Patients with at least five biopsies showing nondysplastic Barrett’s esophagus were statistically as likely to progress to high-grade dysplasia or esophageal adenocarcinoma as patients with a single such biopsy, according to a multicenter prospective registry study reported in the June issue of Clinical Gastroenterology and Hepatology (doi: org/10.1016/j.cgh.2017.02.019).

The findings, which contradict those from another recent multicenter cohort study (Gastroenterology. 2013;145[3]:548-53), highlight the need for more studies before lengthening the time between surveillance biopsies in patients with nondysplastic Barrett’s esophagus, Rajesh Krishnamoorthi, MD, of Mayo Clinic in Rochester, Minn., wrote with his associates.

Barrett’s esophagus is the strongest predictor of esophageal adenocarcinoma, but studies have reported mixed results as to whether the risk of this cancer increases over time or wanes with consecutive biopsies that indicate nondysplasia, the researchers noted. Therefore, they studied the prospective, multicenter Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus registry, excluding patients who progressed to adenocarcinoma within 12 months, had missing data, or had no follow-up biopsies. This approach left 480 subjects for analysis. Patients averaged 63 years of age, 78% were male, the mean length of Barrett’s esophagus was 5.7 cm, and the average time between biopsies was 1.8 years, with a standard deviation of 1.3 years.

A total of 16 patients progressed to high-grade dysplasia or esophageal adenocarcinoma over 1,832 patient-years of follow-up, for an overall annual risk of progression of 0.87%. Two patients progressed to esophageal adenocarcinoma (annual risk, 0.11%; 95% confidence interval, 0.03% to 0.44%), while 14 patients progressed to high-grade dysplasia (annual risk, 0.76%; 95% CI, 0.45% to 1.29%). Eight patients progressed to one of these two outcomes after a single nondysplastic biopsy, three progressed after two such biopsies, three progressed after three such biopsies, none progressed after four such biopsies, and two progressed after five such biopsies. Statistically, patients with at least five consecutive nondysplastic biopsies were no less likely to progress than were patients with only one nondysplastic biopsy (hazard ratio, 0.48; 95% CI, 0.07 to 1.92; P = .32). Hazard ratios for the other groups ranged between 0.0 and 0.85, with no significant difference in estimated risk between groups (P = .68) after controlling for age, sex, and length of Barrett’s esophagus.

The previous multicenter cohort study linked persistently nondysplastic Barrett’s esophagus with a lower rate of progression to esophageal adenocarcinoma, and, based on those findings, the authors suggested lengthening intervals between biopsy surveillance or even stopping surveillance, Dr. Krishnamoorthi and his associates noted. However, that study did not have mutually exclusive groups. “Additional data are required before increasing the interval between surveillance endoscopies based on persistence of nondysplastic Barrett’s esophagus,” they concluded.

The study lacked misclassification bias given long-segment Barrett’s esophagus, and specialized gastrointestinal pathologists interpreted all histology specimens, the researchers noted. “The small number of progressors is a potential limitation, reducing power to assess associations,” they added.

The investigators did not report funding sources. They reported having no conflicts of interest.

Patients with at least five biopsies showing nondysplastic Barrett’s esophagus were statistically as likely to progress to high-grade dysplasia or esophageal adenocarcinoma as patients with a single such biopsy, according to a multicenter prospective registry study reported in the June issue of Clinical Gastroenterology and Hepatology (doi: org/10.1016/j.cgh.2017.02.019).

The findings, which contradict those from another recent multicenter cohort study (Gastroenterology. 2013;145[3]:548-53), highlight the need for more studies before lengthening the time between surveillance biopsies in patients with nondysplastic Barrett’s esophagus, Rajesh Krishnamoorthi, MD, of Mayo Clinic in Rochester, Minn., wrote with his associates.

Barrett’s esophagus is the strongest predictor of esophageal adenocarcinoma, but studies have reported mixed results as to whether the risk of this cancer increases over time or wanes with consecutive biopsies that indicate nondysplasia, the researchers noted. Therefore, they studied the prospective, multicenter Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus registry, excluding patients who progressed to adenocarcinoma within 12 months, had missing data, or had no follow-up biopsies. This approach left 480 subjects for analysis. Patients averaged 63 years of age, 78% were male, the mean length of Barrett’s esophagus was 5.7 cm, and the average time between biopsies was 1.8 years, with a standard deviation of 1.3 years.

A total of 16 patients progressed to high-grade dysplasia or esophageal adenocarcinoma over 1,832 patient-years of follow-up, for an overall annual risk of progression of 0.87%. Two patients progressed to esophageal adenocarcinoma (annual risk, 0.11%; 95% confidence interval, 0.03% to 0.44%), while 14 patients progressed to high-grade dysplasia (annual risk, 0.76%; 95% CI, 0.45% to 1.29%). Eight patients progressed to one of these two outcomes after a single nondysplastic biopsy, three progressed after two such biopsies, three progressed after three such biopsies, none progressed after four such biopsies, and two progressed after five such biopsies. Statistically, patients with at least five consecutive nondysplastic biopsies were no less likely to progress than were patients with only one nondysplastic biopsy (hazard ratio, 0.48; 95% CI, 0.07 to 1.92; P = .32). Hazard ratios for the other groups ranged between 0.0 and 0.85, with no significant difference in estimated risk between groups (P = .68) after controlling for age, sex, and length of Barrett’s esophagus.

The previous multicenter cohort study linked persistently nondysplastic Barrett’s esophagus with a lower rate of progression to esophageal adenocarcinoma, and, based on those findings, the authors suggested lengthening intervals between biopsy surveillance or even stopping surveillance, Dr. Krishnamoorthi and his associates noted. However, that study did not have mutually exclusive groups. “Additional data are required before increasing the interval between surveillance endoscopies based on persistence of nondysplastic Barrett’s esophagus,” they concluded.

The study lacked misclassification bias given long-segment Barrett’s esophagus, and specialized gastrointestinal pathologists interpreted all histology specimens, the researchers noted. “The small number of progressors is a potential limitation, reducing power to assess associations,” they added.

The investigators did not report funding sources. They reported having no conflicts of interest.

Patients with at least five biopsies showing nondysplastic Barrett’s esophagus were statistically as likely to progress to high-grade dysplasia or esophageal adenocarcinoma as patients with a single such biopsy, according to a multicenter prospective registry study reported in the June issue of Clinical Gastroenterology and Hepatology (doi: org/10.1016/j.cgh.2017.02.019).

The findings, which contradict those from another recent multicenter cohort study (Gastroenterology. 2013;145[3]:548-53), highlight the need for more studies before lengthening the time between surveillance biopsies in patients with nondysplastic Barrett’s esophagus, Rajesh Krishnamoorthi, MD, of Mayo Clinic in Rochester, Minn., wrote with his associates.

Barrett’s esophagus is the strongest predictor of esophageal adenocarcinoma, but studies have reported mixed results as to whether the risk of this cancer increases over time or wanes with consecutive biopsies that indicate nondysplasia, the researchers noted. Therefore, they studied the prospective, multicenter Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus registry, excluding patients who progressed to adenocarcinoma within 12 months, had missing data, or had no follow-up biopsies. This approach left 480 subjects for analysis. Patients averaged 63 years of age, 78% were male, the mean length of Barrett’s esophagus was 5.7 cm, and the average time between biopsies was 1.8 years, with a standard deviation of 1.3 years.

A total of 16 patients progressed to high-grade dysplasia or esophageal adenocarcinoma over 1,832 patient-years of follow-up, for an overall annual risk of progression of 0.87%. Two patients progressed to esophageal adenocarcinoma (annual risk, 0.11%; 95% confidence interval, 0.03% to 0.44%), while 14 patients progressed to high-grade dysplasia (annual risk, 0.76%; 95% CI, 0.45% to 1.29%). Eight patients progressed to one of these two outcomes after a single nondysplastic biopsy, three progressed after two such biopsies, three progressed after three such biopsies, none progressed after four such biopsies, and two progressed after five such biopsies. Statistically, patients with at least five consecutive nondysplastic biopsies were no less likely to progress than were patients with only one nondysplastic biopsy (hazard ratio, 0.48; 95% CI, 0.07 to 1.92; P = .32). Hazard ratios for the other groups ranged between 0.0 and 0.85, with no significant difference in estimated risk between groups (P = .68) after controlling for age, sex, and length of Barrett’s esophagus.

The previous multicenter cohort study linked persistently nondysplastic Barrett’s esophagus with a lower rate of progression to esophageal adenocarcinoma, and, based on those findings, the authors suggested lengthening intervals between biopsy surveillance or even stopping surveillance, Dr. Krishnamoorthi and his associates noted. However, that study did not have mutually exclusive groups. “Additional data are required before increasing the interval between surveillance endoscopies based on persistence of nondysplastic Barrett’s esophagus,” they concluded.

The study lacked misclassification bias given long-segment Barrett’s esophagus, and specialized gastrointestinal pathologists interpreted all histology specimens, the researchers noted. “The small number of progressors is a potential limitation, reducing power to assess associations,” they added.

The investigators did not report funding sources. They reported having no conflicts of interest.

Click here to access Combating Public Pathogens in Federal Health Care Systems

Table of Contents

• Open Clinical Trials for Patients With HIV and/or Viral Hepatitis
• HIV Update: Which Single-Tablet Regimens, and When
• Improving Veteran Access to Treatment for Hepatitis C Virus Infection
• Strategies to Improve Hepatocellular Carcinoma Surveillance in Veterans With Hepatitis B Virus Infection
• Heart Transplantation Outcomes in Patients With Hepatitis C Virus Infection: Potential Impact of Newer Antiviral Treatments After Transplantation

Click here to access Combating Public Pathogens in Federal Health Care Systems

Table of Contents

• Open Clinical Trials for Patients With HIV and/or Viral Hepatitis
• HIV Update: Which Single-Tablet Regimens, and When
• Improving Veteran Access to Treatment for Hepatitis C Virus Infection
• Strategies to Improve Hepatocellular Carcinoma Surveillance in Veterans With Hepatitis B Virus Infection
• Heart Transplantation Outcomes in Patients With Hepatitis C Virus Infection: Potential Impact of Newer Antiviral Treatments After Transplantation

Click here to access Combating Public Pathogens in Federal Health Care Systems

Table of Contents

• Open Clinical Trials for Patients With HIV and/or Viral Hepatitis
• HIV Update: Which Single-Tablet Regimens, and When
• Improving Veteran Access to Treatment for Hepatitis C Virus Infection
• Strategies to Improve Hepatocellular Carcinoma Surveillance in Veterans With Hepatitis B Virus Infection
• Heart Transplantation Outcomes in Patients With Hepatitis C Virus Infection: Potential Impact of Newer Antiviral Treatments After Transplantation

Click here to access the June 2017 Digital Edition.

Table of Contents

• A Pathway to Full Practice Authority for Physician Assistants in the VA
• Outcomes Associated With a Multidisciplinary Pain Oversight Committee to Facilitate Management of Chronic Opioid Therapy
• Quality of Chronic Obstructive Pulmonary Disease-Related Health Care in Rural and Urban Clinics
• Three Anomalies and a Complication: Ruptured Noncoronary Sinus of Valsalva Aneurysm, Atrial Septal Aneurysm, and Patent Foramen Ovale
• Orthorexia Nervosa: An Obsession With Healthy Eating
• Interprofessional Education in PACT Primary Care-Mental Health Integration

Click here to access the June 2017 Digital Edition.

Table of Contents

• A Pathway to Full Practice Authority for Physician Assistants in the VA
• Outcomes Associated With a Multidisciplinary Pain Oversight Committee to Facilitate Management of Chronic Opioid Therapy
• Quality of Chronic Obstructive Pulmonary Disease-Related Health Care in Rural and Urban Clinics
• Three Anomalies and a Complication: Ruptured Noncoronary Sinus of Valsalva Aneurysm, Atrial Septal Aneurysm, and Patent Foramen Ovale
• Orthorexia Nervosa: An Obsession With Healthy Eating
• Interprofessional Education in PACT Primary Care-Mental Health Integration

Click here to access the June 2017 Digital Edition.

Table of Contents

• A Pathway to Full Practice Authority for Physician Assistants in the VA
• Outcomes Associated With a Multidisciplinary Pain Oversight Committee to Facilitate Management of Chronic Opioid Therapy
• Quality of Chronic Obstructive Pulmonary Disease-Related Health Care in Rural and Urban Clinics
• Three Anomalies and a Complication: Ruptured Noncoronary Sinus of Valsalva Aneurysm, Atrial Septal Aneurysm, and Patent Foramen Ovale
• Orthorexia Nervosa: An Obsession With Healthy Eating
• Interprofessional Education in PACT Primary Care-Mental Health Integration

What are the long-term clinical effects of wartime traumatic brain injuries (TBIs)? Most are mild, but in general all are incompletely described, say researchers from University of Washington in Seattle and Washington University in St. Louis, Missouri. However, their own study found that service members with even mild concussive TBI often “experienced evolution, not resolution” of symptoms.

The researchers compared the results of 1-year and 5-year clinical evaluations of 50 active-duty U.S. military with acute to subacute concussive blast injury and 44 deployed but uninjured service members. The evaluations included neurobehavioral and neuropsychological performance and mental health burden.

At 5 years, global disability, satisfaction with life, neurobehavioral symptom severity, psychiatric symptom severity, and sleep impairment were significantly worse in patients with concussive blast TBI. Of the patients with concussive blast TBI, 36 (72%) showed decline, compared with only 5 of the combat-deployed group (11%). The researchers also found symptoms of PTSD and depression worsened in the concussive TBI patients. Performance on cognitive measures was no different between the 2 groups. A combination of factors, including neurobehavioral symptom severity, walking ability, and verbal fluency at 1 year after injury, was highly predictive of poor outcomes 5 years later.

“This is one of the first studies to connect the dots from injury to longer term outcomes and it shows that even mild concussions can lead to long-term impairment and continued decline in satisfaction with life,” said lead author Christine L. Mac Donald, PhD. “Most physicians believe that patients will stabilize 6 to 12 months postinjury, but this study challenges that.”

The researchers also found that, although 80% of service members with concussions had sought mental health treatment, only 19% reported that those programs were helpful. The findings advocate for new treatment strategies, the researchers say, to “combat the long-term and extremely costly effect” of these wartime injuries.

What are the long-term clinical effects of wartime traumatic brain injuries (TBIs)? Most are mild, but in general all are incompletely described, say researchers from University of Washington in Seattle and Washington University in St. Louis, Missouri. However, their own study found that service members with even mild concussive TBI often “experienced evolution, not resolution” of symptoms.

The researchers compared the results of 1-year and 5-year clinical evaluations of 50 active-duty U.S. military with acute to subacute concussive blast injury and 44 deployed but uninjured service members. The evaluations included neurobehavioral and neuropsychological performance and mental health burden.

At 5 years, global disability, satisfaction with life, neurobehavioral symptom severity, psychiatric symptom severity, and sleep impairment were significantly worse in patients with concussive blast TBI. Of the patients with concussive blast TBI, 36 (72%) showed decline, compared with only 5 of the combat-deployed group (11%). The researchers also found symptoms of PTSD and depression worsened in the concussive TBI patients. Performance on cognitive measures was no different between the 2 groups. A combination of factors, including neurobehavioral symptom severity, walking ability, and verbal fluency at 1 year after injury, was highly predictive of poor outcomes 5 years later.

“This is one of the first studies to connect the dots from injury to longer term outcomes and it shows that even mild concussions can lead to long-term impairment and continued decline in satisfaction with life,” said lead author Christine L. Mac Donald, PhD. “Most physicians believe that patients will stabilize 6 to 12 months postinjury, but this study challenges that.”

The researchers also found that, although 80% of service members with concussions had sought mental health treatment, only 19% reported that those programs were helpful. The findings advocate for new treatment strategies, the researchers say, to “combat the long-term and extremely costly effect” of these wartime injuries.

What are the long-term clinical effects of wartime traumatic brain injuries (TBIs)? Most are mild, but in general all are incompletely described, say researchers from University of Washington in Seattle and Washington University in St. Louis, Missouri. However, their own study found that service members with even mild concussive TBI often “experienced evolution, not resolution” of symptoms.

The researchers compared the results of 1-year and 5-year clinical evaluations of 50 active-duty U.S. military with acute to subacute concussive blast injury and 44 deployed but uninjured service members. The evaluations included neurobehavioral and neuropsychological performance and mental health burden.

At 5 years, global disability, satisfaction with life, neurobehavioral symptom severity, psychiatric symptom severity, and sleep impairment were significantly worse in patients with concussive blast TBI. Of the patients with concussive blast TBI, 36 (72%) showed decline, compared with only 5 of the combat-deployed group (11%). The researchers also found symptoms of PTSD and depression worsened in the concussive TBI patients. Performance on cognitive measures was no different between the 2 groups. A combination of factors, including neurobehavioral symptom severity, walking ability, and verbal fluency at 1 year after injury, was highly predictive of poor outcomes 5 years later.

“This is one of the first studies to connect the dots from injury to longer term outcomes and it shows that even mild concussions can lead to long-term impairment and continued decline in satisfaction with life,” said lead author Christine L. Mac Donald, PhD. “Most physicians believe that patients will stabilize 6 to 12 months postinjury, but this study challenges that.”

The researchers also found that, although 80% of service members with concussions had sought mental health treatment, only 19% reported that those programs were helpful. The findings advocate for new treatment strategies, the researchers say, to “combat the long-term and extremely costly effect” of these wartime injuries.

The AGA recently partnered with CommonBond (studentloans.gastro.org) to help its members save thousands by refinancing their student loans. Kevin Tin, MD, who is an AGA member, has a student loan story that can certainly offer guidance and perspective to others. Kevin earned his B.S. in health sciences from Stony Brook University and his M.D. from American University of Antigua. He completed his residency at Maimonides Medical Center in Brooklyn, N.Y., where he is currently a gastroenterology fellow.

How was your medical school experience?

My medical school experience was memorable for many reasons, particularly because I had an opportunity to study in Antigua. My time there allowed me to experience a different culture and, ultimately, a different perspective. I believe this taught me how to relate to each of my patients’ individual situations and to see things from their eyes. But, the overall cost of medical school (i.e., tuition, cost of living, medical supplies, and study resources) caught me off guard. By the time I graduated, I had amassed more than $200,000 in student loans; this was not something that I felt prepared to deal with.

How would you describe your initial experience with student loans?

BrianAJackson/Thinkstock

What strategies have you implemented to pay off your student loans?

I’ve learned a few crucial strategies that any physician could, and should, take advantage of to save money on their student loans. First, be sure to spend responsibly while in medical school. I focused on finding free study resources and medical supplies as well as sharing materials with friends and roommates whenever possible. As I mentioned earlier, make small payments when you can; as soon as I entered residency, I started making interest payments on my loans. I wanted to contribute as much as I could, as early as I could, to get out of debt. Second, after graduation, endeavor to live frugally. Although I knew my salary would ultimately increase, I saved as much money as I could and put money toward paying off my loans. Finally, try to refinance your student loans; I refinanced mine with CommonBond. It was an unexpectedly pleasant experience: the website was extremely easy to navigate and any time I needed help, a representative was available to answer my questions. CommonBond also gave me the best rates I could find.
 

What were the benefits of refinancing your student loans?

What is your advice to early-career GIs who have or need to take out loans?

Do your research and do it early. While in medical school, understand what options are available to you and learn to live within your means. In your residency, plan to use a portion of your salary for paying off your student loans, even if it is only a small amount each month. This will reduce the volume of interest that will capitalize, so your loan balance doesn’t grow over time. When you start your full-time job, be financially responsible and limit your spending so you can devote additional funds to paying off your student loans.

If you would like to learn more about student loan refinancing with CommonBond, please visit studentloans.gastro.org. AGA members get a $200 cash bonus for refinancing!
 

Ms. Duggal is vice president of marketing for CommonBond.

The AGA recently partnered with CommonBond (studentloans.gastro.org) to help its members save thousands by refinancing their student loans. Kevin Tin, MD, who is an AGA member, has a student loan story that can certainly offer guidance and perspective to others. Kevin earned his B.S. in health sciences from Stony Brook University and his M.D. from American University of Antigua. He completed his residency at Maimonides Medical Center in Brooklyn, N.Y., where he is currently a gastroenterology fellow.

How was your medical school experience?

My medical school experience was memorable for many reasons, particularly because I had an opportunity to study in Antigua. My time there allowed me to experience a different culture and, ultimately, a different perspective. I believe this taught me how to relate to each of my patients’ individual situations and to see things from their eyes. But, the overall cost of medical school (i.e., tuition, cost of living, medical supplies, and study resources) caught me off guard. By the time I graduated, I had amassed more than $200,000 in student loans; this was not something that I felt prepared to deal with.

How would you describe your initial experience with student loans?

BrianAJackson/Thinkstock

What strategies have you implemented to pay off your student loans?

I’ve learned a few crucial strategies that any physician could, and should, take advantage of to save money on their student loans. First, be sure to spend responsibly while in medical school. I focused on finding free study resources and medical supplies as well as sharing materials with friends and roommates whenever possible. As I mentioned earlier, make small payments when you can; as soon as I entered residency, I started making interest payments on my loans. I wanted to contribute as much as I could, as early as I could, to get out of debt. Second, after graduation, endeavor to live frugally. Although I knew my salary would ultimately increase, I saved as much money as I could and put money toward paying off my loans. Finally, try to refinance your student loans; I refinanced mine with CommonBond. It was an unexpectedly pleasant experience: the website was extremely easy to navigate and any time I needed help, a representative was available to answer my questions. CommonBond also gave me the best rates I could find.
 

What were the benefits of refinancing your student loans?

What is your advice to early-career GIs who have or need to take out loans?

Do your research and do it early. While in medical school, understand what options are available to you and learn to live within your means. In your residency, plan to use a portion of your salary for paying off your student loans, even if it is only a small amount each month. This will reduce the volume of interest that will capitalize, so your loan balance doesn’t grow over time. When you start your full-time job, be financially responsible and limit your spending so you can devote additional funds to paying off your student loans.

If you would like to learn more about student loan refinancing with CommonBond, please visit studentloans.gastro.org. AGA members get a $200 cash bonus for refinancing!
 

Ms. Duggal is vice president of marketing for CommonBond.

The AGA recently partnered with CommonBond (studentloans.gastro.org) to help its members save thousands by refinancing their student loans. Kevin Tin, MD, who is an AGA member, has a student loan story that can certainly offer guidance and perspective to others. Kevin earned his B.S. in health sciences from Stony Brook University and his M.D. from American University of Antigua. He completed his residency at Maimonides Medical Center in Brooklyn, N.Y., where he is currently a gastroenterology fellow.

How was your medical school experience?

My medical school experience was memorable for many reasons, particularly because I had an opportunity to study in Antigua. My time there allowed me to experience a different culture and, ultimately, a different perspective. I believe this taught me how to relate to each of my patients’ individual situations and to see things from their eyes. But, the overall cost of medical school (i.e., tuition, cost of living, medical supplies, and study resources) caught me off guard. By the time I graduated, I had amassed more than $200,000 in student loans; this was not something that I felt prepared to deal with.

How would you describe your initial experience with student loans?

BrianAJackson/Thinkstock

What strategies have you implemented to pay off your student loans?

I’ve learned a few crucial strategies that any physician could, and should, take advantage of to save money on their student loans. First, be sure to spend responsibly while in medical school. I focused on finding free study resources and medical supplies as well as sharing materials with friends and roommates whenever possible. As I mentioned earlier, make small payments when you can; as soon as I entered residency, I started making interest payments on my loans. I wanted to contribute as much as I could, as early as I could, to get out of debt. Second, after graduation, endeavor to live frugally. Although I knew my salary would ultimately increase, I saved as much money as I could and put money toward paying off my loans. Finally, try to refinance your student loans; I refinanced mine with CommonBond. It was an unexpectedly pleasant experience: the website was extremely easy to navigate and any time I needed help, a representative was available to answer my questions. CommonBond also gave me the best rates I could find.
 

What were the benefits of refinancing your student loans?

What is your advice to early-career GIs who have or need to take out loans?

Do your research and do it early. While in medical school, understand what options are available to you and learn to live within your means. In your residency, plan to use a portion of your salary for paying off your student loans, even if it is only a small amount each month. This will reduce the volume of interest that will capitalize, so your loan balance doesn’t grow over time. When you start your full-time job, be financially responsible and limit your spending so you can devote additional funds to paying off your student loans.

If you would like to learn more about student loan refinancing with CommonBond, please visit studentloans.gastro.org. AGA members get a $200 cash bonus for refinancing!
 

Ms. Duggal is vice president of marketing for CommonBond.

The correct answer is C: colonic ischemia.

AGA Institute

AGA Institute

References

1. Zuckerman G.R., et al. Am J Gastroenterol. 2003;98:2018-22.

2. Tanapanpanit O., Pongpirul K. BMJ Case Rep. 2015 Sept. 17;2015.

This article has an accompanying continuing medical education activity, also eligible for MOC credit (see gastrojournal.org for details). Learning Objective: Upon completion of this activity, successful learners will be able to recognize colon single-stripe sign as an endoscopic feature of colonic ischemia.
 

The correct answer is C: colonic ischemia.

AGA Institute

AGA Institute

References

1. Zuckerman G.R., et al. Am J Gastroenterol. 2003;98:2018-22.

2. Tanapanpanit O., Pongpirul K. BMJ Case Rep. 2015 Sept. 17;2015.

This article has an accompanying continuing medical education activity, also eligible for MOC credit (see gastrojournal.org for details). Learning Objective: Upon completion of this activity, successful learners will be able to recognize colon single-stripe sign as an endoscopic feature of colonic ischemia.
 

The correct answer is C: colonic ischemia.

AGA Institute

AGA Institute

References

1. Zuckerman G.R., et al. Am J Gastroenterol. 2003;98:2018-22.

2. Tanapanpanit O., Pongpirul K. BMJ Case Rep. 2015 Sept. 17;2015.

This article has an accompanying continuing medical education activity, also eligible for MOC credit (see gastrojournal.org for details). Learning Objective: Upon completion of this activity, successful learners will be able to recognize colon single-stripe sign as an endoscopic feature of colonic ischemia.
 

Asthma medications comprise several drug classes, including leukotriene antagonists and steroid-based inhalers. These drugs have been implicated in behavioral changes, such as increased hyperactivity, similar to symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD)¹; this scenario is more of a concern in children than adults. This raises the question of whether these medications are physiologically linked to behavioral symptoms because of a suggested association with serotonin.^2,3 If this is the case, it is necessary to identify and evaluate possible psychiatric effects of these asthma agents.

How asthma medications work

Some asthma agents, such as montelukast, act as either leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists. These drugs block production of inflammatory leukotrienes, which cause bronchoconstriction. Leukotrienes also can trigger cytokine synthesis, which can modulate leukotriene receptor function. Therefore, leukotriene antagonists could interfere with cytokine function.^3,4

Corticosteroid inhalers suppress inflammatory genes by reversing histone acetylation of inflammatory genes involved in asthma. These inhalers have been shown to reduce cytokine levels in patients with chronic lung disease and those with moderate to severe asthma.^5,6 Corticosteroids also have been associated with a decrease in serotonin levels, which could contribute to depression.⁷

Possible link between asthma and serotonin

Serotonin plays an integral role in observable, dysfunctional behaviors seen in disorders such as ADHD and ODD. In previous studies, serotonin modulated the cytokine network, and patients with asthma had elevated levels of plasma serotonin.^2,3 These findings imply that asthma medications could be involved in altering levels of both cytokines and serotonin. Pretorius² emphasized the importance of monitoring serotonin levels in children who exhibit behavioral dysfunction based on these observations:

• Persons with asthma presenting with medical symptoms have elevated serotonin levels.
• Decreased serotonin levels have been associated with ADHD and ODD; medications for ADHD have been shown to increase serotonin levels.
• Asthma medications have been shown to decrease serotonin levels.^2,3

Asthma medications might be partially responsible for behavioral disturbances, and therapeutic management should integrate the role of serotonin with asthma therapy.^2,3

Clinical considerations

Therapeutic management of asthma should consider psychiatric conditions and treatments. Future research should investigate the overall predisposition for behavioral dysfunction in persons with respiratory syncytial virus, a precursor for asthma. Once an asthma patient’s risk of a psychiatric disorder has been identified, the clinician can determine the most effective medications for treating the condition. If potential medications or genetic or environmental factors are identified, we might expect a move toward personalized care in the not too distant future.

Asthma medications comprise several drug classes, including leukotriene antagonists and steroid-based inhalers. These drugs have been implicated in behavioral changes, such as increased hyperactivity, similar to symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD)¹; this scenario is more of a concern in children than adults. This raises the question of whether these medications are physiologically linked to behavioral symptoms because of a suggested association with serotonin.^2,3 If this is the case, it is necessary to identify and evaluate possible psychiatric effects of these asthma agents.

How asthma medications work

Some asthma agents, such as montelukast, act as either leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists. These drugs block production of inflammatory leukotrienes, which cause bronchoconstriction. Leukotrienes also can trigger cytokine synthesis, which can modulate leukotriene receptor function. Therefore, leukotriene antagonists could interfere with cytokine function.^3,4

Corticosteroid inhalers suppress inflammatory genes by reversing histone acetylation of inflammatory genes involved in asthma. These inhalers have been shown to reduce cytokine levels in patients with chronic lung disease and those with moderate to severe asthma.^5,6 Corticosteroids also have been associated with a decrease in serotonin levels, which could contribute to depression.⁷

Possible link between asthma and serotonin

Serotonin plays an integral role in observable, dysfunctional behaviors seen in disorders such as ADHD and ODD. In previous studies, serotonin modulated the cytokine network, and patients with asthma had elevated levels of plasma serotonin.^2,3 These findings imply that asthma medications could be involved in altering levels of both cytokines and serotonin. Pretorius² emphasized the importance of monitoring serotonin levels in children who exhibit behavioral dysfunction based on these observations:

• Persons with asthma presenting with medical symptoms have elevated serotonin levels.
• Decreased serotonin levels have been associated with ADHD and ODD; medications for ADHD have been shown to increase serotonin levels.
• Asthma medications have been shown to decrease serotonin levels.^2,3

Asthma medications might be partially responsible for behavioral disturbances, and therapeutic management should integrate the role of serotonin with asthma therapy.^2,3

Clinical considerations

Therapeutic management of asthma should consider psychiatric conditions and treatments. Future research should investigate the overall predisposition for behavioral dysfunction in persons with respiratory syncytial virus, a precursor for asthma. Once an asthma patient’s risk of a psychiatric disorder has been identified, the clinician can determine the most effective medications for treating the condition. If potential medications or genetic or environmental factors are identified, we might expect a move toward personalized care in the not too distant future.

Asthma medications comprise several drug classes, including leukotriene antagonists and steroid-based inhalers. These drugs have been implicated in behavioral changes, such as increased hyperactivity, similar to symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD)¹; this scenario is more of a concern in children than adults. This raises the question of whether these medications are physiologically linked to behavioral symptoms because of a suggested association with serotonin.^2,3 If this is the case, it is necessary to identify and evaluate possible psychiatric effects of these asthma agents.

How asthma medications work

Some asthma agents, such as montelukast, act as either leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists. These drugs block production of inflammatory leukotrienes, which cause bronchoconstriction. Leukotrienes also can trigger cytokine synthesis, which can modulate leukotriene receptor function. Therefore, leukotriene antagonists could interfere with cytokine function.^3,4

Corticosteroid inhalers suppress inflammatory genes by reversing histone acetylation of inflammatory genes involved in asthma. These inhalers have been shown to reduce cytokine levels in patients with chronic lung disease and those with moderate to severe asthma.^5,6 Corticosteroids also have been associated with a decrease in serotonin levels, which could contribute to depression.⁷

Possible link between asthma and serotonin

Serotonin plays an integral role in observable, dysfunctional behaviors seen in disorders such as ADHD and ODD. In previous studies, serotonin modulated the cytokine network, and patients with asthma had elevated levels of plasma serotonin.^2,3 These findings imply that asthma medications could be involved in altering levels of both cytokines and serotonin. Pretorius² emphasized the importance of monitoring serotonin levels in children who exhibit behavioral dysfunction based on these observations:

• Persons with asthma presenting with medical symptoms have elevated serotonin levels.
• Decreased serotonin levels have been associated with ADHD and ODD; medications for ADHD have been shown to increase serotonin levels.
• Asthma medications have been shown to decrease serotonin levels.^2,3

Asthma medications might be partially responsible for behavioral disturbances, and therapeutic management should integrate the role of serotonin with asthma therapy.^2,3

Clinical considerations

Therapeutic management of asthma should consider psychiatric conditions and treatments. Future research should investigate the overall predisposition for behavioral dysfunction in persons with respiratory syncytial virus, a precursor for asthma. Once an asthma patient’s risk of a psychiatric disorder has been identified, the clinician can determine the most effective medications for treating the condition. If potential medications or genetic or environmental factors are identified, we might expect a move toward personalized care in the not too distant future.

Taking over the care of a patient with a complex medication regimen consisting of multiple psycho­tropics is a common experience for many practicing psychiatrists. Increasing attention has been paid to the risks of polypharmacy and the importance of “deprescribing”—reducing or stopping medication—when the risks of a drug outweigh the benefits.^1,2 However, successfully reducing medication burden can be a challenge, particularly when there is fear of decompensation or if the patient is psycho­logically attached to the complex medication regimen.

We describe a pragmatic approach to deprescribing, outlining 6 steps that we have used successfully in several treatment settings, which can assist prescribers facing similar challenges in their own practices.

1. Obtain a detailed history. First compile a comprehensive list of the patient’s medications, including psychotropics, other drugs, and supplements. If necessary, coordinate with your patient’s primary care provider. Then reassess the patient’s history of illness and efficacy of pharmacologic and non-pharmacologic treatments and how the current regimen has evolved. Understand the patient’s course of illness, coping styles, strengths, and vulnerabilities with an eye toward deprescribing.

2. Investigate underlying meaning. Even the most biologically oriented prescribers can benefit from exploring the underlying meaning the patient ascribes to the medication regimen. Common themes include:

• hesitation to relinquish a complex medication regimen because the patient fears decompensation (which could be either realistic or unrealistic)
• attachment to the “sick role”
• interpreting the complex regimen as evidence of the provider’s care and concern.

A series of sensitive conversations exploring these factors and addressing their underlying meaning can help increase a patient’s trust in the process of deprescribing.

3. Assess risk vs benefit. Weigh and educate the patient on the potential risks and benefits of each medication, as well as drug interactions and additive side effects.

4. Start with:
The most risky. Medications with significant risk for serious adverse effects (eg, high doses of a QTc-prolonging medication in a patient with elevated QTc) should be targeted early.

The least likely to be missed. If there are no high-risk medications that need to take priority, discontinuation of a “redundant” medication, such as a low-dose anti­histamine prescribed with multiple other sedating medications, can be an achievable first step. By starting with a medication that the patient is unlikely to miss, the provider can make efficient initial progress while building patient confidence in the deprescribing process.

Medication the patient is most motivated to discontinue. This strategy can enhance the therapeutic alliance and increase the likelihood of successful patient engagement for patients hesitant to decrease medications, so long as there are no significant contraindications to discontinuing the medication.

5. Go slowly. As long as there are no medications that put the patient at risk and require rapid discontinuation, going slowly increases the likelihood of long-term success by:

• permitting careful monitoring for any worsening symptoms
• allowing more time for physiologic readjustment
• enabling the patient and provider to build confidence in the process over time.

With slow discontinuation, normal emotions, such as transient, situationally appropriate anxiety about a life stressor, are less likely to be misinterpreted by the patient or provider as an inability to tolerate medication reduction because there is more opportunity to observe overall trends in symptoms.

6. Replace medications with alternatives. Offering non-pharmacological treatment when possible can greatly facilitate reducing the number of medications. Examples include:

• teaching a patient breathing exercises or mindfulness while preparing to decrease an as needed anxiolytic
• engaging the patient in cognitive-behavioral therapy for insomnia before reducing sleep medications
• working together to identify opportunities for behavioral activation and exercises that are the most achievable for the patient.

This replacement strategy can work in a physiologic sense and address a patient’s fear that medications are “taken away” without alternatives in place.

Although these strategies might not work for every patient and are not recommended for reducing medications that are medically necessary, using this approach will increase the likelihood of long-term success and maintain the patient–provider alliance when reducing unnecessary and potentially risky polypharmacy. An article by Gupta and Cahill¹ describes some similar approaches with additional discussion and considerations.

Taking over the care of a patient with a complex medication regimen consisting of multiple psycho­tropics is a common experience for many practicing psychiatrists. Increasing attention has been paid to the risks of polypharmacy and the importance of “deprescribing”—reducing or stopping medication—when the risks of a drug outweigh the benefits.^1,2 However, successfully reducing medication burden can be a challenge, particularly when there is fear of decompensation or if the patient is psycho­logically attached to the complex medication regimen.

We describe a pragmatic approach to deprescribing, outlining 6 steps that we have used successfully in several treatment settings, which can assist prescribers facing similar challenges in their own practices.

1. Obtain a detailed history. First compile a comprehensive list of the patient’s medications, including psychotropics, other drugs, and supplements. If necessary, coordinate with your patient’s primary care provider. Then reassess the patient’s history of illness and efficacy of pharmacologic and non-pharmacologic treatments and how the current regimen has evolved. Understand the patient’s course of illness, coping styles, strengths, and vulnerabilities with an eye toward deprescribing.

2. Investigate underlying meaning. Even the most biologically oriented prescribers can benefit from exploring the underlying meaning the patient ascribes to the medication regimen. Common themes include:

• hesitation to relinquish a complex medication regimen because the patient fears decompensation (which could be either realistic or unrealistic)
• attachment to the “sick role”
• interpreting the complex regimen as evidence of the provider’s care and concern.

A series of sensitive conversations exploring these factors and addressing their underlying meaning can help increase a patient’s trust in the process of deprescribing.

3. Assess risk vs benefit. Weigh and educate the patient on the potential risks and benefits of each medication, as well as drug interactions and additive side effects.

4. Start with:
The most risky. Medications with significant risk for serious adverse effects (eg, high doses of a QTc-prolonging medication in a patient with elevated QTc) should be targeted early.

The least likely to be missed. If there are no high-risk medications that need to take priority, discontinuation of a “redundant” medication, such as a low-dose anti­histamine prescribed with multiple other sedating medications, can be an achievable first step. By starting with a medication that the patient is unlikely to miss, the provider can make efficient initial progress while building patient confidence in the deprescribing process.

Medication the patient is most motivated to discontinue. This strategy can enhance the therapeutic alliance and increase the likelihood of successful patient engagement for patients hesitant to decrease medications, so long as there are no significant contraindications to discontinuing the medication.

5. Go slowly. As long as there are no medications that put the patient at risk and require rapid discontinuation, going slowly increases the likelihood of long-term success by:

• permitting careful monitoring for any worsening symptoms
• allowing more time for physiologic readjustment
• enabling the patient and provider to build confidence in the process over time.

With slow discontinuation, normal emotions, such as transient, situationally appropriate anxiety about a life stressor, are less likely to be misinterpreted by the patient or provider as an inability to tolerate medication reduction because there is more opportunity to observe overall trends in symptoms.

6. Replace medications with alternatives. Offering non-pharmacological treatment when possible can greatly facilitate reducing the number of medications. Examples include:

• teaching a patient breathing exercises or mindfulness while preparing to decrease an as needed anxiolytic
• engaging the patient in cognitive-behavioral therapy for insomnia before reducing sleep medications
• working together to identify opportunities for behavioral activation and exercises that are the most achievable for the patient.

This replacement strategy can work in a physiologic sense and address a patient’s fear that medications are “taken away” without alternatives in place.

Although these strategies might not work for every patient and are not recommended for reducing medications that are medically necessary, using this approach will increase the likelihood of long-term success and maintain the patient–provider alliance when reducing unnecessary and potentially risky polypharmacy. An article by Gupta and Cahill¹ describes some similar approaches with additional discussion and considerations.

Taking over the care of a patient with a complex medication regimen consisting of multiple psycho­tropics is a common experience for many practicing psychiatrists. Increasing attention has been paid to the risks of polypharmacy and the importance of “deprescribing”—reducing or stopping medication—when the risks of a drug outweigh the benefits.^1,2 However, successfully reducing medication burden can be a challenge, particularly when there is fear of decompensation or if the patient is psycho­logically attached to the complex medication regimen.

We describe a pragmatic approach to deprescribing, outlining 6 steps that we have used successfully in several treatment settings, which can assist prescribers facing similar challenges in their own practices.

1. Obtain a detailed history. First compile a comprehensive list of the patient’s medications, including psychotropics, other drugs, and supplements. If necessary, coordinate with your patient’s primary care provider. Then reassess the patient’s history of illness and efficacy of pharmacologic and non-pharmacologic treatments and how the current regimen has evolved. Understand the patient’s course of illness, coping styles, strengths, and vulnerabilities with an eye toward deprescribing.

2. Investigate underlying meaning. Even the most biologically oriented prescribers can benefit from exploring the underlying meaning the patient ascribes to the medication regimen. Common themes include:

• hesitation to relinquish a complex medication regimen because the patient fears decompensation (which could be either realistic or unrealistic)
• attachment to the “sick role”
• interpreting the complex regimen as evidence of the provider’s care and concern.

A series of sensitive conversations exploring these factors and addressing their underlying meaning can help increase a patient’s trust in the process of deprescribing.

3. Assess risk vs benefit. Weigh and educate the patient on the potential risks and benefits of each medication, as well as drug interactions and additive side effects.

4. Start with:
The most risky. Medications with significant risk for serious adverse effects (eg, high doses of a QTc-prolonging medication in a patient with elevated QTc) should be targeted early.

The least likely to be missed. If there are no high-risk medications that need to take priority, discontinuation of a “redundant” medication, such as a low-dose anti­histamine prescribed with multiple other sedating medications, can be an achievable first step. By starting with a medication that the patient is unlikely to miss, the provider can make efficient initial progress while building patient confidence in the deprescribing process.

Medication the patient is most motivated to discontinue. This strategy can enhance the therapeutic alliance and increase the likelihood of successful patient engagement for patients hesitant to decrease medications, so long as there are no significant contraindications to discontinuing the medication.

5. Go slowly. As long as there are no medications that put the patient at risk and require rapid discontinuation, going slowly increases the likelihood of long-term success by:

• permitting careful monitoring for any worsening symptoms
• allowing more time for physiologic readjustment
• enabling the patient and provider to build confidence in the process over time.

With slow discontinuation, normal emotions, such as transient, situationally appropriate anxiety about a life stressor, are less likely to be misinterpreted by the patient or provider as an inability to tolerate medication reduction because there is more opportunity to observe overall trends in symptoms.

6. Replace medications with alternatives. Offering non-pharmacological treatment when possible can greatly facilitate reducing the number of medications. Examples include:

• teaching a patient breathing exercises or mindfulness while preparing to decrease an as needed anxiolytic
• engaging the patient in cognitive-behavioral therapy for insomnia before reducing sleep medications
• working together to identify opportunities for behavioral activation and exercises that are the most achievable for the patient.

This replacement strategy can work in a physiologic sense and address a patient’s fear that medications are “taken away” without alternatives in place.

Although these strategies might not work for every patient and are not recommended for reducing medications that are medically necessary, using this approach will increase the likelihood of long-term success and maintain the patient–provider alliance when reducing unnecessary and potentially risky polypharmacy. An article by Gupta and Cahill¹ describes some similar approaches with additional discussion and considerations.

CASE Stable with a new diagnosis

Ms. B, age 60, has a history of schizophrenia, which has been stable on clozapine, 500 mg/d, for more than 2 decades. After a series of hospitalizations in her 20s and 30s, clozapine was initiated and she has not required additional inpatient psychiatric care. She has been managed in the outpatient setting with standard biweekly absolute neutrophil count (ANC) monitoring. She lives independently and is an active member in her church.

After experiencing rectal bleeding, Ms. B is diagnosed with rectal carcinoma and is scheduled to undergo chemotherapy and radiation treatment.

[polldaddy:9754786]

The authors’ observations

Both clozapine and chemotherapy carry the risk of immunosuppression, presenting a clinical challenge when choosing an appropriate management strategy. However, the risks of stopping clozapine after a long period of symptom stability are substantial, with a relapse rate up to 50%.¹ Among patients taking clozapine, the risk of agranulocytosis and neutropenia are approximately 0.8% and 3%, respectively, and >80% of agranulocyotis cases occur within the first 18 weeks of treatment.^2,3 Although both clozapine and chemotherapy can lead to neutropenia and agranulocytosis, there currently is no evidence of a synergistic effect on bone marrow suppression with simultaneous use of these therapies² nor is there evidence of the combination leading to sustained marrow suppression.⁴

Because of Ms. B’s positive response to clozapine, the risks associated with discontinuing the medication, and the relatively low risk of clozapine contributing to neutropenia after a long period of stabilization, her outpatient psychiatric providers decide to increase ANC monitoring to weekly while she undergoes cancer treatment.

TREATMENT Neutropenia, psychosis

Ms. B continues clozapine during radiation and chemotherapy, but develops leukopenia and neutropenia with a low of 1,220/μL white blood cells and an ANC of 610/μL. Clozapine is stopped, consistent with current recommendations to hold the drug if the neutrophil count is <1,000/μL in a patient without benign ethnic neutropenia, and her outpatient provider monitors her closely. The treatment team does not restart an antipsychotic immediately after discontinuing clozapine because of the risk that other antipsychotics can cause hematologic toxicity or prolong granulocytopenia associated with clozapine.⁵

Approximately 2 weeks later, Ms. B is admitted to a different hospital for altered mental status and is found to have hypo­natremia and rectal bleeding. The workup suggests that her rectal carcinoma has not fully responded to initial therapies, and she likely will require further treatment. Her mental status improves after hyponatremia resolves, but she reports auditory hallucinations and paranoia. Risperidone, 4 mg/d, is initiated to target psychosis.

After discharge, Ms. B develops bilateral upper extremity tremor, which she finds intolerable and attributes to risperidone. She refuses to continue risperidone or try adjunctive medications to address the tremor, but is willing to consider a different antipsychotic. Olanzapine, 10 mg/d, is initiated and risperidone is slowly tapered. During this time, Ms. B experiences increased paranoia and believes that the Internal Revenue Service is calling her. She misses her next appointment.

Later, the fire department finds Ms. B wandering the streets and brings her to the psychiatric emergency room. During the examination, she is disheveled and withdrawn, and unable to reply to simple questions about diet and sleep. When asked why she was in the street, she says that she left her apartment because it was “too messy.” The treatment team learns that she had walked at least 10 miles from her apartment before sitting down by the side of the road and being picked up by the fire department. She reveals that she left her apartment and continued walking because “a man” told her to do so and threatened to harm her if she stopped.

When Ms. B is admitted to the psychiatric service, she is paranoid, disorganized, and guarded. She remains in her room for most of the day and either refuses to talk to providers or curses at them. She often is seen wearing soiled clothing with her hair mussed. She denies having rectal carcinoma, although she expressed understanding of her medical condition <2 months earlier.

[polldaddy:9754787]

The authors’ observations

Clozapine is considered the most efficacious agent for treatment-resistant schizophrenia.⁶ Although non-compliance is the most common reason for discontinuing clozapine, >20% of patients stop clozapine because of adverse effects.⁷ Clozapine often is a drug of last resort because of the need for frequent monitoring and significant side effects; therefore deciding on a next step when clozapine fails or cannot be continued because of other factors can pose a challenge.

Ms. B’s treatment team gave serious consideration to restarting clozapine. However, because it was likely that Ms. B would undergo another round of chemotherapy and possibly radiation, the risk of neutropenia recurring was considered too high. Lithium has been used successfully to manage neutropenia in patients taking clozapine and, for some, adding lithium could help boost white cell count and allow a successful rechallenge with clozapine.^3,8 However, because of Ms. B’s medical comorbidities, including cancer and chronic kidney disease, adding lithium was not thought to be clinically prudent at that time and the treatment team considered other options.

Olanzapine. Although research is limited, studies suggest olanzapine is the most commonly prescribed medication when a patient has to discontinue clozapine,⁷ with comparable response rates in those with refractory schizophrenia.⁹ Therefore, Ms. B was initially maintained on olanzapine, and the dosage increased to 30 mg over the course of 16 days in the hospital. However, she did not respond to the medication, remaining disorganized and paranoid without any notable improvement in her symptoms therefore other treatment options were explored.

Loxapine. Previous limited case reports have shown loxapine to be effective in treating individuals with refractory schizophrenia, either alone or in combination with other antipsychotics.^10,11 FDA-approved in 1975, loxapine was among the last of the typical antipsychotics brought to the U.S. market before the introduction of clozapine, the first atypical.¹² Loxapine is a dibenzoxazepine that has a molecular structure similar to clozapine.¹³ Unlike clozapine, however, loxapine is not known to cause agranulocytosis.¹⁴ Research suggests that although clozapine is oxidized to metabolites that are cytotoxic, loxapine is not, potentially accounting for their different effects on neutrophils.¹⁵

The efficacy of loxapine has shown to be similar to other typical and atypical antipsychotics, with approximately 70% of patients showing improvement.¹⁴ However, loxapine may be overlooked as an option, possibly because it was not included in the CATIE trial and was the last typical antipsychotic to be approved before atypicals were introduced.¹² First available in oral and IM formulations, there has been increased interest in loxapine recently because of the approval of an inhaled formulation in 2012.¹⁶

Although classified as a typical anti­psychotic, studies have suggested that loxapine acts as an atypical at low dosages.^17,18 Previous work suggests, however, that the side effect profile of loxapine is similar to typical antipsychotics.¹⁴ At dosages <50 mg, it results in fewer cases of extrapyramidal side effects than expected with a typical antipsychotic.¹⁸

Loxapine’s binding profile seems to exist along this spectrum of typical to atypical. Tissue-based binding studies have shown a higher 5-HT2 affinity relative to D2, consistent with atypical antipsychotics.¹⁹ Positron emission tomography studies in humans show 5-HT2 saturation of loxapine to be close to equal to D2 binding in loxapine, thus a slightly lower ratio of 5-HT2 to D2 relative to atypicals, but more than that seen with typical antipsychotics.²⁰ These differences between in vitro and in vivo studies may be secondary to the binding of loxapine’s active metabolites, particularly 7- and 8-hydroxyloxapine, which have more dopaminergic activity. In addition to increased 5-HT2A binding compared with typical antipsychotics, loxapine also has a high affinity for the D4 receptors, as well as interacting with other serotonin receptors 5-HT3, 5-HT6, and 5-HT7. Of note this is a similar pattern of binding affinity as seen in clozapine.¹⁹

It should be noted, however, that loxapine may not be an appropriate treatment in all forms of cancer. Similar to other first-generation antipsychotics, it increases prolactin levels, and thus may have a negative clinical impact on patients with prolactin receptor positive breast cancers.^21,22 Finally, although clozapine can result in significant weight gain, dyslipidemia, and hyperglycemia, unlike many antipsychotics, loxapine has been shown to be weight neutral or result in weight loss,¹⁴ making it an option to consider for patients with type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, or cardiovascular disease.

OUTCOME Improvement, stability

Ms. B begins taking loxapine, 10 mg/d, gradually cross-tapered with olanzapine, increasing loxapine by 10 mg every 2 to 3 days (Figure). After 8 days, when the dosage has reached 40 mg/d, Ms. B’s treatment team begins to observe a consistent change in her behavior. Ms. B comes into the interview room, where previously the team had to see her in her own room because she refused to come out. She also tolerates an extensive interview, even sharing parts of her history without prompting, and is able to discuss her treatment. Ms. B continues to express some paranoia regarding the treatment team. On day 12, receiving loxapine, 50 mg/d, Ms. B says that she likes the new medication and feels she is doing well with it. She becomes less reclusive and begins socializing with other patients. By day 19, receiving loxapine, 80 mg/d, a nurse, who knows Ms. B from the outpatient facility, visits the unit and reports that Ms. B is at her baseline.

At discharge, Ms. B is noted to be “bright,” well organized, neatly dressed, and wearing makeup. Her paranoia and auditory hallucinations have almost completely resolved. She is social, engages appropriately with the treatment team, and is able to describe a plan for self-care after discharge including following up with her oncologist. Her white blood cell counts were carefully monitored throughout her admission and are within normal limits when she is discharged.

One year later, Ms. B remains taking loxapine, 70 mg/d. Although she continues to report mild paranoia, she is living independently in her apartment and attends church regularly.

CASE Stable with a new diagnosis

Ms. B, age 60, has a history of schizophrenia, which has been stable on clozapine, 500 mg/d, for more than 2 decades. After a series of hospitalizations in her 20s and 30s, clozapine was initiated and she has not required additional inpatient psychiatric care. She has been managed in the outpatient setting with standard biweekly absolute neutrophil count (ANC) monitoring. She lives independently and is an active member in her church.

After experiencing rectal bleeding, Ms. B is diagnosed with rectal carcinoma and is scheduled to undergo chemotherapy and radiation treatment.

[polldaddy:9754786]

The authors’ observations

Both clozapine and chemotherapy carry the risk of immunosuppression, presenting a clinical challenge when choosing an appropriate management strategy. However, the risks of stopping clozapine after a long period of symptom stability are substantial, with a relapse rate up to 50%.¹ Among patients taking clozapine, the risk of agranulocytosis and neutropenia are approximately 0.8% and 3%, respectively, and >80% of agranulocyotis cases occur within the first 18 weeks of treatment.^2,3 Although both clozapine and chemotherapy can lead to neutropenia and agranulocytosis, there currently is no evidence of a synergistic effect on bone marrow suppression with simultaneous use of these therapies² nor is there evidence of the combination leading to sustained marrow suppression.⁴

Because of Ms. B’s positive response to clozapine, the risks associated with discontinuing the medication, and the relatively low risk of clozapine contributing to neutropenia after a long period of stabilization, her outpatient psychiatric providers decide to increase ANC monitoring to weekly while she undergoes cancer treatment.

TREATMENT Neutropenia, psychosis

Ms. B continues clozapine during radiation and chemotherapy, but develops leukopenia and neutropenia with a low of 1,220/μL white blood cells and an ANC of 610/μL. Clozapine is stopped, consistent with current recommendations to hold the drug if the neutrophil count is <1,000/μL in a patient without benign ethnic neutropenia, and her outpatient provider monitors her closely. The treatment team does not restart an antipsychotic immediately after discontinuing clozapine because of the risk that other antipsychotics can cause hematologic toxicity or prolong granulocytopenia associated with clozapine.⁵

Approximately 2 weeks later, Ms. B is admitted to a different hospital for altered mental status and is found to have hypo­natremia and rectal bleeding. The workup suggests that her rectal carcinoma has not fully responded to initial therapies, and she likely will require further treatment. Her mental status improves after hyponatremia resolves, but she reports auditory hallucinations and paranoia. Risperidone, 4 mg/d, is initiated to target psychosis.

After discharge, Ms. B develops bilateral upper extremity tremor, which she finds intolerable and attributes to risperidone. She refuses to continue risperidone or try adjunctive medications to address the tremor, but is willing to consider a different antipsychotic. Olanzapine, 10 mg/d, is initiated and risperidone is slowly tapered. During this time, Ms. B experiences increased paranoia and believes that the Internal Revenue Service is calling her. She misses her next appointment.

Later, the fire department finds Ms. B wandering the streets and brings her to the psychiatric emergency room. During the examination, she is disheveled and withdrawn, and unable to reply to simple questions about diet and sleep. When asked why she was in the street, she says that she left her apartment because it was “too messy.” The treatment team learns that she had walked at least 10 miles from her apartment before sitting down by the side of the road and being picked up by the fire department. She reveals that she left her apartment and continued walking because “a man” told her to do so and threatened to harm her if she stopped.

When Ms. B is admitted to the psychiatric service, she is paranoid, disorganized, and guarded. She remains in her room for most of the day and either refuses to talk to providers or curses at them. She often is seen wearing soiled clothing with her hair mussed. She denies having rectal carcinoma, although she expressed understanding of her medical condition <2 months earlier.

[polldaddy:9754787]

The authors’ observations

Clozapine is considered the most efficacious agent for treatment-resistant schizophrenia.⁶ Although non-compliance is the most common reason for discontinuing clozapine, >20% of patients stop clozapine because of adverse effects.⁷ Clozapine often is a drug of last resort because of the need for frequent monitoring and significant side effects; therefore deciding on a next step when clozapine fails or cannot be continued because of other factors can pose a challenge.

Ms. B’s treatment team gave serious consideration to restarting clozapine. However, because it was likely that Ms. B would undergo another round of chemotherapy and possibly radiation, the risk of neutropenia recurring was considered too high. Lithium has been used successfully to manage neutropenia in patients taking clozapine and, for some, adding lithium could help boost white cell count and allow a successful rechallenge with clozapine.^3,8 However, because of Ms. B’s medical comorbidities, including cancer and chronic kidney disease, adding lithium was not thought to be clinically prudent at that time and the treatment team considered other options.

Olanzapine. Although research is limited, studies suggest olanzapine is the most commonly prescribed medication when a patient has to discontinue clozapine,⁷ with comparable response rates in those with refractory schizophrenia.⁹ Therefore, Ms. B was initially maintained on olanzapine, and the dosage increased to 30 mg over the course of 16 days in the hospital. However, she did not respond to the medication, remaining disorganized and paranoid without any notable improvement in her symptoms therefore other treatment options were explored.

Loxapine. Previous limited case reports have shown loxapine to be effective in treating individuals with refractory schizophrenia, either alone or in combination with other antipsychotics.^10,11 FDA-approved in 1975, loxapine was among the last of the typical antipsychotics brought to the U.S. market before the introduction of clozapine, the first atypical.¹² Loxapine is a dibenzoxazepine that has a molecular structure similar to clozapine.¹³ Unlike clozapine, however, loxapine is not known to cause agranulocytosis.¹⁴ Research suggests that although clozapine is oxidized to metabolites that are cytotoxic, loxapine is not, potentially accounting for their different effects on neutrophils.¹⁵

The efficacy of loxapine has shown to be similar to other typical and atypical antipsychotics, with approximately 70% of patients showing improvement.¹⁴ However, loxapine may be overlooked as an option, possibly because it was not included in the CATIE trial and was the last typical antipsychotic to be approved before atypicals were introduced.¹² First available in oral and IM formulations, there has been increased interest in loxapine recently because of the approval of an inhaled formulation in 2012.¹⁶

Although classified as a typical anti­psychotic, studies have suggested that loxapine acts as an atypical at low dosages.^17,18 Previous work suggests, however, that the side effect profile of loxapine is similar to typical antipsychotics.¹⁴ At dosages <50 mg, it results in fewer cases of extrapyramidal side effects than expected with a typical antipsychotic.¹⁸

Loxapine’s binding profile seems to exist along this spectrum of typical to atypical. Tissue-based binding studies have shown a higher 5-HT2 affinity relative to D2, consistent with atypical antipsychotics.¹⁹ Positron emission tomography studies in humans show 5-HT2 saturation of loxapine to be close to equal to D2 binding in loxapine, thus a slightly lower ratio of 5-HT2 to D2 relative to atypicals, but more than that seen with typical antipsychotics.²⁰ These differences between in vitro and in vivo studies may be secondary to the binding of loxapine’s active metabolites, particularly 7- and 8-hydroxyloxapine, which have more dopaminergic activity. In addition to increased 5-HT2A binding compared with typical antipsychotics, loxapine also has a high affinity for the D4 receptors, as well as interacting with other serotonin receptors 5-HT3, 5-HT6, and 5-HT7. Of note this is a similar pattern of binding affinity as seen in clozapine.¹⁹

It should be noted, however, that loxapine may not be an appropriate treatment in all forms of cancer. Similar to other first-generation antipsychotics, it increases prolactin levels, and thus may have a negative clinical impact on patients with prolactin receptor positive breast cancers.^21,22 Finally, although clozapine can result in significant weight gain, dyslipidemia, and hyperglycemia, unlike many antipsychotics, loxapine has been shown to be weight neutral or result in weight loss,¹⁴ making it an option to consider for patients with type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, or cardiovascular disease.

OUTCOME Improvement, stability

Ms. B begins taking loxapine, 10 mg/d, gradually cross-tapered with olanzapine, increasing loxapine by 10 mg every 2 to 3 days (Figure). After 8 days, when the dosage has reached 40 mg/d, Ms. B’s treatment team begins to observe a consistent change in her behavior. Ms. B comes into the interview room, where previously the team had to see her in her own room because she refused to come out. She also tolerates an extensive interview, even sharing parts of her history without prompting, and is able to discuss her treatment. Ms. B continues to express some paranoia regarding the treatment team. On day 12, receiving loxapine, 50 mg/d, Ms. B says that she likes the new medication and feels she is doing well with it. She becomes less reclusive and begins socializing with other patients. By day 19, receiving loxapine, 80 mg/d, a nurse, who knows Ms. B from the outpatient facility, visits the unit and reports that Ms. B is at her baseline.

At discharge, Ms. B is noted to be “bright,” well organized, neatly dressed, and wearing makeup. Her paranoia and auditory hallucinations have almost completely resolved. She is social, engages appropriately with the treatment team, and is able to describe a plan for self-care after discharge including following up with her oncologist. Her white blood cell counts were carefully monitored throughout her admission and are within normal limits when she is discharged.

One year later, Ms. B remains taking loxapine, 70 mg/d. Although she continues to report mild paranoia, she is living independently in her apartment and attends church regularly.

CASE Stable with a new diagnosis

Ms. B, age 60, has a history of schizophrenia, which has been stable on clozapine, 500 mg/d, for more than 2 decades. After a series of hospitalizations in her 20s and 30s, clozapine was initiated and she has not required additional inpatient psychiatric care. She has been managed in the outpatient setting with standard biweekly absolute neutrophil count (ANC) monitoring. She lives independently and is an active member in her church.

After experiencing rectal bleeding, Ms. B is diagnosed with rectal carcinoma and is scheduled to undergo chemotherapy and radiation treatment.

[polldaddy:9754786]

The authors’ observations

Both clozapine and chemotherapy carry the risk of immunosuppression, presenting a clinical challenge when choosing an appropriate management strategy. However, the risks of stopping clozapine after a long period of symptom stability are substantial, with a relapse rate up to 50%.¹ Among patients taking clozapine, the risk of agranulocytosis and neutropenia are approximately 0.8% and 3%, respectively, and >80% of agranulocyotis cases occur within the first 18 weeks of treatment.^2,3 Although both clozapine and chemotherapy can lead to neutropenia and agranulocytosis, there currently is no evidence of a synergistic effect on bone marrow suppression with simultaneous use of these therapies² nor is there evidence of the combination leading to sustained marrow suppression.⁴

Because of Ms. B’s positive response to clozapine, the risks associated with discontinuing the medication, and the relatively low risk of clozapine contributing to neutropenia after a long period of stabilization, her outpatient psychiatric providers decide to increase ANC monitoring to weekly while she undergoes cancer treatment.

TREATMENT Neutropenia, psychosis

Ms. B continues clozapine during radiation and chemotherapy, but develops leukopenia and neutropenia with a low of 1,220/μL white blood cells and an ANC of 610/μL. Clozapine is stopped, consistent with current recommendations to hold the drug if the neutrophil count is <1,000/μL in a patient without benign ethnic neutropenia, and her outpatient provider monitors her closely. The treatment team does not restart an antipsychotic immediately after discontinuing clozapine because of the risk that other antipsychotics can cause hematologic toxicity or prolong granulocytopenia associated with clozapine.⁵

Approximately 2 weeks later, Ms. B is admitted to a different hospital for altered mental status and is found to have hypo­natremia and rectal bleeding. The workup suggests that her rectal carcinoma has not fully responded to initial therapies, and she likely will require further treatment. Her mental status improves after hyponatremia resolves, but she reports auditory hallucinations and paranoia. Risperidone, 4 mg/d, is initiated to target psychosis.

After discharge, Ms. B develops bilateral upper extremity tremor, which she finds intolerable and attributes to risperidone. She refuses to continue risperidone or try adjunctive medications to address the tremor, but is willing to consider a different antipsychotic. Olanzapine, 10 mg/d, is initiated and risperidone is slowly tapered. During this time, Ms. B experiences increased paranoia and believes that the Internal Revenue Service is calling her. She misses her next appointment.

Later, the fire department finds Ms. B wandering the streets and brings her to the psychiatric emergency room. During the examination, she is disheveled and withdrawn, and unable to reply to simple questions about diet and sleep. When asked why she was in the street, she says that she left her apartment because it was “too messy.” The treatment team learns that she had walked at least 10 miles from her apartment before sitting down by the side of the road and being picked up by the fire department. She reveals that she left her apartment and continued walking because “a man” told her to do so and threatened to harm her if she stopped.

When Ms. B is admitted to the psychiatric service, she is paranoid, disorganized, and guarded. She remains in her room for most of the day and either refuses to talk to providers or curses at them. She often is seen wearing soiled clothing with her hair mussed. She denies having rectal carcinoma, although she expressed understanding of her medical condition <2 months earlier.

[polldaddy:9754787]

The authors’ observations

Clozapine is considered the most efficacious agent for treatment-resistant schizophrenia.⁶ Although non-compliance is the most common reason for discontinuing clozapine, >20% of patients stop clozapine because of adverse effects.⁷ Clozapine often is a drug of last resort because of the need for frequent monitoring and significant side effects; therefore deciding on a next step when clozapine fails or cannot be continued because of other factors can pose a challenge.

Ms. B’s treatment team gave serious consideration to restarting clozapine. However, because it was likely that Ms. B would undergo another round of chemotherapy and possibly radiation, the risk of neutropenia recurring was considered too high. Lithium has been used successfully to manage neutropenia in patients taking clozapine and, for some, adding lithium could help boost white cell count and allow a successful rechallenge with clozapine.^3,8 However, because of Ms. B’s medical comorbidities, including cancer and chronic kidney disease, adding lithium was not thought to be clinically prudent at that time and the treatment team considered other options.

Olanzapine. Although research is limited, studies suggest olanzapine is the most commonly prescribed medication when a patient has to discontinue clozapine,⁷ with comparable response rates in those with refractory schizophrenia.⁹ Therefore, Ms. B was initially maintained on olanzapine, and the dosage increased to 30 mg over the course of 16 days in the hospital. However, she did not respond to the medication, remaining disorganized and paranoid without any notable improvement in her symptoms therefore other treatment options were explored.

Loxapine. Previous limited case reports have shown loxapine to be effective in treating individuals with refractory schizophrenia, either alone or in combination with other antipsychotics.^10,11 FDA-approved in 1975, loxapine was among the last of the typical antipsychotics brought to the U.S. market before the introduction of clozapine, the first atypical.¹² Loxapine is a dibenzoxazepine that has a molecular structure similar to clozapine.¹³ Unlike clozapine, however, loxapine is not known to cause agranulocytosis.¹⁴ Research suggests that although clozapine is oxidized to metabolites that are cytotoxic, loxapine is not, potentially accounting for their different effects on neutrophils.¹⁵

The efficacy of loxapine has shown to be similar to other typical and atypical antipsychotics, with approximately 70% of patients showing improvement.¹⁴ However, loxapine may be overlooked as an option, possibly because it was not included in the CATIE trial and was the last typical antipsychotic to be approved before atypicals were introduced.¹² First available in oral and IM formulations, there has been increased interest in loxapine recently because of the approval of an inhaled formulation in 2012.¹⁶

Although classified as a typical anti­psychotic, studies have suggested that loxapine acts as an atypical at low dosages.^17,18 Previous work suggests, however, that the side effect profile of loxapine is similar to typical antipsychotics.¹⁴ At dosages <50 mg, it results in fewer cases of extrapyramidal side effects than expected with a typical antipsychotic.¹⁸

Loxapine’s binding profile seems to exist along this spectrum of typical to atypical. Tissue-based binding studies have shown a higher 5-HT2 affinity relative to D2, consistent with atypical antipsychotics.¹⁹ Positron emission tomography studies in humans show 5-HT2 saturation of loxapine to be close to equal to D2 binding in loxapine, thus a slightly lower ratio of 5-HT2 to D2 relative to atypicals, but more than that seen with typical antipsychotics.²⁰ These differences between in vitro and in vivo studies may be secondary to the binding of loxapine’s active metabolites, particularly 7- and 8-hydroxyloxapine, which have more dopaminergic activity. In addition to increased 5-HT2A binding compared with typical antipsychotics, loxapine also has a high affinity for the D4 receptors, as well as interacting with other serotonin receptors 5-HT3, 5-HT6, and 5-HT7. Of note this is a similar pattern of binding affinity as seen in clozapine.¹⁹

It should be noted, however, that loxapine may not be an appropriate treatment in all forms of cancer. Similar to other first-generation antipsychotics, it increases prolactin levels, and thus may have a negative clinical impact on patients with prolactin receptor positive breast cancers.^21,22 Finally, although clozapine can result in significant weight gain, dyslipidemia, and hyperglycemia, unlike many antipsychotics, loxapine has been shown to be weight neutral or result in weight loss,¹⁴ making it an option to consider for patients with type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, or cardiovascular disease.

OUTCOME Improvement, stability

Ms. B begins taking loxapine, 10 mg/d, gradually cross-tapered with olanzapine, increasing loxapine by 10 mg every 2 to 3 days (Figure). After 8 days, when the dosage has reached 40 mg/d, Ms. B’s treatment team begins to observe a consistent change in her behavior. Ms. B comes into the interview room, where previously the team had to see her in her own room because she refused to come out. She also tolerates an extensive interview, even sharing parts of her history without prompting, and is able to discuss her treatment. Ms. B continues to express some paranoia regarding the treatment team. On day 12, receiving loxapine, 50 mg/d, Ms. B says that she likes the new medication and feels she is doing well with it. She becomes less reclusive and begins socializing with other patients. By day 19, receiving loxapine, 80 mg/d, a nurse, who knows Ms. B from the outpatient facility, visits the unit and reports that Ms. B is at her baseline.

At discharge, Ms. B is noted to be “bright,” well organized, neatly dressed, and wearing makeup. Her paranoia and auditory hallucinations have almost completely resolved. She is social, engages appropriately with the treatment team, and is able to describe a plan for self-care after discharge including following up with her oncologist. Her white blood cell counts were carefully monitored throughout her admission and are within normal limits when she is discharged.

One year later, Ms. B remains taking loxapine, 70 mg/d. Although she continues to report mild paranoia, she is living independently in her apartment and attends church regularly.