The diagnosis in this patient is ulcerative colitis (UC) on the basis of physical examination, laboratory values, and endoscopy. However, this patient has the most extensive form, pancolitis, which means that inflammation and damage extend the entire length of the colon. 

The diagnosis of UC is best made with endoscopy and mucosal biopsy for histopathology. Characteristic findings are abnormal erythematous mucosa, with or without ulceration, extending from the rectum to a part or all of the colon and uniform inflammation, without intervening areas of normal mucosa (skip lesions tend to characterize Crohn disease). Contact bleeding may also be observed, with mucus identified in the lumen of the bowel.

The bowel wall is thin or of normal thickness, but edema, accumulation of fat, and hypertrophy of the muscle layer may give it the appearance of a thickened bowel wall. The disease is largely confined to the mucosa and, to a lesser extent, the submucosa.

Laboratory studies are helpful to exclude other diagnoses and assess the patient's nutritional status, and serologic markers aid in the differential diagnosis of inflammatory bowel disease. Radiographic imaging has an important role in differentiation of UC from Crohn disease. Fistulas or the presence of small bowel disease are seen only in Crohn disease. 

According the American Gastroenterological Association, drug classes for the long-term management of moderate to severe UC include tumor necrosis factor–alpha antagonists, anti-integrin agent (vedolizumab), Janus kinase inhibitor (tofacitinib), interleukin 12/23 antagonist (ustekinumab), and immunomodulators (thiopurines, methotrexate). Most drugs that are initiated for the induction of remission are continued as maintenance therapy if they are effective. This is not the case, however, if corticosteroids or cyclosporine are necessary to induce remission.

This patient's pancolitis presentation is also acute and severe, defined as more than 6 bloody bowel movements per day plus one of the following: fever > 100.4 °F, hemoglobin level < 10.5 g/dL, heart rate > 90 beats/min, erythrocyte sedimentation rate > 30 mm/h, or C-reactive protein level > 30 mg/dL). This requires hospitalization and treatment with intravenous corticosteroids (hydrocortisone 400 mg/d or methylprednisolone 60 mg/d). Considered a medical emergency, the situation requires prompt recognition and multidisciplinary management. In patients who fail therapy with 3-5 days of intravenous corticosteroids, medical rescue therapy is indicated with either infliximab or cyclosporine. If all measures fail, the patient may need emergency surgery.

Hospitalized patients with acute severe UC have short-term colectomy rates of 25%-30%.

Bhupinder S. Anand, MD, Professor, Department of Medicine, Baylor College of Medicine, Houston, TX

Bhupinder S. Anand, MD, has disclosed no relevant financial relationships.

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

The diagnosis in this patient is ulcerative colitis (UC) on the basis of physical examination, laboratory values, and endoscopy. However, this patient has the most extensive form, pancolitis, which means that inflammation and damage extend the entire length of the colon. 

The diagnosis of UC is best made with endoscopy and mucosal biopsy for histopathology. Characteristic findings are abnormal erythematous mucosa, with or without ulceration, extending from the rectum to a part or all of the colon and uniform inflammation, without intervening areas of normal mucosa (skip lesions tend to characterize Crohn disease). Contact bleeding may also be observed, with mucus identified in the lumen of the bowel.

The bowel wall is thin or of normal thickness, but edema, accumulation of fat, and hypertrophy of the muscle layer may give it the appearance of a thickened bowel wall. The disease is largely confined to the mucosa and, to a lesser extent, the submucosa.

Laboratory studies are helpful to exclude other diagnoses and assess the patient's nutritional status, and serologic markers aid in the differential diagnosis of inflammatory bowel disease. Radiographic imaging has an important role in differentiation of UC from Crohn disease. Fistulas or the presence of small bowel disease are seen only in Crohn disease. 

According the American Gastroenterological Association, drug classes for the long-term management of moderate to severe UC include tumor necrosis factor–alpha antagonists, anti-integrin agent (vedolizumab), Janus kinase inhibitor (tofacitinib), interleukin 12/23 antagonist (ustekinumab), and immunomodulators (thiopurines, methotrexate). Most drugs that are initiated for the induction of remission are continued as maintenance therapy if they are effective. This is not the case, however, if corticosteroids or cyclosporine are necessary to induce remission.

This patient's pancolitis presentation is also acute and severe, defined as more than 6 bloody bowel movements per day plus one of the following: fever > 100.4 °F, hemoglobin level < 10.5 g/dL, heart rate > 90 beats/min, erythrocyte sedimentation rate > 30 mm/h, or C-reactive protein level > 30 mg/dL). This requires hospitalization and treatment with intravenous corticosteroids (hydrocortisone 400 mg/d or methylprednisolone 60 mg/d). Considered a medical emergency, the situation requires prompt recognition and multidisciplinary management. In patients who fail therapy with 3-5 days of intravenous corticosteroids, medical rescue therapy is indicated with either infliximab or cyclosporine. If all measures fail, the patient may need emergency surgery.

Hospitalized patients with acute severe UC have short-term colectomy rates of 25%-30%.

Bhupinder S. Anand, MD, Professor, Department of Medicine, Baylor College of Medicine, Houston, TX

Bhupinder S. Anand, MD, has disclosed no relevant financial relationships.

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

The diagnosis in this patient is ulcerative colitis (UC) on the basis of physical examination, laboratory values, and endoscopy. However, this patient has the most extensive form, pancolitis, which means that inflammation and damage extend the entire length of the colon. 

The diagnosis of UC is best made with endoscopy and mucosal biopsy for histopathology. Characteristic findings are abnormal erythematous mucosa, with or without ulceration, extending from the rectum to a part or all of the colon and uniform inflammation, without intervening areas of normal mucosa (skip lesions tend to characterize Crohn disease). Contact bleeding may also be observed, with mucus identified in the lumen of the bowel.

The bowel wall is thin or of normal thickness, but edema, accumulation of fat, and hypertrophy of the muscle layer may give it the appearance of a thickened bowel wall. The disease is largely confined to the mucosa and, to a lesser extent, the submucosa.

Laboratory studies are helpful to exclude other diagnoses and assess the patient's nutritional status, and serologic markers aid in the differential diagnosis of inflammatory bowel disease. Radiographic imaging has an important role in differentiation of UC from Crohn disease. Fistulas or the presence of small bowel disease are seen only in Crohn disease. 

According the American Gastroenterological Association, drug classes for the long-term management of moderate to severe UC include tumor necrosis factor–alpha antagonists, anti-integrin agent (vedolizumab), Janus kinase inhibitor (tofacitinib), interleukin 12/23 antagonist (ustekinumab), and immunomodulators (thiopurines, methotrexate). Most drugs that are initiated for the induction of remission are continued as maintenance therapy if they are effective. This is not the case, however, if corticosteroids or cyclosporine are necessary to induce remission.

This patient's pancolitis presentation is also acute and severe, defined as more than 6 bloody bowel movements per day plus one of the following: fever > 100.4 °F, hemoglobin level < 10.5 g/dL, heart rate > 90 beats/min, erythrocyte sedimentation rate > 30 mm/h, or C-reactive protein level > 30 mg/dL). This requires hospitalization and treatment with intravenous corticosteroids (hydrocortisone 400 mg/d or methylprednisolone 60 mg/d). Considered a medical emergency, the situation requires prompt recognition and multidisciplinary management. In patients who fail therapy with 3-5 days of intravenous corticosteroids, medical rescue therapy is indicated with either infliximab or cyclosporine. If all measures fail, the patient may need emergency surgery.

Hospitalized patients with acute severe UC have short-term colectomy rates of 25%-30%.

Bhupinder S. Anand, MD, Professor, Department of Medicine, Baylor College of Medicine, Houston, TX

Bhupinder S. Anand, MD, has disclosed no relevant financial relationships.

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

Older adults who have spent time in the intensive care unit have double the risk of developing dementia in later years, compared with older adults who have never stayed in the ICU, new research suggests.

“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.

“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.

The findings were presented at the Alzheimer’s Association International Conference.
 

Hidden risk factor?

ICU hospitalization as a result of critical illness has been linked to subsequent cognitive impairment in older patients. However, how ICU hospitalization relates to the long-term risk of developing Alzheimer’s and other age-related dementias is unknown.

“Given the high rate of ICU hospitalization in older persons, especially during the COVID-19 pandemic, it is critical to explore this relationship, Dr. James said.

The Rush team assessed the impact of an ICU stay on dementia risk in 3,822 older adults (mean age, 77 years) without known dementia at baseline participating in five diverse epidemiologic cohorts.

Participants were checked annually for development of Alzheimer’s and all-type dementia using standardized cognitive assessments.

Over an average of 7.8 years, 1,991 (52%) adults had at least one ICU stay; 1,031 (27%) had an ICU stay before study enrollment; and 961 (25%) had an ICU stay during the study period.

In models adjusted for age, sex, education, and race, ICU hospitalization was associated with 63% higher risk of Alzheimer’s dementia (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) and 71% higher risk of all-type dementia (HR, 1.71; 95% CI, 1.48-1.97).

In models further adjusted for other health factors such as vascular risk factors and disease, other chronic medical conditions and functional disabilities, the association was even stronger: ICU hospitalization was associated with roughly double the risk of Alzheimer’s dementia (HR 2.10; 95% CI, 1.66-2.65) and all-type dementia (HR, 2.20; 95% CI, 1.75-2.77).

Dr. James said in an interview that it remains unclear why an ICU stay may raise the dementia risk.

“This study was not designed to assess the causes of the higher risk of dementia in persons who had ICU hospitalizations. However, researchers have looked into a number of factors that could account for this increased risk,” he explained.

One is critical illness itself that leads to hospitalization, which could result in damage to the brain; for example, severe COVID-19 has been shown to directly harm the brain, Dr. James said.

He also noted that specific events experienced during ICU stay have been shown to increase risk for cognitive impairment, including infection and severe sepsis, acute dialysis, neurologic dysfunction and delirium, and sedation.
 

Important work

Commenting on the study, Heather Snyder, PhD, vice president of medical & scientific relations at the Alzheimer’s Association, said what’s interesting about the study is that it looks at individuals in the ICU, regardless of the cause.

“The study shows that having some type of health issue that results in some type of ICU stay is associated with an increased risk of declining cognition,” Dr. Snyder said.

“That’s really important,” she said, “especially given the increase in individuals, particularly those 60 and older, who did experience an ICU stay over the last couple of years and understanding how that might impact their long-term risk related to Alzheimer’s and other changes in memory.”

“If an individual has been in the ICU, that should be part of the conversation with their physician or health care provider,” Dr. Snyder advised.

The study was funded by the National Institute on Aging. Dr. James and Dr. Snyder disclosed no relevant financial relationships.

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

Older adults who have spent time in the intensive care unit have double the risk of developing dementia in later years, compared with older adults who have never stayed in the ICU, new research suggests.

“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.

“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.

The findings were presented at the Alzheimer’s Association International Conference.
 

Hidden risk factor?

ICU hospitalization as a result of critical illness has been linked to subsequent cognitive impairment in older patients. However, how ICU hospitalization relates to the long-term risk of developing Alzheimer’s and other age-related dementias is unknown.

“Given the high rate of ICU hospitalization in older persons, especially during the COVID-19 pandemic, it is critical to explore this relationship, Dr. James said.

The Rush team assessed the impact of an ICU stay on dementia risk in 3,822 older adults (mean age, 77 years) without known dementia at baseline participating in five diverse epidemiologic cohorts.

Participants were checked annually for development of Alzheimer’s and all-type dementia using standardized cognitive assessments.

Over an average of 7.8 years, 1,991 (52%) adults had at least one ICU stay; 1,031 (27%) had an ICU stay before study enrollment; and 961 (25%) had an ICU stay during the study period.

In models adjusted for age, sex, education, and race, ICU hospitalization was associated with 63% higher risk of Alzheimer’s dementia (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) and 71% higher risk of all-type dementia (HR, 1.71; 95% CI, 1.48-1.97).

In models further adjusted for other health factors such as vascular risk factors and disease, other chronic medical conditions and functional disabilities, the association was even stronger: ICU hospitalization was associated with roughly double the risk of Alzheimer’s dementia (HR 2.10; 95% CI, 1.66-2.65) and all-type dementia (HR, 2.20; 95% CI, 1.75-2.77).

Dr. James said in an interview that it remains unclear why an ICU stay may raise the dementia risk.

“This study was not designed to assess the causes of the higher risk of dementia in persons who had ICU hospitalizations. However, researchers have looked into a number of factors that could account for this increased risk,” he explained.

One is critical illness itself that leads to hospitalization, which could result in damage to the brain; for example, severe COVID-19 has been shown to directly harm the brain, Dr. James said.

He also noted that specific events experienced during ICU stay have been shown to increase risk for cognitive impairment, including infection and severe sepsis, acute dialysis, neurologic dysfunction and delirium, and sedation.
 

Important work

Commenting on the study, Heather Snyder, PhD, vice president of medical & scientific relations at the Alzheimer’s Association, said what’s interesting about the study is that it looks at individuals in the ICU, regardless of the cause.

“The study shows that having some type of health issue that results in some type of ICU stay is associated with an increased risk of declining cognition,” Dr. Snyder said.

“That’s really important,” she said, “especially given the increase in individuals, particularly those 60 and older, who did experience an ICU stay over the last couple of years and understanding how that might impact their long-term risk related to Alzheimer’s and other changes in memory.”

“If an individual has been in the ICU, that should be part of the conversation with their physician or health care provider,” Dr. Snyder advised.

The study was funded by the National Institute on Aging. Dr. James and Dr. Snyder disclosed no relevant financial relationships.

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

Older adults who have spent time in the intensive care unit have double the risk of developing dementia in later years, compared with older adults who have never stayed in the ICU, new research suggests.

“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.

“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.

The findings were presented at the Alzheimer’s Association International Conference.
 

Hidden risk factor?

ICU hospitalization as a result of critical illness has been linked to subsequent cognitive impairment in older patients. However, how ICU hospitalization relates to the long-term risk of developing Alzheimer’s and other age-related dementias is unknown.

“Given the high rate of ICU hospitalization in older persons, especially during the COVID-19 pandemic, it is critical to explore this relationship, Dr. James said.

The Rush team assessed the impact of an ICU stay on dementia risk in 3,822 older adults (mean age, 77 years) without known dementia at baseline participating in five diverse epidemiologic cohorts.

Participants were checked annually for development of Alzheimer’s and all-type dementia using standardized cognitive assessments.

Over an average of 7.8 years, 1,991 (52%) adults had at least one ICU stay; 1,031 (27%) had an ICU stay before study enrollment; and 961 (25%) had an ICU stay during the study period.

In models adjusted for age, sex, education, and race, ICU hospitalization was associated with 63% higher risk of Alzheimer’s dementia (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) and 71% higher risk of all-type dementia (HR, 1.71; 95% CI, 1.48-1.97).

In models further adjusted for other health factors such as vascular risk factors and disease, other chronic medical conditions and functional disabilities, the association was even stronger: ICU hospitalization was associated with roughly double the risk of Alzheimer’s dementia (HR 2.10; 95% CI, 1.66-2.65) and all-type dementia (HR, 2.20; 95% CI, 1.75-2.77).

Dr. James said in an interview that it remains unclear why an ICU stay may raise the dementia risk.

“This study was not designed to assess the causes of the higher risk of dementia in persons who had ICU hospitalizations. However, researchers have looked into a number of factors that could account for this increased risk,” he explained.

One is critical illness itself that leads to hospitalization, which could result in damage to the brain; for example, severe COVID-19 has been shown to directly harm the brain, Dr. James said.

He also noted that specific events experienced during ICU stay have been shown to increase risk for cognitive impairment, including infection and severe sepsis, acute dialysis, neurologic dysfunction and delirium, and sedation.
 

Important work

Commenting on the study, Heather Snyder, PhD, vice president of medical & scientific relations at the Alzheimer’s Association, said what’s interesting about the study is that it looks at individuals in the ICU, regardless of the cause.

“The study shows that having some type of health issue that results in some type of ICU stay is associated with an increased risk of declining cognition,” Dr. Snyder said.

“That’s really important,” she said, “especially given the increase in individuals, particularly those 60 and older, who did experience an ICU stay over the last couple of years and understanding how that might impact their long-term risk related to Alzheimer’s and other changes in memory.”

“If an individual has been in the ICU, that should be part of the conversation with their physician or health care provider,” Dr. Snyder advised.

The study was funded by the National Institute on Aging. Dr. James and Dr. Snyder disclosed no relevant financial relationships.

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

Evusheld (AstraZeneca), a medication used to prevent SARS-CoV-2 infection in patients at high risk, has problems: Namely, that supplies of the potentially lifesaving drug outweigh demand.

At least 7 million people who are immunocompromised could benefit from it, as could many others who are undergoing cancer treatment, have received a transplant, or who are allergic to the COVID-19 vaccines. The medication has laboratory-produced antibodies against SARS-CoV-2 and helps the body protect itself. It can slash the chances of becoming infected by 77%, according to the U.S. Food and Drug Administration.

And it’s free to eligible patients (although there may be an out-of-pocket administrative fee in some cases).

Despite all those lifesaving benefits, fewer than 25% of available doses have been used.

To meet demand, the Biden administration secured 1.7 million doses of the medicine, which was granted emergency use authorization by the FDA in December 2021. As of July 25, however, 793,348 doses have been ordered by the administration sites, and only 398,181 doses have been reported as used, a spokesperson for the Department of Health & Human Services tells this news organization.

Each week, a certain amount of doses from the 1.7 million dose stockpile is made available to state and territorial health departments. States have not been asking for their full allotment, the spokesperson said July 28.

Now, HHS and AstraZeneca have taken a number of steps to increase awareness of the medication and access to it.

• On July 27, HHS announced that individual providers and smaller sites of care that don’t currently receive Evusheld through the federal distribution process via the HHS Health Partner Order Portal can now order up to three patient courses of the medicine. These can be 
• Health care providers can use the HHS’s COVID-19 Therapeutics Locator to find Evusheld in their area.
• AstraZeneca has launched a new website with educational materials and says it is working closely with patient and professional groups to inform patients and health care providers.
• A direct-to-consumer ad launched on June 22 and will run in the United States online and on TV (Yahoo, Fox, CBS Sports, MSN, ESPN) and be amplified on social and digital channels through year’s end, an AstraZeneca spokesperson said in an interview.
• AstraZeneca set up a toll-free number for providers: 1-833-EVUSHLD.

Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other health care facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.

Studies have found that the medication decreases the risk of getting COVID-19 for up to 6 months after it is given. The FDA recommends repeat dosing every 6 months with the doses of 300 mg of each monoclonal antibody. In clinical trials, Evusheld reduced the incidence of COVID-19 symptomatic illness by 77%, compared with placebo.

Physicians monitor patients for an hour after administering Evusheld for allergic reactions. Other possible side effects include cardiac events, but they are not common.
 

Doctors and patients weigh in

Physicians – and patients – from the United States to the United Kingdom and beyond are questioning why the medication is underused while lauding the recent efforts to expand access and increase awareness.

The U.S. federal government may have underestimated the amount of communication needed to increase awareness of the medication and its applications, said infectious disease specialist William Schaffner, MD, professor of preventive medicine at Vanderbilt University School of Medicine, Nashville, Tenn.

“HHS hasn’t made a major educational effort to promote it,” he said in an interview.

Many physicians who need to know about it, such as transplant doctors and rheumatologists, are outside the typical public health communications loop, he said.

Eric Topol, MD, director of the Scripps Research Transational Institute and editor-in-chief of Medscape, has taken to social media to bemoan the lack of awareness.

Another infectious disease expert agrees. “In my experience, the awareness of Evusheld is low amongst many patients as well as many providers,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, Baltimore.

“Initially, there were scarce supplies of the drug, and certain hospital systems tiered eligibility based on degrees of immunosuppression, and only the most immunosuppressed were proactively approached for treatment.”

“Also, many community hospitals never initially ordered Evusheld – they may have been crowded out by academic centers who treat many more immunosuppressed patients and may not currently see it as a priority,” Dr. Adalja said in an interview. “As such, many immunosuppressed patients would have to seek treatment at academic medical centers, where the drug is more likely to be available.”

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

Evusheld (AstraZeneca), a medication used to prevent SARS-CoV-2 infection in patients at high risk, has problems: Namely, that supplies of the potentially lifesaving drug outweigh demand.

At least 7 million people who are immunocompromised could benefit from it, as could many others who are undergoing cancer treatment, have received a transplant, or who are allergic to the COVID-19 vaccines. The medication has laboratory-produced antibodies against SARS-CoV-2 and helps the body protect itself. It can slash the chances of becoming infected by 77%, according to the U.S. Food and Drug Administration.

And it’s free to eligible patients (although there may be an out-of-pocket administrative fee in some cases).

Despite all those lifesaving benefits, fewer than 25% of available doses have been used.

To meet demand, the Biden administration secured 1.7 million doses of the medicine, which was granted emergency use authorization by the FDA in December 2021. As of July 25, however, 793,348 doses have been ordered by the administration sites, and only 398,181 doses have been reported as used, a spokesperson for the Department of Health & Human Services tells this news organization.

Each week, a certain amount of doses from the 1.7 million dose stockpile is made available to state and territorial health departments. States have not been asking for their full allotment, the spokesperson said July 28.

Now, HHS and AstraZeneca have taken a number of steps to increase awareness of the medication and access to it.

• On July 27, HHS announced that individual providers and smaller sites of care that don’t currently receive Evusheld through the federal distribution process via the HHS Health Partner Order Portal can now order up to three patient courses of the medicine. These can be 
• Health care providers can use the HHS’s COVID-19 Therapeutics Locator to find Evusheld in their area.
• AstraZeneca has launched a new website with educational materials and says it is working closely with patient and professional groups to inform patients and health care providers.
• A direct-to-consumer ad launched on June 22 and will run in the United States online and on TV (Yahoo, Fox, CBS Sports, MSN, ESPN) and be amplified on social and digital channels through year’s end, an AstraZeneca spokesperson said in an interview.
• AstraZeneca set up a toll-free number for providers: 1-833-EVUSHLD.

Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other health care facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.

Studies have found that the medication decreases the risk of getting COVID-19 for up to 6 months after it is given. The FDA recommends repeat dosing every 6 months with the doses of 300 mg of each monoclonal antibody. In clinical trials, Evusheld reduced the incidence of COVID-19 symptomatic illness by 77%, compared with placebo.

Physicians monitor patients for an hour after administering Evusheld for allergic reactions. Other possible side effects include cardiac events, but they are not common.
 

Doctors and patients weigh in

Physicians – and patients – from the United States to the United Kingdom and beyond are questioning why the medication is underused while lauding the recent efforts to expand access and increase awareness.

The U.S. federal government may have underestimated the amount of communication needed to increase awareness of the medication and its applications, said infectious disease specialist William Schaffner, MD, professor of preventive medicine at Vanderbilt University School of Medicine, Nashville, Tenn.

“HHS hasn’t made a major educational effort to promote it,” he said in an interview.

Many physicians who need to know about it, such as transplant doctors and rheumatologists, are outside the typical public health communications loop, he said.

Eric Topol, MD, director of the Scripps Research Transational Institute and editor-in-chief of Medscape, has taken to social media to bemoan the lack of awareness.

Another infectious disease expert agrees. “In my experience, the awareness of Evusheld is low amongst many patients as well as many providers,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, Baltimore.

“Initially, there were scarce supplies of the drug, and certain hospital systems tiered eligibility based on degrees of immunosuppression, and only the most immunosuppressed were proactively approached for treatment.”

“Also, many community hospitals never initially ordered Evusheld – they may have been crowded out by academic centers who treat many more immunosuppressed patients and may not currently see it as a priority,” Dr. Adalja said in an interview. “As such, many immunosuppressed patients would have to seek treatment at academic medical centers, where the drug is more likely to be available.”

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

Evusheld (AstraZeneca), a medication used to prevent SARS-CoV-2 infection in patients at high risk, has problems: Namely, that supplies of the potentially lifesaving drug outweigh demand.

At least 7 million people who are immunocompromised could benefit from it, as could many others who are undergoing cancer treatment, have received a transplant, or who are allergic to the COVID-19 vaccines. The medication has laboratory-produced antibodies against SARS-CoV-2 and helps the body protect itself. It can slash the chances of becoming infected by 77%, according to the U.S. Food and Drug Administration.

And it’s free to eligible patients (although there may be an out-of-pocket administrative fee in some cases).

Despite all those lifesaving benefits, fewer than 25% of available doses have been used.

To meet demand, the Biden administration secured 1.7 million doses of the medicine, which was granted emergency use authorization by the FDA in December 2021. As of July 25, however, 793,348 doses have been ordered by the administration sites, and only 398,181 doses have been reported as used, a spokesperson for the Department of Health & Human Services tells this news organization.

Each week, a certain amount of doses from the 1.7 million dose stockpile is made available to state and territorial health departments. States have not been asking for their full allotment, the spokesperson said July 28.

Now, HHS and AstraZeneca have taken a number of steps to increase awareness of the medication and access to it.

• On July 27, HHS announced that individual providers and smaller sites of care that don’t currently receive Evusheld through the federal distribution process via the HHS Health Partner Order Portal can now order up to three patient courses of the medicine. These can be 
• Health care providers can use the HHS’s COVID-19 Therapeutics Locator to find Evusheld in their area.
• AstraZeneca has launched a new website with educational materials and says it is working closely with patient and professional groups to inform patients and health care providers.
• A direct-to-consumer ad launched on June 22 and will run in the United States online and on TV (Yahoo, Fox, CBS Sports, MSN, ESPN) and be amplified on social and digital channels through year’s end, an AstraZeneca spokesperson said in an interview.
• AstraZeneca set up a toll-free number for providers: 1-833-EVUSHLD.

Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other health care facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.

Studies have found that the medication decreases the risk of getting COVID-19 for up to 6 months after it is given. The FDA recommends repeat dosing every 6 months with the doses of 300 mg of each monoclonal antibody. In clinical trials, Evusheld reduced the incidence of COVID-19 symptomatic illness by 77%, compared with placebo.

Physicians monitor patients for an hour after administering Evusheld for allergic reactions. Other possible side effects include cardiac events, but they are not common.
 

Doctors and patients weigh in

Physicians – and patients – from the United States to the United Kingdom and beyond are questioning why the medication is underused while lauding the recent efforts to expand access and increase awareness.

The U.S. federal government may have underestimated the amount of communication needed to increase awareness of the medication and its applications, said infectious disease specialist William Schaffner, MD, professor of preventive medicine at Vanderbilt University School of Medicine, Nashville, Tenn.

“HHS hasn’t made a major educational effort to promote it,” he said in an interview.

Many physicians who need to know about it, such as transplant doctors and rheumatologists, are outside the typical public health communications loop, he said.

Eric Topol, MD, director of the Scripps Research Transational Institute and editor-in-chief of Medscape, has taken to social media to bemoan the lack of awareness.

Another infectious disease expert agrees. “In my experience, the awareness of Evusheld is low amongst many patients as well as many providers,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, Baltimore.

“Initially, there were scarce supplies of the drug, and certain hospital systems tiered eligibility based on degrees of immunosuppression, and only the most immunosuppressed were proactively approached for treatment.”

“Also, many community hospitals never initially ordered Evusheld – they may have been crowded out by academic centers who treat many more immunosuppressed patients and may not currently see it as a priority,” Dr. Adalja said in an interview. “As such, many immunosuppressed patients would have to seek treatment at academic medical centers, where the drug is more likely to be available.”

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

Higher adenoma detection rates (ADR) during colonoscopies were associated with lower rates of interim colorectal cancer (CRC), and the relationship held true along a broad range of ADR values, according to a retrospective study.

The new study, published online in JAMA, examined ADRs and rates of interim colorectal cancer among patients in California and Washington State between 2011 and 2017. The authors found a 3% reduction in risk for each additional 1% value of ADR. The reduction in risk held true even at high ADRs.

“It basically reaffirms what we’ve believed for the longest time, and other research work has documented – that interim cancers are higher in association with lower adenoma detection rates. The higher you can get that adenoma detection rate, the more we’re going to be able to lower the [rate of] cancers that develop within 3 years of a colonoscopy,” said Lawrence Kosinski, MD, who was asked to comment on the study.

The study included 735,396 patients with a median age of 61.4 years. Among these patients, 852,624 negative colonoscopies were performed by 383 eligible physicians. Participating physicians had to perform at least 25 screening colonoscopies and 100 total colonoscopies per year. After 2.4 million person-years of follow-up, the researchers observed 619 postcolonoscopy colorectal cancers and 36 related deaths over a median follow-up of 3.25 years.

There was an association between each 1% increase in ADR and a reduced probability of postcolonoscopy CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.96-0.98) and mortality from postcolonoscopy CRC (HR, 0.95; 95% CI, 0.92-0.99).

The median ADR was 28.3%. There was an association between ADR above the median versus below the median and a reduced risk of postcolonoscopy CRC with 1.79 cases versus 3.10 cases per 10,000 person-years, respectively (absolute difference in 7-year risk, –12.2 per 10,000 negative colonoscopies; HR, 0.61; 95% CI, 0.52-0.73). There was a similar reduction in risk of postcolonoscopy CRC-related mortality (0.05 versus 0.22 per 10,000 person-years; absolute difference in 7-year risk, –1.2 per 10,000 negative colonoscopies; HR, 0.26; 95% CI, 0.11-0.65).

These findings may be limited in generalizability to physicians with lower procedure volumes or to populations with different adenoma prevalence.

“Given the strong, consistent associations of higher adenoma detection rates with colonoscopy effectiveness for reducing colorectal cancer incidence and mortality, the current results support more research to identify reliable and readily adoptable methods for increasing adenoma detection rates among physicians with lower values across diverse settings,” the researchers wrote.

The improvement over a broad range of ADRs, along with other recent findings, suggests that there may need to be updates to the use of ADRs as a quality metric, according to an accompanying editorial by Douglas K. Rex, MD, of the division of gastroenterology/hepatology at Indiana University, Indianapolis. For example, it’s possible that ADRs could be measured by averaging values from screening, diagnostic, and surveillance colonoscopy. The editorialist suggested that, if improvements in interim cancer rates continue as ADRs approach 50%, the current view of ADRs, as a minimally acceptable standard, may require reconsideration. Instead, it may be appropriate to continue with a minimum threshold, but add a much higher, aspirational target. Dr. Rex also suggested that highly-variable detection of sessile serrated lesions could be excluded from ADRs in order to reduce variability.
 

Factors to consider

The study is useful, but it doesn’t address the disparity in adenoma detection that exists between individual doctors, according to Dr. Kosinski, founder and chief medical officer of SonarMD and previously director of a large gastroenterology clinic. “Even if you look at doctors who do a minimum of 250 screening colonoscopies in a year, there’s still variability. There was even a study published in 2014 showing ADRs anywhere from 7.4% to 52.5%. The bell curve is broad,” he said.

As patients age, they have a higher frequency of polyps appearing on the right side of the colon, and those polyps are flatter and more easily missed than polyps on the left side. “The variation in ADR is higher on the right side of the colon than it is on the left. Doctors have to really do a very good job of examining that right side of the colon so that they don’t miss the flat polyps,” said Dr. Kosinski.

To improve ADRs, Dr. Kosinski emphasized the need to take the required time out to complete a procedure, despite the tight schedules often faced by ambulatory centers. “It’s the time you take coming out of the colon that’s critical. You owe it to the patient,” he said.

And if a patient hasn’t prepped well enough, it’s better to send the patient home without the procedure than to conduct a poor-quality screening. “If you can’t see the mucosal surface, you can’t tell the patient that they have a negative colonoscopy. If you have to do more cleaning during the procedure, then do more cleaning during the procedure. If you have to cancel the procedure and bring the patient back, it’s better to do that than it is to do an incomplete colonoscopy,” said Dr. Kosinski.

He also stressed the need to make sure that the patient is properly sedated and comfortable “so that you can do the job you’re supposed to do,” he said.

Some authors disclosed relationships with Amgen and the National Cancer Institute. Dr. Rex disclosed relationships with Olympus, Boston Scientific, Aries, and others, all outside the submitted work.

Higher adenoma detection rates (ADR) during colonoscopies were associated with lower rates of interim colorectal cancer (CRC), and the relationship held true along a broad range of ADR values, according to a retrospective study.

The new study, published online in JAMA, examined ADRs and rates of interim colorectal cancer among patients in California and Washington State between 2011 and 2017. The authors found a 3% reduction in risk for each additional 1% value of ADR. The reduction in risk held true even at high ADRs.

“It basically reaffirms what we’ve believed for the longest time, and other research work has documented – that interim cancers are higher in association with lower adenoma detection rates. The higher you can get that adenoma detection rate, the more we’re going to be able to lower the [rate of] cancers that develop within 3 years of a colonoscopy,” said Lawrence Kosinski, MD, who was asked to comment on the study.

The study included 735,396 patients with a median age of 61.4 years. Among these patients, 852,624 negative colonoscopies were performed by 383 eligible physicians. Participating physicians had to perform at least 25 screening colonoscopies and 100 total colonoscopies per year. After 2.4 million person-years of follow-up, the researchers observed 619 postcolonoscopy colorectal cancers and 36 related deaths over a median follow-up of 3.25 years.

There was an association between each 1% increase in ADR and a reduced probability of postcolonoscopy CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.96-0.98) and mortality from postcolonoscopy CRC (HR, 0.95; 95% CI, 0.92-0.99).

The median ADR was 28.3%. There was an association between ADR above the median versus below the median and a reduced risk of postcolonoscopy CRC with 1.79 cases versus 3.10 cases per 10,000 person-years, respectively (absolute difference in 7-year risk, –12.2 per 10,000 negative colonoscopies; HR, 0.61; 95% CI, 0.52-0.73). There was a similar reduction in risk of postcolonoscopy CRC-related mortality (0.05 versus 0.22 per 10,000 person-years; absolute difference in 7-year risk, –1.2 per 10,000 negative colonoscopies; HR, 0.26; 95% CI, 0.11-0.65).

These findings may be limited in generalizability to physicians with lower procedure volumes or to populations with different adenoma prevalence.

“Given the strong, consistent associations of higher adenoma detection rates with colonoscopy effectiveness for reducing colorectal cancer incidence and mortality, the current results support more research to identify reliable and readily adoptable methods for increasing adenoma detection rates among physicians with lower values across diverse settings,” the researchers wrote.

The improvement over a broad range of ADRs, along with other recent findings, suggests that there may need to be updates to the use of ADRs as a quality metric, according to an accompanying editorial by Douglas K. Rex, MD, of the division of gastroenterology/hepatology at Indiana University, Indianapolis. For example, it’s possible that ADRs could be measured by averaging values from screening, diagnostic, and surveillance colonoscopy. The editorialist suggested that, if improvements in interim cancer rates continue as ADRs approach 50%, the current view of ADRs, as a minimally acceptable standard, may require reconsideration. Instead, it may be appropriate to continue with a minimum threshold, but add a much higher, aspirational target. Dr. Rex also suggested that highly-variable detection of sessile serrated lesions could be excluded from ADRs in order to reduce variability.
 

Factors to consider

The study is useful, but it doesn’t address the disparity in adenoma detection that exists between individual doctors, according to Dr. Kosinski, founder and chief medical officer of SonarMD and previously director of a large gastroenterology clinic. “Even if you look at doctors who do a minimum of 250 screening colonoscopies in a year, there’s still variability. There was even a study published in 2014 showing ADRs anywhere from 7.4% to 52.5%. The bell curve is broad,” he said.

As patients age, they have a higher frequency of polyps appearing on the right side of the colon, and those polyps are flatter and more easily missed than polyps on the left side. “The variation in ADR is higher on the right side of the colon than it is on the left. Doctors have to really do a very good job of examining that right side of the colon so that they don’t miss the flat polyps,” said Dr. Kosinski.

To improve ADRs, Dr. Kosinski emphasized the need to take the required time out to complete a procedure, despite the tight schedules often faced by ambulatory centers. “It’s the time you take coming out of the colon that’s critical. You owe it to the patient,” he said.

And if a patient hasn’t prepped well enough, it’s better to send the patient home without the procedure than to conduct a poor-quality screening. “If you can’t see the mucosal surface, you can’t tell the patient that they have a negative colonoscopy. If you have to do more cleaning during the procedure, then do more cleaning during the procedure. If you have to cancel the procedure and bring the patient back, it’s better to do that than it is to do an incomplete colonoscopy,” said Dr. Kosinski.

He also stressed the need to make sure that the patient is properly sedated and comfortable “so that you can do the job you’re supposed to do,” he said.

Some authors disclosed relationships with Amgen and the National Cancer Institute. Dr. Rex disclosed relationships with Olympus, Boston Scientific, Aries, and others, all outside the submitted work.

Higher adenoma detection rates (ADR) during colonoscopies were associated with lower rates of interim colorectal cancer (CRC), and the relationship held true along a broad range of ADR values, according to a retrospective study.

The new study, published online in JAMA, examined ADRs and rates of interim colorectal cancer among patients in California and Washington State between 2011 and 2017. The authors found a 3% reduction in risk for each additional 1% value of ADR. The reduction in risk held true even at high ADRs.

“It basically reaffirms what we’ve believed for the longest time, and other research work has documented – that interim cancers are higher in association with lower adenoma detection rates. The higher you can get that adenoma detection rate, the more we’re going to be able to lower the [rate of] cancers that develop within 3 years of a colonoscopy,” said Lawrence Kosinski, MD, who was asked to comment on the study.

The study included 735,396 patients with a median age of 61.4 years. Among these patients, 852,624 negative colonoscopies were performed by 383 eligible physicians. Participating physicians had to perform at least 25 screening colonoscopies and 100 total colonoscopies per year. After 2.4 million person-years of follow-up, the researchers observed 619 postcolonoscopy colorectal cancers and 36 related deaths over a median follow-up of 3.25 years.

There was an association between each 1% increase in ADR and a reduced probability of postcolonoscopy CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.96-0.98) and mortality from postcolonoscopy CRC (HR, 0.95; 95% CI, 0.92-0.99).

The median ADR was 28.3%. There was an association between ADR above the median versus below the median and a reduced risk of postcolonoscopy CRC with 1.79 cases versus 3.10 cases per 10,000 person-years, respectively (absolute difference in 7-year risk, –12.2 per 10,000 negative colonoscopies; HR, 0.61; 95% CI, 0.52-0.73). There was a similar reduction in risk of postcolonoscopy CRC-related mortality (0.05 versus 0.22 per 10,000 person-years; absolute difference in 7-year risk, –1.2 per 10,000 negative colonoscopies; HR, 0.26; 95% CI, 0.11-0.65).

These findings may be limited in generalizability to physicians with lower procedure volumes or to populations with different adenoma prevalence.

“Given the strong, consistent associations of higher adenoma detection rates with colonoscopy effectiveness for reducing colorectal cancer incidence and mortality, the current results support more research to identify reliable and readily adoptable methods for increasing adenoma detection rates among physicians with lower values across diverse settings,” the researchers wrote.

The improvement over a broad range of ADRs, along with other recent findings, suggests that there may need to be updates to the use of ADRs as a quality metric, according to an accompanying editorial by Douglas K. Rex, MD, of the division of gastroenterology/hepatology at Indiana University, Indianapolis. For example, it’s possible that ADRs could be measured by averaging values from screening, diagnostic, and surveillance colonoscopy. The editorialist suggested that, if improvements in interim cancer rates continue as ADRs approach 50%, the current view of ADRs, as a minimally acceptable standard, may require reconsideration. Instead, it may be appropriate to continue with a minimum threshold, but add a much higher, aspirational target. Dr. Rex also suggested that highly-variable detection of sessile serrated lesions could be excluded from ADRs in order to reduce variability.
 

Factors to consider

The study is useful, but it doesn’t address the disparity in adenoma detection that exists between individual doctors, according to Dr. Kosinski, founder and chief medical officer of SonarMD and previously director of a large gastroenterology clinic. “Even if you look at doctors who do a minimum of 250 screening colonoscopies in a year, there’s still variability. There was even a study published in 2014 showing ADRs anywhere from 7.4% to 52.5%. The bell curve is broad,” he said.

As patients age, they have a higher frequency of polyps appearing on the right side of the colon, and those polyps are flatter and more easily missed than polyps on the left side. “The variation in ADR is higher on the right side of the colon than it is on the left. Doctors have to really do a very good job of examining that right side of the colon so that they don’t miss the flat polyps,” said Dr. Kosinski.

To improve ADRs, Dr. Kosinski emphasized the need to take the required time out to complete a procedure, despite the tight schedules often faced by ambulatory centers. “It’s the time you take coming out of the colon that’s critical. You owe it to the patient,” he said.

And if a patient hasn’t prepped well enough, it’s better to send the patient home without the procedure than to conduct a poor-quality screening. “If you can’t see the mucosal surface, you can’t tell the patient that they have a negative colonoscopy. If you have to do more cleaning during the procedure, then do more cleaning during the procedure. If you have to cancel the procedure and bring the patient back, it’s better to do that than it is to do an incomplete colonoscopy,” said Dr. Kosinski.

He also stressed the need to make sure that the patient is properly sedated and comfortable “so that you can do the job you’re supposed to do,” he said.

Some authors disclosed relationships with Amgen and the National Cancer Institute. Dr. Rex disclosed relationships with Olympus, Boston Scientific, Aries, and others, all outside the submitted work.

Medical malpractice claims can arise in any type of health care setting. The purpose of this article is to discuss the risk of medical malpractice suits in the context of brief “med checks,” which are 15- to 20-minute follow-up appointments for psychiatric outpatient medication management. Similar issues arise in brief new patient and transfer visits.

Malpractice hinges on ‘reasonableness’

Malpractice is an allegation of professional negligence.¹ More specifically, it is an allegation that a clinician violated an existing duty by deviating from the standard of care, and that deviation caused damages.² Medical malpractice claims involve questions about whether there was a deviation from the standard of care (whether the clinician failed to exercise a reasonable degree of skill and care given the context of the situation) and whether there was causation (whether a deviation caused a patient’s damages).³ These are fact-based determinations. Thus, the legal resolution of a malpractice claim is based on the facts of each specific case.

The advisability of 15-minute med checks and the associated limitation on a clinician’s ability to provide talk therapy are beyond the scope of this article. What is clear, however, is that not all brief med check appointments are created equal. Their safety and efficacy are dictated by the milieu in which they exist.

Practically speaking, although many factors need to be considered, the standard of care in a medical malpractice lawsuit is based on reasonableness.^4-6 One strategy to proactively manage your malpractice risk is to consider—either for your existing job or before accepting a new position—whether your agency’s setup for brief med checks will allow you to practice reasonably. This article provides information to help you answer this question and describes a hypothetical case vignette to illustrate how certain factors might help lower the chances of facing a malpractice suit.

Established patients

In med check appointments for established patients, consider the patient population, the availability of pre- and postvisit support services, and contingency plans (Table).

Different patient populations require different levels of treatment. Consider, for example, a patient with anxiety and trauma who is actively engaged with a therapist who works at the same agency as their psychiatrist, where the medication management appointments are solely for selective serotonin reuptake inhibitor refills. Compare that to a dual-diagnosis patient—with a psychotic and substance use disorder—who has had poor medication compliance and frequent rehospitalizations. The first patient is more likely to be reasonably managed in a 15-minute med check. The second patient would need significantly more pre- and postvisit support services. This consideration is relevant from a clinical perspective, and if a bad outcome occurs, from a malpractice perspective. Patient populations are not homogeneous; the reasonableness of a clinician’s actions during a brief med check visit depends on the specific patient.

Pre- and postvisit support services vary greatly from clinic to clinic. They range from clerical support (eg, calling a pharmacy to ensure that a patient’s medication is available for same-day pickup) to nursing support (eg, an injection nurse who is on site and can immediately provide a patient with a missed injection) to case manager support (eg, a case manager to facilitate coordination of care, such as by having a patient fill out record releases and then working to ensure that relevant hospital records are received prior to the next visit). The real-world availability of these services can determine the feasibility of safely conducting a 15-minute med check visit.

Continue to: Regardless of the patient population...

Regardless of the patient population, unexpected situations will arise. It could be a patient with posttraumatic stress disorder who was recently retraumatized and is in the midst of disclosing this new trauma at the end of a 15-minute visit. Or it could be a patient with dual diagnoses who comes to the agency intoxicated and manic, describing a plan to kill his neighbor with a shotgun. A clinician’s ability to meet the standard of care, and act reasonably within the confines of a brief med check structure, can thus depend on whether there are means of adequately managing such emergent situations.

Some clinics have fairly high no-show rates. Leaving no-show slots open for administrative time can provide a means of managing emergent situations. If, however, they are automatically rebooked with walk-ins, brief visits become more challenging. Thus, when assessing contingency plan logistics, consider the no-show rate, what happens when there are no-shows, how many other clinicians are available on a given day, and whether staff is available to provide support (eg, sitting with a patient while waiting for an ambulance).

New and transfer patients

Brief visits for new or transfer patients require the same assessment described above. However, there are additional considerations regarding previsit support services. Some clinics use clinical social workers to perform intake evaluations before a new patient sees the psychiatrist. A high-quality intake evaluation can allow a psychiatrist to focus, in a shorter amount of time, on a patient’s medication needs. An additional time saver is having support staff who will obtain relevant medical records before a patient’s first psychiatric visit. Such actions can greatly increase the efficacy of a new patient appointment for the prescribing clinician.

The reliability of and level of detail assessed in prior evaluations can be particularly relevant when considering a job providing coverage as locum tenens, when all patients will be new to you. Unfortunately, if you are not employed at a clinic, it can be hard to assess this ahead of time. If you know colleagues in the area where you are considering taking a locum position, ask for their opinions about the quality of work at the agency.

Case vignette

Mr. J is a 30-year-old man with schizoaffective disorder. For several years, he has been followed once every 4 weeks at the local clinic. During the first year of treatment, he had numerous hospitalizations due to medication noncompliance, psychotic episodes, and threats of violence against his mother. For the past year, he had been stable on the same dose of an oral antipsychotic medication (risperidone 2 mg twice a day). Then he stopped taking his medication, became increasingly psychotic, and, while holding a butcher knife, threatened to kill his mother. His mother called 911 and Mr. J was hospitalized.

Continue to: While in the hospital...

While in the hospital, Mr. J was restarted on risperidone 2 mg twice a day, and lithium 600 mg twice a day was added. As part of discharge planning, the hospital social worker set up an outpatient appointment with Dr. R, Mr. J’s treating psychiatrist at the clinic. That appointment was scheduled as a 15-minute med check. At the visit, Dr. R did not have or try to obtain a copy of the hospital discharge summary. Mr. J told Dr. R that he had been hospitalized because he had run out of his oral antipsychotic, and that it had been restarted during the hospitalization. Dr. R—who did not know about the recent incident involving a butcher knife or the subsequent medication changes—continued Mr. J’s risperidone, but did not continue his lithium because she did not know it had been added.

Dr. R scheduled a 4-week follow-up visit for Mr. J. Then she went on maternity leave. Because the agency was short-staffed, they hired Dr. C—a locum tenens—to see all of Dr. R’s established patients in 15-minute time slots.

At their first visit, Mr. J told Dr. C that he was gaining too much weight from his antipsychotic and wanted to know if it would be OK to decrease the dose. Dr. C reviewed Dr. R’s last office note but, due to limited time, did not review any other notes. Although Dr. C had 2 no-shows that day, the clinic had a policy that required Dr. C to see walk-ins whenever there was a no-show.

Dr. C did not know of Mr. J’s threats of violence or the medication changes associated with his recent hospitalization (they were not referenced in Dr. R’s last note). Dr. C decreased the dose of Mr. J’s risperidone from 2 mg twice a day to 0.5 mg twice a day. He did not do a violence risk assessment. Two weeks after the visit with Dr. C, Mr. J, who had become increasingly depressed and psychotic, killed his mother and died by suicide.

The estates of Mr. J and his mother filed a medical malpractice lawsuit against Dr. R and Dr. C. Both psychiatrists had a duty to Mr. J. Whether there was a duty to Mr. J’s mother would depend in part on the state’s duty to protect laws. Either way, the malpractice case would hinge on whether the psychiatrists’ conduct fell below the standard of care.

Continue to: In this case...

In this case, the critical issues were Dr. R’s failure to obtain and review the recent hospital records and Dr. C’s decision to decrease the antipsychotic dose. Of particular concern is Dr. C’s decision to decrease the antipsychotic dose without reviewing more information from past records, and the resultant failure to perform a violence risk assessment. These deviations cannot be blamed entirely on the brevity of the med check appointment. They could happen in a clinic that allotted longer time periods for follow-up visits, but they are, however, more likely to occur in a short med check appointment due to time constraints.

The likelihood of these errors could have been reduced by additional support services, as well as more time for Dr. C to see each patient who was new to him. For example, if there had been a support person available to obtain hospital records prior to the postdischarge appointment, Dr. R and Dr. C would have been more likely to be aware of the violent threat associated with Mr. J’s hospitalization. Additionally, if the busy clinicians had contingency plans to assess complicated patients, such as the ability to use no-show time to deal with difficult situations, Dr. C could have taken more time to review past records.

Bottom Line

When working in a setting that involves brief med check appointments, assess the agency structure, and whether it will allow you to practice reasonably. This will be relevant clinically and may reduce the risk of malpractice lawsuits. Reasonableness of a clinician’s actions is a fact-specific question and is influenced by multiple factors, including the patient population, the availability and quality of an agency’s support services, and contingency plans.

Related Resources

• Mossman D. Successfully navigating the 15-minute ‘med check.’ Current Psychiatry. 2010;9(6):40-43.
• Olfson M, Marcus SC. National trends in outpatient psychotherapy. Am J Psychiatry. 2010;167(12):1456-1463.

Drug Brand Names

Lithium • Eskalith, Lithobid
Risperidone • Risperdal

Medical malpractice claims can arise in any type of health care setting. The purpose of this article is to discuss the risk of medical malpractice suits in the context of brief “med checks,” which are 15- to 20-minute follow-up appointments for psychiatric outpatient medication management. Similar issues arise in brief new patient and transfer visits.

Malpractice hinges on ‘reasonableness’

Malpractice is an allegation of professional negligence.¹ More specifically, it is an allegation that a clinician violated an existing duty by deviating from the standard of care, and that deviation caused damages.² Medical malpractice claims involve questions about whether there was a deviation from the standard of care (whether the clinician failed to exercise a reasonable degree of skill and care given the context of the situation) and whether there was causation (whether a deviation caused a patient’s damages).³ These are fact-based determinations. Thus, the legal resolution of a malpractice claim is based on the facts of each specific case.

The advisability of 15-minute med checks and the associated limitation on a clinician’s ability to provide talk therapy are beyond the scope of this article. What is clear, however, is that not all brief med check appointments are created equal. Their safety and efficacy are dictated by the milieu in which they exist.

Practically speaking, although many factors need to be considered, the standard of care in a medical malpractice lawsuit is based on reasonableness.^4-6 One strategy to proactively manage your malpractice risk is to consider—either for your existing job or before accepting a new position—whether your agency’s setup for brief med checks will allow you to practice reasonably. This article provides information to help you answer this question and describes a hypothetical case vignette to illustrate how certain factors might help lower the chances of facing a malpractice suit.

Established patients

In med check appointments for established patients, consider the patient population, the availability of pre- and postvisit support services, and contingency plans (Table).

Different patient populations require different levels of treatment. Consider, for example, a patient with anxiety and trauma who is actively engaged with a therapist who works at the same agency as their psychiatrist, where the medication management appointments are solely for selective serotonin reuptake inhibitor refills. Compare that to a dual-diagnosis patient—with a psychotic and substance use disorder—who has had poor medication compliance and frequent rehospitalizations. The first patient is more likely to be reasonably managed in a 15-minute med check. The second patient would need significantly more pre- and postvisit support services. This consideration is relevant from a clinical perspective, and if a bad outcome occurs, from a malpractice perspective. Patient populations are not homogeneous; the reasonableness of a clinician’s actions during a brief med check visit depends on the specific patient.

Pre- and postvisit support services vary greatly from clinic to clinic. They range from clerical support (eg, calling a pharmacy to ensure that a patient’s medication is available for same-day pickup) to nursing support (eg, an injection nurse who is on site and can immediately provide a patient with a missed injection) to case manager support (eg, a case manager to facilitate coordination of care, such as by having a patient fill out record releases and then working to ensure that relevant hospital records are received prior to the next visit). The real-world availability of these services can determine the feasibility of safely conducting a 15-minute med check visit.

Continue to: Regardless of the patient population...

Regardless of the patient population, unexpected situations will arise. It could be a patient with posttraumatic stress disorder who was recently retraumatized and is in the midst of disclosing this new trauma at the end of a 15-minute visit. Or it could be a patient with dual diagnoses who comes to the agency intoxicated and manic, describing a plan to kill his neighbor with a shotgun. A clinician’s ability to meet the standard of care, and act reasonably within the confines of a brief med check structure, can thus depend on whether there are means of adequately managing such emergent situations.

Some clinics have fairly high no-show rates. Leaving no-show slots open for administrative time can provide a means of managing emergent situations. If, however, they are automatically rebooked with walk-ins, brief visits become more challenging. Thus, when assessing contingency plan logistics, consider the no-show rate, what happens when there are no-shows, how many other clinicians are available on a given day, and whether staff is available to provide support (eg, sitting with a patient while waiting for an ambulance).

New and transfer patients

Brief visits for new or transfer patients require the same assessment described above. However, there are additional considerations regarding previsit support services. Some clinics use clinical social workers to perform intake evaluations before a new patient sees the psychiatrist. A high-quality intake evaluation can allow a psychiatrist to focus, in a shorter amount of time, on a patient’s medication needs. An additional time saver is having support staff who will obtain relevant medical records before a patient’s first psychiatric visit. Such actions can greatly increase the efficacy of a new patient appointment for the prescribing clinician.

The reliability of and level of detail assessed in prior evaluations can be particularly relevant when considering a job providing coverage as locum tenens, when all patients will be new to you. Unfortunately, if you are not employed at a clinic, it can be hard to assess this ahead of time. If you know colleagues in the area where you are considering taking a locum position, ask for their opinions about the quality of work at the agency.

Case vignette

Mr. J is a 30-year-old man with schizoaffective disorder. For several years, he has been followed once every 4 weeks at the local clinic. During the first year of treatment, he had numerous hospitalizations due to medication noncompliance, psychotic episodes, and threats of violence against his mother. For the past year, he had been stable on the same dose of an oral antipsychotic medication (risperidone 2 mg twice a day). Then he stopped taking his medication, became increasingly psychotic, and, while holding a butcher knife, threatened to kill his mother. His mother called 911 and Mr. J was hospitalized.

Continue to: While in the hospital...

While in the hospital, Mr. J was restarted on risperidone 2 mg twice a day, and lithium 600 mg twice a day was added. As part of discharge planning, the hospital social worker set up an outpatient appointment with Dr. R, Mr. J’s treating psychiatrist at the clinic. That appointment was scheduled as a 15-minute med check. At the visit, Dr. R did not have or try to obtain a copy of the hospital discharge summary. Mr. J told Dr. R that he had been hospitalized because he had run out of his oral antipsychotic, and that it had been restarted during the hospitalization. Dr. R—who did not know about the recent incident involving a butcher knife or the subsequent medication changes—continued Mr. J’s risperidone, but did not continue his lithium because she did not know it had been added.

Dr. R scheduled a 4-week follow-up visit for Mr. J. Then she went on maternity leave. Because the agency was short-staffed, they hired Dr. C—a locum tenens—to see all of Dr. R’s established patients in 15-minute time slots.

At their first visit, Mr. J told Dr. C that he was gaining too much weight from his antipsychotic and wanted to know if it would be OK to decrease the dose. Dr. C reviewed Dr. R’s last office note but, due to limited time, did not review any other notes. Although Dr. C had 2 no-shows that day, the clinic had a policy that required Dr. C to see walk-ins whenever there was a no-show.

Dr. C did not know of Mr. J’s threats of violence or the medication changes associated with his recent hospitalization (they were not referenced in Dr. R’s last note). Dr. C decreased the dose of Mr. J’s risperidone from 2 mg twice a day to 0.5 mg twice a day. He did not do a violence risk assessment. Two weeks after the visit with Dr. C, Mr. J, who had become increasingly depressed and psychotic, killed his mother and died by suicide.

The estates of Mr. J and his mother filed a medical malpractice lawsuit against Dr. R and Dr. C. Both psychiatrists had a duty to Mr. J. Whether there was a duty to Mr. J’s mother would depend in part on the state’s duty to protect laws. Either way, the malpractice case would hinge on whether the psychiatrists’ conduct fell below the standard of care.

Continue to: In this case...

In this case, the critical issues were Dr. R’s failure to obtain and review the recent hospital records and Dr. C’s decision to decrease the antipsychotic dose. Of particular concern is Dr. C’s decision to decrease the antipsychotic dose without reviewing more information from past records, and the resultant failure to perform a violence risk assessment. These deviations cannot be blamed entirely on the brevity of the med check appointment. They could happen in a clinic that allotted longer time periods for follow-up visits, but they are, however, more likely to occur in a short med check appointment due to time constraints.

The likelihood of these errors could have been reduced by additional support services, as well as more time for Dr. C to see each patient who was new to him. For example, if there had been a support person available to obtain hospital records prior to the postdischarge appointment, Dr. R and Dr. C would have been more likely to be aware of the violent threat associated with Mr. J’s hospitalization. Additionally, if the busy clinicians had contingency plans to assess complicated patients, such as the ability to use no-show time to deal with difficult situations, Dr. C could have taken more time to review past records.

Bottom Line

When working in a setting that involves brief med check appointments, assess the agency structure, and whether it will allow you to practice reasonably. This will be relevant clinically and may reduce the risk of malpractice lawsuits. Reasonableness of a clinician’s actions is a fact-specific question and is influenced by multiple factors, including the patient population, the availability and quality of an agency’s support services, and contingency plans.

Related Resources

• Mossman D. Successfully navigating the 15-minute ‘med check.’ Current Psychiatry. 2010;9(6):40-43.
• Olfson M, Marcus SC. National trends in outpatient psychotherapy. Am J Psychiatry. 2010;167(12):1456-1463.

Drug Brand Names

Lithium • Eskalith, Lithobid
Risperidone • Risperdal

Medical malpractice claims can arise in any type of health care setting. The purpose of this article is to discuss the risk of medical malpractice suits in the context of brief “med checks,” which are 15- to 20-minute follow-up appointments for psychiatric outpatient medication management. Similar issues arise in brief new patient and transfer visits.

Malpractice hinges on ‘reasonableness’

Malpractice is an allegation of professional negligence.¹ More specifically, it is an allegation that a clinician violated an existing duty by deviating from the standard of care, and that deviation caused damages.² Medical malpractice claims involve questions about whether there was a deviation from the standard of care (whether the clinician failed to exercise a reasonable degree of skill and care given the context of the situation) and whether there was causation (whether a deviation caused a patient’s damages).³ These are fact-based determinations. Thus, the legal resolution of a malpractice claim is based on the facts of each specific case.

The advisability of 15-minute med checks and the associated limitation on a clinician’s ability to provide talk therapy are beyond the scope of this article. What is clear, however, is that not all brief med check appointments are created equal. Their safety and efficacy are dictated by the milieu in which they exist.

Practically speaking, although many factors need to be considered, the standard of care in a medical malpractice lawsuit is based on reasonableness.^4-6 One strategy to proactively manage your malpractice risk is to consider—either for your existing job or before accepting a new position—whether your agency’s setup for brief med checks will allow you to practice reasonably. This article provides information to help you answer this question and describes a hypothetical case vignette to illustrate how certain factors might help lower the chances of facing a malpractice suit.

Established patients

In med check appointments for established patients, consider the patient population, the availability of pre- and postvisit support services, and contingency plans (Table).

Different patient populations require different levels of treatment. Consider, for example, a patient with anxiety and trauma who is actively engaged with a therapist who works at the same agency as their psychiatrist, where the medication management appointments are solely for selective serotonin reuptake inhibitor refills. Compare that to a dual-diagnosis patient—with a psychotic and substance use disorder—who has had poor medication compliance and frequent rehospitalizations. The first patient is more likely to be reasonably managed in a 15-minute med check. The second patient would need significantly more pre- and postvisit support services. This consideration is relevant from a clinical perspective, and if a bad outcome occurs, from a malpractice perspective. Patient populations are not homogeneous; the reasonableness of a clinician’s actions during a brief med check visit depends on the specific patient.

Pre- and postvisit support services vary greatly from clinic to clinic. They range from clerical support (eg, calling a pharmacy to ensure that a patient’s medication is available for same-day pickup) to nursing support (eg, an injection nurse who is on site and can immediately provide a patient with a missed injection) to case manager support (eg, a case manager to facilitate coordination of care, such as by having a patient fill out record releases and then working to ensure that relevant hospital records are received prior to the next visit). The real-world availability of these services can determine the feasibility of safely conducting a 15-minute med check visit.

Continue to: Regardless of the patient population...

Regardless of the patient population, unexpected situations will arise. It could be a patient with posttraumatic stress disorder who was recently retraumatized and is in the midst of disclosing this new trauma at the end of a 15-minute visit. Or it could be a patient with dual diagnoses who comes to the agency intoxicated and manic, describing a plan to kill his neighbor with a shotgun. A clinician’s ability to meet the standard of care, and act reasonably within the confines of a brief med check structure, can thus depend on whether there are means of adequately managing such emergent situations.

Some clinics have fairly high no-show rates. Leaving no-show slots open for administrative time can provide a means of managing emergent situations. If, however, they are automatically rebooked with walk-ins, brief visits become more challenging. Thus, when assessing contingency plan logistics, consider the no-show rate, what happens when there are no-shows, how many other clinicians are available on a given day, and whether staff is available to provide support (eg, sitting with a patient while waiting for an ambulance).

New and transfer patients

Brief visits for new or transfer patients require the same assessment described above. However, there are additional considerations regarding previsit support services. Some clinics use clinical social workers to perform intake evaluations before a new patient sees the psychiatrist. A high-quality intake evaluation can allow a psychiatrist to focus, in a shorter amount of time, on a patient’s medication needs. An additional time saver is having support staff who will obtain relevant medical records before a patient’s first psychiatric visit. Such actions can greatly increase the efficacy of a new patient appointment for the prescribing clinician.

The reliability of and level of detail assessed in prior evaluations can be particularly relevant when considering a job providing coverage as locum tenens, when all patients will be new to you. Unfortunately, if you are not employed at a clinic, it can be hard to assess this ahead of time. If you know colleagues in the area where you are considering taking a locum position, ask for their opinions about the quality of work at the agency.

Case vignette

Mr. J is a 30-year-old man with schizoaffective disorder. For several years, he has been followed once every 4 weeks at the local clinic. During the first year of treatment, he had numerous hospitalizations due to medication noncompliance, psychotic episodes, and threats of violence against his mother. For the past year, he had been stable on the same dose of an oral antipsychotic medication (risperidone 2 mg twice a day). Then he stopped taking his medication, became increasingly psychotic, and, while holding a butcher knife, threatened to kill his mother. His mother called 911 and Mr. J was hospitalized.

Continue to: While in the hospital...

While in the hospital, Mr. J was restarted on risperidone 2 mg twice a day, and lithium 600 mg twice a day was added. As part of discharge planning, the hospital social worker set up an outpatient appointment with Dr. R, Mr. J’s treating psychiatrist at the clinic. That appointment was scheduled as a 15-minute med check. At the visit, Dr. R did not have or try to obtain a copy of the hospital discharge summary. Mr. J told Dr. R that he had been hospitalized because he had run out of his oral antipsychotic, and that it had been restarted during the hospitalization. Dr. R—who did not know about the recent incident involving a butcher knife or the subsequent medication changes—continued Mr. J’s risperidone, but did not continue his lithium because she did not know it had been added.

Dr. R scheduled a 4-week follow-up visit for Mr. J. Then she went on maternity leave. Because the agency was short-staffed, they hired Dr. C—a locum tenens—to see all of Dr. R’s established patients in 15-minute time slots.

At their first visit, Mr. J told Dr. C that he was gaining too much weight from his antipsychotic and wanted to know if it would be OK to decrease the dose. Dr. C reviewed Dr. R’s last office note but, due to limited time, did not review any other notes. Although Dr. C had 2 no-shows that day, the clinic had a policy that required Dr. C to see walk-ins whenever there was a no-show.

Dr. C did not know of Mr. J’s threats of violence or the medication changes associated with his recent hospitalization (they were not referenced in Dr. R’s last note). Dr. C decreased the dose of Mr. J’s risperidone from 2 mg twice a day to 0.5 mg twice a day. He did not do a violence risk assessment. Two weeks after the visit with Dr. C, Mr. J, who had become increasingly depressed and psychotic, killed his mother and died by suicide.

The estates of Mr. J and his mother filed a medical malpractice lawsuit against Dr. R and Dr. C. Both psychiatrists had a duty to Mr. J. Whether there was a duty to Mr. J’s mother would depend in part on the state’s duty to protect laws. Either way, the malpractice case would hinge on whether the psychiatrists’ conduct fell below the standard of care.

Continue to: In this case...

In this case, the critical issues were Dr. R’s failure to obtain and review the recent hospital records and Dr. C’s decision to decrease the antipsychotic dose. Of particular concern is Dr. C’s decision to decrease the antipsychotic dose without reviewing more information from past records, and the resultant failure to perform a violence risk assessment. These deviations cannot be blamed entirely on the brevity of the med check appointment. They could happen in a clinic that allotted longer time periods for follow-up visits, but they are, however, more likely to occur in a short med check appointment due to time constraints.

The likelihood of these errors could have been reduced by additional support services, as well as more time for Dr. C to see each patient who was new to him. For example, if there had been a support person available to obtain hospital records prior to the postdischarge appointment, Dr. R and Dr. C would have been more likely to be aware of the violent threat associated with Mr. J’s hospitalization. Additionally, if the busy clinicians had contingency plans to assess complicated patients, such as the ability to use no-show time to deal with difficult situations, Dr. C could have taken more time to review past records.

Bottom Line

When working in a setting that involves brief med check appointments, assess the agency structure, and whether it will allow you to practice reasonably. This will be relevant clinically and may reduce the risk of malpractice lawsuits. Reasonableness of a clinician’s actions is a fact-specific question and is influenced by multiple factors, including the patient population, the availability and quality of an agency’s support services, and contingency plans.

Related Resources

• Mossman D. Successfully navigating the 15-minute ‘med check.’ Current Psychiatry. 2010;9(6):40-43.
• Olfson M, Marcus SC. National trends in outpatient psychotherapy. Am J Psychiatry. 2010;167(12):1456-1463.

Drug Brand Names

Lithium • Eskalith, Lithobid
Risperidone • Risperdal

Nonsuicidal self-injury (NSSI) is the direct and deliberate destruction of body tissue without intent to die.¹ Common forms of NSSI include cutting, burning, scraping/scratching skin, biting, hitting, and interfering with wound healing.² Functional theories suggest that NSSI temporarily alleviates overwhelming negative emotions and can produce feelings of relief, resulting in a reinforcing effect.³

NSSI has been shown to be a risk factor for future suicide attempts.⁴ A 2018 study found that NSSI is associated with an increased risk of subsequent suicidal ideation (odds ratio [OR] 2.8), suicide plan (OR 3.0), and suicide attempt (OR 5.5).⁵ NSSI is also associated with individuals who had suicidal ideation and formed a suicide plan, and individuals who had a suicide plan and attempted suicide (ORs 1.7 to 2.1).⁵ Another study found that 70% of adolescents who engage in NSSI have attempted suicide during their lifetime, and 55% have multiple attempts.⁶

Given the overlap between suicide attempts and NSSI, performing a thorough suicide risk assessment (which is beyond the scope of this article) is crucial. This article describes the static and dynamic risk factors for NSSI in adolescents and adults, which can help us perform a suicide risk assessment and allow us to formulate an appropriate treatment plan that includes safety-based interventions.

NSSI risk factors for adolescents

From developing sexual identity and undergoing puberty to achieving increased independence from their parents and developing a sense of autonomy, adolescents undergo many biological, psychological, and social changes before reaching adulthood.⁷ Data suggest that NSSI often begins in adolescence, with a typical onset at age 13 or 14.³ Community studies show that one-third to one-half of adolescents in the United States have engaged in NSSI.^8,9 Previously, NSSI during adolescence was associated with 3 major diagnostic categories: eating disorders, developmental disabilities, and borderline personality disorder (BPD).¹⁰ However, recent data suggest that NSSI is also common outside of these categories. Here we describe static and dynamic risk factors for NSSI in adolescents (Table 1^11-42). Table 2^11-42 summarizes the studies of NSSI in adolescents that we reviewed.

Static risk factors

Female adolescents and adults engage in NSSI at higher rates than males. The difference is larger in clinical populations compared to the general population.¹¹

A large portion of research about NSSI has been conducted in studies in which the majority of participants were White.¹² Most studies report a higher prevalence of NSSI among non-Hispanic White youth,¹³ but some suggest other ethnic groups may also experience high rates of self-harm and NSSI.^13-15 Several studies have demonstrated high rates of self-harm among South Asian adult females compared with White adult females, but this difference may be less pronounced in adolescents.¹⁴ One study in the United Kingdom found that White females age 10 to 14 had higher rates of self-harm compared to South Asian females,¹⁴ while another found that risk and rates of self-harm in young South Asian people varied by city and country of origin.¹⁵ Young Black females¹⁵ and young Black males¹³ also may be at an increased risk of self-harm. One review found that Black females were more likely to self-harm than Asian or White groups.¹⁵

Several studies suggest that sexual minority adolescents (SMA) (eg, lesbian, gay, bisexual, transgender, queer) are at greater risk for NSSI than heterosexual adolescents.¹⁶ SMA have been shown to engage in a significantly greater frequency of NSSI and more types of NSSI than heterosexual adolescents.¹⁶ Furthermore, on the Inventory of Statements about Self-Injury, SMA self-reported using NSSI for intrapersonal functions (eg, for affect regulation, antisuicide, self-punishment) significantly greater than their heterosexual peers; however, there were no significant differences between the 2 groups on interpersonal functions (eg, autonomy, interpersonal boundaries, peer bonding, sensation-seeking).¹⁶

Continue to: Transgender and gender nonconfirming...

Transgender and gender nonconfirming (GNC) youth are at a particularly high risk for NSSI; 30% to 45.5% of transgender adolescents report self-injury.¹⁷ Factors shown to distinguish transgender/GNC youth who engage in NSSI from those who do not include having a mental health problem, depression, running away from home, substance use, lower self-esteem/greater self-criticism, experiencing transphobia victimization, and having more interpersonal problems.^18,19 Among transgender/GNC youth, those whose biological sex is female are more likely to report NSSI than those whose biological sex is male (ie, transgendered adolescent males are more likely to report NSSI than transgendered adolescent females).^18,19

Most forms of childhood maltreatment have been associated with NSSI. In a recently published review, Liu et al²⁰ found that childhood maltreatment (including sexual abuse, physical abuse, emotional abuse, and physical neglect) was associated with an increased risk for NSSI. However, conflicting evidence suggests that when confounders are removed, only childhood emotional abuse was directly associated with NSSI.²¹ Current evidence is modest for childhood emotional neglect as a risk factor for NSSI.²⁰

Increasing research is investigating the biological processes that may be implicated in NSSI. Some studies suggest that endogenous opioids,²² monoamine neurotransmitters,²² and the hypothalamic-pituitary-adrenal (HPA) axis²³ may play a role in NSSI. Compared to healthy controls, adolescents engaging in NSSI have been shown to have lower pain intensity (P = .036), higher pain thresholds (P = .040), and lower beta-endorphins (endogenous opioid hormones involved in mediating stress and pain) (P = .002).²⁴ There may be alterations in the HPA axis among adolescents who engage in NSSI, more specifically stronger cortisol awakening responses.²³ Both functional and standard MRI have been used to study the neurobiology of NSSI. One study demonstrated differences in functional connectivity between brain areas linked to neuroregulation of emotions in adolescents who engage in NSSI,²⁵ while another found volume reduction in the insula of these adolescents, which suggests a possible neurobiological reason for impulsivity and the increased risk of suicidal behavior.²⁶

Dynamic risk factors

Research has repeatedly shown bullying is a risk factor for NSSI.²⁷ One study found that younger children who were victimized reported significantly more NSSI than older children.²⁸ New data suggest that perpetrators of bullying are also at risk for deliberate self-harm behavior (SHB), which this study defined as a behavior that is intended to cause self-harm but without suicidal intent and having a nonfatal outcome.²⁹ Victims of cyberbullying also are at a greater risk for self-harm, suicidal behaviors, and suicide attempt.³⁰ To a lesser extent, cyberbullying perpetrators are at greater risk for suicidal behaviors and suicidal ideation.³⁰ Bullying is a risk factor for NSSI not only in adolescence, but also in adulthood. Lereya et al³¹ found that victims of bullying in childhood and early adolescence were more likely to have mental health problems (including anxiety and depression) and more likely to engage in SHB—which this study defined as hurting oneself on purpose in any way—as adults.

The effects of internet use on adolescents’ mental health also has been investigated. A recent review that explored the relationship between all types of internet use (general use, internet addiction, social media, self-harm websites, forums, etc) and SHB/suicidal behavior found that young people with internet addiction, high levels of internet use, and a tendency to view websites with self-harm or suicidal content were at higher risk of engaging in SHB/suicidal behavior.³² This study did not use a specific definition for SHB or suicidal behavior.³²

Continue to: Membership in certain youth...

Membership in certain youth subcultures (eg, emo or goth) has been evaluated as potential risk factors for depression and deliberate self-harm. Bowes et al³³ found that for each unit increase in goth affiliation (not at all, not very much, somewhat, more than somewhat, very much), youth were 1.52 times more likely to engage in SHB; these researchers also reported a dose-response association between goth identification and future SHB. This study asked participants if they have ever tried to harm or hurt themselves in any manner, but did not distinguish between individuals who had harmed themselves with and without suicidal intent.³³

Personality traits such as impulsiveness and loneliness have been linked to NSSI among adolescents.^34,35 A recent study found that adolescents who met the proposed DSM-5 diagnostic criteria for NSSI scored higher on the Barratt Impulsiveness Scale, specifically in measures of:

• motor impulsiveness (ie, acting without thinking)
• attentional impulsiveness (ie, making decisions quickly)
• impulsiveness due to lack of planning (ie, failure to plan for the future).³⁴

This study also found that adolescents who identified as being lonely based on scores on the Brazilian Loneliness Scale were at a higher risk for NSSI.³⁴

A recent systematic review (32 studies) and meta-analysis (9 studies) found that school absenteeism was associated with a risk of self-harm (pooled aOR 1.37, P = .01) and suicidal ideation (pooled aOR 1.20, P = .03).³⁶ This study suggested that school absenteeism, an important marker of social exclusion, was associated with both SHB and suicidal ideation in young people.³⁶ It defined SHB as any act of self-injury or self-poisoning, regardless of intent.³⁶

Finally, family-related factors have been associated with an increased risk of NSSI. One study of 11,814 children age 9 and 10 revealed that high family conflict (OR 1.09; 95% CI, 1.05 to 1.14) and low parental monitoring (OR 0.95; 95% CI, 0.93 to 0.98) were associated with NSSI.³⁷ A smaller, community-based study found that adolescents with NSSI reported significantly less maternal support and warmth than nonclinical controls, but a cause-and-effect relationship has not yet been determined.³⁸ Parental history alone may influence adolescents’ risk of NSSI. A study that included nearly 76,000 youth found that adolescents with perceived parental alcohol problems had higher odds of self-injury, suicidal ideation, and suicide attempts.³⁹ Adolescents exposed to maternal or paternal adversities were also at a higher risk of self-harm (hazard ratio 1.5 to 5.4 among males, 1.7 to 3.9 among females).⁴⁰

Continue to: NSSI risk factors for adults

NSSI risk factors for adults

Although data regarding the prevalence of NSSI in adults are lacking, available studies report a 12-month prevalence of 0.9%² and a lifetime prevalence of 5.5% to 5.9%.⁴³ There is a significant overlap in risk factors for NSSI in adolescent and adult populations, but there are also many important differences. The static and dynamic risk factors for NSSI in adults are described in Table 3.^44-66 Table 4^44-66 summarizes the studies of NSSI in adults that we reviewed.

Static risk factors

Research findings regarding the prevalence of NSSI based on gender are varied. For years, it has been believed that women are more likely to engage in NSSI than men. Recent meta-analyses that have examined this relationship closely found that the gender difference is larger for clinical samples compared to community samples and more pronounced in younger individuals.¹¹

As is the case with adolescents, there may be ethnic variations in rates of self-harm and NSSI among adults. A 2013 study by Chesin et al⁴⁴ found that Asian and White young adults experience higher rates of NSSI than their Hispanic and Black counterparts. Evidence suggests that relative rates of self-harm for older South Asian adults are lower than in older White adults.¹⁵

Compared to heterosexual or cisgender individuals, members of sexual and gender minorities have a higher past-year and lifetime prevalence of NSSI.⁴⁵ One study found that the weighted effect size between sexual orientation and NSSI had an OR of 3 (95% CI, 2.46 to 3.66), indicating a medium-to-large effect.⁴⁶ Bisexual and transgender individuals appear to be at the highest risk for NSSI when compared to members of other sexual and gender minority groups.⁴⁵ One review that included mostly cross-sectional studies found that individuals identifying as bisexual had up to 6 times the odds of engaging in NSSI when compared to those of other sexual orientations.⁴⁷

Incarceration is a risk factor for NSSI. The rates of NSSI in criminal justice settings are higher (up to 61%) than in the general adult population (approximately 4%).⁴⁸ Recent research found that NSSI serves similar functions in correctional and non-correctional settings, primarily to regulate emotions.⁴⁸ However, there is also evidence of higher rates of NSSI being motivated by an attempt to influence the environment (ie, engaging in NSSI in order to be transferred to another prison unit) compared to NSSI in community settings.⁴⁸

Continue to: Though less robust than data...

Though less robust than data published regarding adolescents, the role of biological processes in adults engaging in NSSI has also been studied. A 2021 study by Störkel et al⁴⁹ found that levels of salivary beta-endorphins were significantly lower in adults immediately before engaging in NSSI compared to after NSSI. Furthermore, adults who engage in NSSI have lower levels of met-enkephalin (P < .01), an opioid growth factor, compared to adults who have never engaged in NSSI.²²

Dynamic risk factors

Individuals who engage in NSSI often report substance use, but there is little data on whether substance use is an independent risk factor for NSSI. Although limited, recent evidence suggests illicit substance use in both adolescents⁴¹ and adults⁵⁰ increases risk for NSSI. Richardson et al⁵⁰ found that the use of barbiturates, opiates, and sedatives significantly increased the frequency of NSSI, whereas use of marijuana, phencyclidine, and medications used to treat anxiety significantly increased the severity of NSSI. A smaller study conducted in South Africa found that individuals who engage in substance use and NSSI were more likely to be male (P < .001).⁵¹

Eating disorders and NSSI are highly comorbid.⁵² The lifetime prevalence of NSSI among individuals with eating disorders ranges from 20.6%to 37.1%.^52,53 Results are inconsistent regarding which eating disorders (if any) are greater risk factors for NSSI. One study found that the prevalence of NSSI in patients with bulimia nervosa was 32.7% (95% CI, 26.9% to 39.1%) vs 21.8% in patients with anorexia nervosa (95% CI, 18.5% to 25.6%).⁵⁴ Another study found that individuals with binge eating/purging–type eating disorders reported engaging in NSSI more frequently than those with other types of eating disorders.⁵⁵ Among patients with eating disorders who reported NSSI, risk factors included younger age of onset, more negative self-evaluation, more impulsive behavior, concomitant substance use, history of suicide attempts, childhood abuse, and peer aggression.^53,55 Body image dissatisfaction and self-criticism, even in individuals not formally diagnosed with an eating disorder, are small but significant predictors of NSSI.^56,57

Mood disorders have also been linked to NSSI.^58,59 Anxiety disorders (including generalized anxiety disorder, social phobia, panic disorder, and agoraphobia) as well as anxiety-related disorders such as obsessive-compulsive disorder have been significantly associated with NSSI (P < .001), but this relationship decreased in strength when mood instability was removed as a confounder.⁵⁸ Among patients with anxiety and anxiety-related disorders, panic disorder and posttraumatic stress disorder (PTSD) have shown the strongest association with NSSI, with pooled aORs of 2.67 and 2.06, respectively.⁵⁹

Recent studies have examined the association of other mental health disorders and symptoms with NSSI, including psychosis⁶⁰ and dissociative symptoms.⁶¹ One study found that paranoia, thought control, and auditory hallucinations were significantly associated with NSSI⁶⁰; however, after controlling for concomitant BPD, only paranoia was significantly associated with NSSI.⁶⁰ Individuals diagnosed with dissociative disorders were more likely than patients without such disorders to endorse NSSI and suicide attempts.⁶¹

Continue to: Emotional dysregulation...

Emotional dysregulation (EDR)—defined as difficulty understanding, recognizing, and managing one’s emotions—has been researched extensively in relation to NSSI.⁶² A recent review that included studies of both adolescents and adults reported a significant association between EDR and NSSI, with an OR of 2.40 (95% CI, 2.01 to 2.86).⁶² A larger effect size was observed between EDR and lifetime NSSI (OR 3.21; 95% CI, 2.63 to 3.91) compared to past-year NSSI (OR 2.32; 95% CI, 1.84 to 2.92).⁶² Patient age, sex, and sample type (clinical vs community) were not significant moderators of strength between the reported associations.⁶²

Studies examining intimate partner violence (IPV) and NSSI have found that young adults who engage in IPV (both as victims and as perpetrators) are more likely to report NSSI.^63-65 Researchers have proposed that anxiety over abandonment may explain this relationship.⁶⁴ A recent study found that individuals with bidirectional IPV (ie, both victimization and perpetration) engaged in NSSI at a higher prevalence than those engaging in unidirectional IPV or no IPV.⁶⁵ This suggests that relationship violence in general (rather than just being a victim of IPV) may be a risk factor for NSSI.⁶⁵

Finally, studies suggest that adolescents and adults who have sleep problems (insomnia, short sleep duration, long sleep onset latency, waking after sleep onset, and poor quality sleep) are more likely to report self-harm or NSSI than those without sleep problems.^42,66 In adults, this relationship is partially mediated by depressive symptoms, EDR, and PTSD.⁶⁶ In adolescents, depressive symptoms are a mediator for this relationship.⁴²

Bottom Line

Nonsuicidal self-injury (NSSI) is a significant health concern due to its association with suicide attempts. Although there are similarities in NSSI risk factors between adolescents and adults, there are also important differences. Understanding these differences is necessary to develop appropriate treatment plans.

Related Resources

• American Foundation for Suicide Prevention. https://afsp.org/
• Cipriano A, Cella S, Cotrufo P. Nonsuicidal self-injury: a systematic review. Front Psych. 2017;8:1946. doi:10.3389/ fpsyg.2017.01946
• Gold LH, Frierson RL, eds. Textbook of Suicide Risk Assessment and Management. 3rd ed. American Psychiatric Association Publishing; 2020.

Nonsuicidal self-injury (NSSI) is the direct and deliberate destruction of body tissue without intent to die.¹ Common forms of NSSI include cutting, burning, scraping/scratching skin, biting, hitting, and interfering with wound healing.² Functional theories suggest that NSSI temporarily alleviates overwhelming negative emotions and can produce feelings of relief, resulting in a reinforcing effect.³

NSSI has been shown to be a risk factor for future suicide attempts.⁴ A 2018 study found that NSSI is associated with an increased risk of subsequent suicidal ideation (odds ratio [OR] 2.8), suicide plan (OR 3.0), and suicide attempt (OR 5.5).⁵ NSSI is also associated with individuals who had suicidal ideation and formed a suicide plan, and individuals who had a suicide plan and attempted suicide (ORs 1.7 to 2.1).⁵ Another study found that 70% of adolescents who engage in NSSI have attempted suicide during their lifetime, and 55% have multiple attempts.⁶

Given the overlap between suicide attempts and NSSI, performing a thorough suicide risk assessment (which is beyond the scope of this article) is crucial. This article describes the static and dynamic risk factors for NSSI in adolescents and adults, which can help us perform a suicide risk assessment and allow us to formulate an appropriate treatment plan that includes safety-based interventions.

NSSI risk factors for adolescents

From developing sexual identity and undergoing puberty to achieving increased independence from their parents and developing a sense of autonomy, adolescents undergo many biological, psychological, and social changes before reaching adulthood.⁷ Data suggest that NSSI often begins in adolescence, with a typical onset at age 13 or 14.³ Community studies show that one-third to one-half of adolescents in the United States have engaged in NSSI.^8,9 Previously, NSSI during adolescence was associated with 3 major diagnostic categories: eating disorders, developmental disabilities, and borderline personality disorder (BPD).¹⁰ However, recent data suggest that NSSI is also common outside of these categories. Here we describe static and dynamic risk factors for NSSI in adolescents (Table 1^11-42). Table 2^11-42 summarizes the studies of NSSI in adolescents that we reviewed.

Static risk factors

Female adolescents and adults engage in NSSI at higher rates than males. The difference is larger in clinical populations compared to the general population.¹¹

A large portion of research about NSSI has been conducted in studies in which the majority of participants were White.¹² Most studies report a higher prevalence of NSSI among non-Hispanic White youth,¹³ but some suggest other ethnic groups may also experience high rates of self-harm and NSSI.^13-15 Several studies have demonstrated high rates of self-harm among South Asian adult females compared with White adult females, but this difference may be less pronounced in adolescents.¹⁴ One study in the United Kingdom found that White females age 10 to 14 had higher rates of self-harm compared to South Asian females,¹⁴ while another found that risk and rates of self-harm in young South Asian people varied by city and country of origin.¹⁵ Young Black females¹⁵ and young Black males¹³ also may be at an increased risk of self-harm. One review found that Black females were more likely to self-harm than Asian or White groups.¹⁵

Several studies suggest that sexual minority adolescents (SMA) (eg, lesbian, gay, bisexual, transgender, queer) are at greater risk for NSSI than heterosexual adolescents.¹⁶ SMA have been shown to engage in a significantly greater frequency of NSSI and more types of NSSI than heterosexual adolescents.¹⁶ Furthermore, on the Inventory of Statements about Self-Injury, SMA self-reported using NSSI for intrapersonal functions (eg, for affect regulation, antisuicide, self-punishment) significantly greater than their heterosexual peers; however, there were no significant differences between the 2 groups on interpersonal functions (eg, autonomy, interpersonal boundaries, peer bonding, sensation-seeking).¹⁶

Continue to: Transgender and gender nonconfirming...

Transgender and gender nonconfirming (GNC) youth are at a particularly high risk for NSSI; 30% to 45.5% of transgender adolescents report self-injury.¹⁷ Factors shown to distinguish transgender/GNC youth who engage in NSSI from those who do not include having a mental health problem, depression, running away from home, substance use, lower self-esteem/greater self-criticism, experiencing transphobia victimization, and having more interpersonal problems.^18,19 Among transgender/GNC youth, those whose biological sex is female are more likely to report NSSI than those whose biological sex is male (ie, transgendered adolescent males are more likely to report NSSI than transgendered adolescent females).^18,19

Most forms of childhood maltreatment have been associated with NSSI. In a recently published review, Liu et al²⁰ found that childhood maltreatment (including sexual abuse, physical abuse, emotional abuse, and physical neglect) was associated with an increased risk for NSSI. However, conflicting evidence suggests that when confounders are removed, only childhood emotional abuse was directly associated with NSSI.²¹ Current evidence is modest for childhood emotional neglect as a risk factor for NSSI.²⁰

Increasing research is investigating the biological processes that may be implicated in NSSI. Some studies suggest that endogenous opioids,²² monoamine neurotransmitters,²² and the hypothalamic-pituitary-adrenal (HPA) axis²³ may play a role in NSSI. Compared to healthy controls, adolescents engaging in NSSI have been shown to have lower pain intensity (P = .036), higher pain thresholds (P = .040), and lower beta-endorphins (endogenous opioid hormones involved in mediating stress and pain) (P = .002).²⁴ There may be alterations in the HPA axis among adolescents who engage in NSSI, more specifically stronger cortisol awakening responses.²³ Both functional and standard MRI have been used to study the neurobiology of NSSI. One study demonstrated differences in functional connectivity between brain areas linked to neuroregulation of emotions in adolescents who engage in NSSI,²⁵ while another found volume reduction in the insula of these adolescents, which suggests a possible neurobiological reason for impulsivity and the increased risk of suicidal behavior.²⁶

Dynamic risk factors

Research has repeatedly shown bullying is a risk factor for NSSI.²⁷ One study found that younger children who were victimized reported significantly more NSSI than older children.²⁸ New data suggest that perpetrators of bullying are also at risk for deliberate self-harm behavior (SHB), which this study defined as a behavior that is intended to cause self-harm but without suicidal intent and having a nonfatal outcome.²⁹ Victims of cyberbullying also are at a greater risk for self-harm, suicidal behaviors, and suicide attempt.³⁰ To a lesser extent, cyberbullying perpetrators are at greater risk for suicidal behaviors and suicidal ideation.³⁰ Bullying is a risk factor for NSSI not only in adolescence, but also in adulthood. Lereya et al³¹ found that victims of bullying in childhood and early adolescence were more likely to have mental health problems (including anxiety and depression) and more likely to engage in SHB—which this study defined as hurting oneself on purpose in any way—as adults.

The effects of internet use on adolescents’ mental health also has been investigated. A recent review that explored the relationship between all types of internet use (general use, internet addiction, social media, self-harm websites, forums, etc) and SHB/suicidal behavior found that young people with internet addiction, high levels of internet use, and a tendency to view websites with self-harm or suicidal content were at higher risk of engaging in SHB/suicidal behavior.³² This study did not use a specific definition for SHB or suicidal behavior.³²

Continue to: Membership in certain youth...

Membership in certain youth subcultures (eg, emo or goth) has been evaluated as potential risk factors for depression and deliberate self-harm. Bowes et al³³ found that for each unit increase in goth affiliation (not at all, not very much, somewhat, more than somewhat, very much), youth were 1.52 times more likely to engage in SHB; these researchers also reported a dose-response association between goth identification and future SHB. This study asked participants if they have ever tried to harm or hurt themselves in any manner, but did not distinguish between individuals who had harmed themselves with and without suicidal intent.³³

Personality traits such as impulsiveness and loneliness have been linked to NSSI among adolescents.^34,35 A recent study found that adolescents who met the proposed DSM-5 diagnostic criteria for NSSI scored higher on the Barratt Impulsiveness Scale, specifically in measures of:

• motor impulsiveness (ie, acting without thinking)
• attentional impulsiveness (ie, making decisions quickly)
• impulsiveness due to lack of planning (ie, failure to plan for the future).³⁴

This study also found that adolescents who identified as being lonely based on scores on the Brazilian Loneliness Scale were at a higher risk for NSSI.³⁴

A recent systematic review (32 studies) and meta-analysis (9 studies) found that school absenteeism was associated with a risk of self-harm (pooled aOR 1.37, P = .01) and suicidal ideation (pooled aOR 1.20, P = .03).³⁶ This study suggested that school absenteeism, an important marker of social exclusion, was associated with both SHB and suicidal ideation in young people.³⁶ It defined SHB as any act of self-injury or self-poisoning, regardless of intent.³⁶

Finally, family-related factors have been associated with an increased risk of NSSI. One study of 11,814 children age 9 and 10 revealed that high family conflict (OR 1.09; 95% CI, 1.05 to 1.14) and low parental monitoring (OR 0.95; 95% CI, 0.93 to 0.98) were associated with NSSI.³⁷ A smaller, community-based study found that adolescents with NSSI reported significantly less maternal support and warmth than nonclinical controls, but a cause-and-effect relationship has not yet been determined.³⁸ Parental history alone may influence adolescents’ risk of NSSI. A study that included nearly 76,000 youth found that adolescents with perceived parental alcohol problems had higher odds of self-injury, suicidal ideation, and suicide attempts.³⁹ Adolescents exposed to maternal or paternal adversities were also at a higher risk of self-harm (hazard ratio 1.5 to 5.4 among males, 1.7 to 3.9 among females).⁴⁰

Continue to: NSSI risk factors for adults

NSSI risk factors for adults

Although data regarding the prevalence of NSSI in adults are lacking, available studies report a 12-month prevalence of 0.9%² and a lifetime prevalence of 5.5% to 5.9%.⁴³ There is a significant overlap in risk factors for NSSI in adolescent and adult populations, but there are also many important differences. The static and dynamic risk factors for NSSI in adults are described in Table 3.^44-66 Table 4^44-66 summarizes the studies of NSSI in adults that we reviewed.

Static risk factors

Research findings regarding the prevalence of NSSI based on gender are varied. For years, it has been believed that women are more likely to engage in NSSI than men. Recent meta-analyses that have examined this relationship closely found that the gender difference is larger for clinical samples compared to community samples and more pronounced in younger individuals.¹¹

As is the case with adolescents, there may be ethnic variations in rates of self-harm and NSSI among adults. A 2013 study by Chesin et al⁴⁴ found that Asian and White young adults experience higher rates of NSSI than their Hispanic and Black counterparts. Evidence suggests that relative rates of self-harm for older South Asian adults are lower than in older White adults.¹⁵

Compared to heterosexual or cisgender individuals, members of sexual and gender minorities have a higher past-year and lifetime prevalence of NSSI.⁴⁵ One study found that the weighted effect size between sexual orientation and NSSI had an OR of 3 (95% CI, 2.46 to 3.66), indicating a medium-to-large effect.⁴⁶ Bisexual and transgender individuals appear to be at the highest risk for NSSI when compared to members of other sexual and gender minority groups.⁴⁵ One review that included mostly cross-sectional studies found that individuals identifying as bisexual had up to 6 times the odds of engaging in NSSI when compared to those of other sexual orientations.⁴⁷

Incarceration is a risk factor for NSSI. The rates of NSSI in criminal justice settings are higher (up to 61%) than in the general adult population (approximately 4%).⁴⁸ Recent research found that NSSI serves similar functions in correctional and non-correctional settings, primarily to regulate emotions.⁴⁸ However, there is also evidence of higher rates of NSSI being motivated by an attempt to influence the environment (ie, engaging in NSSI in order to be transferred to another prison unit) compared to NSSI in community settings.⁴⁸

Continue to: Though less robust than data...

Though less robust than data published regarding adolescents, the role of biological processes in adults engaging in NSSI has also been studied. A 2021 study by Störkel et al⁴⁹ found that levels of salivary beta-endorphins were significantly lower in adults immediately before engaging in NSSI compared to after NSSI. Furthermore, adults who engage in NSSI have lower levels of met-enkephalin (P < .01), an opioid growth factor, compared to adults who have never engaged in NSSI.²²

Dynamic risk factors

Individuals who engage in NSSI often report substance use, but there is little data on whether substance use is an independent risk factor for NSSI. Although limited, recent evidence suggests illicit substance use in both adolescents⁴¹ and adults⁵⁰ increases risk for NSSI. Richardson et al⁵⁰ found that the use of barbiturates, opiates, and sedatives significantly increased the frequency of NSSI, whereas use of marijuana, phencyclidine, and medications used to treat anxiety significantly increased the severity of NSSI. A smaller study conducted in South Africa found that individuals who engage in substance use and NSSI were more likely to be male (P < .001).⁵¹

Eating disorders and NSSI are highly comorbid.⁵² The lifetime prevalence of NSSI among individuals with eating disorders ranges from 20.6%to 37.1%.^52,53 Results are inconsistent regarding which eating disorders (if any) are greater risk factors for NSSI. One study found that the prevalence of NSSI in patients with bulimia nervosa was 32.7% (95% CI, 26.9% to 39.1%) vs 21.8% in patients with anorexia nervosa (95% CI, 18.5% to 25.6%).⁵⁴ Another study found that individuals with binge eating/purging–type eating disorders reported engaging in NSSI more frequently than those with other types of eating disorders.⁵⁵ Among patients with eating disorders who reported NSSI, risk factors included younger age of onset, more negative self-evaluation, more impulsive behavior, concomitant substance use, history of suicide attempts, childhood abuse, and peer aggression.^53,55 Body image dissatisfaction and self-criticism, even in individuals not formally diagnosed with an eating disorder, are small but significant predictors of NSSI.^56,57

Mood disorders have also been linked to NSSI.^58,59 Anxiety disorders (including generalized anxiety disorder, social phobia, panic disorder, and agoraphobia) as well as anxiety-related disorders such as obsessive-compulsive disorder have been significantly associated with NSSI (P < .001), but this relationship decreased in strength when mood instability was removed as a confounder.⁵⁸ Among patients with anxiety and anxiety-related disorders, panic disorder and posttraumatic stress disorder (PTSD) have shown the strongest association with NSSI, with pooled aORs of 2.67 and 2.06, respectively.⁵⁹

Recent studies have examined the association of other mental health disorders and symptoms with NSSI, including psychosis⁶⁰ and dissociative symptoms.⁶¹ One study found that paranoia, thought control, and auditory hallucinations were significantly associated with NSSI⁶⁰; however, after controlling for concomitant BPD, only paranoia was significantly associated with NSSI.⁶⁰ Individuals diagnosed with dissociative disorders were more likely than patients without such disorders to endorse NSSI and suicide attempts.⁶¹

Continue to: Emotional dysregulation...

Emotional dysregulation (EDR)—defined as difficulty understanding, recognizing, and managing one’s emotions—has been researched extensively in relation to NSSI.⁶² A recent review that included studies of both adolescents and adults reported a significant association between EDR and NSSI, with an OR of 2.40 (95% CI, 2.01 to 2.86).⁶² A larger effect size was observed between EDR and lifetime NSSI (OR 3.21; 95% CI, 2.63 to 3.91) compared to past-year NSSI (OR 2.32; 95% CI, 1.84 to 2.92).⁶² Patient age, sex, and sample type (clinical vs community) were not significant moderators of strength between the reported associations.⁶²

Studies examining intimate partner violence (IPV) and NSSI have found that young adults who engage in IPV (both as victims and as perpetrators) are more likely to report NSSI.^63-65 Researchers have proposed that anxiety over abandonment may explain this relationship.⁶⁴ A recent study found that individuals with bidirectional IPV (ie, both victimization and perpetration) engaged in NSSI at a higher prevalence than those engaging in unidirectional IPV or no IPV.⁶⁵ This suggests that relationship violence in general (rather than just being a victim of IPV) may be a risk factor for NSSI.⁶⁵

Finally, studies suggest that adolescents and adults who have sleep problems (insomnia, short sleep duration, long sleep onset latency, waking after sleep onset, and poor quality sleep) are more likely to report self-harm or NSSI than those without sleep problems.^42,66 In adults, this relationship is partially mediated by depressive symptoms, EDR, and PTSD.⁶⁶ In adolescents, depressive symptoms are a mediator for this relationship.⁴²

Bottom Line

Nonsuicidal self-injury (NSSI) is a significant health concern due to its association with suicide attempts. Although there are similarities in NSSI risk factors between adolescents and adults, there are also important differences. Understanding these differences is necessary to develop appropriate treatment plans.

Related Resources

• American Foundation for Suicide Prevention. https://afsp.org/
• Cipriano A, Cella S, Cotrufo P. Nonsuicidal self-injury: a systematic review. Front Psych. 2017;8:1946. doi:10.3389/ fpsyg.2017.01946
• Gold LH, Frierson RL, eds. Textbook of Suicide Risk Assessment and Management. 3rd ed. American Psychiatric Association Publishing; 2020.

Nonsuicidal self-injury (NSSI) is the direct and deliberate destruction of body tissue without intent to die.¹ Common forms of NSSI include cutting, burning, scraping/scratching skin, biting, hitting, and interfering with wound healing.² Functional theories suggest that NSSI temporarily alleviates overwhelming negative emotions and can produce feelings of relief, resulting in a reinforcing effect.³

NSSI has been shown to be a risk factor for future suicide attempts.⁴ A 2018 study found that NSSI is associated with an increased risk of subsequent suicidal ideation (odds ratio [OR] 2.8), suicide plan (OR 3.0), and suicide attempt (OR 5.5).⁵ NSSI is also associated with individuals who had suicidal ideation and formed a suicide plan, and individuals who had a suicide plan and attempted suicide (ORs 1.7 to 2.1).⁵ Another study found that 70% of adolescents who engage in NSSI have attempted suicide during their lifetime, and 55% have multiple attempts.⁶

Given the overlap between suicide attempts and NSSI, performing a thorough suicide risk assessment (which is beyond the scope of this article) is crucial. This article describes the static and dynamic risk factors for NSSI in adolescents and adults, which can help us perform a suicide risk assessment and allow us to formulate an appropriate treatment plan that includes safety-based interventions.

NSSI risk factors for adolescents

From developing sexual identity and undergoing puberty to achieving increased independence from their parents and developing a sense of autonomy, adolescents undergo many biological, psychological, and social changes before reaching adulthood.⁷ Data suggest that NSSI often begins in adolescence, with a typical onset at age 13 or 14.³ Community studies show that one-third to one-half of adolescents in the United States have engaged in NSSI.^8,9 Previously, NSSI during adolescence was associated with 3 major diagnostic categories: eating disorders, developmental disabilities, and borderline personality disorder (BPD).¹⁰ However, recent data suggest that NSSI is also common outside of these categories. Here we describe static and dynamic risk factors for NSSI in adolescents (Table 1^11-42). Table 2^11-42 summarizes the studies of NSSI in adolescents that we reviewed.

Static risk factors

Female adolescents and adults engage in NSSI at higher rates than males. The difference is larger in clinical populations compared to the general population.¹¹

A large portion of research about NSSI has been conducted in studies in which the majority of participants were White.¹² Most studies report a higher prevalence of NSSI among non-Hispanic White youth,¹³ but some suggest other ethnic groups may also experience high rates of self-harm and NSSI.^13-15 Several studies have demonstrated high rates of self-harm among South Asian adult females compared with White adult females, but this difference may be less pronounced in adolescents.¹⁴ One study in the United Kingdom found that White females age 10 to 14 had higher rates of self-harm compared to South Asian females,¹⁴ while another found that risk and rates of self-harm in young South Asian people varied by city and country of origin.¹⁵ Young Black females¹⁵ and young Black males¹³ also may be at an increased risk of self-harm. One review found that Black females were more likely to self-harm than Asian or White groups.¹⁵

Several studies suggest that sexual minority adolescents (SMA) (eg, lesbian, gay, bisexual, transgender, queer) are at greater risk for NSSI than heterosexual adolescents.¹⁶ SMA have been shown to engage in a significantly greater frequency of NSSI and more types of NSSI than heterosexual adolescents.¹⁶ Furthermore, on the Inventory of Statements about Self-Injury, SMA self-reported using NSSI for intrapersonal functions (eg, for affect regulation, antisuicide, self-punishment) significantly greater than their heterosexual peers; however, there were no significant differences between the 2 groups on interpersonal functions (eg, autonomy, interpersonal boundaries, peer bonding, sensation-seeking).¹⁶

Continue to: Transgender and gender nonconfirming...

Transgender and gender nonconfirming (GNC) youth are at a particularly high risk for NSSI; 30% to 45.5% of transgender adolescents report self-injury.¹⁷ Factors shown to distinguish transgender/GNC youth who engage in NSSI from those who do not include having a mental health problem, depression, running away from home, substance use, lower self-esteem/greater self-criticism, experiencing transphobia victimization, and having more interpersonal problems.^18,19 Among transgender/GNC youth, those whose biological sex is female are more likely to report NSSI than those whose biological sex is male (ie, transgendered adolescent males are more likely to report NSSI than transgendered adolescent females).^18,19

Most forms of childhood maltreatment have been associated with NSSI. In a recently published review, Liu et al²⁰ found that childhood maltreatment (including sexual abuse, physical abuse, emotional abuse, and physical neglect) was associated with an increased risk for NSSI. However, conflicting evidence suggests that when confounders are removed, only childhood emotional abuse was directly associated with NSSI.²¹ Current evidence is modest for childhood emotional neglect as a risk factor for NSSI.²⁰

Increasing research is investigating the biological processes that may be implicated in NSSI. Some studies suggest that endogenous opioids,²² monoamine neurotransmitters,²² and the hypothalamic-pituitary-adrenal (HPA) axis²³ may play a role in NSSI. Compared to healthy controls, adolescents engaging in NSSI have been shown to have lower pain intensity (P = .036), higher pain thresholds (P = .040), and lower beta-endorphins (endogenous opioid hormones involved in mediating stress and pain) (P = .002).²⁴ There may be alterations in the HPA axis among adolescents who engage in NSSI, more specifically stronger cortisol awakening responses.²³ Both functional and standard MRI have been used to study the neurobiology of NSSI. One study demonstrated differences in functional connectivity between brain areas linked to neuroregulation of emotions in adolescents who engage in NSSI,²⁵ while another found volume reduction in the insula of these adolescents, which suggests a possible neurobiological reason for impulsivity and the increased risk of suicidal behavior.²⁶

Dynamic risk factors

Research has repeatedly shown bullying is a risk factor for NSSI.²⁷ One study found that younger children who were victimized reported significantly more NSSI than older children.²⁸ New data suggest that perpetrators of bullying are also at risk for deliberate self-harm behavior (SHB), which this study defined as a behavior that is intended to cause self-harm but without suicidal intent and having a nonfatal outcome.²⁹ Victims of cyberbullying also are at a greater risk for self-harm, suicidal behaviors, and suicide attempt.³⁰ To a lesser extent, cyberbullying perpetrators are at greater risk for suicidal behaviors and suicidal ideation.³⁰ Bullying is a risk factor for NSSI not only in adolescence, but also in adulthood. Lereya et al³¹ found that victims of bullying in childhood and early adolescence were more likely to have mental health problems (including anxiety and depression) and more likely to engage in SHB—which this study defined as hurting oneself on purpose in any way—as adults.

The effects of internet use on adolescents’ mental health also has been investigated. A recent review that explored the relationship between all types of internet use (general use, internet addiction, social media, self-harm websites, forums, etc) and SHB/suicidal behavior found that young people with internet addiction, high levels of internet use, and a tendency to view websites with self-harm or suicidal content were at higher risk of engaging in SHB/suicidal behavior.³² This study did not use a specific definition for SHB or suicidal behavior.³²

Continue to: Membership in certain youth...

Membership in certain youth subcultures (eg, emo or goth) has been evaluated as potential risk factors for depression and deliberate self-harm. Bowes et al³³ found that for each unit increase in goth affiliation (not at all, not very much, somewhat, more than somewhat, very much), youth were 1.52 times more likely to engage in SHB; these researchers also reported a dose-response association between goth identification and future SHB. This study asked participants if they have ever tried to harm or hurt themselves in any manner, but did not distinguish between individuals who had harmed themselves with and without suicidal intent.³³

Personality traits such as impulsiveness and loneliness have been linked to NSSI among adolescents.^34,35 A recent study found that adolescents who met the proposed DSM-5 diagnostic criteria for NSSI scored higher on the Barratt Impulsiveness Scale, specifically in measures of:

• motor impulsiveness (ie, acting without thinking)
• attentional impulsiveness (ie, making decisions quickly)
• impulsiveness due to lack of planning (ie, failure to plan for the future).³⁴

This study also found that adolescents who identified as being lonely based on scores on the Brazilian Loneliness Scale were at a higher risk for NSSI.³⁴

A recent systematic review (32 studies) and meta-analysis (9 studies) found that school absenteeism was associated with a risk of self-harm (pooled aOR 1.37, P = .01) and suicidal ideation (pooled aOR 1.20, P = .03).³⁶ This study suggested that school absenteeism, an important marker of social exclusion, was associated with both SHB and suicidal ideation in young people.³⁶ It defined SHB as any act of self-injury or self-poisoning, regardless of intent.³⁶

Finally, family-related factors have been associated with an increased risk of NSSI. One study of 11,814 children age 9 and 10 revealed that high family conflict (OR 1.09; 95% CI, 1.05 to 1.14) and low parental monitoring (OR 0.95; 95% CI, 0.93 to 0.98) were associated with NSSI.³⁷ A smaller, community-based study found that adolescents with NSSI reported significantly less maternal support and warmth than nonclinical controls, but a cause-and-effect relationship has not yet been determined.³⁸ Parental history alone may influence adolescents’ risk of NSSI. A study that included nearly 76,000 youth found that adolescents with perceived parental alcohol problems had higher odds of self-injury, suicidal ideation, and suicide attempts.³⁹ Adolescents exposed to maternal or paternal adversities were also at a higher risk of self-harm (hazard ratio 1.5 to 5.4 among males, 1.7 to 3.9 among females).⁴⁰

Continue to: NSSI risk factors for adults

NSSI risk factors for adults

Although data regarding the prevalence of NSSI in adults are lacking, available studies report a 12-month prevalence of 0.9%² and a lifetime prevalence of 5.5% to 5.9%.⁴³ There is a significant overlap in risk factors for NSSI in adolescent and adult populations, but there are also many important differences. The static and dynamic risk factors for NSSI in adults are described in Table 3.^44-66 Table 4^44-66 summarizes the studies of NSSI in adults that we reviewed.

Static risk factors

Research findings regarding the prevalence of NSSI based on gender are varied. For years, it has been believed that women are more likely to engage in NSSI than men. Recent meta-analyses that have examined this relationship closely found that the gender difference is larger for clinical samples compared to community samples and more pronounced in younger individuals.¹¹

As is the case with adolescents, there may be ethnic variations in rates of self-harm and NSSI among adults. A 2013 study by Chesin et al⁴⁴ found that Asian and White young adults experience higher rates of NSSI than their Hispanic and Black counterparts. Evidence suggests that relative rates of self-harm for older South Asian adults are lower than in older White adults.¹⁵

Compared to heterosexual or cisgender individuals, members of sexual and gender minorities have a higher past-year and lifetime prevalence of NSSI.⁴⁵ One study found that the weighted effect size between sexual orientation and NSSI had an OR of 3 (95% CI, 2.46 to 3.66), indicating a medium-to-large effect.⁴⁶ Bisexual and transgender individuals appear to be at the highest risk for NSSI when compared to members of other sexual and gender minority groups.⁴⁵ One review that included mostly cross-sectional studies found that individuals identifying as bisexual had up to 6 times the odds of engaging in NSSI when compared to those of other sexual orientations.⁴⁷

Incarceration is a risk factor for NSSI. The rates of NSSI in criminal justice settings are higher (up to 61%) than in the general adult population (approximately 4%).⁴⁸ Recent research found that NSSI serves similar functions in correctional and non-correctional settings, primarily to regulate emotions.⁴⁸ However, there is also evidence of higher rates of NSSI being motivated by an attempt to influence the environment (ie, engaging in NSSI in order to be transferred to another prison unit) compared to NSSI in community settings.⁴⁸

Continue to: Though less robust than data...

Though less robust than data published regarding adolescents, the role of biological processes in adults engaging in NSSI has also been studied. A 2021 study by Störkel et al⁴⁹ found that levels of salivary beta-endorphins were significantly lower in adults immediately before engaging in NSSI compared to after NSSI. Furthermore, adults who engage in NSSI have lower levels of met-enkephalin (P < .01), an opioid growth factor, compared to adults who have never engaged in NSSI.²²

Dynamic risk factors

Individuals who engage in NSSI often report substance use, but there is little data on whether substance use is an independent risk factor for NSSI. Although limited, recent evidence suggests illicit substance use in both adolescents⁴¹ and adults⁵⁰ increases risk for NSSI. Richardson et al⁵⁰ found that the use of barbiturates, opiates, and sedatives significantly increased the frequency of NSSI, whereas use of marijuana, phencyclidine, and medications used to treat anxiety significantly increased the severity of NSSI. A smaller study conducted in South Africa found that individuals who engage in substance use and NSSI were more likely to be male (P < .001).⁵¹

Eating disorders and NSSI are highly comorbid.⁵² The lifetime prevalence of NSSI among individuals with eating disorders ranges from 20.6%to 37.1%.^52,53 Results are inconsistent regarding which eating disorders (if any) are greater risk factors for NSSI. One study found that the prevalence of NSSI in patients with bulimia nervosa was 32.7% (95% CI, 26.9% to 39.1%) vs 21.8% in patients with anorexia nervosa (95% CI, 18.5% to 25.6%).⁵⁴ Another study found that individuals with binge eating/purging–type eating disorders reported engaging in NSSI more frequently than those with other types of eating disorders.⁵⁵ Among patients with eating disorders who reported NSSI, risk factors included younger age of onset, more negative self-evaluation, more impulsive behavior, concomitant substance use, history of suicide attempts, childhood abuse, and peer aggression.^53,55 Body image dissatisfaction and self-criticism, even in individuals not formally diagnosed with an eating disorder, are small but significant predictors of NSSI.^56,57

Mood disorders have also been linked to NSSI.^58,59 Anxiety disorders (including generalized anxiety disorder, social phobia, panic disorder, and agoraphobia) as well as anxiety-related disorders such as obsessive-compulsive disorder have been significantly associated with NSSI (P < .001), but this relationship decreased in strength when mood instability was removed as a confounder.⁵⁸ Among patients with anxiety and anxiety-related disorders, panic disorder and posttraumatic stress disorder (PTSD) have shown the strongest association with NSSI, with pooled aORs of 2.67 and 2.06, respectively.⁵⁹

Recent studies have examined the association of other mental health disorders and symptoms with NSSI, including psychosis⁶⁰ and dissociative symptoms.⁶¹ One study found that paranoia, thought control, and auditory hallucinations were significantly associated with NSSI⁶⁰; however, after controlling for concomitant BPD, only paranoia was significantly associated with NSSI.⁶⁰ Individuals diagnosed with dissociative disorders were more likely than patients without such disorders to endorse NSSI and suicide attempts.⁶¹

Continue to: Emotional dysregulation...

Emotional dysregulation (EDR)—defined as difficulty understanding, recognizing, and managing one’s emotions—has been researched extensively in relation to NSSI.⁶² A recent review that included studies of both adolescents and adults reported a significant association between EDR and NSSI, with an OR of 2.40 (95% CI, 2.01 to 2.86).⁶² A larger effect size was observed between EDR and lifetime NSSI (OR 3.21; 95% CI, 2.63 to 3.91) compared to past-year NSSI (OR 2.32; 95% CI, 1.84 to 2.92).⁶² Patient age, sex, and sample type (clinical vs community) were not significant moderators of strength between the reported associations.⁶²

Studies examining intimate partner violence (IPV) and NSSI have found that young adults who engage in IPV (both as victims and as perpetrators) are more likely to report NSSI.^63-65 Researchers have proposed that anxiety over abandonment may explain this relationship.⁶⁴ A recent study found that individuals with bidirectional IPV (ie, both victimization and perpetration) engaged in NSSI at a higher prevalence than those engaging in unidirectional IPV or no IPV.⁶⁵ This suggests that relationship violence in general (rather than just being a victim of IPV) may be a risk factor for NSSI.⁶⁵

Finally, studies suggest that adolescents and adults who have sleep problems (insomnia, short sleep duration, long sleep onset latency, waking after sleep onset, and poor quality sleep) are more likely to report self-harm or NSSI than those without sleep problems.^42,66 In adults, this relationship is partially mediated by depressive symptoms, EDR, and PTSD.⁶⁶ In adolescents, depressive symptoms are a mediator for this relationship.⁴²

Bottom Line

Nonsuicidal self-injury (NSSI) is a significant health concern due to its association with suicide attempts. Although there are similarities in NSSI risk factors between adolescents and adults, there are also important differences. Understanding these differences is necessary to develop appropriate treatment plans.

Related Resources

• American Foundation for Suicide Prevention. https://afsp.org/
• Cipriano A, Cella S, Cotrufo P. Nonsuicidal self-injury: a systematic review. Front Psych. 2017;8:1946. doi:10.3389/ fpsyg.2017.01946
• Gold LH, Frierson RL, eds. Textbook of Suicide Risk Assessment and Management. 3rd ed. American Psychiatric Association Publishing; 2020.

Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.

CASE REPORT

Bizarre behavior and isolation

Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.

Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.

Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is one of the most common forms of autoimmune encephalitis that can present with symptoms of psychosis.¹

In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.^2,3

What does anti-NMDA receptor encephalitis look like?

Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al⁴ proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.⁵ Such groupings make this the most common clinical finding (95%)⁵ but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.^6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.⁸ One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.² In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.⁹

History and review of systems

Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.¹⁰ Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.¹¹ A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.⁷

Continue to: Another indication is the presence...

Another indication is the presence of new seizures within 1 year of presenting with psychotic symptoms.¹⁰ The possibility of undiagnosed seizures should be considered in a patient with psychosis who has episodes of unresponsiveness, dissociative episodes, or seizure-like activity that is thought to be psychogenic but has not been fully evaluated. Seizures in autoimmune encephalitis involve deep structures in the brain and can be present without overt epileptiform activity on EEG, but rather causing only bilateral slowing that is often described as nonspecific.¹²

In a young patient presenting with first-episode psychosis, a recent diagnosis of cancer or abnormal finding in the ovaries increases the likelihood of autoimmune encephalitis.⁴ Historically, however, this type of medical history has been irrelevant to psychosis. Although rare, any person presenting with first-episode psychosis and a history of herpes simplex virus (HSV) encephalitis should be evaluated for autoimmune encephalitis because anti-NMDA receptor antibodies have been reported to be present in approximately one-third of these patients.¹³ Finally, the report of focal neurologic symptoms, including neck stiffness or neck pain, should raise concern, although sensory, working memory, and cognitive deficits may be difficult to fully distinguish from common somatic and cognitive symptoms in a primary psychiatric presentation.

Table 1 lists 4 questions to ask patients who present with first-episode psychosis that may not usually be part of a typical evaluation.

CASE CONTINUED

Uncooperative with examination

In the ED, Ms. L’s heart rate is 101 beats per minute and her blood pressure is 102/72 mm Hg. Her body mass index (BMI) is 22, which suggests an approximate 8-pound weight loss since her BMI was last assessed. Ms. L responds to questions with 1- to 6-word sentences, without clear verbigeration. Though her speech is not pressured, it is of increased rate. Her gaze scans the room, occasionally becoming fixed for 5 to 10 seconds but is aborted by the interviewer’s comment on this behavior. Ms. L efficiently and accurately spells WORLD backwards, then asks “Why?” and refuses to engage in further cognitive testing, stating “Not doing that.” When the interviewer asks “Why not?” she responds “Not doing that.” Her cranial nerves are intact, and she refuses cerebellar testing or requests to assess tone. There are no observed stereotypies, posturing, or echopraxia.

While not necessary for a diagnosis of autoimmune encephalitis, short-term memory loss is a common cognitive finding across studies.^5-7 A common clinical finding from a mental status exam is speech disorders, including (but not limited to) increased rates of speech or decreased verbal output.⁷ Autonomic instability—including tachycardia, markedly labile blood pressures, and orthostasis—all increase the likelihood of autoimmune encephalitis.¹⁴ Interpreting a patient’s vital sign changes can be confounded if they are agitated or anxious, or if they are taking an antipsychotic that produces adverse anticholinergic effects. However, vital sign abnormalities that precede medication administration or do not correlate with fluctuations in mental status increase suspicion for an autoimmune encephalitis.

Continue to: In the absence of the adverse effect...

In the absence of the adverse effect of a medication, orthostasis is uncommon in a well-hydrated young person. Some guidelines⁴ suggest that symptoms of catatonia should be considered a red flag for autoimmune encephalitis. According to the Bush-Francis Catatonia Rating Scale, commonly identified features include immobility, staring, mutism, posturing, withdrawal, rigidity, and gegenhalten.¹⁵ Catatonia is common among patients with anti-NDMA receptor encephalitis, though it may not be initially present and could emerge later.² However, there are documented cases of autoimmune encephalitis where the patient had only isolated features of catatonia, such as echolalia or mutism.²

CASE CONTINUED

History helps narrow the diagnosis

Ms. L’s parents say their daughter has not had prior contact with a therapist or psychiatrist, previous psychiatric diagnoses, hospitalizations, suicide attempts, self-injury, or binging or purging behaviors. Ms. L’s paternal grandfather was diagnosed with schizophrenia, but he is currently employed, lives alone, and has not taken medication for many years. Her mother has hypothyroidism. Ms. L was born at full term via vaginal delivery without cardiac defects or a neonatal intensive care unit stay. Her mother said she did not have postpartum depression or anxiety, a complicated pregnancy, or exposure to tobacco, alcohol, or illicit drug use. Ms. L has no history of childhood seizures or head injury with loss of consciousness. She is an only child, born and raised in a house in a metropolitan area, walked at 13 months, did not require early intervention or speech therapy, and met normal language milestones.

She attended kindergarten at age 6 and progressed throughout public school without regressions in reading, writing, or behavioral manifestations, and did not require a 504 Plan or individualized education program. Ms. L graduated high school in the top 30% of her class, was socially active, and attended a local college. In college, she achieved honor roll, enrolled in a sorority, and was a part of a research lab. Her only medication is oral contraception. She consumes alcohol socially, and reports no cannabis, cigarette, or vaping use. Ms. L says she does not use hallucinogens, stimulants, opiates, or cocaine, and her roommate and family confirm this. She denies recent travel and is sexually active. Ms. L’s urinary and serum toxicology are unremarkable, human chorionic gonadotropin is undetectable, and her sodium level is 133 mEq/L. A measure of serum neutrophils is 6.8 x 10⁹/L and serum lymphocytes is 1.7 x 10⁹/L. Her parents adamantly request a Neurology consultation and further workup, including a lumbar puncture (LP), EEG, and brain imaging (MRI).

This information is useful in ruling out other potential causes of psychosis, such as substance-induced psychosis and neurodevelopmental disorders that can present with psychosis. Additionally, neurodevelopmental abnormalities and psychiatric prodromal symptoms are known precedents in individuals who develop a primary psychotic disorder such as schizophrenia.¹⁶ A family history that includes a psychotic illness may increase the likelihood of a primary psychotic disorder in offspring; however, clinicians must also consider the accuracy of diagnosis in the family, as this can often be inaccurate or influenced by historical cultural bias. We recommend further elucidating the likelihood of a genetic predisposition to a primary psychotic disorder by clarifying familial medication history and functionality.

For example, the fact that Ms. L’s grandfather has not taken medication for many years and has a high degree of functioning and/or absence of cognitive deficits would lower our suspicion for an accurate diagnosis of schizophrenia (given the typical cognitive decline with untreated illness). Another piece of family history relevant to autoimmune encephalitis includes the propensity for autoimmune disorders, but expert opinion on this matter is mixed.¹⁷ Ms. L’s mother has hypothyroidism, which is commonly caused by a prior episode of Hashimoto’s autoimmune thyroiditis. Some physicians advocate for measuring antithyroid antibodies and erythrocyte sedimentation rate or C-reactive protein to gauge the level of autoimmunity, but the usefulness of these measures for detecting autoimmune encephalitis is unclear. These serum markers can be useful in detecting additional important etiologies such as systemic infection or systemic inflammation, and there are conditions such as steroid-responsive encephalopathy with associated thyroiditis, which, as the name suggests, responds to steroids rather than other psychotropic medications. Other risk factors for autoimmune encephalitis include being female, being young, having viral infections (eg, HSV), prior tumor burden, and being in the postpartum period.¹⁸ Some experts also suggest the presence of neurologic symptoms 4 weeks after the first psychiatric or cognitive symptom presentation increases the likelihood of anti-NMDA receptor encephalitis, and a lack of neurologic symptoms would make this diagnosis less likely.^6,19

Continue to: Another item of interest...

Another item of interest in Ms. L’s case is her parents’ request for a Neurology consultation and further workup, as there is an association between caregiver request for workup and eventual diagnosis.⁶ While the etiology of this phenomenon is unclear, the literature suggests individuals with autoimmune encephalitis who initially present to Psychiatry experience longer delays to the appropriate treatment with immunomodulatory therapy than those who first present to Neurology.²⁰

Laboratory and diagnostic testing

Guasp et al² recommend EEG, MRI, and serum autoimmune antibodies (ie, screening for anti-NMDA receptor antibodies) for patients who present with first-episode psychosis, even in the absence of some of the red flags previously discussed. A recent economic analysis suggested screening all patients with first-episode psychosis for serum antibodies may be cost-effective.²¹ Since there can be false positives from serum testing, a positive result should be followed by CSF testing. Serum antibody testing will miss cases where anti-NMDA receptor antibodies are present only in CSF, which is why Guasp et al² recommend ancillary screening with EEG and MRI.Screening all first-episode psychosis patients with EEG and MRI would represent a major change to psychiatric practice and would be beyond the current practical capabilities of many facilities that treat people with new-onset psychosis. Additional evidence is needed before such a change would be required. These suggestions are supported by studies that found most patients with anti-NMDA receptor encephalitis do not initially present with focal neurologic findings, though the majority (95%) do have EEG abnormalities.^2,20,22

For patients whose presentations include features concerning for anti-NMDA receptor encephalitis, an EEG and MRI are reasonable. In a review of EEG abnormalities in anti-NMDA receptor encephalitis, Gillinder et al²³ noted that while 30% did not have initial findings, 83.6% of those with confirmed anti-NMDA receptor encephalitis demonstrated EEG abnormalities; the most common were generalized slowing, delta slowing, and focal abnormalities. Discovering an extreme delta-brush activity on EEG is specific for anti-NMDA receptor encephalitis, but its absence is not fully informative. Practically, slowing can be a nonspecific manifestation of encephalopathy or a medication effect, and many people who present with first-episode psychosis will have recently received antipsychotics, which alter EEG frequency. In a study of EEG changes with antipsychotics, Centorrino et al²⁴ found that generalized background slowing into the theta range across all antipsychotics was not significantly different from control participants, while theta to delta range slowing occurred in 8.2% of those receiving antipsychotics vs 3.3% of controls. Clozapine and olanzapine may be associated with greater EEG abnormalities, while haloperidol and quetiapine contribute a lower risk.²⁵ For young patients with first-episode psychosis without a clear alternative explanation, we advocate for further autoimmune encephalitis workup among all individuals with generalized theta or delta wave slowing.

Because these medication effects are most likely to decrease specificity but not sensitivity of EEG for autoimmune encephalitis, a normal EEG without slowing can be reassuring.²⁶ Moreover, for patients who receive neuroimaging, an MRI may detect inflammation that is not visible on CT. The concerning findings for anti-NMDA receptor encephalitis are temporal or multifocal T2 hyperintensities, though the MRI is normal in most cases and thus should not be reassuring if other concerning features are present.²⁷

The role of lumbar puncture

Another area of active debate surrounds the usefulness and timing of LP. Guasp et al² proposed that all individuals with first-episode psychosis and focal neurologic findings should receive LP and CSF antineuronal antibody testing. They recommend that patients with first-episode psychosis without focal neurologic findings also should receive LP and CSF testing if ≥1 of the following is present:

• slowing on EEG
• temporal or multifocal T2 hyperintensities on MRI
• positive anti-NMDA receptor antibody in the serum.²

Continue to: Evidence suggests that basic CSF parameters...

Evidence suggests that basic CSF parameters, such as elevated protein and white blood cell counts, are some of the most sensitive and specific tests for autoimmune encephalitis.² Thus, if the patient is amenable and logistical factors are in place, it may be reasonable to pursue LP earlier in some cases without waiting for serum antibody assays to return (these results can take several weeks). CSF inflammatory changes without neuronal antibodies should lead to other diagnostic considerations (eg, systemic inflammatory disease, psychosis attributed to systemic lupus erythematosus).⁷ While nonspecific, serum laboratory values that may increase suspicion of anti-NMDA receptor encephalitis include hyponatremia⁶ and an elevated neutrophil-to-lymphocyte ratio (NLR).²⁸ An NLR >4 in conjunction with CSF albumin-to- serum albumin ratio >7 is associated with impaired blood brain barrier integrity and a worse prognosis for those with anti-NMDA receptor encephalitis.²⁸

Additional clinical features that may sway decisions in favor of obtaining LP despite negative findings on EEG, MRI, and serum antibodies include increased adverse reactions to antipsychotics (eg, neuroleptic malignant syndrome), prodromal infectious symptoms, known tumor, or new-onset neurologic symptoms after initial evaluation.^2,8

Table 2 summarizes key features of laboratory and diagnostic findings in anti-NMDA receptor encephalitis.

When should you pursue a more extensive workup?

There are some practical tools and rating scales to help clinicians conceptualize risk for autoimmune encephalitis. For psychiatric purposes, however, many of these scales assume that LP, MRI, and EEG have already been completed, and thus it is challenging to incorporate them into psychiatric practice. One such tool is the Antibody Prevalence in Epilepsy and Encephalopathy scale; a score ≥4 is 98% sensitive and 78% to 84% specific for predicting antineural autoantibody positivity.¹⁰ Table 3 describes warning signs that may be useful in helping clinicians decide how urgently to pursue a more extensive workup in the possibility of autoimmune encephalitis.

The importance of catching anti-NMDA receptor encephalitis is underscored by the fact that appropriate treatment is very different than for primary psychosis, and outcomes worsen with delay to appropriate treatment.²⁰ Without treatment, severe cases may progress to autonomic instability, altered consciousness, and respiratory compromise warranting admission to an intensive care unit. While the details are beyond the scope of this review, the recommended treatment for confirmed cases of anti-NMDA receptor encephalitis includes tumor removal (if indicated), reducing inflammation (steroids), removing antibodies via IV immunoglobulins, or plasma exchange.^8,29 Progression of the disease may warrant consideration of rituximab or cyclophosphamide. In nonresponsive cases, third-line treatments include proteasome inhibitors or interleukin-6 receptor antagonists.⁸ For patients with severe catatonia, some studies have investigated the utility of electroconvulsive therapy.³⁰ Conceptually, clinicians may consider the utility of antipsychotics as similar to recommendations for hyperactive delirium for the management of psychotic symptoms, agitation, or insomnia. However, given the risk for antipsychotic intolerance, using the lowest effective dose and vigilant screening for the emergence of extrapyramidal symptoms, fever, and autonomic instability is recommended.

CASE CONTINUED

Finally, something objective

Ms. L receives haloperidol 2 mg and undergoes an MRI without contrast. Findings are unremarkable. A spot EEG notes diffuse background slowing in the theta range, prompting lumbar puncture. Findings note 0.40 g/L, 0.2 g/L, and 3.5 for the total protein, albumin, and albumin/CSF-serum quotient (QAlb), respectively; all values are within normal limits. A mild lymphocytic pleocytosis is present as evidenced by a cell count of 35 cells/µL. The CSF is sent for qualitative examination of immunoglobulin G and electrophoresis of proteins in the CSF and serum, of which an increased concentration of restricted bands (oligoclonal bands) in the CSF but not the serum would indicate findings of oligoclonal bands. CSF is sent for detection of anti-NMDA receptor antibodies by indirect immunofluorescence, with a plan to involve an interdisciplinary team for treatment if the antibodies return positive and to manage the case symptomatically in the interim.

Bottom Line

A small subpopulation of patients who present with apparent first-episode psychosis will have symptoms caused by autoimmune encephalitis (specifically, anti-NMDA receptor encephalitis). We provide 4 screening questions to determine when to pursue a workup for an autoimmune encephalitis, and describe relevant clinical symptoms and warning signs to help differentiate the 2 conditions.

Related Resources

• Askandaryan AS, Naqvi A, Varughese A, et al. Anti-N-methyl-D-aspartate receptor encephalitis: neuropsychiatric and multidisciplinary approach to a patient not responding to first-line treatment. Cureus. 2022;14(6):e25751.
• Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.

Drug Brand Names

Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Rituximab • Rituxan

Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.

CASE REPORT

Bizarre behavior and isolation

Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.

Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.

Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is one of the most common forms of autoimmune encephalitis that can present with symptoms of psychosis.¹

In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.^2,3

What does anti-NMDA receptor encephalitis look like?

Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al⁴ proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.⁵ Such groupings make this the most common clinical finding (95%)⁵ but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.^6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.⁸ One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.² In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.⁹

History and review of systems

Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.¹⁰ Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.¹¹ A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.⁷

Continue to: Another indication is the presence...

Another indication is the presence of new seizures within 1 year of presenting with psychotic symptoms.¹⁰ The possibility of undiagnosed seizures should be considered in a patient with psychosis who has episodes of unresponsiveness, dissociative episodes, or seizure-like activity that is thought to be psychogenic but has not been fully evaluated. Seizures in autoimmune encephalitis involve deep structures in the brain and can be present without overt epileptiform activity on EEG, but rather causing only bilateral slowing that is often described as nonspecific.¹²

In a young patient presenting with first-episode psychosis, a recent diagnosis of cancer or abnormal finding in the ovaries increases the likelihood of autoimmune encephalitis.⁴ Historically, however, this type of medical history has been irrelevant to psychosis. Although rare, any person presenting with first-episode psychosis and a history of herpes simplex virus (HSV) encephalitis should be evaluated for autoimmune encephalitis because anti-NMDA receptor antibodies have been reported to be present in approximately one-third of these patients.¹³ Finally, the report of focal neurologic symptoms, including neck stiffness or neck pain, should raise concern, although sensory, working memory, and cognitive deficits may be difficult to fully distinguish from common somatic and cognitive symptoms in a primary psychiatric presentation.

Table 1 lists 4 questions to ask patients who present with first-episode psychosis that may not usually be part of a typical evaluation.

CASE CONTINUED

Uncooperative with examination

In the ED, Ms. L’s heart rate is 101 beats per minute and her blood pressure is 102/72 mm Hg. Her body mass index (BMI) is 22, which suggests an approximate 8-pound weight loss since her BMI was last assessed. Ms. L responds to questions with 1- to 6-word sentences, without clear verbigeration. Though her speech is not pressured, it is of increased rate. Her gaze scans the room, occasionally becoming fixed for 5 to 10 seconds but is aborted by the interviewer’s comment on this behavior. Ms. L efficiently and accurately spells WORLD backwards, then asks “Why?” and refuses to engage in further cognitive testing, stating “Not doing that.” When the interviewer asks “Why not?” she responds “Not doing that.” Her cranial nerves are intact, and she refuses cerebellar testing or requests to assess tone. There are no observed stereotypies, posturing, or echopraxia.

While not necessary for a diagnosis of autoimmune encephalitis, short-term memory loss is a common cognitive finding across studies.^5-7 A common clinical finding from a mental status exam is speech disorders, including (but not limited to) increased rates of speech or decreased verbal output.⁷ Autonomic instability—including tachycardia, markedly labile blood pressures, and orthostasis—all increase the likelihood of autoimmune encephalitis.¹⁴ Interpreting a patient’s vital sign changes can be confounded if they are agitated or anxious, or if they are taking an antipsychotic that produces adverse anticholinergic effects. However, vital sign abnormalities that precede medication administration or do not correlate with fluctuations in mental status increase suspicion for an autoimmune encephalitis.

Continue to: In the absence of the adverse effect...

In the absence of the adverse effect of a medication, orthostasis is uncommon in a well-hydrated young person. Some guidelines⁴ suggest that symptoms of catatonia should be considered a red flag for autoimmune encephalitis. According to the Bush-Francis Catatonia Rating Scale, commonly identified features include immobility, staring, mutism, posturing, withdrawal, rigidity, and gegenhalten.¹⁵ Catatonia is common among patients with anti-NDMA receptor encephalitis, though it may not be initially present and could emerge later.² However, there are documented cases of autoimmune encephalitis where the patient had only isolated features of catatonia, such as echolalia or mutism.²

CASE CONTINUED

History helps narrow the diagnosis

Ms. L’s parents say their daughter has not had prior contact with a therapist or psychiatrist, previous psychiatric diagnoses, hospitalizations, suicide attempts, self-injury, or binging or purging behaviors. Ms. L’s paternal grandfather was diagnosed with schizophrenia, but he is currently employed, lives alone, and has not taken medication for many years. Her mother has hypothyroidism. Ms. L was born at full term via vaginal delivery without cardiac defects or a neonatal intensive care unit stay. Her mother said she did not have postpartum depression or anxiety, a complicated pregnancy, or exposure to tobacco, alcohol, or illicit drug use. Ms. L has no history of childhood seizures or head injury with loss of consciousness. She is an only child, born and raised in a house in a metropolitan area, walked at 13 months, did not require early intervention or speech therapy, and met normal language milestones.

She attended kindergarten at age 6 and progressed throughout public school without regressions in reading, writing, or behavioral manifestations, and did not require a 504 Plan or individualized education program. Ms. L graduated high school in the top 30% of her class, was socially active, and attended a local college. In college, she achieved honor roll, enrolled in a sorority, and was a part of a research lab. Her only medication is oral contraception. She consumes alcohol socially, and reports no cannabis, cigarette, or vaping use. Ms. L says she does not use hallucinogens, stimulants, opiates, or cocaine, and her roommate and family confirm this. She denies recent travel and is sexually active. Ms. L’s urinary and serum toxicology are unremarkable, human chorionic gonadotropin is undetectable, and her sodium level is 133 mEq/L. A measure of serum neutrophils is 6.8 x 10⁹/L and serum lymphocytes is 1.7 x 10⁹/L. Her parents adamantly request a Neurology consultation and further workup, including a lumbar puncture (LP), EEG, and brain imaging (MRI).

This information is useful in ruling out other potential causes of psychosis, such as substance-induced psychosis and neurodevelopmental disorders that can present with psychosis. Additionally, neurodevelopmental abnormalities and psychiatric prodromal symptoms are known precedents in individuals who develop a primary psychotic disorder such as schizophrenia.¹⁶ A family history that includes a psychotic illness may increase the likelihood of a primary psychotic disorder in offspring; however, clinicians must also consider the accuracy of diagnosis in the family, as this can often be inaccurate or influenced by historical cultural bias. We recommend further elucidating the likelihood of a genetic predisposition to a primary psychotic disorder by clarifying familial medication history and functionality.

For example, the fact that Ms. L’s grandfather has not taken medication for many years and has a high degree of functioning and/or absence of cognitive deficits would lower our suspicion for an accurate diagnosis of schizophrenia (given the typical cognitive decline with untreated illness). Another piece of family history relevant to autoimmune encephalitis includes the propensity for autoimmune disorders, but expert opinion on this matter is mixed.¹⁷ Ms. L’s mother has hypothyroidism, which is commonly caused by a prior episode of Hashimoto’s autoimmune thyroiditis. Some physicians advocate for measuring antithyroid antibodies and erythrocyte sedimentation rate or C-reactive protein to gauge the level of autoimmunity, but the usefulness of these measures for detecting autoimmune encephalitis is unclear. These serum markers can be useful in detecting additional important etiologies such as systemic infection or systemic inflammation, and there are conditions such as steroid-responsive encephalopathy with associated thyroiditis, which, as the name suggests, responds to steroids rather than other psychotropic medications. Other risk factors for autoimmune encephalitis include being female, being young, having viral infections (eg, HSV), prior tumor burden, and being in the postpartum period.¹⁸ Some experts also suggest the presence of neurologic symptoms 4 weeks after the first psychiatric or cognitive symptom presentation increases the likelihood of anti-NMDA receptor encephalitis, and a lack of neurologic symptoms would make this diagnosis less likely.^6,19

Continue to: Another item of interest...

Another item of interest in Ms. L’s case is her parents’ request for a Neurology consultation and further workup, as there is an association between caregiver request for workup and eventual diagnosis.⁶ While the etiology of this phenomenon is unclear, the literature suggests individuals with autoimmune encephalitis who initially present to Psychiatry experience longer delays to the appropriate treatment with immunomodulatory therapy than those who first present to Neurology.²⁰

Laboratory and diagnostic testing

Guasp et al² recommend EEG, MRI, and serum autoimmune antibodies (ie, screening for anti-NMDA receptor antibodies) for patients who present with first-episode psychosis, even in the absence of some of the red flags previously discussed. A recent economic analysis suggested screening all patients with first-episode psychosis for serum antibodies may be cost-effective.²¹ Since there can be false positives from serum testing, a positive result should be followed by CSF testing. Serum antibody testing will miss cases where anti-NMDA receptor antibodies are present only in CSF, which is why Guasp et al² recommend ancillary screening with EEG and MRI.Screening all first-episode psychosis patients with EEG and MRI would represent a major change to psychiatric practice and would be beyond the current practical capabilities of many facilities that treat people with new-onset psychosis. Additional evidence is needed before such a change would be required. These suggestions are supported by studies that found most patients with anti-NMDA receptor encephalitis do not initially present with focal neurologic findings, though the majority (95%) do have EEG abnormalities.^2,20,22

For patients whose presentations include features concerning for anti-NMDA receptor encephalitis, an EEG and MRI are reasonable. In a review of EEG abnormalities in anti-NMDA receptor encephalitis, Gillinder et al²³ noted that while 30% did not have initial findings, 83.6% of those with confirmed anti-NMDA receptor encephalitis demonstrated EEG abnormalities; the most common were generalized slowing, delta slowing, and focal abnormalities. Discovering an extreme delta-brush activity on EEG is specific for anti-NMDA receptor encephalitis, but its absence is not fully informative. Practically, slowing can be a nonspecific manifestation of encephalopathy or a medication effect, and many people who present with first-episode psychosis will have recently received antipsychotics, which alter EEG frequency. In a study of EEG changes with antipsychotics, Centorrino et al²⁴ found that generalized background slowing into the theta range across all antipsychotics was not significantly different from control participants, while theta to delta range slowing occurred in 8.2% of those receiving antipsychotics vs 3.3% of controls. Clozapine and olanzapine may be associated with greater EEG abnormalities, while haloperidol and quetiapine contribute a lower risk.²⁵ For young patients with first-episode psychosis without a clear alternative explanation, we advocate for further autoimmune encephalitis workup among all individuals with generalized theta or delta wave slowing.

Because these medication effects are most likely to decrease specificity but not sensitivity of EEG for autoimmune encephalitis, a normal EEG without slowing can be reassuring.²⁶ Moreover, for patients who receive neuroimaging, an MRI may detect inflammation that is not visible on CT. The concerning findings for anti-NMDA receptor encephalitis are temporal or multifocal T2 hyperintensities, though the MRI is normal in most cases and thus should not be reassuring if other concerning features are present.²⁷

The role of lumbar puncture

Another area of active debate surrounds the usefulness and timing of LP. Guasp et al² proposed that all individuals with first-episode psychosis and focal neurologic findings should receive LP and CSF antineuronal antibody testing. They recommend that patients with first-episode psychosis without focal neurologic findings also should receive LP and CSF testing if ≥1 of the following is present:

• slowing on EEG
• temporal or multifocal T2 hyperintensities on MRI
• positive anti-NMDA receptor antibody in the serum.²

Continue to: Evidence suggests that basic CSF parameters...

Evidence suggests that basic CSF parameters, such as elevated protein and white blood cell counts, are some of the most sensitive and specific tests for autoimmune encephalitis.² Thus, if the patient is amenable and logistical factors are in place, it may be reasonable to pursue LP earlier in some cases without waiting for serum antibody assays to return (these results can take several weeks). CSF inflammatory changes without neuronal antibodies should lead to other diagnostic considerations (eg, systemic inflammatory disease, psychosis attributed to systemic lupus erythematosus).⁷ While nonspecific, serum laboratory values that may increase suspicion of anti-NMDA receptor encephalitis include hyponatremia⁶ and an elevated neutrophil-to-lymphocyte ratio (NLR).²⁸ An NLR >4 in conjunction with CSF albumin-to- serum albumin ratio >7 is associated with impaired blood brain barrier integrity and a worse prognosis for those with anti-NMDA receptor encephalitis.²⁸

Additional clinical features that may sway decisions in favor of obtaining LP despite negative findings on EEG, MRI, and serum antibodies include increased adverse reactions to antipsychotics (eg, neuroleptic malignant syndrome), prodromal infectious symptoms, known tumor, or new-onset neurologic symptoms after initial evaluation.^2,8

Table 2 summarizes key features of laboratory and diagnostic findings in anti-NMDA receptor encephalitis.

When should you pursue a more extensive workup?

There are some practical tools and rating scales to help clinicians conceptualize risk for autoimmune encephalitis. For psychiatric purposes, however, many of these scales assume that LP, MRI, and EEG have already been completed, and thus it is challenging to incorporate them into psychiatric practice. One such tool is the Antibody Prevalence in Epilepsy and Encephalopathy scale; a score ≥4 is 98% sensitive and 78% to 84% specific for predicting antineural autoantibody positivity.¹⁰ Table 3 describes warning signs that may be useful in helping clinicians decide how urgently to pursue a more extensive workup in the possibility of autoimmune encephalitis.

The importance of catching anti-NMDA receptor encephalitis is underscored by the fact that appropriate treatment is very different than for primary psychosis, and outcomes worsen with delay to appropriate treatment.²⁰ Without treatment, severe cases may progress to autonomic instability, altered consciousness, and respiratory compromise warranting admission to an intensive care unit. While the details are beyond the scope of this review, the recommended treatment for confirmed cases of anti-NMDA receptor encephalitis includes tumor removal (if indicated), reducing inflammation (steroids), removing antibodies via IV immunoglobulins, or plasma exchange.^8,29 Progression of the disease may warrant consideration of rituximab or cyclophosphamide. In nonresponsive cases, third-line treatments include proteasome inhibitors or interleukin-6 receptor antagonists.⁸ For patients with severe catatonia, some studies have investigated the utility of electroconvulsive therapy.³⁰ Conceptually, clinicians may consider the utility of antipsychotics as similar to recommendations for hyperactive delirium for the management of psychotic symptoms, agitation, or insomnia. However, given the risk for antipsychotic intolerance, using the lowest effective dose and vigilant screening for the emergence of extrapyramidal symptoms, fever, and autonomic instability is recommended.

CASE CONTINUED

Finally, something objective

Ms. L receives haloperidol 2 mg and undergoes an MRI without contrast. Findings are unremarkable. A spot EEG notes diffuse background slowing in the theta range, prompting lumbar puncture. Findings note 0.40 g/L, 0.2 g/L, and 3.5 for the total protein, albumin, and albumin/CSF-serum quotient (QAlb), respectively; all values are within normal limits. A mild lymphocytic pleocytosis is present as evidenced by a cell count of 35 cells/µL. The CSF is sent for qualitative examination of immunoglobulin G and electrophoresis of proteins in the CSF and serum, of which an increased concentration of restricted bands (oligoclonal bands) in the CSF but not the serum would indicate findings of oligoclonal bands. CSF is sent for detection of anti-NMDA receptor antibodies by indirect immunofluorescence, with a plan to involve an interdisciplinary team for treatment if the antibodies return positive and to manage the case symptomatically in the interim.

Bottom Line

A small subpopulation of patients who present with apparent first-episode psychosis will have symptoms caused by autoimmune encephalitis (specifically, anti-NMDA receptor encephalitis). We provide 4 screening questions to determine when to pursue a workup for an autoimmune encephalitis, and describe relevant clinical symptoms and warning signs to help differentiate the 2 conditions.

Related Resources

• Askandaryan AS, Naqvi A, Varughese A, et al. Anti-N-methyl-D-aspartate receptor encephalitis: neuropsychiatric and multidisciplinary approach to a patient not responding to first-line treatment. Cureus. 2022;14(6):e25751.
• Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.

Drug Brand Names

Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Rituximab • Rituxan

Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.

CASE REPORT

Bizarre behavior and isolation

Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.

Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.

Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is one of the most common forms of autoimmune encephalitis that can present with symptoms of psychosis.¹

In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.^2,3

What does anti-NMDA receptor encephalitis look like?

Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al⁴ proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.⁵ Such groupings make this the most common clinical finding (95%)⁵ but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.^6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.⁸ One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.² In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.⁹

History and review of systems

Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.¹⁰ Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.¹¹ A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.⁷

Continue to: Another indication is the presence...

Another indication is the presence of new seizures within 1 year of presenting with psychotic symptoms.¹⁰ The possibility of undiagnosed seizures should be considered in a patient with psychosis who has episodes of unresponsiveness, dissociative episodes, or seizure-like activity that is thought to be psychogenic but has not been fully evaluated. Seizures in autoimmune encephalitis involve deep structures in the brain and can be present without overt epileptiform activity on EEG, but rather causing only bilateral slowing that is often described as nonspecific.¹²

In a young patient presenting with first-episode psychosis, a recent diagnosis of cancer or abnormal finding in the ovaries increases the likelihood of autoimmune encephalitis.⁴ Historically, however, this type of medical history has been irrelevant to psychosis. Although rare, any person presenting with first-episode psychosis and a history of herpes simplex virus (HSV) encephalitis should be evaluated for autoimmune encephalitis because anti-NMDA receptor antibodies have been reported to be present in approximately one-third of these patients.¹³ Finally, the report of focal neurologic symptoms, including neck stiffness or neck pain, should raise concern, although sensory, working memory, and cognitive deficits may be difficult to fully distinguish from common somatic and cognitive symptoms in a primary psychiatric presentation.

Table 1 lists 4 questions to ask patients who present with first-episode psychosis that may not usually be part of a typical evaluation.

CASE CONTINUED

Uncooperative with examination

In the ED, Ms. L’s heart rate is 101 beats per minute and her blood pressure is 102/72 mm Hg. Her body mass index (BMI) is 22, which suggests an approximate 8-pound weight loss since her BMI was last assessed. Ms. L responds to questions with 1- to 6-word sentences, without clear verbigeration. Though her speech is not pressured, it is of increased rate. Her gaze scans the room, occasionally becoming fixed for 5 to 10 seconds but is aborted by the interviewer’s comment on this behavior. Ms. L efficiently and accurately spells WORLD backwards, then asks “Why?” and refuses to engage in further cognitive testing, stating “Not doing that.” When the interviewer asks “Why not?” she responds “Not doing that.” Her cranial nerves are intact, and she refuses cerebellar testing or requests to assess tone. There are no observed stereotypies, posturing, or echopraxia.

While not necessary for a diagnosis of autoimmune encephalitis, short-term memory loss is a common cognitive finding across studies.^5-7 A common clinical finding from a mental status exam is speech disorders, including (but not limited to) increased rates of speech or decreased verbal output.⁷ Autonomic instability—including tachycardia, markedly labile blood pressures, and orthostasis—all increase the likelihood of autoimmune encephalitis.¹⁴ Interpreting a patient’s vital sign changes can be confounded if they are agitated or anxious, or if they are taking an antipsychotic that produces adverse anticholinergic effects. However, vital sign abnormalities that precede medication administration or do not correlate with fluctuations in mental status increase suspicion for an autoimmune encephalitis.

Continue to: In the absence of the adverse effect...

In the absence of the adverse effect of a medication, orthostasis is uncommon in a well-hydrated young person. Some guidelines⁴ suggest that symptoms of catatonia should be considered a red flag for autoimmune encephalitis. According to the Bush-Francis Catatonia Rating Scale, commonly identified features include immobility, staring, mutism, posturing, withdrawal, rigidity, and gegenhalten.¹⁵ Catatonia is common among patients with anti-NDMA receptor encephalitis, though it may not be initially present and could emerge later.² However, there are documented cases of autoimmune encephalitis where the patient had only isolated features of catatonia, such as echolalia or mutism.²

CASE CONTINUED

History helps narrow the diagnosis

Ms. L’s parents say their daughter has not had prior contact with a therapist or psychiatrist, previous psychiatric diagnoses, hospitalizations, suicide attempts, self-injury, or binging or purging behaviors. Ms. L’s paternal grandfather was diagnosed with schizophrenia, but he is currently employed, lives alone, and has not taken medication for many years. Her mother has hypothyroidism. Ms. L was born at full term via vaginal delivery without cardiac defects or a neonatal intensive care unit stay. Her mother said she did not have postpartum depression or anxiety, a complicated pregnancy, or exposure to tobacco, alcohol, or illicit drug use. Ms. L has no history of childhood seizures or head injury with loss of consciousness. She is an only child, born and raised in a house in a metropolitan area, walked at 13 months, did not require early intervention or speech therapy, and met normal language milestones.

She attended kindergarten at age 6 and progressed throughout public school without regressions in reading, writing, or behavioral manifestations, and did not require a 504 Plan or individualized education program. Ms. L graduated high school in the top 30% of her class, was socially active, and attended a local college. In college, she achieved honor roll, enrolled in a sorority, and was a part of a research lab. Her only medication is oral contraception. She consumes alcohol socially, and reports no cannabis, cigarette, or vaping use. Ms. L says she does not use hallucinogens, stimulants, opiates, or cocaine, and her roommate and family confirm this. She denies recent travel and is sexually active. Ms. L’s urinary and serum toxicology are unremarkable, human chorionic gonadotropin is undetectable, and her sodium level is 133 mEq/L. A measure of serum neutrophils is 6.8 x 10⁹/L and serum lymphocytes is 1.7 x 10⁹/L. Her parents adamantly request a Neurology consultation and further workup, including a lumbar puncture (LP), EEG, and brain imaging (MRI).

This information is useful in ruling out other potential causes of psychosis, such as substance-induced psychosis and neurodevelopmental disorders that can present with psychosis. Additionally, neurodevelopmental abnormalities and psychiatric prodromal symptoms are known precedents in individuals who develop a primary psychotic disorder such as schizophrenia.¹⁶ A family history that includes a psychotic illness may increase the likelihood of a primary psychotic disorder in offspring; however, clinicians must also consider the accuracy of diagnosis in the family, as this can often be inaccurate or influenced by historical cultural bias. We recommend further elucidating the likelihood of a genetic predisposition to a primary psychotic disorder by clarifying familial medication history and functionality.

For example, the fact that Ms. L’s grandfather has not taken medication for many years and has a high degree of functioning and/or absence of cognitive deficits would lower our suspicion for an accurate diagnosis of schizophrenia (given the typical cognitive decline with untreated illness). Another piece of family history relevant to autoimmune encephalitis includes the propensity for autoimmune disorders, but expert opinion on this matter is mixed.¹⁷ Ms. L’s mother has hypothyroidism, which is commonly caused by a prior episode of Hashimoto’s autoimmune thyroiditis. Some physicians advocate for measuring antithyroid antibodies and erythrocyte sedimentation rate or C-reactive protein to gauge the level of autoimmunity, but the usefulness of these measures for detecting autoimmune encephalitis is unclear. These serum markers can be useful in detecting additional important etiologies such as systemic infection or systemic inflammation, and there are conditions such as steroid-responsive encephalopathy with associated thyroiditis, which, as the name suggests, responds to steroids rather than other psychotropic medications. Other risk factors for autoimmune encephalitis include being female, being young, having viral infections (eg, HSV), prior tumor burden, and being in the postpartum period.¹⁸ Some experts also suggest the presence of neurologic symptoms 4 weeks after the first psychiatric or cognitive symptom presentation increases the likelihood of anti-NMDA receptor encephalitis, and a lack of neurologic symptoms would make this diagnosis less likely.^6,19

Continue to: Another item of interest...

Another item of interest in Ms. L’s case is her parents’ request for a Neurology consultation and further workup, as there is an association between caregiver request for workup and eventual diagnosis.⁶ While the etiology of this phenomenon is unclear, the literature suggests individuals with autoimmune encephalitis who initially present to Psychiatry experience longer delays to the appropriate treatment with immunomodulatory therapy than those who first present to Neurology.²⁰

Laboratory and diagnostic testing

Guasp et al² recommend EEG, MRI, and serum autoimmune antibodies (ie, screening for anti-NMDA receptor antibodies) for patients who present with first-episode psychosis, even in the absence of some of the red flags previously discussed. A recent economic analysis suggested screening all patients with first-episode psychosis for serum antibodies may be cost-effective.²¹ Since there can be false positives from serum testing, a positive result should be followed by CSF testing. Serum antibody testing will miss cases where anti-NMDA receptor antibodies are present only in CSF, which is why Guasp et al² recommend ancillary screening with EEG and MRI.Screening all first-episode psychosis patients with EEG and MRI would represent a major change to psychiatric practice and would be beyond the current practical capabilities of many facilities that treat people with new-onset psychosis. Additional evidence is needed before such a change would be required. These suggestions are supported by studies that found most patients with anti-NMDA receptor encephalitis do not initially present with focal neurologic findings, though the majority (95%) do have EEG abnormalities.^2,20,22

For patients whose presentations include features concerning for anti-NMDA receptor encephalitis, an EEG and MRI are reasonable. In a review of EEG abnormalities in anti-NMDA receptor encephalitis, Gillinder et al²³ noted that while 30% did not have initial findings, 83.6% of those with confirmed anti-NMDA receptor encephalitis demonstrated EEG abnormalities; the most common were generalized slowing, delta slowing, and focal abnormalities. Discovering an extreme delta-brush activity on EEG is specific for anti-NMDA receptor encephalitis, but its absence is not fully informative. Practically, slowing can be a nonspecific manifestation of encephalopathy or a medication effect, and many people who present with first-episode psychosis will have recently received antipsychotics, which alter EEG frequency. In a study of EEG changes with antipsychotics, Centorrino et al²⁴ found that generalized background slowing into the theta range across all antipsychotics was not significantly different from control participants, while theta to delta range slowing occurred in 8.2% of those receiving antipsychotics vs 3.3% of controls. Clozapine and olanzapine may be associated with greater EEG abnormalities, while haloperidol and quetiapine contribute a lower risk.²⁵ For young patients with first-episode psychosis without a clear alternative explanation, we advocate for further autoimmune encephalitis workup among all individuals with generalized theta or delta wave slowing.

Because these medication effects are most likely to decrease specificity but not sensitivity of EEG for autoimmune encephalitis, a normal EEG without slowing can be reassuring.²⁶ Moreover, for patients who receive neuroimaging, an MRI may detect inflammation that is not visible on CT. The concerning findings for anti-NMDA receptor encephalitis are temporal or multifocal T2 hyperintensities, though the MRI is normal in most cases and thus should not be reassuring if other concerning features are present.²⁷

The role of lumbar puncture

Another area of active debate surrounds the usefulness and timing of LP. Guasp et al² proposed that all individuals with first-episode psychosis and focal neurologic findings should receive LP and CSF antineuronal antibody testing. They recommend that patients with first-episode psychosis without focal neurologic findings also should receive LP and CSF testing if ≥1 of the following is present:

• slowing on EEG
• temporal or multifocal T2 hyperintensities on MRI
• positive anti-NMDA receptor antibody in the serum.²

Continue to: Evidence suggests that basic CSF parameters...

Evidence suggests that basic CSF parameters, such as elevated protein and white blood cell counts, are some of the most sensitive and specific tests for autoimmune encephalitis.² Thus, if the patient is amenable and logistical factors are in place, it may be reasonable to pursue LP earlier in some cases without waiting for serum antibody assays to return (these results can take several weeks). CSF inflammatory changes without neuronal antibodies should lead to other diagnostic considerations (eg, systemic inflammatory disease, psychosis attributed to systemic lupus erythematosus).⁷ While nonspecific, serum laboratory values that may increase suspicion of anti-NMDA receptor encephalitis include hyponatremia⁶ and an elevated neutrophil-to-lymphocyte ratio (NLR).²⁸ An NLR >4 in conjunction with CSF albumin-to- serum albumin ratio >7 is associated with impaired blood brain barrier integrity and a worse prognosis for those with anti-NMDA receptor encephalitis.²⁸

Additional clinical features that may sway decisions in favor of obtaining LP despite negative findings on EEG, MRI, and serum antibodies include increased adverse reactions to antipsychotics (eg, neuroleptic malignant syndrome), prodromal infectious symptoms, known tumor, or new-onset neurologic symptoms after initial evaluation.^2,8

Table 2 summarizes key features of laboratory and diagnostic findings in anti-NMDA receptor encephalitis.

When should you pursue a more extensive workup?

There are some practical tools and rating scales to help clinicians conceptualize risk for autoimmune encephalitis. For psychiatric purposes, however, many of these scales assume that LP, MRI, and EEG have already been completed, and thus it is challenging to incorporate them into psychiatric practice. One such tool is the Antibody Prevalence in Epilepsy and Encephalopathy scale; a score ≥4 is 98% sensitive and 78% to 84% specific for predicting antineural autoantibody positivity.¹⁰ Table 3 describes warning signs that may be useful in helping clinicians decide how urgently to pursue a more extensive workup in the possibility of autoimmune encephalitis.

The importance of catching anti-NMDA receptor encephalitis is underscored by the fact that appropriate treatment is very different than for primary psychosis, and outcomes worsen with delay to appropriate treatment.²⁰ Without treatment, severe cases may progress to autonomic instability, altered consciousness, and respiratory compromise warranting admission to an intensive care unit. While the details are beyond the scope of this review, the recommended treatment for confirmed cases of anti-NMDA receptor encephalitis includes tumor removal (if indicated), reducing inflammation (steroids), removing antibodies via IV immunoglobulins, or plasma exchange.^8,29 Progression of the disease may warrant consideration of rituximab or cyclophosphamide. In nonresponsive cases, third-line treatments include proteasome inhibitors or interleukin-6 receptor antagonists.⁸ For patients with severe catatonia, some studies have investigated the utility of electroconvulsive therapy.³⁰ Conceptually, clinicians may consider the utility of antipsychotics as similar to recommendations for hyperactive delirium for the management of psychotic symptoms, agitation, or insomnia. However, given the risk for antipsychotic intolerance, using the lowest effective dose and vigilant screening for the emergence of extrapyramidal symptoms, fever, and autonomic instability is recommended.

CASE CONTINUED

Finally, something objective

Ms. L receives haloperidol 2 mg and undergoes an MRI without contrast. Findings are unremarkable. A spot EEG notes diffuse background slowing in the theta range, prompting lumbar puncture. Findings note 0.40 g/L, 0.2 g/L, and 3.5 for the total protein, albumin, and albumin/CSF-serum quotient (QAlb), respectively; all values are within normal limits. A mild lymphocytic pleocytosis is present as evidenced by a cell count of 35 cells/µL. The CSF is sent for qualitative examination of immunoglobulin G and electrophoresis of proteins in the CSF and serum, of which an increased concentration of restricted bands (oligoclonal bands) in the CSF but not the serum would indicate findings of oligoclonal bands. CSF is sent for detection of anti-NMDA receptor antibodies by indirect immunofluorescence, with a plan to involve an interdisciplinary team for treatment if the antibodies return positive and to manage the case symptomatically in the interim.

Bottom Line

A small subpopulation of patients who present with apparent first-episode psychosis will have symptoms caused by autoimmune encephalitis (specifically, anti-NMDA receptor encephalitis). We provide 4 screening questions to determine when to pursue a workup for an autoimmune encephalitis, and describe relevant clinical symptoms and warning signs to help differentiate the 2 conditions.

Related Resources

• Askandaryan AS, Naqvi A, Varughese A, et al. Anti-N-methyl-D-aspartate receptor encephalitis: neuropsychiatric and multidisciplinary approach to a patient not responding to first-line treatment. Cureus. 2022;14(6):e25751.
• Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.

Drug Brand Names

Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Rituximab • Rituxan

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Ms. B, age 60, presents to the clinic with high blood pressure, hyperlipidemia, type 2 diabetes mellitus, depression, and anxiety. Her blood pressure is 138/82 mm Hg and pulse is 70 beats per minute. Her body mass index (BMI) is 41, which indicates she is obese. She has always struggled with her weight and has tried diet and lifestyle modifications, as well as medications, for the past 5 years with no success. Her current medication regimen includes lisinopril 40 mg daily, amlodipine 5 mg daily, atorvastatin 40 mg daily, metformin 500 mg twice daily, dulaglutide 0.75 mg weekly, lithium 600 mg daily, venlafaxine extended-release (XR) 150 mg daily, and alprazolam 0.5 mg as needed up to twice daily. Due to Ms. B’s BMI and because she has ≥1 comorbid health condition, her primary care physician refers her to a gastro­enterologist to discuss gastric bypass surgery options.

Ms. B is scheduled for Roux-en-Y gastric bypass surgery. You need to determine if any changes should be made to her psycho­tropic medications after she undergoes this surgery.

There are multiple types of bariatric surgeries, including Roux-en-Y gastric bypass, sleeve gastrectomy, laparoscopic adjustable gastric band, and biliopancreatic diversion with duodenal switch (BPD/DS) (Figure^1-4). These procedures all restrict the stomach’s capacity to hold food. In most cases, they also bypass areas of absorption in the intestine and cause increased secretion of hormones in the gut, including (but not limited to) peptide­-YY (PYY) and glucagon-like peptide 1 (GLP-1). These hormonal changes impact several factors, including satiety, hunger, and blood sugar levels.⁵

Roux-en-Y is commonly referred to as the gold standard of weight loss surgery. It divides the top of the stomach into a smaller stomach pouch that connects directly to the small intestine to facilitate smaller meals and alters the release of gut hormones. Additionally, a segment of the small intestine that normally absorbs nutrients and medications is completely bypassed. In contrast, the sleeve gastrectomy removes approximately 80% of the stomach, consequently reducing the amount of food that can be consumed. The greatest impact of the sleeve gastrectomy procedure appears to result from changes in gut hormones. The adjustable gastric band procedure works by placing a band around the upper portion of the stomach to create a small pouch above the band to satisfy hunger with a smaller amount of food. Lastly, BPD/DS is a procedure that creates a tubular stomach pouch and bypasses a large portion of the small intestine. Like the gastric bypass and sleeve gastrectomy, BPD/DS affects gut hormones impacting hunger, satiety, and blood sugar control.

How bariatric surgery can affect drug absorption

As illustrated in the Table,^6-19 each type of bariatric surgery may impact drug absorption differently depending on the mechanism by which the stomach is restricted.

Drug malabsorption is a concern for clinicians with patients who have undergone bariatric surgery. There is limited research measuring changes in psychotropic exposure and outcomes following bariatric surgery. A 2009 literature review by Padwal et al⁷ found that one-third of the 26 studies evaluated provided evidence of decreased absorption following bariatric surgery in patients taking medications that had intrinsic poor absorption, high lipophilicity, and/or undergo enterohepatic recirculation. In a review that included a small study of patients taking selective serotonin reuptake inhibitors or venlafaxine, Godini et al⁸ demonstrated that although there was a notable decrease in drug absorption closely following the surgery, drug absorption recovered for some patients 1 month after Roux-en-Y surgery. These reviews suggest patients who have undergone any form of bariatric surgery must be observed closely because drug absorption may vary based on the individual, the medication administered, and the amount of time postprocedure.

Until more research becomes available, current evidence supports recommendations to assist patients who have a decreased ability to absorb medications after gastric bypass surgery by switching from an extended-release formulation to an immediate-release or solution formulation. This allows patients to rely less on gastric mixing and unpredictable changes in drug release from extended- or controlled-release formulations.

Continue to: Aside from altered...

Aside from altered pharmacokinetics after bariatric surgery, many patients experience an increased risk of self-harm and suicide.²⁰ Therefore, a continued emphasis on and reinforcement of proper antidepressant use and adjustment in these patients is important. This can be facilitated through frequent follow-up visits, either in-person or via telehealth.

Understanding the effect of bariatric surgery on drug absorption is critical to identifying a potential need to adjust a medication dose or formulation after the surgery. Available evidence and data suggest it is reasonable to switch from an extended- or sustained-release formulation to an immediate-release formulation, and to monitor patients more frequently immediately following the surgery.

CASE CONTINUED

Immediately following surgery, Ms. B’s care team adjusts her medication regimen. To account for the change in her stomach size and composition, and therefore its absorption process, the team changes the venlafaxine dosage from venlafaxine XR 150 mg daily to venlafaxine immediate-release 75 mg twice daily. Ms. B is also monitored more frequently following the procedure to determine if additional adjustments to her medication dosage or therapy frequency are necessary. Eight weeks following surgery, Ms. B has lost 16 pounds and is reintroducing more solid foods into her diet. She struggles with some increased anxiety and depression approximately 1 month after surgery, but that improves after her clinicians decide to increase the venlafaxine dose to 75 mg 3 times a day. Her lithium level was also monitored more closely for the first month after the procedure to decrease the risk of lithium toxicity.

Related Resources

• Colvin C, Tsia W, Silverman AL, et al. Nothing up his sleeve: decompensation after bariatric surgery. Current Psychiatry. 2021;20(4):15-19. doi:10.12788/cp.010

Drug Brand Names

Alprazolam • Xanax
Amlodipine • Norvasc
Atorvastatin • Lipitor
Dulaglutide • Trulicity
Lisinopril • Zestril, Prinivil
Lithium • Eskalith, Lithobid
Metformin • Glucophage
Olanzapine • Zyprexa
Venlafaxine • Effexor

Ms. B, age 60, presents to the clinic with high blood pressure, hyperlipidemia, type 2 diabetes mellitus, depression, and anxiety. Her blood pressure is 138/82 mm Hg and pulse is 70 beats per minute. Her body mass index (BMI) is 41, which indicates she is obese. She has always struggled with her weight and has tried diet and lifestyle modifications, as well as medications, for the past 5 years with no success. Her current medication regimen includes lisinopril 40 mg daily, amlodipine 5 mg daily, atorvastatin 40 mg daily, metformin 500 mg twice daily, dulaglutide 0.75 mg weekly, lithium 600 mg daily, venlafaxine extended-release (XR) 150 mg daily, and alprazolam 0.5 mg as needed up to twice daily. Due to Ms. B’s BMI and because she has ≥1 comorbid health condition, her primary care physician refers her to a gastro­enterologist to discuss gastric bypass surgery options.

Ms. B is scheduled for Roux-en-Y gastric bypass surgery. You need to determine if any changes should be made to her psycho­tropic medications after she undergoes this surgery.

There are multiple types of bariatric surgeries, including Roux-en-Y gastric bypass, sleeve gastrectomy, laparoscopic adjustable gastric band, and biliopancreatic diversion with duodenal switch (BPD/DS) (Figure^1-4). These procedures all restrict the stomach’s capacity to hold food. In most cases, they also bypass areas of absorption in the intestine and cause increased secretion of hormones in the gut, including (but not limited to) peptide­-YY (PYY) and glucagon-like peptide 1 (GLP-1). These hormonal changes impact several factors, including satiety, hunger, and blood sugar levels.⁵

Roux-en-Y is commonly referred to as the gold standard of weight loss surgery. It divides the top of the stomach into a smaller stomach pouch that connects directly to the small intestine to facilitate smaller meals and alters the release of gut hormones. Additionally, a segment of the small intestine that normally absorbs nutrients and medications is completely bypassed. In contrast, the sleeve gastrectomy removes approximately 80% of the stomach, consequently reducing the amount of food that can be consumed. The greatest impact of the sleeve gastrectomy procedure appears to result from changes in gut hormones. The adjustable gastric band procedure works by placing a band around the upper portion of the stomach to create a small pouch above the band to satisfy hunger with a smaller amount of food. Lastly, BPD/DS is a procedure that creates a tubular stomach pouch and bypasses a large portion of the small intestine. Like the gastric bypass and sleeve gastrectomy, BPD/DS affects gut hormones impacting hunger, satiety, and blood sugar control.

How bariatric surgery can affect drug absorption

As illustrated in the Table,^6-19 each type of bariatric surgery may impact drug absorption differently depending on the mechanism by which the stomach is restricted.

Drug malabsorption is a concern for clinicians with patients who have undergone bariatric surgery. There is limited research measuring changes in psychotropic exposure and outcomes following bariatric surgery. A 2009 literature review by Padwal et al⁷ found that one-third of the 26 studies evaluated provided evidence of decreased absorption following bariatric surgery in patients taking medications that had intrinsic poor absorption, high lipophilicity, and/or undergo enterohepatic recirculation. In a review that included a small study of patients taking selective serotonin reuptake inhibitors or venlafaxine, Godini et al⁸ demonstrated that although there was a notable decrease in drug absorption closely following the surgery, drug absorption recovered for some patients 1 month after Roux-en-Y surgery. These reviews suggest patients who have undergone any form of bariatric surgery must be observed closely because drug absorption may vary based on the individual, the medication administered, and the amount of time postprocedure.

Until more research becomes available, current evidence supports recommendations to assist patients who have a decreased ability to absorb medications after gastric bypass surgery by switching from an extended-release formulation to an immediate-release or solution formulation. This allows patients to rely less on gastric mixing and unpredictable changes in drug release from extended- or controlled-release formulations.

Continue to: Aside from altered...

Aside from altered pharmacokinetics after bariatric surgery, many patients experience an increased risk of self-harm and suicide.²⁰ Therefore, a continued emphasis on and reinforcement of proper antidepressant use and adjustment in these patients is important. This can be facilitated through frequent follow-up visits, either in-person or via telehealth.

Understanding the effect of bariatric surgery on drug absorption is critical to identifying a potential need to adjust a medication dose or formulation after the surgery. Available evidence and data suggest it is reasonable to switch from an extended- or sustained-release formulation to an immediate-release formulation, and to monitor patients more frequently immediately following the surgery.

CASE CONTINUED

Immediately following surgery, Ms. B’s care team adjusts her medication regimen. To account for the change in her stomach size and composition, and therefore its absorption process, the team changes the venlafaxine dosage from venlafaxine XR 150 mg daily to venlafaxine immediate-release 75 mg twice daily. Ms. B is also monitored more frequently following the procedure to determine if additional adjustments to her medication dosage or therapy frequency are necessary. Eight weeks following surgery, Ms. B has lost 16 pounds and is reintroducing more solid foods into her diet. She struggles with some increased anxiety and depression approximately 1 month after surgery, but that improves after her clinicians decide to increase the venlafaxine dose to 75 mg 3 times a day. Her lithium level was also monitored more closely for the first month after the procedure to decrease the risk of lithium toxicity.

Related Resources

• Colvin C, Tsia W, Silverman AL, et al. Nothing up his sleeve: decompensation after bariatric surgery. Current Psychiatry. 2021;20(4):15-19. doi:10.12788/cp.010

Drug Brand Names

Alprazolam • Xanax
Amlodipine • Norvasc
Atorvastatin • Lipitor
Dulaglutide • Trulicity
Lisinopril • Zestril, Prinivil
Lithium • Eskalith, Lithobid
Metformin • Glucophage
Olanzapine • Zyprexa
Venlafaxine • Effexor

Ms. B, age 60, presents to the clinic with high blood pressure, hyperlipidemia, type 2 diabetes mellitus, depression, and anxiety. Her blood pressure is 138/82 mm Hg and pulse is 70 beats per minute. Her body mass index (BMI) is 41, which indicates she is obese. She has always struggled with her weight and has tried diet and lifestyle modifications, as well as medications, for the past 5 years with no success. Her current medication regimen includes lisinopril 40 mg daily, amlodipine 5 mg daily, atorvastatin 40 mg daily, metformin 500 mg twice daily, dulaglutide 0.75 mg weekly, lithium 600 mg daily, venlafaxine extended-release (XR) 150 mg daily, and alprazolam 0.5 mg as needed up to twice daily. Due to Ms. B’s BMI and because she has ≥1 comorbid health condition, her primary care physician refers her to a gastro­enterologist to discuss gastric bypass surgery options.

Ms. B is scheduled for Roux-en-Y gastric bypass surgery. You need to determine if any changes should be made to her psycho­tropic medications after she undergoes this surgery.

There are multiple types of bariatric surgeries, including Roux-en-Y gastric bypass, sleeve gastrectomy, laparoscopic adjustable gastric band, and biliopancreatic diversion with duodenal switch (BPD/DS) (Figure^1-4). These procedures all restrict the stomach’s capacity to hold food. In most cases, they also bypass areas of absorption in the intestine and cause increased secretion of hormones in the gut, including (but not limited to) peptide­-YY (PYY) and glucagon-like peptide 1 (GLP-1). These hormonal changes impact several factors, including satiety, hunger, and blood sugar levels.⁵

Roux-en-Y is commonly referred to as the gold standard of weight loss surgery. It divides the top of the stomach into a smaller stomach pouch that connects directly to the small intestine to facilitate smaller meals and alters the release of gut hormones. Additionally, a segment of the small intestine that normally absorbs nutrients and medications is completely bypassed. In contrast, the sleeve gastrectomy removes approximately 80% of the stomach, consequently reducing the amount of food that can be consumed. The greatest impact of the sleeve gastrectomy procedure appears to result from changes in gut hormones. The adjustable gastric band procedure works by placing a band around the upper portion of the stomach to create a small pouch above the band to satisfy hunger with a smaller amount of food. Lastly, BPD/DS is a procedure that creates a tubular stomach pouch and bypasses a large portion of the small intestine. Like the gastric bypass and sleeve gastrectomy, BPD/DS affects gut hormones impacting hunger, satiety, and blood sugar control.

How bariatric surgery can affect drug absorption

As illustrated in the Table,^6-19 each type of bariatric surgery may impact drug absorption differently depending on the mechanism by which the stomach is restricted.

Drug malabsorption is a concern for clinicians with patients who have undergone bariatric surgery. There is limited research measuring changes in psychotropic exposure and outcomes following bariatric surgery. A 2009 literature review by Padwal et al⁷ found that one-third of the 26 studies evaluated provided evidence of decreased absorption following bariatric surgery in patients taking medications that had intrinsic poor absorption, high lipophilicity, and/or undergo enterohepatic recirculation. In a review that included a small study of patients taking selective serotonin reuptake inhibitors or venlafaxine, Godini et al⁸ demonstrated that although there was a notable decrease in drug absorption closely following the surgery, drug absorption recovered for some patients 1 month after Roux-en-Y surgery. These reviews suggest patients who have undergone any form of bariatric surgery must be observed closely because drug absorption may vary based on the individual, the medication administered, and the amount of time postprocedure.

Until more research becomes available, current evidence supports recommendations to assist patients who have a decreased ability to absorb medications after gastric bypass surgery by switching from an extended-release formulation to an immediate-release or solution formulation. This allows patients to rely less on gastric mixing and unpredictable changes in drug release from extended- or controlled-release formulations.

Continue to: Aside from altered...

Aside from altered pharmacokinetics after bariatric surgery, many patients experience an increased risk of self-harm and suicide.²⁰ Therefore, a continued emphasis on and reinforcement of proper antidepressant use and adjustment in these patients is important. This can be facilitated through frequent follow-up visits, either in-person or via telehealth.

Understanding the effect of bariatric surgery on drug absorption is critical to identifying a potential need to adjust a medication dose or formulation after the surgery. Available evidence and data suggest it is reasonable to switch from an extended- or sustained-release formulation to an immediate-release formulation, and to monitor patients more frequently immediately following the surgery.

CASE CONTINUED

Immediately following surgery, Ms. B’s care team adjusts her medication regimen. To account for the change in her stomach size and composition, and therefore its absorption process, the team changes the venlafaxine dosage from venlafaxine XR 150 mg daily to venlafaxine immediate-release 75 mg twice daily. Ms. B is also monitored more frequently following the procedure to determine if additional adjustments to her medication dosage or therapy frequency are necessary. Eight weeks following surgery, Ms. B has lost 16 pounds and is reintroducing more solid foods into her diet. She struggles with some increased anxiety and depression approximately 1 month after surgery, but that improves after her clinicians decide to increase the venlafaxine dose to 75 mg 3 times a day. Her lithium level was also monitored more closely for the first month after the procedure to decrease the risk of lithium toxicity.

Related Resources

• Colvin C, Tsia W, Silverman AL, et al. Nothing up his sleeve: decompensation after bariatric surgery. Current Psychiatry. 2021;20(4):15-19. doi:10.12788/cp.010

Drug Brand Names

Alprazolam • Xanax
Amlodipine • Norvasc
Atorvastatin • Lipitor
Dulaglutide • Trulicity
Lisinopril • Zestril, Prinivil
Lithium • Eskalith, Lithobid
Metformin • Glucophage
Olanzapine • Zyprexa
Venlafaxine • Effexor

CASE Psychotic episode in a patient with HIV

Mr. F, age 32, has schizophrenia and HIV. He presents to the emergency department with auditory and visual hallucinations in addition to paranoia. The treatment team refers him to the state psychiatric facility on an involuntary hold. Mr. F has had multiple previous hospitalizations, none of which had resulted in successful treatment. According to his most recent records, Mr. F failed to improve while taking olanzapine. Upon examination, Mr. F reports he hears command auditory hallucinations to hurt others and endorses paranoia. He is agitated, with a constricted affect, and his thought content is paranoid, disorganized, and circumstantial. Mr. F provides vague and evasive answers upon admission. His physical examination is unremarkable. He has an eighth-grade education level and limited insight into his illnesses. His Positive and Negative Syndrome Scale (PANSS) score is 122, indicating severe symptoms. The PANSS score is formulated based on 30 items, each scored between 1 and 7. Higher scores indicate more severe symptoms.

[polldaddy:11167946]

The authors’ observations

Compared to other medically ill patients, those with AIDS are 7 times more likely to experience EPS associated with antipsychotics. This may be a result of HIV infiltration of the basal ganglia causing regional changes that predispose these patients to EPS.

[polldaddy:11167948]

TREATMENT Haloperidol and antiretroviral therapy

The treatment team decides to start Mr. F on haloperidol for his psychotic symptoms as well as bictegravir, emtricitabine, and tenofovir for HIV. One week after admission, the team starts Mr. F on haloperidol decanoate 150 mg IM, and continues oral haloperidol and antiretroviral therapy. Mr. F reports some improvement in his hallucinations and appears to have reduced paranoia. He attends psychotherapy treatment groups over the next several days and scores 80 on a retrospective PANSS assessment (Figure 1). Mr. F receives haloperidol decanoate 200 mg IM 28 days after his first dose, and his oral haloperidol dose is reduced.

During the following 2 weeks, Mr. F endorses continued improvement of his symptoms and insight and begins discharge planning by calling his sister to discuss living arrangements. However, his mental state begins to decline; he becomes paranoid, withdrawn, and irritable, and endorses increased hallucinations. His PANSS score is 87, and he scores 11 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment. MoCA scores range from 0 to 30, with scores <10 indicating severe impairment, 10 to 17 indicating moderate impairment, 18 to 25 indicating mild impairment, and 26 to 30 considered normal. Figure 2 shows a timeline of Mr. F’s MoCA scores during treatment.

The treatment team increases the dose of haloperidol, and Mr. F continues to receive haloperidol deaconate injections monthly. After an adequate trial of haloperidol, the patient exhibits only partial response to treatment—his symptoms wax and wane—and he continues to display limited insight into both his mental illness and HIV diagnosis. Another PANSS assessment yields an essentially unchanged score of 88.

After a discussion of risks and benefits, Mr. F consents to initiating clozapine. The treatment team starts clozapine 25 mg/d and increases the dosage to 400 mg in the evening with a concomitant clozapine level of 487 ng/mL. Mr. F’s absolute neutrophil count was within normal limits (2,500 to 6,000 µL) during this period for weekly complete blood cell count monitoring. Over the next few weeks, his MoCA score increases to 17 and PANSS score decreases to 52. Haloperidol decanoate 200 mg IM is discontinued 3 days after Mr. F received a dose of clozapine 400 mg at bedtime. After an additional 2 weeks of clozapine at the same dosage, Mr. F scores 20 on the MoCA, an increase of 9 points from his baseline score while receiving haloperidol. There is a washout period for haloperidol decanoate and oral haloperidol before he completes a third MoCA. Mr. F participates in a discussion regarding his HIV diagnosis and the importance of consistently continuing treatment for this chronic infection. After some education, he has a better understanding of his condition and is more insightful about wanting to remain compliant with clozapine and bictegravir, emtricitabine, and tenofovir for his HIV.

The authors’ observations

Many patients receive treatment for comorbid HIV and schizophrenia. Patients with schizophrenia and other psychoses are at increased risk of contracting HIV due to numerous psychosocial factors, including an increased frequency of illicit drug use as well as an increased propensity for high-risk sexual behaviors secondary to impaired neurocognitive functioning, delusions, and victimization.¹ In addition to deficits in functioning related to psychiatric illness, patients with HIV also experience virus-related neurocognitive insults. After crossing the blood-brain barrier, HIV viral proteins circulate in the blood, inducing brain endothelial cells to release cytokines, causing neuroinflammation.²

Continue to: Recently, inflammation and inflammatory...

Recently, inflammation and inflammatory biomarkers have become an important topic of psychiatric research. A meta-analysis by Fraguas et al³ concluded that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first-episode psychosis. Based on this evidence, inflammation associated with untreated HIV infection may compound the pre-existing neurocognitive decline seen in patients with schizophrenia and other psychoses, thereby contributing to poor outcomes and treatment-resistant pathology.

Clozapine has been the superior treatment for refractory and nonrefractory schizophrenia.⁴ Factor et al⁵ report there are limited basal ganglia reserves in patients with HIV, which make clozapine the preferred option due to its low potential for causing EPS.

In this case, starting Mr. F on clozapine and titrating to therapeutic blood levels was associated with improved MoCA scores. Low MoCA scores could be due to untreated HIV, as well as inadequately treated psychosis. For Mr. F, improved MoCA scores were associated with increased insight into his HIV. It is important to note that Mr. F’s improved MoCA score also coincided with discontinuing monthly haloperidol decanoate injections. Haloperidol and its metabolites are believed to cause some neuro­toxicity at high doses, and can contribute to cognitive impairment. This may partially explain the increased MoCA score after Mr. F stopped receiving haloperidol decanoate monthly injections.⁶ For the first time, he felt the need to be on antiretroviral therapy for his HIV, and was able to understand the chronic nature of HIV infection.

The benefit of clozapine treatment for patients with schizophrenia and comorbid HIV extends beyond symptomatic control. Long-term and consistent treatment of schizophrenia can be a stepping stone for improving many psychosocial factors. Improved insight allows patients to better understand their illness, treatment regimen, and follow-up needs. Improved self-care contributes to increased adherence to treatment regimens and overall health.

It is likely that patients who are consistently treated for schizophrenia will also have an increased capacity to understand their HIV diagnosis. With gained understanding, patients may be more likely to adhere to highly active antiretroviral therapy (HAART) for HIV and attend follow-up appointments with infectious disease or primary care physicians. Furthermore, with adherence to HAART therapy, patients can enjoy improved quality and duration of life by raising CD4 counts and preventing progression to AIDS and AIDS-related infections.

Continue to: In the case of...

In the case of Mr. F, we noted significant improvement in MoCA scores following treatment with clozapine. This led to improved insight into understanding the chronicity of HIV, understanding the complications of not being treated, and adherence to HAART medication. Improved cognition, as evidenced by an increased MoCA score, can significantly improve patient insight and adherence with medication.⁷ Insight into illness is particularly important when managing a patient with a chronic infectious illness such as HIV, where consistency with the medication regimen can decrease mortality and improve quality of life.⁸ Furthermore, with close monitoring, clozapine was a safe treatment option for this patient with HIV and schizophrenia.

Bottom Line

Patients with schizophrenia are at an increased risk of contracting HIV, and untreated schizophrenia decreases the likelihood patients will adhere to highly active antiretroviral therapy (HAART). Clozapine treatment in comorbid HIV and schizophrenia can improve cognition and insight into HIV diagnosis, possibly increasing the likelihood patients will remain compliant with HAART.

Related Resources

• Diduch MN, Campbell RH, Borovicka M, et al. Treating psychosis in patients with HIV/AIDS. Current Psychiatry. 2018;17(5):35-36,41-44,46.

Drug Brand Names

Bictegravir, emtricitabine, and tenofovir • Biktarvy
Clozapine • Clozaril
Haloperidol • Haldol
Haloperidol decanoate • Haldol decanoate
Olanzapine • Zyprexa
Ziprasidone • Geodon

CASE Psychotic episode in a patient with HIV

Mr. F, age 32, has schizophrenia and HIV. He presents to the emergency department with auditory and visual hallucinations in addition to paranoia. The treatment team refers him to the state psychiatric facility on an involuntary hold. Mr. F has had multiple previous hospitalizations, none of which had resulted in successful treatment. According to his most recent records, Mr. F failed to improve while taking olanzapine. Upon examination, Mr. F reports he hears command auditory hallucinations to hurt others and endorses paranoia. He is agitated, with a constricted affect, and his thought content is paranoid, disorganized, and circumstantial. Mr. F provides vague and evasive answers upon admission. His physical examination is unremarkable. He has an eighth-grade education level and limited insight into his illnesses. His Positive and Negative Syndrome Scale (PANSS) score is 122, indicating severe symptoms. The PANSS score is formulated based on 30 items, each scored between 1 and 7. Higher scores indicate more severe symptoms.

[polldaddy:11167946]

The authors’ observations

Compared to other medically ill patients, those with AIDS are 7 times more likely to experience EPS associated with antipsychotics. This may be a result of HIV infiltration of the basal ganglia causing regional changes that predispose these patients to EPS.

[polldaddy:11167948]

TREATMENT Haloperidol and antiretroviral therapy

The treatment team decides to start Mr. F on haloperidol for his psychotic symptoms as well as bictegravir, emtricitabine, and tenofovir for HIV. One week after admission, the team starts Mr. F on haloperidol decanoate 150 mg IM, and continues oral haloperidol and antiretroviral therapy. Mr. F reports some improvement in his hallucinations and appears to have reduced paranoia. He attends psychotherapy treatment groups over the next several days and scores 80 on a retrospective PANSS assessment (Figure 1). Mr. F receives haloperidol decanoate 200 mg IM 28 days after his first dose, and his oral haloperidol dose is reduced.

During the following 2 weeks, Mr. F endorses continued improvement of his symptoms and insight and begins discharge planning by calling his sister to discuss living arrangements. However, his mental state begins to decline; he becomes paranoid, withdrawn, and irritable, and endorses increased hallucinations. His PANSS score is 87, and he scores 11 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment. MoCA scores range from 0 to 30, with scores <10 indicating severe impairment, 10 to 17 indicating moderate impairment, 18 to 25 indicating mild impairment, and 26 to 30 considered normal. Figure 2 shows a timeline of Mr. F’s MoCA scores during treatment.

The treatment team increases the dose of haloperidol, and Mr. F continues to receive haloperidol deaconate injections monthly. After an adequate trial of haloperidol, the patient exhibits only partial response to treatment—his symptoms wax and wane—and he continues to display limited insight into both his mental illness and HIV diagnosis. Another PANSS assessment yields an essentially unchanged score of 88.

After a discussion of risks and benefits, Mr. F consents to initiating clozapine. The treatment team starts clozapine 25 mg/d and increases the dosage to 400 mg in the evening with a concomitant clozapine level of 487 ng/mL. Mr. F’s absolute neutrophil count was within normal limits (2,500 to 6,000 µL) during this period for weekly complete blood cell count monitoring. Over the next few weeks, his MoCA score increases to 17 and PANSS score decreases to 52. Haloperidol decanoate 200 mg IM is discontinued 3 days after Mr. F received a dose of clozapine 400 mg at bedtime. After an additional 2 weeks of clozapine at the same dosage, Mr. F scores 20 on the MoCA, an increase of 9 points from his baseline score while receiving haloperidol. There is a washout period for haloperidol decanoate and oral haloperidol before he completes a third MoCA. Mr. F participates in a discussion regarding his HIV diagnosis and the importance of consistently continuing treatment for this chronic infection. After some education, he has a better understanding of his condition and is more insightful about wanting to remain compliant with clozapine and bictegravir, emtricitabine, and tenofovir for his HIV.

The authors’ observations

Many patients receive treatment for comorbid HIV and schizophrenia. Patients with schizophrenia and other psychoses are at increased risk of contracting HIV due to numerous psychosocial factors, including an increased frequency of illicit drug use as well as an increased propensity for high-risk sexual behaviors secondary to impaired neurocognitive functioning, delusions, and victimization.¹ In addition to deficits in functioning related to psychiatric illness, patients with HIV also experience virus-related neurocognitive insults. After crossing the blood-brain barrier, HIV viral proteins circulate in the blood, inducing brain endothelial cells to release cytokines, causing neuroinflammation.²

Continue to: Recently, inflammation and inflammatory...

Recently, inflammation and inflammatory biomarkers have become an important topic of psychiatric research. A meta-analysis by Fraguas et al³ concluded that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first-episode psychosis. Based on this evidence, inflammation associated with untreated HIV infection may compound the pre-existing neurocognitive decline seen in patients with schizophrenia and other psychoses, thereby contributing to poor outcomes and treatment-resistant pathology.

Clozapine has been the superior treatment for refractory and nonrefractory schizophrenia.⁴ Factor et al⁵ report there are limited basal ganglia reserves in patients with HIV, which make clozapine the preferred option due to its low potential for causing EPS.

In this case, starting Mr. F on clozapine and titrating to therapeutic blood levels was associated with improved MoCA scores. Low MoCA scores could be due to untreated HIV, as well as inadequately treated psychosis. For Mr. F, improved MoCA scores were associated with increased insight into his HIV. It is important to note that Mr. F’s improved MoCA score also coincided with discontinuing monthly haloperidol decanoate injections. Haloperidol and its metabolites are believed to cause some neuro­toxicity at high doses, and can contribute to cognitive impairment. This may partially explain the increased MoCA score after Mr. F stopped receiving haloperidol decanoate monthly injections.⁶ For the first time, he felt the need to be on antiretroviral therapy for his HIV, and was able to understand the chronic nature of HIV infection.

The benefit of clozapine treatment for patients with schizophrenia and comorbid HIV extends beyond symptomatic control. Long-term and consistent treatment of schizophrenia can be a stepping stone for improving many psychosocial factors. Improved insight allows patients to better understand their illness, treatment regimen, and follow-up needs. Improved self-care contributes to increased adherence to treatment regimens and overall health.

It is likely that patients who are consistently treated for schizophrenia will also have an increased capacity to understand their HIV diagnosis. With gained understanding, patients may be more likely to adhere to highly active antiretroviral therapy (HAART) for HIV and attend follow-up appointments with infectious disease or primary care physicians. Furthermore, with adherence to HAART therapy, patients can enjoy improved quality and duration of life by raising CD4 counts and preventing progression to AIDS and AIDS-related infections.

Continue to: In the case of...

In the case of Mr. F, we noted significant improvement in MoCA scores following treatment with clozapine. This led to improved insight into understanding the chronicity of HIV, understanding the complications of not being treated, and adherence to HAART medication. Improved cognition, as evidenced by an increased MoCA score, can significantly improve patient insight and adherence with medication.⁷ Insight into illness is particularly important when managing a patient with a chronic infectious illness such as HIV, where consistency with the medication regimen can decrease mortality and improve quality of life.⁸ Furthermore, with close monitoring, clozapine was a safe treatment option for this patient with HIV and schizophrenia.

Bottom Line

Patients with schizophrenia are at an increased risk of contracting HIV, and untreated schizophrenia decreases the likelihood patients will adhere to highly active antiretroviral therapy (HAART). Clozapine treatment in comorbid HIV and schizophrenia can improve cognition and insight into HIV diagnosis, possibly increasing the likelihood patients will remain compliant with HAART.

Related Resources

• Diduch MN, Campbell RH, Borovicka M, et al. Treating psychosis in patients with HIV/AIDS. Current Psychiatry. 2018;17(5):35-36,41-44,46.

Drug Brand Names

Bictegravir, emtricitabine, and tenofovir • Biktarvy
Clozapine • Clozaril
Haloperidol • Haldol
Haloperidol decanoate • Haldol decanoate
Olanzapine • Zyprexa
Ziprasidone • Geodon

CASE Psychotic episode in a patient with HIV

Mr. F, age 32, has schizophrenia and HIV. He presents to the emergency department with auditory and visual hallucinations in addition to paranoia. The treatment team refers him to the state psychiatric facility on an involuntary hold. Mr. F has had multiple previous hospitalizations, none of which had resulted in successful treatment. According to his most recent records, Mr. F failed to improve while taking olanzapine. Upon examination, Mr. F reports he hears command auditory hallucinations to hurt others and endorses paranoia. He is agitated, with a constricted affect, and his thought content is paranoid, disorganized, and circumstantial. Mr. F provides vague and evasive answers upon admission. His physical examination is unremarkable. He has an eighth-grade education level and limited insight into his illnesses. His Positive and Negative Syndrome Scale (PANSS) score is 122, indicating severe symptoms. The PANSS score is formulated based on 30 items, each scored between 1 and 7. Higher scores indicate more severe symptoms.

[polldaddy:11167946]

The authors’ observations

Compared to other medically ill patients, those with AIDS are 7 times more likely to experience EPS associated with antipsychotics. This may be a result of HIV infiltration of the basal ganglia causing regional changes that predispose these patients to EPS.

[polldaddy:11167948]

TREATMENT Haloperidol and antiretroviral therapy

The treatment team decides to start Mr. F on haloperidol for his psychotic symptoms as well as bictegravir, emtricitabine, and tenofovir for HIV. One week after admission, the team starts Mr. F on haloperidol decanoate 150 mg IM, and continues oral haloperidol and antiretroviral therapy. Mr. F reports some improvement in his hallucinations and appears to have reduced paranoia. He attends psychotherapy treatment groups over the next several days and scores 80 on a retrospective PANSS assessment (Figure 1). Mr. F receives haloperidol decanoate 200 mg IM 28 days after his first dose, and his oral haloperidol dose is reduced.

During the following 2 weeks, Mr. F endorses continued improvement of his symptoms and insight and begins discharge planning by calling his sister to discuss living arrangements. However, his mental state begins to decline; he becomes paranoid, withdrawn, and irritable, and endorses increased hallucinations. His PANSS score is 87, and he scores 11 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment. MoCA scores range from 0 to 30, with scores <10 indicating severe impairment, 10 to 17 indicating moderate impairment, 18 to 25 indicating mild impairment, and 26 to 30 considered normal. Figure 2 shows a timeline of Mr. F’s MoCA scores during treatment.

The treatment team increases the dose of haloperidol, and Mr. F continues to receive haloperidol deaconate injections monthly. After an adequate trial of haloperidol, the patient exhibits only partial response to treatment—his symptoms wax and wane—and he continues to display limited insight into both his mental illness and HIV diagnosis. Another PANSS assessment yields an essentially unchanged score of 88.

After a discussion of risks and benefits, Mr. F consents to initiating clozapine. The treatment team starts clozapine 25 mg/d and increases the dosage to 400 mg in the evening with a concomitant clozapine level of 487 ng/mL. Mr. F’s absolute neutrophil count was within normal limits (2,500 to 6,000 µL) during this period for weekly complete blood cell count monitoring. Over the next few weeks, his MoCA score increases to 17 and PANSS score decreases to 52. Haloperidol decanoate 200 mg IM is discontinued 3 days after Mr. F received a dose of clozapine 400 mg at bedtime. After an additional 2 weeks of clozapine at the same dosage, Mr. F scores 20 on the MoCA, an increase of 9 points from his baseline score while receiving haloperidol. There is a washout period for haloperidol decanoate and oral haloperidol before he completes a third MoCA. Mr. F participates in a discussion regarding his HIV diagnosis and the importance of consistently continuing treatment for this chronic infection. After some education, he has a better understanding of his condition and is more insightful about wanting to remain compliant with clozapine and bictegravir, emtricitabine, and tenofovir for his HIV.

The authors’ observations

Many patients receive treatment for comorbid HIV and schizophrenia. Patients with schizophrenia and other psychoses are at increased risk of contracting HIV due to numerous psychosocial factors, including an increased frequency of illicit drug use as well as an increased propensity for high-risk sexual behaviors secondary to impaired neurocognitive functioning, delusions, and victimization.¹ In addition to deficits in functioning related to psychiatric illness, patients with HIV also experience virus-related neurocognitive insults. After crossing the blood-brain barrier, HIV viral proteins circulate in the blood, inducing brain endothelial cells to release cytokines, causing neuroinflammation.²

Continue to: Recently, inflammation and inflammatory...

Recently, inflammation and inflammatory biomarkers have become an important topic of psychiatric research. A meta-analysis by Fraguas et al³ concluded that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first-episode psychosis. Based on this evidence, inflammation associated with untreated HIV infection may compound the pre-existing neurocognitive decline seen in patients with schizophrenia and other psychoses, thereby contributing to poor outcomes and treatment-resistant pathology.

Clozapine has been the superior treatment for refractory and nonrefractory schizophrenia.⁴ Factor et al⁵ report there are limited basal ganglia reserves in patients with HIV, which make clozapine the preferred option due to its low potential for causing EPS.

In this case, starting Mr. F on clozapine and titrating to therapeutic blood levels was associated with improved MoCA scores. Low MoCA scores could be due to untreated HIV, as well as inadequately treated psychosis. For Mr. F, improved MoCA scores were associated with increased insight into his HIV. It is important to note that Mr. F’s improved MoCA score also coincided with discontinuing monthly haloperidol decanoate injections. Haloperidol and its metabolites are believed to cause some neuro­toxicity at high doses, and can contribute to cognitive impairment. This may partially explain the increased MoCA score after Mr. F stopped receiving haloperidol decanoate monthly injections.⁶ For the first time, he felt the need to be on antiretroviral therapy for his HIV, and was able to understand the chronic nature of HIV infection.

The benefit of clozapine treatment for patients with schizophrenia and comorbid HIV extends beyond symptomatic control. Long-term and consistent treatment of schizophrenia can be a stepping stone for improving many psychosocial factors. Improved insight allows patients to better understand their illness, treatment regimen, and follow-up needs. Improved self-care contributes to increased adherence to treatment regimens and overall health.

It is likely that patients who are consistently treated for schizophrenia will also have an increased capacity to understand their HIV diagnosis. With gained understanding, patients may be more likely to adhere to highly active antiretroviral therapy (HAART) for HIV and attend follow-up appointments with infectious disease or primary care physicians. Furthermore, with adherence to HAART therapy, patients can enjoy improved quality and duration of life by raising CD4 counts and preventing progression to AIDS and AIDS-related infections.

Continue to: In the case of...

In the case of Mr. F, we noted significant improvement in MoCA scores following treatment with clozapine. This led to improved insight into understanding the chronicity of HIV, understanding the complications of not being treated, and adherence to HAART medication. Improved cognition, as evidenced by an increased MoCA score, can significantly improve patient insight and adherence with medication.⁷ Insight into illness is particularly important when managing a patient with a chronic infectious illness such as HIV, where consistency with the medication regimen can decrease mortality and improve quality of life.⁸ Furthermore, with close monitoring, clozapine was a safe treatment option for this patient with HIV and schizophrenia.

Bottom Line

Patients with schizophrenia are at an increased risk of contracting HIV, and untreated schizophrenia decreases the likelihood patients will adhere to highly active antiretroviral therapy (HAART). Clozapine treatment in comorbid HIV and schizophrenia can improve cognition and insight into HIV diagnosis, possibly increasing the likelihood patients will remain compliant with HAART.

Related Resources

• Diduch MN, Campbell RH, Borovicka M, et al. Treating psychosis in patients with HIV/AIDS. Current Psychiatry. 2018;17(5):35-36,41-44,46.

Drug Brand Names

Bictegravir, emtricitabine, and tenofovir • Biktarvy
Clozapine • Clozaril
Haloperidol • Haldol
Haloperidol decanoate • Haldol decanoate
Olanzapine • Zyprexa
Ziprasidone • Geodon