paclitaxel have been published previously.^78,79

Results

Of 2113 patients with recorded prescriptions, 1297 patients (61.4%) received 109 cancer drugs, including 96 antineoplastics, 7 disease-modifying antirheumatic agents, 4 biologic response modifiers, and 2 calcitonin gene-related peptides. Fourteen antineoplastic agents had complete data from JPC, while others were noted for combination therapies or treatment switches from the PDTS (Table 1). Seventy-six cancer drugs were prescribed with antidepressants in 489 patients (eAppendix).

The JPC provided 2242 entries for 2210 patients, ranging in age from 2 months to 88 years (mean, 56 years), documenting treatment from September 1988 to January 2023. Thirty-two patients had duplicate entries due to multiple cancer locations or occurrences. Of the 2242 patients, 1541 (68.7%) were aged > 50 years, 975 patients (43.5%) had cancers that were stage III or IV, and 1267 (56.5%) had cancers that were stage 0, I, II, or not applicable/unknown. There were 51 different types of cancer: breast, lung, testicular, endometrial, and ovarian were most common (n ≥ 100 patients). Forty-two cancer types were documented among 750 patients prescribed antidepressants (Table 2).

The CAPER database recorded 8882 unique diagnoses for 2104 patients, while PDTS noted 1089 unique prescriptions within 273 therapeutic codes for 2113 patients. Nine therapeutic codes (opiate agonists, adrenals, cathartics-laxatives, nonsteroidal anti-inflammatory agents, antihistamines for GI conditions, 5-HT3 receptor antagonists, analgesics and antipyretic miscellanea, antineoplastic agents, and proton-pump inhibitors) and 8 drugs (dexamethasone, prochlorperazine, ondansetron, docusate, acetaminophen, ibuprofen, oxycodone, and polyethylene glycol 3350) were associated with > 1000 patients (≥ 50%). Patients had between 1 and 275 unique health conditions and filled 1 to 108 prescriptions. The mean (SD) number of diagnoses and prescriptions was 50 (28) and 29 (12), respectively. Of the 273 therapeutic codes, 30 groups were analyzed, with others categorized into miscellaneous groups such as lotions, vaccines, and devices. Significant differences in mean number of prescriptions were found for patients taking antidepressants compared to those not (P < .05), except for anticonvulsants and antipsychotics (P = .12 and .09, respectively) (Table 3).

Antidepressants

Of the 2113 patients with recorded prescriptions, 750 (35.5%) were dispensed 17 different antidepressants. Among these 17 antidepressants, 183 (8.7%) patients received duloxetine, 158 (7.5%) received venlafaxine, 118 (5.6%) received trazodone, and 107 (5.1%) received sertraline (Figure 1, Table 4). Of the 750 patients, 509 (67.9%) received 1 antidepressant, 168 (22.4%) received 2, 60 (8.0%) received 3, and 13 (1.7%) received > 3. Combinations varied, but only duloxetine and trazodone were prescribed to > 10 patients.

Antidepressants were prescribed annually at an overall mean (SD) rate of 23% (5%) from 2003 to 2022 (Figure 2). Patients on antidepressants during systemic therapy had a greater number of diagnosed medical conditions and received more prescription medications compared to those not taking antidepressants (P < .001) (Figure 3). The 745 patients taking antidepressants in CAPER data had between 1 and 275 diagnosed medical issues, with a mean (SD) of 55 (31) vs a range of 1 to 209 and a mean (SD) of 46 (26) for the 1359 patients not taking antidepressants. The 750 patients on antidepressants in PDTS data had between 8 and 108 prescriptions dispensed, with a mean (SD) of 32 (12), vs a range of 1 to 65 prescriptions and a mean (SD) of 29 (12) for 1363 patients not taking antidepressants.

Discussion

The JPC DoD Cancer Registry includes information on cancer types, stages, treatment regimens, and physicians’ notes, while noncancer drugs are sourced from the PDTS database. The pharmacy uses a different documentation system, leading to varied classifications.

Database reliance has its drawbacks. For example, megestrol is coded as a cancer drug, although it’s primarily used for endometrial or gynecologic cancers. Many drugs have multiple therapeutic codes assigned to them, including 10 antineoplastic agents: diclofenac, Bacillus Calmette-Guérin (BCG), megestrol acetate, tamoxifen, anastrozole, letrozole, leuprolide, goserelin, degarelix, and fluorouracil. Diclofenac, BCG, and mitomycin have been repurposed for cancer treatment.^84-87 From 2003 to 2023, diclofenac was prescribed to 350 patients for mild-to-moderate pain, with only 2 patients receiving it for cancer in 2018. FDA-approved for bladder cancer in 1990, BCG was prescribed for cancer treatment for 1 patient in 2021 after being used for vaccines between 2003 and 2018. Tamoxifen, used for hormone receptor-positive breast cancer from 2004 to 2017 with 53 patients, switched to estrogen agonist-antagonists from 2017 to 2023 with 123 patients. Only a few of the 168 patients were prescribed tamoxifen using both codes.^88-91 Anastrozole and letrozole were coded as antiestrogens for 7 and 18 patients, respectively, while leuprolide and goserelin were coded as gonadotropins for 59 and 18 patients. Degarelix was coded as antigonadotropins, fluorouracil as skin and mucous membrane agents miscellaneous, and megestrol acetate as progestins for 7, 6, and 3 patients, respectively. Duloxetine was given to 186 patients, primarily for depression from 2005 to 2023, with 7 patients treated for fibromyalgia from 2022 to 2023.

Antidepressants Observed

Tables 1 and 5 provide insight into the FDA approval of 14 antineoplastics and antidepressants and their CYP metabolic pathways.^92-122 In Table 4, the most prescribed antidepressant classes are SNRIs, SRMs, SSRIs, TeCAs, NDRIs, and TCAs. This trend highlights a preference for newer medications with weak CYP inhibition. A total of 349 patients were prescribed SSRIs, 343 SNRIs, 119 SRMs, 109 TCAs, 83 TeCAs, and 79 NDRIs. MAOIs, SMRAs, and NMDARAs were not observed in this dataset. While there are instances of dextromethorphan-bupropion and sertraline-escitalopram being dispensed together, it remains unclear whether these were NMDARA combinations.

Among the 14 specific antineoplastic agents, 10 are metabolized by CYP isoenzymes, primarily CYP3A4. Duloxetine neither inhibits nor is metabolized by CYP3A4, a reason it is often recommended, following venlafaxine.

Both duloxetine and venlafaxine are used off-label for chemotherapy-induced peripheral neuropathy related to paclitaxel and docetaxel. According to the CYP metabolized pathway, duloxetine tends to have more favorable DDIs than venlafaxine. In PDTS data, 371 patients were treated with paclitaxel and 180 with docetaxel, with respective antidepressant prescriptions of 156 and 70. Of the 156 patients dispensed paclitaxel, 62 (40%) were dispensed with duloxetine compared to 43 (28%) with venlafaxine. Of the 70 patients dispensed docetaxel, 23 (33%) received duloxetine vs 24 (34%) with venlafaxine.

Of 85 patients prescribed duloxetine, 75 received it with either paclitaxel or docetaxel (5 received both). Five patients had documented AEs (1 neuropathy related). Of 67 patients prescribed venlafaxine, 66 received it with either paclitaxel or docetaxel. Two patients had documented AEs (1 was neuropathy related, the same patient who received duloxetine). Of the 687 patients treated with paclitaxel and 337 with docetaxel in all databases, 4 experienced neuropathic AEs from both medications.⁷⁹

Antidepressants can increase the risk of bleeding, especially when combined with blood thinners, and may elevate blood pressure, particularly alongside stimulants. Of the 554 patients prescribed 9 different anticoagulants, enoxaparin, apixaban, and rivaroxaban were the most common (each > 100 patients). Among these, 201 patients (36%) received both anticoagulants and antidepressants: duloxetine for 64 patients, venlafaxine for 30, trazodone for 35, and sertraline for 26. There were no data available to assess bleeding rates related to the evaluation of DDIs between these medication classes.

Antidepressants can be prescribed for erectile dysfunction. Of the 148 patients prescribed an antidepressant for erectile dysfunction, duloxetine, trazodone, and mirtazapine were the most common. Antidepressant preferences varied by cancer type. Duloxetine was the only antidepressant used for all types of cancer. Venlafaxine, duloxetine, trazodone, sertraline, and escitalopram were the most prescribed antidepressants for breast cancer, while duloxetine, mirtazapine, citalopram, sertraline, and trazodone were the most prescribed for lung cancer. Sertraline, duloxetine, trazodone, amitriptyline, and escitalopram were most common for testicular cancer. Duloxetine, venlafaxine, trazodone, amitriptyline, and sertraline were the most prescribed for endometrial cancer, while duloxetine, venlafaxine, amitriptyline, citalopram, and sertraline were most prescribed for ovarian cancer.

The broadness of International Statistical Classification of Diseases, Tenth Revision codes made it challenging to identify nondepression diagnoses in the analyzed population. However, if all antidepressants were prescribed to treat depression, service members with cancer exhibited a higher depression rate (35%) than the general population (25%). Of 2104 patients, 191 (9.1%) had mood disorders, and 706 (33.6%) had mental disorders: 346 (49.0%) had 1 diagnosis, and 360 (51.0%) had multiple diagnoses. The percentage of diagnoses varied yearly, with notable drops in 2003, 2007, 2011, 2014, and 2018, and peaks in 2006, 2008, 2013, 2017, and 2022. This fluctuation was influenced by events like the establishment of PDTS in 2002, the 2008 economic recession, a hospital relocation in 2011, the 2014 Ebola outbreak, and the COVID-19 pandemic. Although the number of patients receiving antidepressants increased from 2019 to 2022, the overall percentage of patients receiving them did not significantly change from 2003 to 2022, aligning with previous research.^5,125

Many medications have potential uses beyond what is detailed in the prescribing information. Antidepressants can relieve pain, while pain medications may help with depression. Opioids were once thought to effectively treat depression, but this perspective has changed with a greater understanding of their risks, including misuse.^126-131 Pain is a severe and often unbearable AE of cancer. Of 2113 patients, 92% received opioids; 34% received both opioids and antidepressants; 2% received only antidepressants; and 7% received neither. This study didn’t clarify whether those on opioids alone recognized their depression or if those on both were aware of their dependence. While SSRIs are generally not addictive, they can lead to physical dependence, and any medication can be abused if not managed properly.^132-134

Conclusions

This retrospective study analyzes data from antineoplastic agents used in systemic cancer treatment between 1988 and 2023, with a particular focus on the use of antidepressants. Data on antidepressant prescriptions are incomplete and specific to these agents, which means the findings cannot be generalized to all antidepressants. Hence, the results indicate that patients taking antidepressants had more diagnosed health issues and received more medications compared to patients who were not on these drugs.

This study underscores the need for further research into the effects of antidepressants on cancer treatment, utilizing all data from the DoD Cancer Registry. Future research should explore DDIs between antidepressants and other cancer and noncancer medications, as this study did not assess AE documentation, unlike in studies involving erlotinib, gefitinib, and paclitaxel.^78,79 Further investigation is needed to evaluate the impact of discontinuing antidepressant use during cancer treatment. This comprehensive overview provides insights for clinicians to help them make informed decisions regarding the prescription of antidepressants in the context of cancer treatment.