The benefits of influenza vaccination are clear to those in the medical community. Yet misinformation and unfounded fears continue to discourage some people from getting a flu shot. During the 2018–2019 influenza season, only 45% of US adults and 63% of children were vaccinated.¹

‘IT DOESN’T WORK FOR MANY PEOPLE’

Multiple studies have shown that the flu vaccine prevents millions of flu cases and flu-related doctor’s visits each year. During the 2016–2017 flu season, flu vaccine prevented an estimated 5.3 million influenza cases, 2.6 million influenza-associated medical visits, and 85,000 influenza-associated hospitalizations.²

Several viral and host factors affect vaccine effectiveness. In seasons when the vaccine viruses have matched circulating strains, flu vaccine has been shown to reduce the following:

• The risk of having to go to the doctor with flu by 40% to 60%
• Children’s risk of flu-related death and intensive care unit (ICU) admission by 74%
• The risk in adults of flu-associated hospitalizations by 40% and ICU admission by 82%
• The rate of cardiac events in people with heart disease
• Hospitalizations in people with diabetes or underlying chronic lung disease.³

In people hospitalized with influenza despite receiving the flu vaccine for the season, studies have shown that receiving the flu vaccine shortens the average duration of hospitalization, reduces the chance of ICU admission by 59%, shortens the duration of ICU stay by 4 days, and reduces deaths.³

‘IT TARGETS THE WRONG VIRUS’

Selecting an effective influenza vaccine is a challenge. Every year, the World Health Organization and the CDC decide on the influenza strains expected to circulate in the upcoming flu season in the Northern Hemisphere, based on data for circulating strains in the Southern Hemisphere. This decision takes place about 7 months before the expected onset of the flu season. Flu viruses may mutate between the time the decision is made and the time the vaccine is administered (as well as after the flu season starts). Also, vaccine production in eggs needs time, which is why this decision must be made several months ahead of the flu season.

Vaccine effectiveness varies by virus serotype. Vaccines are typically less effective against influenza A H3N2 viruses than against influenza A H1N1 and influenza B viruses. Effectiveness also varies from season to season depending on how close the vaccine serotypes match the circulating serotypes, but some effectiveness is retained even in seasons when some of the serotypes don’t match circulating viruses. For example, in the 2017–2018 season, when the influenza A H3N2 vaccine serotype did not match the circulating serotype, the overall effectiveness in preventing medically attended, laboratory-confirmed influenza virus infection was 36%.⁵

A universal flu vaccine that does not need to be updated annually is the ultimate solution, but according to the National Institute of Allergy and Infectious Diseases, such a vaccine is likely several years away.⁶

‘IT MAKES PEOPLE SICK’

Pain at the injection site of a flu shot occurs in 10% to 65% of people, lasts less than 2 days, and does not usually interfere with daily activities.⁷

Systemic symptoms such as fever, malaise, and myalgia may occur in people who have had no previous exposure to the influenza virus antigens in the vaccine, particularly in children. In adults, the frequency of systemic symptoms after the flu shot is similar to that with placebo.

The Vaccine Adverse Event Reporting System, which has been capturing data since 1990, shows that the influenza vaccine accounted for 5.7% of people who developed malaise after receiving any vaccine.⁸

The injectable inactivated influenza vaccine cannot biologically cause an influenza virus-related illness, since the inactivated vaccine viruses can elicit a protective immune response but cannot replicate. The nasal live-attenuated flu vaccine can in theory cause acute illness in the person receiving it, but because it is cold-adapted, it multiplies only in the colder environment of the nasal epithelium, not in the lower airways where the temperature is higher. Consequently, the vaccine virus triggers immunity by multiplying in the nose, but doesn’t infect the lungs.

From 10% to 50% of people who receive the nasal live-attenuated vaccine develop runny nose, wheezing, headache, vomiting, muscle aches, fever, sore throat, or cough shortly after receiving the vaccine, but these symptoms are usually mild and short-lived.

The most common reactions people have to flu vaccines are considerably less severe than the symptoms caused by actual flu illness.

While influenza illness results in natural immunity to the specific viral serotype causing it, this illness results in hospitalization in 2% and is fatal in 0.16% of people. Influenza vaccine results in immunity to the serotypes included in the vaccine, and multiple studies have not found a causal relationship between vaccination and death.⁹

In the United States, 3,000 to 6,000 people per year develop Guillain-Barré syndrome, or 1 to 2 of every 100,000, which translates to 80 to 160 cases per week.¹⁰ While the exact cause of Guillain-Barré syndrome is unknown, about two-thirds of people have an acute diarrheal or respiratory illness within 3 months before the onset of symptoms. In 1976, the estimated attributable risk of influenza vaccine-related Guillain-Barré syndrome in the US adult population was 1 case per 100,000 in the 6 weeks after vaccination.¹¹ Studies in subsequent influenza seasons have not shown similar findings.¹² In fact, one study showed that the risk of developing Guillain-Barré syndrome was 15 times higher after influenza illness than after influenza vaccination.¹³

Since 5% to 15% of the US population develop symptomatic influenza annually,¹⁴ the decision to vaccinate with respect to the risk of Guillain-Barré syndrome should be obvious: vaccinate. The correct question to ask before influenza vaccination should be, “Have you previously developed Guillain-Barré syndrome within 6 weeks after receiving the flu vaccine?” If the answer is yes, the CDC considers this a caution, not a contraindication against receiving the influenza vaccine, since the benefit may still outweigh the risk.

‘I GOT THE FLU SHOT AND STILL GOT SICK’

The flu vaccine does not prevent illnesses caused by other viruses or bacteria that can make people sick during flu season. Influenza, the common cold, and streptococcal pharyngitis can have similar symptoms that make it difficult for patients—and, frequently, even healthcare providers—to distinguish between these illnesses with certainty.

One study suggested that influenza vaccine recipients had an increased risk of virologically confirmed noninfluenza respiratory viral infections,¹⁵ citing the phenomenon of virus interference that was described in the 1940s¹⁶ as a potential explanation. In essence, people protected against influenza by the vaccine may lack temporary nonspecific immunity against other respiratory viruses. However, these findings have not been replicated in subsequent studies.¹⁷

Viral gastroenteritis, mistakenly called “stomach flu,” is also not prevented by influenza vaccination.

‘I’M ALLERGIC TO EGGS’

The prevalence of egg allergy in US children is 0.5% to 2.5%.¹⁸ Most outgrow it by school age, but in one-third, the allergy persists into adulthood.

In general, people who can eat lightly cooked eggs (eg, scrambled eggs) without a reaction are unlikely to be allergic. On the other hand, the fact that egg-allergic people may tolerate egg included in baked products does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reaction to eggs and egg-containing foods, in addition to skin or blood testing for immunoglobulin E directed against egg proteins.¹⁹

Most currently available influenza vaccines are prepared by propagation of virus in embryonated eggs and so may contain trace amounts of egg proteins such as ovalbumin, with the exception of the inactivated quadri­valent recombinant influenza vaccine (Flublok) and the inactivated quadrivalent cell culture-based vaccine (Flucelvax).

The ACIP recommends that persons with a history of urticaria (hives) after exposure to eggs should receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Persons who report having angioedema, respiratory distress, lightheadedness, or recurrent vomiting, or who required epinephrine or another emergency medical intervention after exposure to eggs, should receive the influenza vaccine in an inpatient or outpatient medical setting under the supervision of a healthcare provider who is able to recognize and manage severe allergic reactions.

A history of severe allergic reaction such as anaphylaxis to a previous dose of any influenza vaccine, regardless of the vaccine component (including eggs) suspected of being responsible for the reaction, is a contraindication to influenza vaccination. The ACIP recommends that vaccine providers consider observing patients for 15 minutes after administration of any vaccine (regardless of history of egg allergy) to decrease the risk of injury should syncope occur.²⁰

‘I DON’T WANT TO PUT POISONOUS MERCURY IN MY BODY’

A process of biomagnification of methylmercury occurs when humans eat large fish that have eaten smaller fish. Thus, larger fish such as shark can be hazardous for women who are or may become pregnant, for nursing mothers, and for young children, while smaller fish such as herring are relatively safe.

As a precautionary measure, thimerosal was taken out of childhood vaccines in the United States in 2001. Thimerosal-free influenza vaccine formulations include the nasal live-attenuated flu vaccine, the inactivated quadrivalent recombinant influenza vaccine, and the inactivated quadrivalent cell culture-based vaccine.

‘I DON’T LIKE NEEDLES’

At least 10% of US adults have aichmophobia, the fear of sharp objects including needles.²² Vasovagal syncope is the most common manifestation. Behavioral therapy, topical anesthetics, and systemic anxiolytics have variable efficacy in treating needle phobia. For those who are absolutely averse to needles, the nasal flu vaccine is an appropriate alternative.

‘I DON’T WANT TO TAKE ANYTHING THAT CAN MESS WITH MY OTHER MEDICATIONS’

Some immunosuppressive medications may decrease influenza vaccine immunogenicity. Concomitant administration of the inactivated influenza vaccine with other vaccines is safe and does not alter immunogenicity of other vaccines.¹ The live-attenuated influenza vaccine is contraindicated in children and adolescents taking aspirin or other salicylates due to the risk of Reye syndrome.

A recent systematic review and meta-analysis showed that the inactivated influenza vaccine is not associated with asthma exacerbation.²³ However, the nasal live-attenuated influenza vaccine is contraindicated in children 2 to 4 years old who have asthma and should be used with caution in persons with asthma 5 years old and older. In the systematic review, influenza vaccine prevented 59% to 78% of asthma attacks leading to emergency visits or hospitalization.²³ In other immune-mediated diseases such as rheumatoid arthritis, influenza vaccine does not precipitate exacerbations.²⁴

‘I HAD AN ORGAN TRANSPLANT, AND I’M AFRAID THE FLU SHOT WILL CAUSE ORGAN REJECTION’

A study of 51,730 kidney transplant recipients found that receipt of the inactivated influenza vaccine in the first year after transplant was associated with a lower risk of subsequent allograft loss (adjusted hazard ratio 0.77; 95% confidence interval 0.69–0.85; P < .001) and death (adjusted hazard ratio 0.82; 95% confidence interval 0.76–0.89; P < .001).²⁵ In the same study, although acute rejection in the first year was not associated with influenza vaccination, influenza infection in the first year was associated with rejection (odds ratio 1.58; 95% confidence interval 1.10–2.26; P < 0.001), but not with graft loss or death. Solid organ transplant recipients should receive the inactivated influenza vaccine starting 3 months after transplant.²⁶

Influenza vaccination has not been shown to precipitate graft-vs-host disease in hematopoietic stem cell transplant recipients. These patients should also receive the inactivated influenza vaccine starting 3 to 6 months after transplant.²⁷

The nasal live-attenuated influenza vaccine is contraindicated in these immunocompromised patients.

‘I’M PREGNANT, AND I DON’T WANT TO EXPOSE MY UNBORN BABY TO ANYTHING POTENTIALLY HARMFUL’

The morbidity and mortality risk from influenza is high in children under 2 years old because of low immunogenicity to flu vaccine. This is particularly true in children younger than 6 months, but the vaccine is not recommended in this population. The best way to protect infants is for all household members to be vaccinated against the flu.

Equally important, morbidity and mortality risk from influenza is much higher in pregnant women than in the general population. Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants. A recently published study showed that 18% of infants who developed influenza required hospitalization.²⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively. Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.²⁹ A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.³⁰

Healthcare providers should try to understand the public’s misconceptions³¹ about seasonal influenza and influenza vaccines in order to best address them.

The benefits of influenza vaccination are clear to those in the medical community. Yet misinformation and unfounded fears continue to discourage some people from getting a flu shot. During the 2018–2019 influenza season, only 45% of US adults and 63% of children were vaccinated.¹

‘IT DOESN’T WORK FOR MANY PEOPLE’

Multiple studies have shown that the flu vaccine prevents millions of flu cases and flu-related doctor’s visits each year. During the 2016–2017 flu season, flu vaccine prevented an estimated 5.3 million influenza cases, 2.6 million influenza-associated medical visits, and 85,000 influenza-associated hospitalizations.²

Several viral and host factors affect vaccine effectiveness. In seasons when the vaccine viruses have matched circulating strains, flu vaccine has been shown to reduce the following:

• The risk of having to go to the doctor with flu by 40% to 60%
• Children’s risk of flu-related death and intensive care unit (ICU) admission by 74%
• The risk in adults of flu-associated hospitalizations by 40% and ICU admission by 82%
• The rate of cardiac events in people with heart disease
• Hospitalizations in people with diabetes or underlying chronic lung disease.³

In people hospitalized with influenza despite receiving the flu vaccine for the season, studies have shown that receiving the flu vaccine shortens the average duration of hospitalization, reduces the chance of ICU admission by 59%, shortens the duration of ICU stay by 4 days, and reduces deaths.³

‘IT TARGETS THE WRONG VIRUS’

Selecting an effective influenza vaccine is a challenge. Every year, the World Health Organization and the CDC decide on the influenza strains expected to circulate in the upcoming flu season in the Northern Hemisphere, based on data for circulating strains in the Southern Hemisphere. This decision takes place about 7 months before the expected onset of the flu season. Flu viruses may mutate between the time the decision is made and the time the vaccine is administered (as well as after the flu season starts). Also, vaccine production in eggs needs time, which is why this decision must be made several months ahead of the flu season.

Vaccine effectiveness varies by virus serotype. Vaccines are typically less effective against influenza A H3N2 viruses than against influenza A H1N1 and influenza B viruses. Effectiveness also varies from season to season depending on how close the vaccine serotypes match the circulating serotypes, but some effectiveness is retained even in seasons when some of the serotypes don’t match circulating viruses. For example, in the 2017–2018 season, when the influenza A H3N2 vaccine serotype did not match the circulating serotype, the overall effectiveness in preventing medically attended, laboratory-confirmed influenza virus infection was 36%.⁵

A universal flu vaccine that does not need to be updated annually is the ultimate solution, but according to the National Institute of Allergy and Infectious Diseases, such a vaccine is likely several years away.⁶

‘IT MAKES PEOPLE SICK’

Pain at the injection site of a flu shot occurs in 10% to 65% of people, lasts less than 2 days, and does not usually interfere with daily activities.⁷

Systemic symptoms such as fever, malaise, and myalgia may occur in people who have had no previous exposure to the influenza virus antigens in the vaccine, particularly in children. In adults, the frequency of systemic symptoms after the flu shot is similar to that with placebo.

The Vaccine Adverse Event Reporting System, which has been capturing data since 1990, shows that the influenza vaccine accounted for 5.7% of people who developed malaise after receiving any vaccine.⁸

The injectable inactivated influenza vaccine cannot biologically cause an influenza virus-related illness, since the inactivated vaccine viruses can elicit a protective immune response but cannot replicate. The nasal live-attenuated flu vaccine can in theory cause acute illness in the person receiving it, but because it is cold-adapted, it multiplies only in the colder environment of the nasal epithelium, not in the lower airways where the temperature is higher. Consequently, the vaccine virus triggers immunity by multiplying in the nose, but doesn’t infect the lungs.

From 10% to 50% of people who receive the nasal live-attenuated vaccine develop runny nose, wheezing, headache, vomiting, muscle aches, fever, sore throat, or cough shortly after receiving the vaccine, but these symptoms are usually mild and short-lived.

The most common reactions people have to flu vaccines are considerably less severe than the symptoms caused by actual flu illness.

While influenza illness results in natural immunity to the specific viral serotype causing it, this illness results in hospitalization in 2% and is fatal in 0.16% of people. Influenza vaccine results in immunity to the serotypes included in the vaccine, and multiple studies have not found a causal relationship between vaccination and death.⁹

In the United States, 3,000 to 6,000 people per year develop Guillain-Barré syndrome, or 1 to 2 of every 100,000, which translates to 80 to 160 cases per week.¹⁰ While the exact cause of Guillain-Barré syndrome is unknown, about two-thirds of people have an acute diarrheal or respiratory illness within 3 months before the onset of symptoms. In 1976, the estimated attributable risk of influenza vaccine-related Guillain-Barré syndrome in the US adult population was 1 case per 100,000 in the 6 weeks after vaccination.¹¹ Studies in subsequent influenza seasons have not shown similar findings.¹² In fact, one study showed that the risk of developing Guillain-Barré syndrome was 15 times higher after influenza illness than after influenza vaccination.¹³

Since 5% to 15% of the US population develop symptomatic influenza annually,¹⁴ the decision to vaccinate with respect to the risk of Guillain-Barré syndrome should be obvious: vaccinate. The correct question to ask before influenza vaccination should be, “Have you previously developed Guillain-Barré syndrome within 6 weeks after receiving the flu vaccine?” If the answer is yes, the CDC considers this a caution, not a contraindication against receiving the influenza vaccine, since the benefit may still outweigh the risk.

‘I GOT THE FLU SHOT AND STILL GOT SICK’

The flu vaccine does not prevent illnesses caused by other viruses or bacteria that can make people sick during flu season. Influenza, the common cold, and streptococcal pharyngitis can have similar symptoms that make it difficult for patients—and, frequently, even healthcare providers—to distinguish between these illnesses with certainty.

One study suggested that influenza vaccine recipients had an increased risk of virologically confirmed noninfluenza respiratory viral infections,¹⁵ citing the phenomenon of virus interference that was described in the 1940s¹⁶ as a potential explanation. In essence, people protected against influenza by the vaccine may lack temporary nonspecific immunity against other respiratory viruses. However, these findings have not been replicated in subsequent studies.¹⁷

Viral gastroenteritis, mistakenly called “stomach flu,” is also not prevented by influenza vaccination.

‘I’M ALLERGIC TO EGGS’

The prevalence of egg allergy in US children is 0.5% to 2.5%.¹⁸ Most outgrow it by school age, but in one-third, the allergy persists into adulthood.

In general, people who can eat lightly cooked eggs (eg, scrambled eggs) without a reaction are unlikely to be allergic. On the other hand, the fact that egg-allergic people may tolerate egg included in baked products does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reaction to eggs and egg-containing foods, in addition to skin or blood testing for immunoglobulin E directed against egg proteins.¹⁹

Most currently available influenza vaccines are prepared by propagation of virus in embryonated eggs and so may contain trace amounts of egg proteins such as ovalbumin, with the exception of the inactivated quadri­valent recombinant influenza vaccine (Flublok) and the inactivated quadrivalent cell culture-based vaccine (Flucelvax).

The ACIP recommends that persons with a history of urticaria (hives) after exposure to eggs should receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Persons who report having angioedema, respiratory distress, lightheadedness, or recurrent vomiting, or who required epinephrine or another emergency medical intervention after exposure to eggs, should receive the influenza vaccine in an inpatient or outpatient medical setting under the supervision of a healthcare provider who is able to recognize and manage severe allergic reactions.

A history of severe allergic reaction such as anaphylaxis to a previous dose of any influenza vaccine, regardless of the vaccine component (including eggs) suspected of being responsible for the reaction, is a contraindication to influenza vaccination. The ACIP recommends that vaccine providers consider observing patients for 15 minutes after administration of any vaccine (regardless of history of egg allergy) to decrease the risk of injury should syncope occur.²⁰

‘I DON’T WANT TO PUT POISONOUS MERCURY IN MY BODY’

A process of biomagnification of methylmercury occurs when humans eat large fish that have eaten smaller fish. Thus, larger fish such as shark can be hazardous for women who are or may become pregnant, for nursing mothers, and for young children, while smaller fish such as herring are relatively safe.

As a precautionary measure, thimerosal was taken out of childhood vaccines in the United States in 2001. Thimerosal-free influenza vaccine formulations include the nasal live-attenuated flu vaccine, the inactivated quadrivalent recombinant influenza vaccine, and the inactivated quadrivalent cell culture-based vaccine.

‘I DON’T LIKE NEEDLES’

At least 10% of US adults have aichmophobia, the fear of sharp objects including needles.²² Vasovagal syncope is the most common manifestation. Behavioral therapy, topical anesthetics, and systemic anxiolytics have variable efficacy in treating needle phobia. For those who are absolutely averse to needles, the nasal flu vaccine is an appropriate alternative.

‘I DON’T WANT TO TAKE ANYTHING THAT CAN MESS WITH MY OTHER MEDICATIONS’

Some immunosuppressive medications may decrease influenza vaccine immunogenicity. Concomitant administration of the inactivated influenza vaccine with other vaccines is safe and does not alter immunogenicity of other vaccines.¹ The live-attenuated influenza vaccine is contraindicated in children and adolescents taking aspirin or other salicylates due to the risk of Reye syndrome.

A recent systematic review and meta-analysis showed that the inactivated influenza vaccine is not associated with asthma exacerbation.²³ However, the nasal live-attenuated influenza vaccine is contraindicated in children 2 to 4 years old who have asthma and should be used with caution in persons with asthma 5 years old and older. In the systematic review, influenza vaccine prevented 59% to 78% of asthma attacks leading to emergency visits or hospitalization.²³ In other immune-mediated diseases such as rheumatoid arthritis, influenza vaccine does not precipitate exacerbations.²⁴

‘I HAD AN ORGAN TRANSPLANT, AND I’M AFRAID THE FLU SHOT WILL CAUSE ORGAN REJECTION’

A study of 51,730 kidney transplant recipients found that receipt of the inactivated influenza vaccine in the first year after transplant was associated with a lower risk of subsequent allograft loss (adjusted hazard ratio 0.77; 95% confidence interval 0.69–0.85; P < .001) and death (adjusted hazard ratio 0.82; 95% confidence interval 0.76–0.89; P < .001).²⁵ In the same study, although acute rejection in the first year was not associated with influenza vaccination, influenza infection in the first year was associated with rejection (odds ratio 1.58; 95% confidence interval 1.10–2.26; P < 0.001), but not with graft loss or death. Solid organ transplant recipients should receive the inactivated influenza vaccine starting 3 months after transplant.²⁶

Influenza vaccination has not been shown to precipitate graft-vs-host disease in hematopoietic stem cell transplant recipients. These patients should also receive the inactivated influenza vaccine starting 3 to 6 months after transplant.²⁷

The nasal live-attenuated influenza vaccine is contraindicated in these immunocompromised patients.

‘I’M PREGNANT, AND I DON’T WANT TO EXPOSE MY UNBORN BABY TO ANYTHING POTENTIALLY HARMFUL’

The morbidity and mortality risk from influenza is high in children under 2 years old because of low immunogenicity to flu vaccine. This is particularly true in children younger than 6 months, but the vaccine is not recommended in this population. The best way to protect infants is for all household members to be vaccinated against the flu.

Equally important, morbidity and mortality risk from influenza is much higher in pregnant women than in the general population. Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants. A recently published study showed that 18% of infants who developed influenza required hospitalization.²⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively. Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.²⁹ A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.³⁰

Healthcare providers should try to understand the public’s misconceptions³¹ about seasonal influenza and influenza vaccines in order to best address them.

The benefits of influenza vaccination are clear to those in the medical community. Yet misinformation and unfounded fears continue to discourage some people from getting a flu shot. During the 2018–2019 influenza season, only 45% of US adults and 63% of children were vaccinated.¹

‘IT DOESN’T WORK FOR MANY PEOPLE’

Multiple studies have shown that the flu vaccine prevents millions of flu cases and flu-related doctor’s visits each year. During the 2016–2017 flu season, flu vaccine prevented an estimated 5.3 million influenza cases, 2.6 million influenza-associated medical visits, and 85,000 influenza-associated hospitalizations.²

Several viral and host factors affect vaccine effectiveness. In seasons when the vaccine viruses have matched circulating strains, flu vaccine has been shown to reduce the following:

• The risk of having to go to the doctor with flu by 40% to 60%
• Children’s risk of flu-related death and intensive care unit (ICU) admission by 74%
• The risk in adults of flu-associated hospitalizations by 40% and ICU admission by 82%
• The rate of cardiac events in people with heart disease
• Hospitalizations in people with diabetes or underlying chronic lung disease.³

In people hospitalized with influenza despite receiving the flu vaccine for the season, studies have shown that receiving the flu vaccine shortens the average duration of hospitalization, reduces the chance of ICU admission by 59%, shortens the duration of ICU stay by 4 days, and reduces deaths.³

‘IT TARGETS THE WRONG VIRUS’

Selecting an effective influenza vaccine is a challenge. Every year, the World Health Organization and the CDC decide on the influenza strains expected to circulate in the upcoming flu season in the Northern Hemisphere, based on data for circulating strains in the Southern Hemisphere. This decision takes place about 7 months before the expected onset of the flu season. Flu viruses may mutate between the time the decision is made and the time the vaccine is administered (as well as after the flu season starts). Also, vaccine production in eggs needs time, which is why this decision must be made several months ahead of the flu season.

Vaccine effectiveness varies by virus serotype. Vaccines are typically less effective against influenza A H3N2 viruses than against influenza A H1N1 and influenza B viruses. Effectiveness also varies from season to season depending on how close the vaccine serotypes match the circulating serotypes, but some effectiveness is retained even in seasons when some of the serotypes don’t match circulating viruses. For example, in the 2017–2018 season, when the influenza A H3N2 vaccine serotype did not match the circulating serotype, the overall effectiveness in preventing medically attended, laboratory-confirmed influenza virus infection was 36%.⁵

A universal flu vaccine that does not need to be updated annually is the ultimate solution, but according to the National Institute of Allergy and Infectious Diseases, such a vaccine is likely several years away.⁶

‘IT MAKES PEOPLE SICK’

Pain at the injection site of a flu shot occurs in 10% to 65% of people, lasts less than 2 days, and does not usually interfere with daily activities.⁷

Systemic symptoms such as fever, malaise, and myalgia may occur in people who have had no previous exposure to the influenza virus antigens in the vaccine, particularly in children. In adults, the frequency of systemic symptoms after the flu shot is similar to that with placebo.

The Vaccine Adverse Event Reporting System, which has been capturing data since 1990, shows that the influenza vaccine accounted for 5.7% of people who developed malaise after receiving any vaccine.⁸

The injectable inactivated influenza vaccine cannot biologically cause an influenza virus-related illness, since the inactivated vaccine viruses can elicit a protective immune response but cannot replicate. The nasal live-attenuated flu vaccine can in theory cause acute illness in the person receiving it, but because it is cold-adapted, it multiplies only in the colder environment of the nasal epithelium, not in the lower airways where the temperature is higher. Consequently, the vaccine virus triggers immunity by multiplying in the nose, but doesn’t infect the lungs.

From 10% to 50% of people who receive the nasal live-attenuated vaccine develop runny nose, wheezing, headache, vomiting, muscle aches, fever, sore throat, or cough shortly after receiving the vaccine, but these symptoms are usually mild and short-lived.

The most common reactions people have to flu vaccines are considerably less severe than the symptoms caused by actual flu illness.

While influenza illness results in natural immunity to the specific viral serotype causing it, this illness results in hospitalization in 2% and is fatal in 0.16% of people. Influenza vaccine results in immunity to the serotypes included in the vaccine, and multiple studies have not found a causal relationship between vaccination and death.⁹

In the United States, 3,000 to 6,000 people per year develop Guillain-Barré syndrome, or 1 to 2 of every 100,000, which translates to 80 to 160 cases per week.¹⁰ While the exact cause of Guillain-Barré syndrome is unknown, about two-thirds of people have an acute diarrheal or respiratory illness within 3 months before the onset of symptoms. In 1976, the estimated attributable risk of influenza vaccine-related Guillain-Barré syndrome in the US adult population was 1 case per 100,000 in the 6 weeks after vaccination.¹¹ Studies in subsequent influenza seasons have not shown similar findings.¹² In fact, one study showed that the risk of developing Guillain-Barré syndrome was 15 times higher after influenza illness than after influenza vaccination.¹³

Since 5% to 15% of the US population develop symptomatic influenza annually,¹⁴ the decision to vaccinate with respect to the risk of Guillain-Barré syndrome should be obvious: vaccinate. The correct question to ask before influenza vaccination should be, “Have you previously developed Guillain-Barré syndrome within 6 weeks after receiving the flu vaccine?” If the answer is yes, the CDC considers this a caution, not a contraindication against receiving the influenza vaccine, since the benefit may still outweigh the risk.

‘I GOT THE FLU SHOT AND STILL GOT SICK’

The flu vaccine does not prevent illnesses caused by other viruses or bacteria that can make people sick during flu season. Influenza, the common cold, and streptococcal pharyngitis can have similar symptoms that make it difficult for patients—and, frequently, even healthcare providers—to distinguish between these illnesses with certainty.

One study suggested that influenza vaccine recipients had an increased risk of virologically confirmed noninfluenza respiratory viral infections,¹⁵ citing the phenomenon of virus interference that was described in the 1940s¹⁶ as a potential explanation. In essence, people protected against influenza by the vaccine may lack temporary nonspecific immunity against other respiratory viruses. However, these findings have not been replicated in subsequent studies.¹⁷

Viral gastroenteritis, mistakenly called “stomach flu,” is also not prevented by influenza vaccination.

‘I’M ALLERGIC TO EGGS’

The prevalence of egg allergy in US children is 0.5% to 2.5%.¹⁸ Most outgrow it by school age, but in one-third, the allergy persists into adulthood.

In general, people who can eat lightly cooked eggs (eg, scrambled eggs) without a reaction are unlikely to be allergic. On the other hand, the fact that egg-allergic people may tolerate egg included in baked products does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reaction to eggs and egg-containing foods, in addition to skin or blood testing for immunoglobulin E directed against egg proteins.¹⁹

Most currently available influenza vaccines are prepared by propagation of virus in embryonated eggs and so may contain trace amounts of egg proteins such as ovalbumin, with the exception of the inactivated quadri­valent recombinant influenza vaccine (Flublok) and the inactivated quadrivalent cell culture-based vaccine (Flucelvax).

The ACIP recommends that persons with a history of urticaria (hives) after exposure to eggs should receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Persons who report having angioedema, respiratory distress, lightheadedness, or recurrent vomiting, or who required epinephrine or another emergency medical intervention after exposure to eggs, should receive the influenza vaccine in an inpatient or outpatient medical setting under the supervision of a healthcare provider who is able to recognize and manage severe allergic reactions.

A history of severe allergic reaction such as anaphylaxis to a previous dose of any influenza vaccine, regardless of the vaccine component (including eggs) suspected of being responsible for the reaction, is a contraindication to influenza vaccination. The ACIP recommends that vaccine providers consider observing patients for 15 minutes after administration of any vaccine (regardless of history of egg allergy) to decrease the risk of injury should syncope occur.²⁰

‘I DON’T WANT TO PUT POISONOUS MERCURY IN MY BODY’

A process of biomagnification of methylmercury occurs when humans eat large fish that have eaten smaller fish. Thus, larger fish such as shark can be hazardous for women who are or may become pregnant, for nursing mothers, and for young children, while smaller fish such as herring are relatively safe.

As a precautionary measure, thimerosal was taken out of childhood vaccines in the United States in 2001. Thimerosal-free influenza vaccine formulations include the nasal live-attenuated flu vaccine, the inactivated quadrivalent recombinant influenza vaccine, and the inactivated quadrivalent cell culture-based vaccine.

‘I DON’T LIKE NEEDLES’

At least 10% of US adults have aichmophobia, the fear of sharp objects including needles.²² Vasovagal syncope is the most common manifestation. Behavioral therapy, topical anesthetics, and systemic anxiolytics have variable efficacy in treating needle phobia. For those who are absolutely averse to needles, the nasal flu vaccine is an appropriate alternative.

‘I DON’T WANT TO TAKE ANYTHING THAT CAN MESS WITH MY OTHER MEDICATIONS’

Some immunosuppressive medications may decrease influenza vaccine immunogenicity. Concomitant administration of the inactivated influenza vaccine with other vaccines is safe and does not alter immunogenicity of other vaccines.¹ The live-attenuated influenza vaccine is contraindicated in children and adolescents taking aspirin or other salicylates due to the risk of Reye syndrome.

A recent systematic review and meta-analysis showed that the inactivated influenza vaccine is not associated with asthma exacerbation.²³ However, the nasal live-attenuated influenza vaccine is contraindicated in children 2 to 4 years old who have asthma and should be used with caution in persons with asthma 5 years old and older. In the systematic review, influenza vaccine prevented 59% to 78% of asthma attacks leading to emergency visits or hospitalization.²³ In other immune-mediated diseases such as rheumatoid arthritis, influenza vaccine does not precipitate exacerbations.²⁴

‘I HAD AN ORGAN TRANSPLANT, AND I’M AFRAID THE FLU SHOT WILL CAUSE ORGAN REJECTION’

A study of 51,730 kidney transplant recipients found that receipt of the inactivated influenza vaccine in the first year after transplant was associated with a lower risk of subsequent allograft loss (adjusted hazard ratio 0.77; 95% confidence interval 0.69–0.85; P < .001) and death (adjusted hazard ratio 0.82; 95% confidence interval 0.76–0.89; P < .001).²⁵ In the same study, although acute rejection in the first year was not associated with influenza vaccination, influenza infection in the first year was associated with rejection (odds ratio 1.58; 95% confidence interval 1.10–2.26; P < 0.001), but not with graft loss or death. Solid organ transplant recipients should receive the inactivated influenza vaccine starting 3 months after transplant.²⁶

Influenza vaccination has not been shown to precipitate graft-vs-host disease in hematopoietic stem cell transplant recipients. These patients should also receive the inactivated influenza vaccine starting 3 to 6 months after transplant.²⁷

The nasal live-attenuated influenza vaccine is contraindicated in these immunocompromised patients.

‘I’M PREGNANT, AND I DON’T WANT TO EXPOSE MY UNBORN BABY TO ANYTHING POTENTIALLY HARMFUL’

The morbidity and mortality risk from influenza is high in children under 2 years old because of low immunogenicity to flu vaccine. This is particularly true in children younger than 6 months, but the vaccine is not recommended in this population. The best way to protect infants is for all household members to be vaccinated against the flu.

Equally important, morbidity and mortality risk from influenza is much higher in pregnant women than in the general population. Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants. A recently published study showed that 18% of infants who developed influenza required hospitalization.²⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively. Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.²⁹ A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.³⁰

Healthcare providers should try to understand the public’s misconceptions³¹ about seasonal influenza and influenza vaccines in order to best address them.

To the Editor: In their paper on colorectal cancer screening, Mankaney and colleagues noted the increasing rates of colorectal cancer in young adults in the United States.¹ Recent epidemiologic data demonstrate an increasing incidence of the disease in people ages 40 through 49 since the mid-1990s.² Even though screening starting at age 45 is not uniformly accepted,¹ there is evidence supporting earlier screening.

During the mid-1990s, the US government mandated that all enriched flour and uncooked cereal grains were to be fortified with folic acid in order to prevent births complicated by neural tube defects.³ Subsequently, there was a 2-fold increase in plasma folate concentrations and, disturbingly, a temporally associated significant increase in the incidence of colorectal cancer.³

Notably, a US trial⁴ testing the efficacy of folic acid 1 mg taken daily for 6 years to prevent colorectal adenomas in those with a history of colorectal adenomas failed to show a reduction in adenoma risk. Instead, participants randomized to folic acid exhibited a significantly increased risk of an advanced adenoma. Another trial,⁵ conducted in the Netherlands, where there is no mandatory folic acid fortification, investigated folic acid 400 µg and vitamin B₁₂ 500 µg daily over 2 to 3 years for the prevention of osteoporotic fractures. The group randomized to the vitamins had a nearly 2-fold increase in the risk of colorectal cancer.

Folic acid can be a double-edged sword.^3,5 Although folic acid intake may protect against carcinogenesis through increased genetic stability, if precancerous or neoplastic cells are present, excess folic acid may promote cancer by increasing DNA synthesis and cell proliferation. Cancer cells have folic acid receptors.

Since screening colonoscopy is typically done in individuals over 50, advanced adenomas from folic acid exposure in people younger than 50 likely go undiagnosed. Therefore, colorectal cancer screening should start at a younger age in countries where folic acid fortification is mandatory.

To the Editor: In their paper on colorectal cancer screening, Mankaney and colleagues noted the increasing rates of colorectal cancer in young adults in the United States.¹ Recent epidemiologic data demonstrate an increasing incidence of the disease in people ages 40 through 49 since the mid-1990s.² Even though screening starting at age 45 is not uniformly accepted,¹ there is evidence supporting earlier screening.

During the mid-1990s, the US government mandated that all enriched flour and uncooked cereal grains were to be fortified with folic acid in order to prevent births complicated by neural tube defects.³ Subsequently, there was a 2-fold increase in plasma folate concentrations and, disturbingly, a temporally associated significant increase in the incidence of colorectal cancer.³

Notably, a US trial⁴ testing the efficacy of folic acid 1 mg taken daily for 6 years to prevent colorectal adenomas in those with a history of colorectal adenomas failed to show a reduction in adenoma risk. Instead, participants randomized to folic acid exhibited a significantly increased risk of an advanced adenoma. Another trial,⁵ conducted in the Netherlands, where there is no mandatory folic acid fortification, investigated folic acid 400 µg and vitamin B₁₂ 500 µg daily over 2 to 3 years for the prevention of osteoporotic fractures. The group randomized to the vitamins had a nearly 2-fold increase in the risk of colorectal cancer.

Folic acid can be a double-edged sword.^3,5 Although folic acid intake may protect against carcinogenesis through increased genetic stability, if precancerous or neoplastic cells are present, excess folic acid may promote cancer by increasing DNA synthesis and cell proliferation. Cancer cells have folic acid receptors.

Since screening colonoscopy is typically done in individuals over 50, advanced adenomas from folic acid exposure in people younger than 50 likely go undiagnosed. Therefore, colorectal cancer screening should start at a younger age in countries where folic acid fortification is mandatory.

To the Editor: In their paper on colorectal cancer screening, Mankaney and colleagues noted the increasing rates of colorectal cancer in young adults in the United States.¹ Recent epidemiologic data demonstrate an increasing incidence of the disease in people ages 40 through 49 since the mid-1990s.² Even though screening starting at age 45 is not uniformly accepted,¹ there is evidence supporting earlier screening.

During the mid-1990s, the US government mandated that all enriched flour and uncooked cereal grains were to be fortified with folic acid in order to prevent births complicated by neural tube defects.³ Subsequently, there was a 2-fold increase in plasma folate concentrations and, disturbingly, a temporally associated significant increase in the incidence of colorectal cancer.³

Notably, a US trial⁴ testing the efficacy of folic acid 1 mg taken daily for 6 years to prevent colorectal adenomas in those with a history of colorectal adenomas failed to show a reduction in adenoma risk. Instead, participants randomized to folic acid exhibited a significantly increased risk of an advanced adenoma. Another trial,⁵ conducted in the Netherlands, where there is no mandatory folic acid fortification, investigated folic acid 400 µg and vitamin B₁₂ 500 µg daily over 2 to 3 years for the prevention of osteoporotic fractures. The group randomized to the vitamins had a nearly 2-fold increase in the risk of colorectal cancer.

Folic acid can be a double-edged sword.^3,5 Although folic acid intake may protect against carcinogenesis through increased genetic stability, if precancerous or neoplastic cells are present, excess folic acid may promote cancer by increasing DNA synthesis and cell proliferation. Cancer cells have folic acid receptors.

Since screening colonoscopy is typically done in individuals over 50, advanced adenomas from folic acid exposure in people younger than 50 likely go undiagnosed. Therefore, colorectal cancer screening should start at a younger age in countries where folic acid fortification is mandatory.

To the Editor: In the article, “Colorectal cancer screening: Choosing the right test,” the authors offer an excellent review, but restrict the discussion to just 2 of the many options. Screening compliance improves when clinicians and patients can select their preferred screening approach, and other noninvasive or minimally invasive approaches also deserve consideration and may well be superior. It is important that both the patient and the healthcare provider be fully aware of the advantages and disadvantages of each method.

The article is overly generous in its description of the accuracy and sensitivity of optical colonoscopy. The statement that colonoscopy visualizes the entire colon in more than 98% of cases is not supported by the biomedical literature or clinical experience. The measure of colonoscopy accuracy is best quantified by a review of more than 15,000 tandem colonoscopies that showed an average polyp miss rate of 22% using standard colonoscopes, and a 69% polyp miss rate compared with full-spectrum colonoscopes with greater fields of view.^1–3 Between 5% and 10% of colonoscopies are technically incomplete and do not reach the cecum. Only 35% of colonoscopy bowel preps are excellent, and 21% are so poor that the procedure cannot be completed.^4–8 Colorectal cancers are frequently missed at colonoscopy, with a rate of 7% quoted in the literature for interval cancer development.^9–16 Studies of computed tomography colonography (virtual colonoscopy) have confirmed that between 10% and 20% of the colonic mucosa is hidden from view on optical colonoscopy by tall haustral mucosal folds.^17,18 The operator variation measured by adenoma detection rates can exceed a 10-fold differential.

Colonoscopy is an important and valuable diagnostic and therapeutic tool. The disadvantages include significant cancer and polyp miss rates, high discomfort, high expense, potentially life-threatening complications, time- and resource-intensive utilization, high loss of patient work productivity, challenging and frequently inadequate preparation, higher risk of metachronous cancer and polyp spread, and high operator variability of quality.^19–24 Unfortunately, while colonoscopy is an important tool, it does not come anywhere close to a score of 98% and should not be considered the gold standard for colorectal cancer screening.²⁵

To the Editor: In the article, “Colorectal cancer screening: Choosing the right test,” the authors offer an excellent review, but restrict the discussion to just 2 of the many options. Screening compliance improves when clinicians and patients can select their preferred screening approach, and other noninvasive or minimally invasive approaches also deserve consideration and may well be superior. It is important that both the patient and the healthcare provider be fully aware of the advantages and disadvantages of each method.

The article is overly generous in its description of the accuracy and sensitivity of optical colonoscopy. The statement that colonoscopy visualizes the entire colon in more than 98% of cases is not supported by the biomedical literature or clinical experience. The measure of colonoscopy accuracy is best quantified by a review of more than 15,000 tandem colonoscopies that showed an average polyp miss rate of 22% using standard colonoscopes, and a 69% polyp miss rate compared with full-spectrum colonoscopes with greater fields of view.^1–3 Between 5% and 10% of colonoscopies are technically incomplete and do not reach the cecum. Only 35% of colonoscopy bowel preps are excellent, and 21% are so poor that the procedure cannot be completed.^4–8 Colorectal cancers are frequently missed at colonoscopy, with a rate of 7% quoted in the literature for interval cancer development.^9–16 Studies of computed tomography colonography (virtual colonoscopy) have confirmed that between 10% and 20% of the colonic mucosa is hidden from view on optical colonoscopy by tall haustral mucosal folds.^17,18 The operator variation measured by adenoma detection rates can exceed a 10-fold differential.

Colonoscopy is an important and valuable diagnostic and therapeutic tool. The disadvantages include significant cancer and polyp miss rates, high discomfort, high expense, potentially life-threatening complications, time- and resource-intensive utilization, high loss of patient work productivity, challenging and frequently inadequate preparation, higher risk of metachronous cancer and polyp spread, and high operator variability of quality.^19–24 Unfortunately, while colonoscopy is an important tool, it does not come anywhere close to a score of 98% and should not be considered the gold standard for colorectal cancer screening.²⁵

To the Editor: In the article, “Colorectal cancer screening: Choosing the right test,” the authors offer an excellent review, but restrict the discussion to just 2 of the many options. Screening compliance improves when clinicians and patients can select their preferred screening approach, and other noninvasive or minimally invasive approaches also deserve consideration and may well be superior. It is important that both the patient and the healthcare provider be fully aware of the advantages and disadvantages of each method.

The article is overly generous in its description of the accuracy and sensitivity of optical colonoscopy. The statement that colonoscopy visualizes the entire colon in more than 98% of cases is not supported by the biomedical literature or clinical experience. The measure of colonoscopy accuracy is best quantified by a review of more than 15,000 tandem colonoscopies that showed an average polyp miss rate of 22% using standard colonoscopes, and a 69% polyp miss rate compared with full-spectrum colonoscopes with greater fields of view.^1–3 Between 5% and 10% of colonoscopies are technically incomplete and do not reach the cecum. Only 35% of colonoscopy bowel preps are excellent, and 21% are so poor that the procedure cannot be completed.^4–8 Colorectal cancers are frequently missed at colonoscopy, with a rate of 7% quoted in the literature for interval cancer development.^9–16 Studies of computed tomography colonography (virtual colonoscopy) have confirmed that between 10% and 20% of the colonic mucosa is hidden from view on optical colonoscopy by tall haustral mucosal folds.^17,18 The operator variation measured by adenoma detection rates can exceed a 10-fold differential.

Colonoscopy is an important and valuable diagnostic and therapeutic tool. The disadvantages include significant cancer and polyp miss rates, high discomfort, high expense, potentially life-threatening complications, time- and resource-intensive utilization, high loss of patient work productivity, challenging and frequently inadequate preparation, higher risk of metachronous cancer and polyp spread, and high operator variability of quality.^19–24 Unfortunately, while colonoscopy is an important tool, it does not come anywhere close to a score of 98% and should not be considered the gold standard for colorectal cancer screening.²⁵

In Reply: We thank the readers for their interest in our paper.

Drs. Goldstein, Mascitelli, and Rauf point out the concerning epidemiologic increase in the incidence of colorectal cancer (CRC) among individuals under the age of 50 and suggest folate as a potential cause.¹

The underlying cause of the rise in incidence is unknown, and many environmental and lifestyle risk factors have been proposed.^2–4 Black men have historically had and continue to have the highest incidence of and stage-adjusted mortality from CRC, but the rise of CRC in the young is a phenomenon in whites.¹ Furthermore, these cancers are left-sided. Other known and proposed risk factors associated with this phenomenon include dietary and lifestyle factors such as alcohol consumption, smoking, obesity, and consumption of processed and red meat.^5–7

The cohort effect of rising colon and rectal cancer incidence in younger individuals is likely due to changes in the microbiome. Antibiotic exposure is widespread and has been conjectured as a cause, as has folate supplementation, which began in the United States in 1998. Folic acid has been shown to be associated with both protective and harmful effects on colorectal neoplasia.^8,9 While Goldstein et al recommend CRC screening starting at an early age in countries with folate supplementation, countries without folate supplementation have also noted a rise in early-onset CRC. For example, in Azerbaijan, the mean age at diagnosis of CRC in 546 individuals was 55.2 ± 11.5, and 23% had an age lower than 40 years. Nearly 60% presented at an advanced stage, and the majority of lesions were in the rectum.¹⁰

The impact of the confounding variables and risk factors resulting in the epidemiologic shift in young patients with CRC, along with the biology of the cancers, should be teased out. Once these are known, population screening guidelines can be adjusted. Until then, practitioners should personalize recommendations based on individual risk factors and promptly investigate colonic symptoms, no matter the age of the patient.

We also thank Drs. Joseph Weiss, Nancy Cetel, and Danielle Weiss for their thoughtful analysis of our article. Our intent was to highlight 2 of the most utilized options available for CRC screening and surveillance in the United States. As we pointed out, the choice of test depends on patient preference, family history, and the likelihood of compliance. The goal of any screening program is outreach and adherence, which is optimized when patients are offered a choice of tests.^11–13Table 1 from our article shows the options available.¹⁴

When discussing these options with patients, several factors should be taken into consideration. It is important that patients have an understanding of how tests are performed: stool-based vs imaging, bowel prep vs no prep, and frequency of testing.¹⁵ Any screening test short of colonoscopy that is positive leads to colonoscopy. Also, programmatic noncolonoscopic screening tests require a system of patient navigation for both positive and negative results. An individual may be more likely to complete 1 test such as screening colonoscopy every 10 years vs another test annually.

A common misconception about computed tomography colonography is that it is similar to computed tomography of the abdomen with a focus on the colon. Individuals may still have to undergo a bowel preparation and dietary restrictions before the procedure. Furthermore, a rectal catheter is used to insufflate and distend the colon prior to capturing images, which many patients find uncomfortable.¹⁶ Finally, the incidental discovery of extracolonic lesions may result in unnecessary testing.¹⁷

The sensitivity and specificity of each test and operator variability in accuracy and quality should also be highlighted. For example, the sensitivity of a one-time fecal immunochemical test to detect an advanced adenoma may be as low as 25%.¹⁸ All testing modalities are diagnostic, but only colonoscopy is therapeutic.

We agree that clinicians who perform CRC screening have an armamentarium of tests to offer, and the advantages and disadvantages of each should be carefully considered and individualized.

In Reply: We thank the readers for their interest in our paper.

Drs. Goldstein, Mascitelli, and Rauf point out the concerning epidemiologic increase in the incidence of colorectal cancer (CRC) among individuals under the age of 50 and suggest folate as a potential cause.¹

The underlying cause of the rise in incidence is unknown, and many environmental and lifestyle risk factors have been proposed.^2–4 Black men have historically had and continue to have the highest incidence of and stage-adjusted mortality from CRC, but the rise of CRC in the young is a phenomenon in whites.¹ Furthermore, these cancers are left-sided. Other known and proposed risk factors associated with this phenomenon include dietary and lifestyle factors such as alcohol consumption, smoking, obesity, and consumption of processed and red meat.^5–7

The cohort effect of rising colon and rectal cancer incidence in younger individuals is likely due to changes in the microbiome. Antibiotic exposure is widespread and has been conjectured as a cause, as has folate supplementation, which began in the United States in 1998. Folic acid has been shown to be associated with both protective and harmful effects on colorectal neoplasia.^8,9 While Goldstein et al recommend CRC screening starting at an early age in countries with folate supplementation, countries without folate supplementation have also noted a rise in early-onset CRC. For example, in Azerbaijan, the mean age at diagnosis of CRC in 546 individuals was 55.2 ± 11.5, and 23% had an age lower than 40 years. Nearly 60% presented at an advanced stage, and the majority of lesions were in the rectum.¹⁰

The impact of the confounding variables and risk factors resulting in the epidemiologic shift in young patients with CRC, along with the biology of the cancers, should be teased out. Once these are known, population screening guidelines can be adjusted. Until then, practitioners should personalize recommendations based on individual risk factors and promptly investigate colonic symptoms, no matter the age of the patient.

We also thank Drs. Joseph Weiss, Nancy Cetel, and Danielle Weiss for their thoughtful analysis of our article. Our intent was to highlight 2 of the most utilized options available for CRC screening and surveillance in the United States. As we pointed out, the choice of test depends on patient preference, family history, and the likelihood of compliance. The goal of any screening program is outreach and adherence, which is optimized when patients are offered a choice of tests.^11–13Table 1 from our article shows the options available.¹⁴

When discussing these options with patients, several factors should be taken into consideration. It is important that patients have an understanding of how tests are performed: stool-based vs imaging, bowel prep vs no prep, and frequency of testing.¹⁵ Any screening test short of colonoscopy that is positive leads to colonoscopy. Also, programmatic noncolonoscopic screening tests require a system of patient navigation for both positive and negative results. An individual may be more likely to complete 1 test such as screening colonoscopy every 10 years vs another test annually.

A common misconception about computed tomography colonography is that it is similar to computed tomography of the abdomen with a focus on the colon. Individuals may still have to undergo a bowel preparation and dietary restrictions before the procedure. Furthermore, a rectal catheter is used to insufflate and distend the colon prior to capturing images, which many patients find uncomfortable.¹⁶ Finally, the incidental discovery of extracolonic lesions may result in unnecessary testing.¹⁷

The sensitivity and specificity of each test and operator variability in accuracy and quality should also be highlighted. For example, the sensitivity of a one-time fecal immunochemical test to detect an advanced adenoma may be as low as 25%.¹⁸ All testing modalities are diagnostic, but only colonoscopy is therapeutic.

We agree that clinicians who perform CRC screening have an armamentarium of tests to offer, and the advantages and disadvantages of each should be carefully considered and individualized.

In Reply: We thank the readers for their interest in our paper.

Drs. Goldstein, Mascitelli, and Rauf point out the concerning epidemiologic increase in the incidence of colorectal cancer (CRC) among individuals under the age of 50 and suggest folate as a potential cause.¹

The underlying cause of the rise in incidence is unknown, and many environmental and lifestyle risk factors have been proposed.^2–4 Black men have historically had and continue to have the highest incidence of and stage-adjusted mortality from CRC, but the rise of CRC in the young is a phenomenon in whites.¹ Furthermore, these cancers are left-sided. Other known and proposed risk factors associated with this phenomenon include dietary and lifestyle factors such as alcohol consumption, smoking, obesity, and consumption of processed and red meat.^5–7

The cohort effect of rising colon and rectal cancer incidence in younger individuals is likely due to changes in the microbiome. Antibiotic exposure is widespread and has been conjectured as a cause, as has folate supplementation, which began in the United States in 1998. Folic acid has been shown to be associated with both protective and harmful effects on colorectal neoplasia.^8,9 While Goldstein et al recommend CRC screening starting at an early age in countries with folate supplementation, countries without folate supplementation have also noted a rise in early-onset CRC. For example, in Azerbaijan, the mean age at diagnosis of CRC in 546 individuals was 55.2 ± 11.5, and 23% had an age lower than 40 years. Nearly 60% presented at an advanced stage, and the majority of lesions were in the rectum.¹⁰

The impact of the confounding variables and risk factors resulting in the epidemiologic shift in young patients with CRC, along with the biology of the cancers, should be teased out. Once these are known, population screening guidelines can be adjusted. Until then, practitioners should personalize recommendations based on individual risk factors and promptly investigate colonic symptoms, no matter the age of the patient.

We also thank Drs. Joseph Weiss, Nancy Cetel, and Danielle Weiss for their thoughtful analysis of our article. Our intent was to highlight 2 of the most utilized options available for CRC screening and surveillance in the United States. As we pointed out, the choice of test depends on patient preference, family history, and the likelihood of compliance. The goal of any screening program is outreach and adherence, which is optimized when patients are offered a choice of tests.^11–13Table 1 from our article shows the options available.¹⁴

When discussing these options with patients, several factors should be taken into consideration. It is important that patients have an understanding of how tests are performed: stool-based vs imaging, bowel prep vs no prep, and frequency of testing.¹⁵ Any screening test short of colonoscopy that is positive leads to colonoscopy. Also, programmatic noncolonoscopic screening tests require a system of patient navigation for both positive and negative results. An individual may be more likely to complete 1 test such as screening colonoscopy every 10 years vs another test annually.

A common misconception about computed tomography colonography is that it is similar to computed tomography of the abdomen with a focus on the colon. Individuals may still have to undergo a bowel preparation and dietary restrictions before the procedure. Furthermore, a rectal catheter is used to insufflate and distend the colon prior to capturing images, which many patients find uncomfortable.¹⁶ Finally, the incidental discovery of extracolonic lesions may result in unnecessary testing.¹⁷

The sensitivity and specificity of each test and operator variability in accuracy and quality should also be highlighted. For example, the sensitivity of a one-time fecal immunochemical test to detect an advanced adenoma may be as low as 25%.¹⁸ All testing modalities are diagnostic, but only colonoscopy is therapeutic.

We agree that clinicians who perform CRC screening have an armamentarium of tests to offer, and the advantages and disadvantages of each should be carefully considered and individualized.

Advances in neuroimaging over the past 25 years have allowed for an increasingly sophisticated understanding of the structural and functional brain abnormalities associated with psychiatric disease.¹ It has been postulated that a better understanding of aberrant brain circuitry in psychiatric illness will be critical for transforming the diagnosis and treatment of these illnesses.² In fact, in 2008, the National Institute of Mental Health launched the Research Domain Criteria project to reformulate psychiatric diagnosis based on biologic underpinnings.³

In the midst of these scientific advances and the increased availability of neuroimaging, some private clinics have begun to offer routine brain scans as part of a comprehensive psychiatric evaluation.^4-7 These clinics suggest that single-photon emission computed tomography (SPECT) of the brain can provide objective, reliable psychiatric diagnoses. Unfortunately, using SPECT for psychiatric diagnosis lacks empirical support and carries risks, including exposing patients to radioisotopes and detracting from empirically validated treatments.⁸ Nonetheless, given the current diagnostic challenges in psychiatry, it is understandable that patients, parents, and clinicians alike have reported high receptivity to the use of neuroimaging for psychiatric diagnosis and treatment planning.⁹

While neuroimaging is central to the search for improved understanding of the biologic foundations of mental illness, progress in identifying biomarkers has been disappointing. There are currently no neuroimaging biomarkers that can reliably distinguish patients from controls, and no empirical evidence supports the use of neuroimaging in diagnosing psychiatric conditions.¹⁰ The current standard of clinical care is to use neuroimaging to diagnose neurologic diseases that are masquerading as psychiatric disorders. However, given the rapid advances and availability of this technology, determining if and when neuroimaging is clinically indicated will likely soon become increasingly complex. Prior to the widespread availability of this technology, it is worth considering the potential advantages and pitfalls to the adoption of neuroimaging in psychiatry. In this article, we:

• outline arguments that support the use of neuroimaging in psychiatry, and some of the limitations
• discuss special considerations for patients with first-episode psychosis (FEP) and forensic psychiatry
• suggest guidelines for best-practice models based on the current evidence.

Advantages of widespread use of neuroimaging in psychiatry

Currently, neuroimaging is used in psychiatry to rule out neurologic disorders such as seizures, tumors, or infectious illness that might be causing psychiatric symptoms. If neuroimaging were routinely used for this purpose, one theoretical advantage would be increased neurologic diagnostic accuracy. Furthermore, increased adoption of neuroimaging may eventually help broaden the phenotype of neurologic disorders. In other words, psychiatric symptoms may be more common in neurologic disorders than we currently recognize. A second advantage might be that early and definitive exclusion of a structural neurologic disorder may help patients and families more readily accept a psychiatric diagnosis and appropriate treatment.

In the future, if biomarkers of psychiatric illness are discerned, using neuroimaging for diagnosis, assessment, and treatment planning may help increase objectivity and reduce the stigma associated with mental illness. Currently, psychiatric diagnoses are based on emotional and behavioral self-report and clinical observations. It is not uncommon for patients to receive different diagnoses and even conflicting recommendations from different clinicians. Tools that aid objective diagnosis will likely improve the reliability of the diagnosis and help in assessing treatment response. Also, concrete biomarkers that respond to treatment may help align psychiatric disorders with other medical illnesses, thereby decreasing stigma.

Cautions against routine neuroimaging

There are several potential pitfalls to the routine use of neuroimaging in psychiatry. First, clinical psychiatry is centered on clinical acumen and the doctor–patient relationship. Many psychiatric clinicians are not accustomed to using lab measures or tests to support the diagnostic process or treatment planning. Psychiatrists may be resistant to technologies that threaten clinical acumen, the power of the therapeutic relationship, and the value of getting to know patients over time.¹¹ Overreliance on neuroimaging for psychiatric diagnosis also carries the risk of becoming overly reductionistic. This approach may overemphasize the biologic aspects of mental illness, while excluding social and psychological factors that may be responsive to treatment.

Second, the widespread use of neuroimaging is likely to result in many incidental findings. This is especially relevant because abnormality does not establish causality. Incidental findings may cause unnecessary anxiety for patients and families, particularly if there are minimal treatment options.

Continue to: Third, it remains unclear...

Third, it remains unclear whether widespread neuroimaging in psychiatry will be cost-effective. Unless imaging results are tied to effective treatments, neuroimaging is unlikely to result in cost savings. Presently, patients who can afford out-of-pocket care might be able to access neuroimaging. If neuroimaging were shown to improve clinical outcomes but remains costly, this unequal distribution of resources would create an ethical quandary.

Finally, neuroimaging is complex and almost certainly not as objective as one might hope. Interpreting images will require specialized knowledge and skills that are beyond those of currently certified general psychiatrists.¹² Because there is a great deal of overlap in brain anomalies across psychiatric illnesses, it is unclear whether using neuroimaging for diagnostic purposes will eclipse a thorough clinical assessment. For example, the amygdala and insula show activation across a range of anxiety disorders. Abnormal amygdala activation has also been reported in depression, bipolar disorder, schizophrenia, and psychopathy.¹³

In addition, psychiatric comorbidity is common. It is unclear how much neuro­imaging will add diagnostically when a patient presents with multiple psychiatric disorders. Comorbidity of psychiatric and neurologic disorders also is common. A neurologic illness that is detectable by structural neuroimaging does not necessarily exclude the presence of a psychiatric disorder. This poses yet another challenge to developing reliable, valid neuroimaging techniques for clinical use.

Areas of controversy

First-episode psychosis. Current practice guidelines for neuroimaging in patients with FEP are inconsistent. The Canadian Choosing Wisely Guidelines recommend against routinely ordering neuroimaging in first-episode psychoses in the absence of signs or symptoms that suggest intracranial pathology.¹⁴ Similarly, the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia recommends ordering neuroimaging in patients for whom the clinical picture is unclear or when examination reveals abnormal findings.¹⁵ In contrast, the Australian Clinical Guidelines for Early Psychosis recommend that all patients with FEP receive brain MRI.¹⁶ Freudenreich et al¹⁷ describe 2 philosophies regarding the initial medical workup of FEP: (1) a comprehensive medical workup requires extensive testing, and (2) in their natural histories, most illnesses eventually declare themselves.

Despite this inconsistency, the overall evidence does not seem to support routine brain imaging for patients with FEP in the absence of neurologic or cognitive impairment. A systematic review of 16 studies assessing the clinical utility of structural neuroimaging in FEP found that there was “insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment.”¹⁸

Continue to: Forensic psychiatry

Forensic psychiatry. Two academic disciplines—neuroethics and neurolaw—attempt to study how medications and neuroimaging could impact forensic psychiatry.¹⁹ And in this golden age of neuroscience, psychiatrists specializing in forensics may be increasingly asked to opine on brain scans. This requires specific thoughtfulness and attention because forensic psychiatrists must “distinguish neuroscience from neuro-nonsense.”²⁰ These specialists will need to consider the Daubert standard, which resulted from the 1993 case Daubert v Merrell Dow Pharmaceuticals, Inc.²¹ In this case, the US Supreme Court ruled that evidence must be “‘generally accepted’ as reliable in the relevant scientific community” to be admissible. According to the Daubert standard, “evidentiary reliability” is based on scientific validity.²¹

How should we use neuroimaging?

While neuroimaging is a quickly evolving research tool, empirical support for its clinical use remains limited. The hope is that future neuroimaging research will yield biomarker profiles for mental illness, identification of risk factors, and predictors of vulnerability and treatment response, which will allow for more targeted treatments.¹

The current standard of clinical care for using neuroimaging in psychiatry is to diagnose neurologic diseases. Although there are no consensus guidelines for when to order imaging, it is reasonable to consider imaging when a patient has²²:

• abrupt onset of symptoms
• change in level of consciousness
• deficits in neurologic or cognitive examination
• a history of head trauma (with loss of consciousness), whole-brain radiation, neuro­logic comorbidities, or cancer
• late onset of symptoms (age >50)
• atypical presentation of psychiatric illness.

Advances in neuroimaging over the past 25 years have allowed for an increasingly sophisticated understanding of the structural and functional brain abnormalities associated with psychiatric disease.¹ It has been postulated that a better understanding of aberrant brain circuitry in psychiatric illness will be critical for transforming the diagnosis and treatment of these illnesses.² In fact, in 2008, the National Institute of Mental Health launched the Research Domain Criteria project to reformulate psychiatric diagnosis based on biologic underpinnings.³

In the midst of these scientific advances and the increased availability of neuroimaging, some private clinics have begun to offer routine brain scans as part of a comprehensive psychiatric evaluation.^4-7 These clinics suggest that single-photon emission computed tomography (SPECT) of the brain can provide objective, reliable psychiatric diagnoses. Unfortunately, using SPECT for psychiatric diagnosis lacks empirical support and carries risks, including exposing patients to radioisotopes and detracting from empirically validated treatments.⁸ Nonetheless, given the current diagnostic challenges in psychiatry, it is understandable that patients, parents, and clinicians alike have reported high receptivity to the use of neuroimaging for psychiatric diagnosis and treatment planning.⁹

While neuroimaging is central to the search for improved understanding of the biologic foundations of mental illness, progress in identifying biomarkers has been disappointing. There are currently no neuroimaging biomarkers that can reliably distinguish patients from controls, and no empirical evidence supports the use of neuroimaging in diagnosing psychiatric conditions.¹⁰ The current standard of clinical care is to use neuroimaging to diagnose neurologic diseases that are masquerading as psychiatric disorders. However, given the rapid advances and availability of this technology, determining if and when neuroimaging is clinically indicated will likely soon become increasingly complex. Prior to the widespread availability of this technology, it is worth considering the potential advantages and pitfalls to the adoption of neuroimaging in psychiatry. In this article, we:

• outline arguments that support the use of neuroimaging in psychiatry, and some of the limitations
• discuss special considerations for patients with first-episode psychosis (FEP) and forensic psychiatry
• suggest guidelines for best-practice models based on the current evidence.

Advantages of widespread use of neuroimaging in psychiatry

Currently, neuroimaging is used in psychiatry to rule out neurologic disorders such as seizures, tumors, or infectious illness that might be causing psychiatric symptoms. If neuroimaging were routinely used for this purpose, one theoretical advantage would be increased neurologic diagnostic accuracy. Furthermore, increased adoption of neuroimaging may eventually help broaden the phenotype of neurologic disorders. In other words, psychiatric symptoms may be more common in neurologic disorders than we currently recognize. A second advantage might be that early and definitive exclusion of a structural neurologic disorder may help patients and families more readily accept a psychiatric diagnosis and appropriate treatment.

In the future, if biomarkers of psychiatric illness are discerned, using neuroimaging for diagnosis, assessment, and treatment planning may help increase objectivity and reduce the stigma associated with mental illness. Currently, psychiatric diagnoses are based on emotional and behavioral self-report and clinical observations. It is not uncommon for patients to receive different diagnoses and even conflicting recommendations from different clinicians. Tools that aid objective diagnosis will likely improve the reliability of the diagnosis and help in assessing treatment response. Also, concrete biomarkers that respond to treatment may help align psychiatric disorders with other medical illnesses, thereby decreasing stigma.

Cautions against routine neuroimaging

There are several potential pitfalls to the routine use of neuroimaging in psychiatry. First, clinical psychiatry is centered on clinical acumen and the doctor–patient relationship. Many psychiatric clinicians are not accustomed to using lab measures or tests to support the diagnostic process or treatment planning. Psychiatrists may be resistant to technologies that threaten clinical acumen, the power of the therapeutic relationship, and the value of getting to know patients over time.¹¹ Overreliance on neuroimaging for psychiatric diagnosis also carries the risk of becoming overly reductionistic. This approach may overemphasize the biologic aspects of mental illness, while excluding social and psychological factors that may be responsive to treatment.

Second, the widespread use of neuroimaging is likely to result in many incidental findings. This is especially relevant because abnormality does not establish causality. Incidental findings may cause unnecessary anxiety for patients and families, particularly if there are minimal treatment options.

Continue to: Third, it remains unclear...

Third, it remains unclear whether widespread neuroimaging in psychiatry will be cost-effective. Unless imaging results are tied to effective treatments, neuroimaging is unlikely to result in cost savings. Presently, patients who can afford out-of-pocket care might be able to access neuroimaging. If neuroimaging were shown to improve clinical outcomes but remains costly, this unequal distribution of resources would create an ethical quandary.

Finally, neuroimaging is complex and almost certainly not as objective as one might hope. Interpreting images will require specialized knowledge and skills that are beyond those of currently certified general psychiatrists.¹² Because there is a great deal of overlap in brain anomalies across psychiatric illnesses, it is unclear whether using neuroimaging for diagnostic purposes will eclipse a thorough clinical assessment. For example, the amygdala and insula show activation across a range of anxiety disorders. Abnormal amygdala activation has also been reported in depression, bipolar disorder, schizophrenia, and psychopathy.¹³

In addition, psychiatric comorbidity is common. It is unclear how much neuro­imaging will add diagnostically when a patient presents with multiple psychiatric disorders. Comorbidity of psychiatric and neurologic disorders also is common. A neurologic illness that is detectable by structural neuroimaging does not necessarily exclude the presence of a psychiatric disorder. This poses yet another challenge to developing reliable, valid neuroimaging techniques for clinical use.

Areas of controversy

First-episode psychosis. Current practice guidelines for neuroimaging in patients with FEP are inconsistent. The Canadian Choosing Wisely Guidelines recommend against routinely ordering neuroimaging in first-episode psychoses in the absence of signs or symptoms that suggest intracranial pathology.¹⁴ Similarly, the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia recommends ordering neuroimaging in patients for whom the clinical picture is unclear or when examination reveals abnormal findings.¹⁵ In contrast, the Australian Clinical Guidelines for Early Psychosis recommend that all patients with FEP receive brain MRI.¹⁶ Freudenreich et al¹⁷ describe 2 philosophies regarding the initial medical workup of FEP: (1) a comprehensive medical workup requires extensive testing, and (2) in their natural histories, most illnesses eventually declare themselves.

Despite this inconsistency, the overall evidence does not seem to support routine brain imaging for patients with FEP in the absence of neurologic or cognitive impairment. A systematic review of 16 studies assessing the clinical utility of structural neuroimaging in FEP found that there was “insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment.”¹⁸

Continue to: Forensic psychiatry

Forensic psychiatry. Two academic disciplines—neuroethics and neurolaw—attempt to study how medications and neuroimaging could impact forensic psychiatry.¹⁹ And in this golden age of neuroscience, psychiatrists specializing in forensics may be increasingly asked to opine on brain scans. This requires specific thoughtfulness and attention because forensic psychiatrists must “distinguish neuroscience from neuro-nonsense.”²⁰ These specialists will need to consider the Daubert standard, which resulted from the 1993 case Daubert v Merrell Dow Pharmaceuticals, Inc.²¹ In this case, the US Supreme Court ruled that evidence must be “‘generally accepted’ as reliable in the relevant scientific community” to be admissible. According to the Daubert standard, “evidentiary reliability” is based on scientific validity.²¹

How should we use neuroimaging?

While neuroimaging is a quickly evolving research tool, empirical support for its clinical use remains limited. The hope is that future neuroimaging research will yield biomarker profiles for mental illness, identification of risk factors, and predictors of vulnerability and treatment response, which will allow for more targeted treatments.¹

The current standard of clinical care for using neuroimaging in psychiatry is to diagnose neurologic diseases. Although there are no consensus guidelines for when to order imaging, it is reasonable to consider imaging when a patient has²²:

• abrupt onset of symptoms
• change in level of consciousness
• deficits in neurologic or cognitive examination
• a history of head trauma (with loss of consciousness), whole-brain radiation, neuro­logic comorbidities, or cancer
• late onset of symptoms (age >50)
• atypical presentation of psychiatric illness.

Advances in neuroimaging over the past 25 years have allowed for an increasingly sophisticated understanding of the structural and functional brain abnormalities associated with psychiatric disease.¹ It has been postulated that a better understanding of aberrant brain circuitry in psychiatric illness will be critical for transforming the diagnosis and treatment of these illnesses.² In fact, in 2008, the National Institute of Mental Health launched the Research Domain Criteria project to reformulate psychiatric diagnosis based on biologic underpinnings.³

In the midst of these scientific advances and the increased availability of neuroimaging, some private clinics have begun to offer routine brain scans as part of a comprehensive psychiatric evaluation.^4-7 These clinics suggest that single-photon emission computed tomography (SPECT) of the brain can provide objective, reliable psychiatric diagnoses. Unfortunately, using SPECT for psychiatric diagnosis lacks empirical support and carries risks, including exposing patients to radioisotopes and detracting from empirically validated treatments.⁸ Nonetheless, given the current diagnostic challenges in psychiatry, it is understandable that patients, parents, and clinicians alike have reported high receptivity to the use of neuroimaging for psychiatric diagnosis and treatment planning.⁹

While neuroimaging is central to the search for improved understanding of the biologic foundations of mental illness, progress in identifying biomarkers has been disappointing. There are currently no neuroimaging biomarkers that can reliably distinguish patients from controls, and no empirical evidence supports the use of neuroimaging in diagnosing psychiatric conditions.¹⁰ The current standard of clinical care is to use neuroimaging to diagnose neurologic diseases that are masquerading as psychiatric disorders. However, given the rapid advances and availability of this technology, determining if and when neuroimaging is clinically indicated will likely soon become increasingly complex. Prior to the widespread availability of this technology, it is worth considering the potential advantages and pitfalls to the adoption of neuroimaging in psychiatry. In this article, we:

• outline arguments that support the use of neuroimaging in psychiatry, and some of the limitations
• discuss special considerations for patients with first-episode psychosis (FEP) and forensic psychiatry
• suggest guidelines for best-practice models based on the current evidence.

Advantages of widespread use of neuroimaging in psychiatry

Currently, neuroimaging is used in psychiatry to rule out neurologic disorders such as seizures, tumors, or infectious illness that might be causing psychiatric symptoms. If neuroimaging were routinely used for this purpose, one theoretical advantage would be increased neurologic diagnostic accuracy. Furthermore, increased adoption of neuroimaging may eventually help broaden the phenotype of neurologic disorders. In other words, psychiatric symptoms may be more common in neurologic disorders than we currently recognize. A second advantage might be that early and definitive exclusion of a structural neurologic disorder may help patients and families more readily accept a psychiatric diagnosis and appropriate treatment.

In the future, if biomarkers of psychiatric illness are discerned, using neuroimaging for diagnosis, assessment, and treatment planning may help increase objectivity and reduce the stigma associated with mental illness. Currently, psychiatric diagnoses are based on emotional and behavioral self-report and clinical observations. It is not uncommon for patients to receive different diagnoses and even conflicting recommendations from different clinicians. Tools that aid objective diagnosis will likely improve the reliability of the diagnosis and help in assessing treatment response. Also, concrete biomarkers that respond to treatment may help align psychiatric disorders with other medical illnesses, thereby decreasing stigma.

Cautions against routine neuroimaging

There are several potential pitfalls to the routine use of neuroimaging in psychiatry. First, clinical psychiatry is centered on clinical acumen and the doctor–patient relationship. Many psychiatric clinicians are not accustomed to using lab measures or tests to support the diagnostic process or treatment planning. Psychiatrists may be resistant to technologies that threaten clinical acumen, the power of the therapeutic relationship, and the value of getting to know patients over time.¹¹ Overreliance on neuroimaging for psychiatric diagnosis also carries the risk of becoming overly reductionistic. This approach may overemphasize the biologic aspects of mental illness, while excluding social and psychological factors that may be responsive to treatment.

Second, the widespread use of neuroimaging is likely to result in many incidental findings. This is especially relevant because abnormality does not establish causality. Incidental findings may cause unnecessary anxiety for patients and families, particularly if there are minimal treatment options.

Continue to: Third, it remains unclear...

Third, it remains unclear whether widespread neuroimaging in psychiatry will be cost-effective. Unless imaging results are tied to effective treatments, neuroimaging is unlikely to result in cost savings. Presently, patients who can afford out-of-pocket care might be able to access neuroimaging. If neuroimaging were shown to improve clinical outcomes but remains costly, this unequal distribution of resources would create an ethical quandary.

Finally, neuroimaging is complex and almost certainly not as objective as one might hope. Interpreting images will require specialized knowledge and skills that are beyond those of currently certified general psychiatrists.¹² Because there is a great deal of overlap in brain anomalies across psychiatric illnesses, it is unclear whether using neuroimaging for diagnostic purposes will eclipse a thorough clinical assessment. For example, the amygdala and insula show activation across a range of anxiety disorders. Abnormal amygdala activation has also been reported in depression, bipolar disorder, schizophrenia, and psychopathy.¹³

In addition, psychiatric comorbidity is common. It is unclear how much neuro­imaging will add diagnostically when a patient presents with multiple psychiatric disorders. Comorbidity of psychiatric and neurologic disorders also is common. A neurologic illness that is detectable by structural neuroimaging does not necessarily exclude the presence of a psychiatric disorder. This poses yet another challenge to developing reliable, valid neuroimaging techniques for clinical use.

Areas of controversy

First-episode psychosis. Current practice guidelines for neuroimaging in patients with FEP are inconsistent. The Canadian Choosing Wisely Guidelines recommend against routinely ordering neuroimaging in first-episode psychoses in the absence of signs or symptoms that suggest intracranial pathology.¹⁴ Similarly, the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia recommends ordering neuroimaging in patients for whom the clinical picture is unclear or when examination reveals abnormal findings.¹⁵ In contrast, the Australian Clinical Guidelines for Early Psychosis recommend that all patients with FEP receive brain MRI.¹⁶ Freudenreich et al¹⁷ describe 2 philosophies regarding the initial medical workup of FEP: (1) a comprehensive medical workup requires extensive testing, and (2) in their natural histories, most illnesses eventually declare themselves.

Despite this inconsistency, the overall evidence does not seem to support routine brain imaging for patients with FEP in the absence of neurologic or cognitive impairment. A systematic review of 16 studies assessing the clinical utility of structural neuroimaging in FEP found that there was “insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment.”¹⁸

Continue to: Forensic psychiatry

Forensic psychiatry. Two academic disciplines—neuroethics and neurolaw—attempt to study how medications and neuroimaging could impact forensic psychiatry.¹⁹ And in this golden age of neuroscience, psychiatrists specializing in forensics may be increasingly asked to opine on brain scans. This requires specific thoughtfulness and attention because forensic psychiatrists must “distinguish neuroscience from neuro-nonsense.”²⁰ These specialists will need to consider the Daubert standard, which resulted from the 1993 case Daubert v Merrell Dow Pharmaceuticals, Inc.²¹ In this case, the US Supreme Court ruled that evidence must be “‘generally accepted’ as reliable in the relevant scientific community” to be admissible. According to the Daubert standard, “evidentiary reliability” is based on scientific validity.²¹

How should we use neuroimaging?

While neuroimaging is a quickly evolving research tool, empirical support for its clinical use remains limited. The hope is that future neuroimaging research will yield biomarker profiles for mental illness, identification of risk factors, and predictors of vulnerability and treatment response, which will allow for more targeted treatments.¹

The current standard of clinical care for using neuroimaging in psychiatry is to diagnose neurologic diseases. Although there are no consensus guidelines for when to order imaging, it is reasonable to consider imaging when a patient has²²:

• abrupt onset of symptoms
• change in level of consciousness
• deficits in neurologic or cognitive examination
• a history of head trauma (with loss of consciousness), whole-brain radiation, neuro­logic comorbidities, or cancer
• late onset of symptoms (age >50)
• atypical presentation of psychiatric illness.

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

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The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

Although they are rare, in-flight psychiatric emergencies occur because of large numbers of passengers, nonstop flights over longer distances, delayed flights, cramped cabins, and/or alcohol consumption.^1,2 Psychiatric symptoms and substance intoxication/withdrawal each represent up to 3% of all in-flight emergencies, and in most cases (90%), the primary presentation is acute anxiety.^1,2 Common in-flight psychiatric differential diagnoses include depression, psychosis, personality disorders, and somatization.¹

When a passenger requires medical or psychiatric treatment, the flight crew often requests aid from any trained medical professionals who are on board to augment their capabilities and resources (eg, the flight crew’s training, ground-based medical support).¹ In the United States, off-duty medical professionals are not legally required to assist during an in-flight medical emergency.¹ The Aviation Medical Assistance Act of 1998 protects passengers who provide medical assistance from liability, except in cases of gross negligence or willful misconduct.^1,3 Flights outside of the United States are governed by a complex combination of public and private international laws.¹ Here I suggest how to initiate care during in-flight psychiatric emergencies, and offer therapeutic options to employ for a passenger who is exhibiting psychiatric symptoms.

What to do first

Before volunteering to assist in a mental health emergency, consider your capabilities and limitations. Do not volunteer if you are under the influence of alcohol, illicit substances, or any medications (prescription or over-the-counter) that could affect your judgment.

Inform the flight crew that you are a mental health clinician, and outline your current clinical expertise. While the flight crew obtains the medical emergency kit, work to establish rapport with the passenger to identify the psychiatric problem and help de-escalate the situation. Initiate care by¹:

• eliciting a psychiatric history
• inquiring about any use of alcohol, illicit substances, or other mood-altering substances (eg, type, amount, and time of use)
• identifying any use of psychotropic medications (eg, doses, last dose taken, and if these agents are on the aircraft).

The Federal Aviation Administration has minimum requirements for the contents of medical emergency kits aboard US airlines.^1,4 However, they are not required to contain antipsychotics, naloxone, or benzodiazepines.^1,4 Although you may have limited medical resources at your disposal, you can still help passengers in the following ways¹:

Monitor vital signs and mental status changes, identify signs and symptoms of intoxication or withdrawal, and assess for respiratory distress. Provide reassurance to the passenger if appropriate.¹

Administer naloxone (if available) for suspected opioid ingestion.¹ Antiemetics, which are available in these medical kits, can be used if needed. Encourage passengers to remain hydrated and use oxygen as needed.

Continue to: If verbal de-escalation is ineffective...

If verbal de-escalation is ineffective, consider administering a benzodiazepine or antipsychotic (if available).¹ If the passenger is combative, refer to the flight crew for the airline’s security protocols, which may include restraining the passenger or diverting the aircraft. Safety takes priority over attempts at medical management.

If the passenger has respiratory distress, instruct the flight crew to contact ground-based medical support for additional recommendations.¹

A challenging situation

Ultimately, the pilot coordinates with the flight dispatcher to manage all operational decisions for the aircraft and is responsible for decisions regarding flight diversion.¹ In-flight medical volunteers, the flight crew, and ground-based medical experts can offer recommendations for care.¹ Cruising at altitudes of 30,000 to 40,000 feet with limited medical equipment, often hours away from the closest medical facility, will create unfamiliar challenges for any medical professional who volunteers for in-flight psychiatric emergencies.¹

Although they are rare, in-flight psychiatric emergencies occur because of large numbers of passengers, nonstop flights over longer distances, delayed flights, cramped cabins, and/or alcohol consumption.^1,2 Psychiatric symptoms and substance intoxication/withdrawal each represent up to 3% of all in-flight emergencies, and in most cases (90%), the primary presentation is acute anxiety.^1,2 Common in-flight psychiatric differential diagnoses include depression, psychosis, personality disorders, and somatization.¹

When a passenger requires medical or psychiatric treatment, the flight crew often requests aid from any trained medical professionals who are on board to augment their capabilities and resources (eg, the flight crew’s training, ground-based medical support).¹ In the United States, off-duty medical professionals are not legally required to assist during an in-flight medical emergency.¹ The Aviation Medical Assistance Act of 1998 protects passengers who provide medical assistance from liability, except in cases of gross negligence or willful misconduct.^1,3 Flights outside of the United States are governed by a complex combination of public and private international laws.¹ Here I suggest how to initiate care during in-flight psychiatric emergencies, and offer therapeutic options to employ for a passenger who is exhibiting psychiatric symptoms.

What to do first

Before volunteering to assist in a mental health emergency, consider your capabilities and limitations. Do not volunteer if you are under the influence of alcohol, illicit substances, or any medications (prescription or over-the-counter) that could affect your judgment.

Inform the flight crew that you are a mental health clinician, and outline your current clinical expertise. While the flight crew obtains the medical emergency kit, work to establish rapport with the passenger to identify the psychiatric problem and help de-escalate the situation. Initiate care by¹:

• eliciting a psychiatric history
• inquiring about any use of alcohol, illicit substances, or other mood-altering substances (eg, type, amount, and time of use)
• identifying any use of psychotropic medications (eg, doses, last dose taken, and if these agents are on the aircraft).

The Federal Aviation Administration has minimum requirements for the contents of medical emergency kits aboard US airlines.^1,4 However, they are not required to contain antipsychotics, naloxone, or benzodiazepines.^1,4 Although you may have limited medical resources at your disposal, you can still help passengers in the following ways¹:

Monitor vital signs and mental status changes, identify signs and symptoms of intoxication or withdrawal, and assess for respiratory distress. Provide reassurance to the passenger if appropriate.¹

Administer naloxone (if available) for suspected opioid ingestion.¹ Antiemetics, which are available in these medical kits, can be used if needed. Encourage passengers to remain hydrated and use oxygen as needed.

Continue to: If verbal de-escalation is ineffective...

If verbal de-escalation is ineffective, consider administering a benzodiazepine or antipsychotic (if available).¹ If the passenger is combative, refer to the flight crew for the airline’s security protocols, which may include restraining the passenger or diverting the aircraft. Safety takes priority over attempts at medical management.

If the passenger has respiratory distress, instruct the flight crew to contact ground-based medical support for additional recommendations.¹

A challenging situation

Ultimately, the pilot coordinates with the flight dispatcher to manage all operational decisions for the aircraft and is responsible for decisions regarding flight diversion.¹ In-flight medical volunteers, the flight crew, and ground-based medical experts can offer recommendations for care.¹ Cruising at altitudes of 30,000 to 40,000 feet with limited medical equipment, often hours away from the closest medical facility, will create unfamiliar challenges for any medical professional who volunteers for in-flight psychiatric emergencies.¹

Although they are rare, in-flight psychiatric emergencies occur because of large numbers of passengers, nonstop flights over longer distances, delayed flights, cramped cabins, and/or alcohol consumption.^1,2 Psychiatric symptoms and substance intoxication/withdrawal each represent up to 3% of all in-flight emergencies, and in most cases (90%), the primary presentation is acute anxiety.^1,2 Common in-flight psychiatric differential diagnoses include depression, psychosis, personality disorders, and somatization.¹

When a passenger requires medical or psychiatric treatment, the flight crew often requests aid from any trained medical professionals who are on board to augment their capabilities and resources (eg, the flight crew’s training, ground-based medical support).¹ In the United States, off-duty medical professionals are not legally required to assist during an in-flight medical emergency.¹ The Aviation Medical Assistance Act of 1998 protects passengers who provide medical assistance from liability, except in cases of gross negligence or willful misconduct.^1,3 Flights outside of the United States are governed by a complex combination of public and private international laws.¹ Here I suggest how to initiate care during in-flight psychiatric emergencies, and offer therapeutic options to employ for a passenger who is exhibiting psychiatric symptoms.

What to do first

Before volunteering to assist in a mental health emergency, consider your capabilities and limitations. Do not volunteer if you are under the influence of alcohol, illicit substances, or any medications (prescription or over-the-counter) that could affect your judgment.

Inform the flight crew that you are a mental health clinician, and outline your current clinical expertise. While the flight crew obtains the medical emergency kit, work to establish rapport with the passenger to identify the psychiatric problem and help de-escalate the situation. Initiate care by¹:

• eliciting a psychiatric history
• inquiring about any use of alcohol, illicit substances, or other mood-altering substances (eg, type, amount, and time of use)
• identifying any use of psychotropic medications (eg, doses, last dose taken, and if these agents are on the aircraft).

The Federal Aviation Administration has minimum requirements for the contents of medical emergency kits aboard US airlines.^1,4 However, they are not required to contain antipsychotics, naloxone, or benzodiazepines.^1,4 Although you may have limited medical resources at your disposal, you can still help passengers in the following ways¹:

Monitor vital signs and mental status changes, identify signs and symptoms of intoxication or withdrawal, and assess for respiratory distress. Provide reassurance to the passenger if appropriate.¹

Administer naloxone (if available) for suspected opioid ingestion.¹ Antiemetics, which are available in these medical kits, can be used if needed. Encourage passengers to remain hydrated and use oxygen as needed.

Continue to: If verbal de-escalation is ineffective...

If verbal de-escalation is ineffective, consider administering a benzodiazepine or antipsychotic (if available).¹ If the passenger is combative, refer to the flight crew for the airline’s security protocols, which may include restraining the passenger or diverting the aircraft. Safety takes priority over attempts at medical management.

If the passenger has respiratory distress, instruct the flight crew to contact ground-based medical support for additional recommendations.¹

A challenging situation

Ultimately, the pilot coordinates with the flight dispatcher to manage all operational decisions for the aircraft and is responsible for decisions regarding flight diversion.¹ In-flight medical volunteers, the flight crew, and ground-based medical experts can offer recommendations for care.¹ Cruising at altitudes of 30,000 to 40,000 feet with limited medical equipment, often hours away from the closest medical facility, will create unfamiliar challenges for any medical professional who volunteers for in-flight psychiatric emergencies.¹

Note: Dr. Nasrallah has withdrawn his candidacy for APA President-Elect. For a statement of explanation click here.

I have been informed by the American Psychiatric Association (APA) Nominating Committee that I am a candidate for the position of APA President-Elect. I am honored to be nominated along with 2 other esteemed psychiatrists, David C. Henderson, MD, and Vivian B. Pender, MD.

You have all known me for many years as Editor-in-Chief of this journal, and probably have read many of my 150 editorials in which I frequently discussed and commented on not only the challenges that face psychiatry, but also the great promise and bright future of our evolving clinical neuro­science medical specialty. You can access all of these at MDedge.com/psychiatry/editor.

In this pre-election editorial, I would like to tell you about my qualifications as a candidate for this critical national psychiatry leadership role. Most of you are APA members who will have the opportunity to vote for the candidate of your choice from January 2 to 31, 2020. I hope that you will support my candidacy after learning about my long-standing involvement within the APA governance, as well as my 3 decades of academic leadership experience and productivity. You also know where I stand on the issues from my writings in Current Psychiatry.

APA involvement

• President, Missouri Psychiatric Physicians Association District Branch (2017-2018)
• President, Cincinnati Psychiatric Society (2007-2009)
• President, Ohio Psychiatric Physi­cians Foundation (2008-2013)
• Editor, Ohio Psychiatric Physicians Association (OPPA) Newsletter (Insight Matters) (2003-2008)
• Executive Council, OPPA (2003-2013)
• APA Council on Research (1993-2000)
• APA Committee on Research in Psychiatric Treatments (1992-1995)
• APA Task Force on Schizophrenia (1998-1999)
• President, Ohio Psychiatric Asso­ciation Education and Research Foundation (1987-1994)

Academic track record

• Served as Chief of Psychiatry, VA Medical Center, Iowa City, Iowa for 6 years; Chair, Department of Psychiatry, The Ohio State University for 12 years; Chair, Department of Psychiatry, Saint Louis University for 6 years; and Associate Dean, University of Cincinnati for 4 years
• Published >700 articles, 570 abstracts, and 14 books
• Recruited and developed dozens of faculty members; supervised and mentored hundreds of residents, many of whom became medical directors, department chairs, and/or distinguished clinicians
• Received numerous awards and recognitions for clinical, teaching, and research excellence
• Serve as Editor for 3 journals (Current Psychiatry, Schizophrenia Research, and Biomarkers in Neuro­­­­psychiatry)

Statement of vision and priorities

I am very optimistic about the future of psychiatry. The breakthroughs and advances in neuroscience all bolster the scientific basis of psychiatric disorders, and will lead to many novel treatments in the future. Psychiatry is a medical specialty that is now much more integrated into the “big tent” of medicine. Psychiatrists are physicians, and I believe the name of our association must reflect that. I was successful in changing the names of 2 district branches to include “physicians” (Ohio Psychiatric Physicians Association and Missouri Psychiatric Physicians Association). If elected, I will propose to the Board of Trustees and the APA members that we change our name to the American Psychiatric Physicians Association, which will emphasize our medical identity within mental health. In its 175-year history, the APA has experienced 2 previous name changes.

I believe the strengths of the APA far exceed its weaknesses, and its opportunities outnumber its threats. However, the following perennial challenges must be forcefully addressed by all of us:

1. The pernicious and discriminatory dogma of stigma must be shattered for the sake of patients, their families, their psychiatrists, and the profession.
2. Pre-authorization is essentially the insurance companies practicing medicine without a license when, without ever actually examining the patient, they tell physicians what they should or should not prescribe. That’s felonious!
3. Competent and safe prescribing is the culmination of extensive medical training (approximately 14,000 hours) and psychologists do not qualify.
4. Board certification fees must be reduced, and recertification (Maintenance of Certification) must be simpler and less onerous.
5. Effective parity laws must have teeth, not just words!
6. Patient care, not computer care! Electronic health records must be more user-friendly and less time-consuming.
7. Patients with psychiatric illness who have relapsed must be surrounded by compassionate medical professionals in a hospital setting, not by armed guards in a jail or prison.
8. The shortage of psychiatrists can be remedied if the government funds additional residency slots as it did in the 1960s and 1970s. The number of applicants for psychiatric training is rapidly rising, but the number of residency slots has not changed for decades. Approximately 100 US medical school graduates did not match last year, along with >1,000 international medical graduate applicants.
9. Lawyers have clients; psychiatrists have patients (as do cardiologists, neuro­logists, and oncologists). The term “clients” de-medicalizes psychiatric disorders and does not evoke public support or compassion.
10. Psychotherapy is in fact a neurobiologic treatment that repairs the mind via neuroplasticity and synaptogenesis. It should get the same respect as pharmacotherapy.
11. Untether psychiatric reimbursement from “time”! Psychiatric assessment and treatment are medical procedures. Excising depression, psychosis, panic attacks, or suicidal urges are to the mind what surgery is to the body.
12. Clinical psychiatrists have much to offer for medical advances. Their observations generate hypotheses, and if these are published as a case report or letter to the editor, researchers can conduct hypothesis-testing and discover new treatments thanks to astute clinicians.
13. The FDA should allow clinical trials to investigate treatments of symptoms, not (often heterogenous) DSM diagnoses. This will enable “off-label use” of medication, which often is necessary.

Continue to: Annual dues

Annual dues. The APA is a great organization that should continue to re-invent itself and re-engineer its procedures and business practices to generate additional revenue streams that could help reduce its annual dues. I know many members who complain about the APA dues, and former members who dropped out because of what they consider to be high dues. I try to remind them that the dues are on average a modest .3% to .5% of a psychiatrist’s annual income, and that all of us must unite within our association in order to have the collective power to achieve our goals and solve our challenges.

Public education. The APA must intensify public education across all media platforms. This will help dispel myths, eliminate stigma, enforce parity, and portray psychiatry as a medical and scientific discipline. We have a great story to tell about how neurologic circuitry generates the mind and its mental functions, and the neuro­biologic foundations of psychiatric brain disorders.

The APA should advocate for (and perhaps organize) an annual mental health check-up (online) in children, adolescents, adults, and the elderly for early detection and intervention.

Collaborative care. We should have close relationships with obstetricians to help prevent neurodevelopmental pathology due to perinatal complications as well as to manage depression in women in the pre- and postpartum phases. Collaborative care with pediatricians, family physicians, internists, and neurologists is necessary to integrate physical and mental health care for our patients, many of whom have multiple medical comorbidities and premature mortality.

Lobbying. The APA must intensify its lobbying to address the unacceptably high rate of suicide, addiction-related deaths, posttraumatic stress disorder due to trauma in children and adults, threats to mental health due to climate change and pollution, refugee mental health, stressful political zeitgeist, and the woefully high rate of uninsured or under-insured individuals.

Continue to: Industry

Industry. There are many significant unmet treatment needs in psychiatry. Approximately 82% of DSM disorders do not have any FDA-approved medication. The APA should constructively engage the pharmaceutical industry (the only entity that develops medications for our patients!) to do more research and development of therapies for conditions with no approved treatments, and to explore new mechanisms of action for more effective or tolerable psychiatric medications. Importantly, the APA should urge major pharmaceutical companies not to abandon neuropsychiatric disorders because they afflict tens of millions of US citizens and are the top causes of long-term disabilities.

Journals. The APA should consider rebranding its journals as “JAPA,” similar to JAMA, which will widen its influence and generate revenue to fund various priorities.

Telepsychiatry. And why can’t the APA create a national telepsychiatry network to meet the needs of underserved populations who have very little access to psychiatric care as in many rural areas? Private companies have filled that space, but the APA and its members can do it better, and this can become a benefit of membership.

Brain bank. Finally, the APA should consider establishing a “Brain Bank” of various psychiatric subspecialties to consult and advise the military, college administrators, corporations, and government agencies about strategies and tactics to solve many problems that arise from overt or covert psychiatric illnesses among their employees, staff, students, or constituents.

The APA cannot solve all societal problems, but it has the moral authority and clinical/scientific depth and gravitas to create an agenda of solutions and to partner with many other stakeholders to achieve mutual societal health goals.

Note: Dr. Nasrallah has withdrawn his candidacy for APA President-Elect. For a statement of explanation click here.

I have been informed by the American Psychiatric Association (APA) Nominating Committee that I am a candidate for the position of APA President-Elect. I am honored to be nominated along with 2 other esteemed psychiatrists, David C. Henderson, MD, and Vivian B. Pender, MD.

You have all known me for many years as Editor-in-Chief of this journal, and probably have read many of my 150 editorials in which I frequently discussed and commented on not only the challenges that face psychiatry, but also the great promise and bright future of our evolving clinical neuro­science medical specialty. You can access all of these at MDedge.com/psychiatry/editor.

In this pre-election editorial, I would like to tell you about my qualifications as a candidate for this critical national psychiatry leadership role. Most of you are APA members who will have the opportunity to vote for the candidate of your choice from January 2 to 31, 2020. I hope that you will support my candidacy after learning about my long-standing involvement within the APA governance, as well as my 3 decades of academic leadership experience and productivity. You also know where I stand on the issues from my writings in Current Psychiatry.

APA involvement

• President, Missouri Psychiatric Physicians Association District Branch (2017-2018)
• President, Cincinnati Psychiatric Society (2007-2009)
• President, Ohio Psychiatric Physi­cians Foundation (2008-2013)
• Editor, Ohio Psychiatric Physicians Association (OPPA) Newsletter (Insight Matters) (2003-2008)
• Executive Council, OPPA (2003-2013)
• APA Council on Research (1993-2000)
• APA Committee on Research in Psychiatric Treatments (1992-1995)
• APA Task Force on Schizophrenia (1998-1999)
• President, Ohio Psychiatric Asso­ciation Education and Research Foundation (1987-1994)

Academic track record

• Served as Chief of Psychiatry, VA Medical Center, Iowa City, Iowa for 6 years; Chair, Department of Psychiatry, The Ohio State University for 12 years; Chair, Department of Psychiatry, Saint Louis University for 6 years; and Associate Dean, University of Cincinnati for 4 years
• Published >700 articles, 570 abstracts, and 14 books
• Recruited and developed dozens of faculty members; supervised and mentored hundreds of residents, many of whom became medical directors, department chairs, and/or distinguished clinicians
• Received numerous awards and recognitions for clinical, teaching, and research excellence
• Serve as Editor for 3 journals (Current Psychiatry, Schizophrenia Research, and Biomarkers in Neuro­­­­psychiatry)

Statement of vision and priorities

I am very optimistic about the future of psychiatry. The breakthroughs and advances in neuroscience all bolster the scientific basis of psychiatric disorders, and will lead to many novel treatments in the future. Psychiatry is a medical specialty that is now much more integrated into the “big tent” of medicine. Psychiatrists are physicians, and I believe the name of our association must reflect that. I was successful in changing the names of 2 district branches to include “physicians” (Ohio Psychiatric Physicians Association and Missouri Psychiatric Physicians Association). If elected, I will propose to the Board of Trustees and the APA members that we change our name to the American Psychiatric Physicians Association, which will emphasize our medical identity within mental health. In its 175-year history, the APA has experienced 2 previous name changes.

I believe the strengths of the APA far exceed its weaknesses, and its opportunities outnumber its threats. However, the following perennial challenges must be forcefully addressed by all of us:

1. The pernicious and discriminatory dogma of stigma must be shattered for the sake of patients, their families, their psychiatrists, and the profession.
2. Pre-authorization is essentially the insurance companies practicing medicine without a license when, without ever actually examining the patient, they tell physicians what they should or should not prescribe. That’s felonious!
3. Competent and safe prescribing is the culmination of extensive medical training (approximately 14,000 hours) and psychologists do not qualify.
4. Board certification fees must be reduced, and recertification (Maintenance of Certification) must be simpler and less onerous.
5. Effective parity laws must have teeth, not just words!
6. Patient care, not computer care! Electronic health records must be more user-friendly and less time-consuming.
7. Patients with psychiatric illness who have relapsed must be surrounded by compassionate medical professionals in a hospital setting, not by armed guards in a jail or prison.
8. The shortage of psychiatrists can be remedied if the government funds additional residency slots as it did in the 1960s and 1970s. The number of applicants for psychiatric training is rapidly rising, but the number of residency slots has not changed for decades. Approximately 100 US medical school graduates did not match last year, along with >1,000 international medical graduate applicants.
9. Lawyers have clients; psychiatrists have patients (as do cardiologists, neuro­logists, and oncologists). The term “clients” de-medicalizes psychiatric disorders and does not evoke public support or compassion.
10. Psychotherapy is in fact a neurobiologic treatment that repairs the mind via neuroplasticity and synaptogenesis. It should get the same respect as pharmacotherapy.
11. Untether psychiatric reimbursement from “time”! Psychiatric assessment and treatment are medical procedures. Excising depression, psychosis, panic attacks, or suicidal urges are to the mind what surgery is to the body.
12. Clinical psychiatrists have much to offer for medical advances. Their observations generate hypotheses, and if these are published as a case report or letter to the editor, researchers can conduct hypothesis-testing and discover new treatments thanks to astute clinicians.
13. The FDA should allow clinical trials to investigate treatments of symptoms, not (often heterogenous) DSM diagnoses. This will enable “off-label use” of medication, which often is necessary.

Continue to: Annual dues

Annual dues. The APA is a great organization that should continue to re-invent itself and re-engineer its procedures and business practices to generate additional revenue streams that could help reduce its annual dues. I know many members who complain about the APA dues, and former members who dropped out because of what they consider to be high dues. I try to remind them that the dues are on average a modest .3% to .5% of a psychiatrist’s annual income, and that all of us must unite within our association in order to have the collective power to achieve our goals and solve our challenges.

Public education. The APA must intensify public education across all media platforms. This will help dispel myths, eliminate stigma, enforce parity, and portray psychiatry as a medical and scientific discipline. We have a great story to tell about how neurologic circuitry generates the mind and its mental functions, and the neuro­biologic foundations of psychiatric brain disorders.

The APA should advocate for (and perhaps organize) an annual mental health check-up (online) in children, adolescents, adults, and the elderly for early detection and intervention.

Collaborative care. We should have close relationships with obstetricians to help prevent neurodevelopmental pathology due to perinatal complications as well as to manage depression in women in the pre- and postpartum phases. Collaborative care with pediatricians, family physicians, internists, and neurologists is necessary to integrate physical and mental health care for our patients, many of whom have multiple medical comorbidities and premature mortality.

Lobbying. The APA must intensify its lobbying to address the unacceptably high rate of suicide, addiction-related deaths, posttraumatic stress disorder due to trauma in children and adults, threats to mental health due to climate change and pollution, refugee mental health, stressful political zeitgeist, and the woefully high rate of uninsured or under-insured individuals.

Continue to: Industry

Industry. There are many significant unmet treatment needs in psychiatry. Approximately 82% of DSM disorders do not have any FDA-approved medication. The APA should constructively engage the pharmaceutical industry (the only entity that develops medications for our patients!) to do more research and development of therapies for conditions with no approved treatments, and to explore new mechanisms of action for more effective or tolerable psychiatric medications. Importantly, the APA should urge major pharmaceutical companies not to abandon neuropsychiatric disorders because they afflict tens of millions of US citizens and are the top causes of long-term disabilities.

Journals. The APA should consider rebranding its journals as “JAPA,” similar to JAMA, which will widen its influence and generate revenue to fund various priorities.

Telepsychiatry. And why can’t the APA create a national telepsychiatry network to meet the needs of underserved populations who have very little access to psychiatric care as in many rural areas? Private companies have filled that space, but the APA and its members can do it better, and this can become a benefit of membership.

Brain bank. Finally, the APA should consider establishing a “Brain Bank” of various psychiatric subspecialties to consult and advise the military, college administrators, corporations, and government agencies about strategies and tactics to solve many problems that arise from overt or covert psychiatric illnesses among their employees, staff, students, or constituents.

The APA cannot solve all societal problems, but it has the moral authority and clinical/scientific depth and gravitas to create an agenda of solutions and to partner with many other stakeholders to achieve mutual societal health goals.

Note: Dr. Nasrallah has withdrawn his candidacy for APA President-Elect. For a statement of explanation click here.

I have been informed by the American Psychiatric Association (APA) Nominating Committee that I am a candidate for the position of APA President-Elect. I am honored to be nominated along with 2 other esteemed psychiatrists, David C. Henderson, MD, and Vivian B. Pender, MD.

You have all known me for many years as Editor-in-Chief of this journal, and probably have read many of my 150 editorials in which I frequently discussed and commented on not only the challenges that face psychiatry, but also the great promise and bright future of our evolving clinical neuro­science medical specialty. You can access all of these at MDedge.com/psychiatry/editor.

In this pre-election editorial, I would like to tell you about my qualifications as a candidate for this critical national psychiatry leadership role. Most of you are APA members who will have the opportunity to vote for the candidate of your choice from January 2 to 31, 2020. I hope that you will support my candidacy after learning about my long-standing involvement within the APA governance, as well as my 3 decades of academic leadership experience and productivity. You also know where I stand on the issues from my writings in Current Psychiatry.

APA involvement

• President, Missouri Psychiatric Physicians Association District Branch (2017-2018)
• President, Cincinnati Psychiatric Society (2007-2009)
• President, Ohio Psychiatric Physi­cians Foundation (2008-2013)
• Editor, Ohio Psychiatric Physicians Association (OPPA) Newsletter (Insight Matters) (2003-2008)
• Executive Council, OPPA (2003-2013)
• APA Council on Research (1993-2000)
• APA Committee on Research in Psychiatric Treatments (1992-1995)
• APA Task Force on Schizophrenia (1998-1999)
• President, Ohio Psychiatric Asso­ciation Education and Research Foundation (1987-1994)

Academic track record

• Served as Chief of Psychiatry, VA Medical Center, Iowa City, Iowa for 6 years; Chair, Department of Psychiatry, The Ohio State University for 12 years; Chair, Department of Psychiatry, Saint Louis University for 6 years; and Associate Dean, University of Cincinnati for 4 years
• Published >700 articles, 570 abstracts, and 14 books
• Recruited and developed dozens of faculty members; supervised and mentored hundreds of residents, many of whom became medical directors, department chairs, and/or distinguished clinicians
• Received numerous awards and recognitions for clinical, teaching, and research excellence
• Serve as Editor for 3 journals (Current Psychiatry, Schizophrenia Research, and Biomarkers in Neuro­­­­psychiatry)

Statement of vision and priorities

I am very optimistic about the future of psychiatry. The breakthroughs and advances in neuroscience all bolster the scientific basis of psychiatric disorders, and will lead to many novel treatments in the future. Psychiatry is a medical specialty that is now much more integrated into the “big tent” of medicine. Psychiatrists are physicians, and I believe the name of our association must reflect that. I was successful in changing the names of 2 district branches to include “physicians” (Ohio Psychiatric Physicians Association and Missouri Psychiatric Physicians Association). If elected, I will propose to the Board of Trustees and the APA members that we change our name to the American Psychiatric Physicians Association, which will emphasize our medical identity within mental health. In its 175-year history, the APA has experienced 2 previous name changes.

I believe the strengths of the APA far exceed its weaknesses, and its opportunities outnumber its threats. However, the following perennial challenges must be forcefully addressed by all of us:

1. The pernicious and discriminatory dogma of stigma must be shattered for the sake of patients, their families, their psychiatrists, and the profession.
2. Pre-authorization is essentially the insurance companies practicing medicine without a license when, without ever actually examining the patient, they tell physicians what they should or should not prescribe. That’s felonious!
3. Competent and safe prescribing is the culmination of extensive medical training (approximately 14,000 hours) and psychologists do not qualify.
4. Board certification fees must be reduced, and recertification (Maintenance of Certification) must be simpler and less onerous.
5. Effective parity laws must have teeth, not just words!
6. Patient care, not computer care! Electronic health records must be more user-friendly and less time-consuming.
7. Patients with psychiatric illness who have relapsed must be surrounded by compassionate medical professionals in a hospital setting, not by armed guards in a jail or prison.
8. The shortage of psychiatrists can be remedied if the government funds additional residency slots as it did in the 1960s and 1970s. The number of applicants for psychiatric training is rapidly rising, but the number of residency slots has not changed for decades. Approximately 100 US medical school graduates did not match last year, along with >1,000 international medical graduate applicants.
9. Lawyers have clients; psychiatrists have patients (as do cardiologists, neuro­logists, and oncologists). The term “clients” de-medicalizes psychiatric disorders and does not evoke public support or compassion.
10. Psychotherapy is in fact a neurobiologic treatment that repairs the mind via neuroplasticity and synaptogenesis. It should get the same respect as pharmacotherapy.
11. Untether psychiatric reimbursement from “time”! Psychiatric assessment and treatment are medical procedures. Excising depression, psychosis, panic attacks, or suicidal urges are to the mind what surgery is to the body.
12. Clinical psychiatrists have much to offer for medical advances. Their observations generate hypotheses, and if these are published as a case report or letter to the editor, researchers can conduct hypothesis-testing and discover new treatments thanks to astute clinicians.
13. The FDA should allow clinical trials to investigate treatments of symptoms, not (often heterogenous) DSM diagnoses. This will enable “off-label use” of medication, which often is necessary.

Continue to: Annual dues

Annual dues. The APA is a great organization that should continue to re-invent itself and re-engineer its procedures and business practices to generate additional revenue streams that could help reduce its annual dues. I know many members who complain about the APA dues, and former members who dropped out because of what they consider to be high dues. I try to remind them that the dues are on average a modest .3% to .5% of a psychiatrist’s annual income, and that all of us must unite within our association in order to have the collective power to achieve our goals and solve our challenges.

Public education. The APA must intensify public education across all media platforms. This will help dispel myths, eliminate stigma, enforce parity, and portray psychiatry as a medical and scientific discipline. We have a great story to tell about how neurologic circuitry generates the mind and its mental functions, and the neuro­biologic foundations of psychiatric brain disorders.

The APA should advocate for (and perhaps organize) an annual mental health check-up (online) in children, adolescents, adults, and the elderly for early detection and intervention.

Collaborative care. We should have close relationships with obstetricians to help prevent neurodevelopmental pathology due to perinatal complications as well as to manage depression in women in the pre- and postpartum phases. Collaborative care with pediatricians, family physicians, internists, and neurologists is necessary to integrate physical and mental health care for our patients, many of whom have multiple medical comorbidities and premature mortality.

Lobbying. The APA must intensify its lobbying to address the unacceptably high rate of suicide, addiction-related deaths, posttraumatic stress disorder due to trauma in children and adults, threats to mental health due to climate change and pollution, refugee mental health, stressful political zeitgeist, and the woefully high rate of uninsured or under-insured individuals.

Continue to: Industry

Industry. There are many significant unmet treatment needs in psychiatry. Approximately 82% of DSM disorders do not have any FDA-approved medication. The APA should constructively engage the pharmaceutical industry (the only entity that develops medications for our patients!) to do more research and development of therapies for conditions with no approved treatments, and to explore new mechanisms of action for more effective or tolerable psychiatric medications. Importantly, the APA should urge major pharmaceutical companies not to abandon neuropsychiatric disorders because they afflict tens of millions of US citizens and are the top causes of long-term disabilities.

Journals. The APA should consider rebranding its journals as “JAPA,” similar to JAMA, which will widen its influence and generate revenue to fund various priorities.

Telepsychiatry. And why can’t the APA create a national telepsychiatry network to meet the needs of underserved populations who have very little access to psychiatric care as in many rural areas? Private companies have filled that space, but the APA and its members can do it better, and this can become a benefit of membership.

Brain bank. Finally, the APA should consider establishing a “Brain Bank” of various psychiatric subspecialties to consult and advise the military, college administrators, corporations, and government agencies about strategies and tactics to solve many problems that arise from overt or covert psychiatric illnesses among their employees, staff, students, or constituents.

The APA cannot solve all societal problems, but it has the moral authority and clinical/scientific depth and gravitas to create an agenda of solutions and to partner with many other stakeholders to achieve mutual societal health goals.

The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is a well-established protocol that attempts to measure the degree of alcohol and benzodiazepine withdrawal. The CIWA-Ar scale measures 10 domains and indexes the severity of withdrawal on a scale from 0 to 67; scores >8 are generally considered to be indicative of at least mild-to-moderate withdrawal, and scores >20 represent significant withdrawal.¹ Despite its common use in many medical settings, the CIWA-Ar scale has been impugned as a less-than-reliable index of true alcohol withdrawal² and has the potential for misuse among ordering physicians.³ In this case report, I describe a malingering patient who intentionally and successfully feigned symptoms of alcohol withdrawal, which demonstrates that the purposeful reproduction of symptoms measured by the CIWA-Ar scale can render the protocol clinically useless.

CASE REPORT

Mr. G, a 63-year-old African-American man, was admitted to the general medical floor with a chief complaint of alcohol withdrawal. He had a history of alcohol use disorder, severe, and unspecified depression. He said he had been drinking a gallon of wine plus “a fifth” of vodka every day for the past 1.5 months. More than 1 year ago, he had been admitted for alcohol withdrawal with subsequent delirium tremens, but he denied having any other psychiatric history.

In the emergency department, Mr. G was given IV lorazepam, 6 mg total, for alcohol withdrawal. He was reported to be “scoring” on the CIWA-Ar scale with apparently uncontrollable tremulousness, visual hallucinations, and confusion. His vitals were within normal limits, his mean corpuscular volume and lipase level were within normal limits, and the rest of his presentation was largely unremarkable.

Once admitted to the general medical floor, he continued to receive benzodiazepines for what was documented as severe alcohol withdrawal. When clinical staff were not in the room, the patient was observed to be resting comfortably without tremulousness. When the patient was seen by the psychiatry consultation service, he produced full body tremulousness with marked shoulder and hip thrusting. His account of how much he had been drinking contradicted the amount he reported to other teams in the hospital. When the consulting psychiatrist appeared unimpressed by his full body jerking, the patient abruptly pointed to the corner of the room and yelled “What is that?” when nothing was there. When the primary medical team suggested to the patient that his vitals were within normal limits and he did not appear to be in true alcohol withdrawal, the patient escalated the degree of his full body jerking.

Over the next few days, the patient routinely would tell clinical staff “I’m having DTs.” He also specifically requested lorazepam. After consultation, the medical and psychiatry teams determined the patient was feigning symptoms of alcohol withdrawal. The lorazepam was discontinued, and the patient was discharged home with outpatient psychiatric follow-up.

Limitations of the CIWA-Ar scale

The CIWA-Ar scale is intended to guide the need for medications, such as benzodiazepines, to help mitigate symptoms of alcohol withdrawal. Symptom-triggered benzodiazepine treatment has been shown to be superior to fixed-schedule dosing.⁴ However, symptom-triggered treatment is problematic in the setting of feigned symptoms.

When psychiatrists and nurses calculate a CIWA-Ar score, they rely on both subjective accounts of a patient’s withdrawal severity as well as objective signs, such as vitals and a physical examination. Many of the elements included in the CIWA-Ar scale can be easily feigned (Table). Feigned alcohol withdrawal may fall into 2 categories: (1) the false reporting of subjective symptoms, and (2) the false portrayal of objective signs.

Continue to: The false reporting...

The false reporting of subjective symptoms can include the reported presence of nausea or vomiting, anxiety, tactile hallucinations, auditory hallucinations, headache or head fullness, and visual hallucinations. The false portrayal of objective signs can include the feigning of tremulousness, agitation, and confusion (eg, incorrectly answering orienting questions). In both categories, the simple presence of these signs or symptoms, whether falsely reported or falsely portrayed, would cause the patient to “score” on the CIWA-Ar scale.

Thus, the need to effectively rule out feigned symptoms is essential because inappropriate dosing of benzodiazepines can be dangerous, costly, and utilize limited hospital resources that could otherwise be diverted to a patient with a true medical or psychiatric illness. In these instances, it is crucial to pay close attention to vital signs because these are more reliable indices of withdrawal. A patient’s ability to purposefully feign symptoms of alcohol withdrawal highlights the limitations of the CIWA-Ar scale as a validated measure of alcohol withdrawal, and renders it effectively useless in the setting of either malingering or factitious disorder.

Resnick⁵ describes malingering as either pure malingering, partial malingering, or false imputation. Pure malingering refers to the feigning of a nonexistent disorder or illness. Partial malingering refers to the exaggeration of symptoms that are present, but to a lesser degree. False imputation refers to the attribution of symptoms from a separate disorder to one the patient knows is unrelated (eg, attributing chronic low back pain from a prior sports injury to a recent motor vehicle accident). In Mr. G’s case, he had multiple prior admissions for true, non-feigned alcohol withdrawal with subsequent delirium tremens. His knowledge of the signs and symptoms of alcohol withdrawal therefore helped him make calculated efforts to manipulate clinical staff in his quest to obtain benzodiazepines. Whether this was pure or partial malingering remained unclear because Mr. G’s true level of withdrawal could not be adequately assessed.

Potentially serious consequences

The CIWA-Ar scale is among the most widely used scales to determine the level of alcohol withdrawal and need for subsequent benzodiazepine treatment. However, its effective use is limited because it relies on subjective symptoms and objective signs that can be easily feigned or manipulated. In the setting of malingering or factitious disorder, when a patient is feigning symptoms of alcohol withdrawal, the CIWA-Ar scale may be rendered clinically useless. This can lead to dangerous iatrogenic adverse effects, lengthy and nontherapeutic hospital stays, and an increasing financial burden on health care systems.

The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is a well-established protocol that attempts to measure the degree of alcohol and benzodiazepine withdrawal. The CIWA-Ar scale measures 10 domains and indexes the severity of withdrawal on a scale from 0 to 67; scores >8 are generally considered to be indicative of at least mild-to-moderate withdrawal, and scores >20 represent significant withdrawal.¹ Despite its common use in many medical settings, the CIWA-Ar scale has been impugned as a less-than-reliable index of true alcohol withdrawal² and has the potential for misuse among ordering physicians.³ In this case report, I describe a malingering patient who intentionally and successfully feigned symptoms of alcohol withdrawal, which demonstrates that the purposeful reproduction of symptoms measured by the CIWA-Ar scale can render the protocol clinically useless.

CASE REPORT

Mr. G, a 63-year-old African-American man, was admitted to the general medical floor with a chief complaint of alcohol withdrawal. He had a history of alcohol use disorder, severe, and unspecified depression. He said he had been drinking a gallon of wine plus “a fifth” of vodka every day for the past 1.5 months. More than 1 year ago, he had been admitted for alcohol withdrawal with subsequent delirium tremens, but he denied having any other psychiatric history.

In the emergency department, Mr. G was given IV lorazepam, 6 mg total, for alcohol withdrawal. He was reported to be “scoring” on the CIWA-Ar scale with apparently uncontrollable tremulousness, visual hallucinations, and confusion. His vitals were within normal limits, his mean corpuscular volume and lipase level were within normal limits, and the rest of his presentation was largely unremarkable.

Once admitted to the general medical floor, he continued to receive benzodiazepines for what was documented as severe alcohol withdrawal. When clinical staff were not in the room, the patient was observed to be resting comfortably without tremulousness. When the patient was seen by the psychiatry consultation service, he produced full body tremulousness with marked shoulder and hip thrusting. His account of how much he had been drinking contradicted the amount he reported to other teams in the hospital. When the consulting psychiatrist appeared unimpressed by his full body jerking, the patient abruptly pointed to the corner of the room and yelled “What is that?” when nothing was there. When the primary medical team suggested to the patient that his vitals were within normal limits and he did not appear to be in true alcohol withdrawal, the patient escalated the degree of his full body jerking.

Over the next few days, the patient routinely would tell clinical staff “I’m having DTs.” He also specifically requested lorazepam. After consultation, the medical and psychiatry teams determined the patient was feigning symptoms of alcohol withdrawal. The lorazepam was discontinued, and the patient was discharged home with outpatient psychiatric follow-up.

Limitations of the CIWA-Ar scale

The CIWA-Ar scale is intended to guide the need for medications, such as benzodiazepines, to help mitigate symptoms of alcohol withdrawal. Symptom-triggered benzodiazepine treatment has been shown to be superior to fixed-schedule dosing.⁴ However, symptom-triggered treatment is problematic in the setting of feigned symptoms.

When psychiatrists and nurses calculate a CIWA-Ar score, they rely on both subjective accounts of a patient’s withdrawal severity as well as objective signs, such as vitals and a physical examination. Many of the elements included in the CIWA-Ar scale can be easily feigned (Table). Feigned alcohol withdrawal may fall into 2 categories: (1) the false reporting of subjective symptoms, and (2) the false portrayal of objective signs.

Continue to: The false reporting...

The false reporting of subjective symptoms can include the reported presence of nausea or vomiting, anxiety, tactile hallucinations, auditory hallucinations, headache or head fullness, and visual hallucinations. The false portrayal of objective signs can include the feigning of tremulousness, agitation, and confusion (eg, incorrectly answering orienting questions). In both categories, the simple presence of these signs or symptoms, whether falsely reported or falsely portrayed, would cause the patient to “score” on the CIWA-Ar scale.

Thus, the need to effectively rule out feigned symptoms is essential because inappropriate dosing of benzodiazepines can be dangerous, costly, and utilize limited hospital resources that could otherwise be diverted to a patient with a true medical or psychiatric illness. In these instances, it is crucial to pay close attention to vital signs because these are more reliable indices of withdrawal. A patient’s ability to purposefully feign symptoms of alcohol withdrawal highlights the limitations of the CIWA-Ar scale as a validated measure of alcohol withdrawal, and renders it effectively useless in the setting of either malingering or factitious disorder.

Resnick⁵ describes malingering as either pure malingering, partial malingering, or false imputation. Pure malingering refers to the feigning of a nonexistent disorder or illness. Partial malingering refers to the exaggeration of symptoms that are present, but to a lesser degree. False imputation refers to the attribution of symptoms from a separate disorder to one the patient knows is unrelated (eg, attributing chronic low back pain from a prior sports injury to a recent motor vehicle accident). In Mr. G’s case, he had multiple prior admissions for true, non-feigned alcohol withdrawal with subsequent delirium tremens. His knowledge of the signs and symptoms of alcohol withdrawal therefore helped him make calculated efforts to manipulate clinical staff in his quest to obtain benzodiazepines. Whether this was pure or partial malingering remained unclear because Mr. G’s true level of withdrawal could not be adequately assessed.

Potentially serious consequences

The CIWA-Ar scale is among the most widely used scales to determine the level of alcohol withdrawal and need for subsequent benzodiazepine treatment. However, its effective use is limited because it relies on subjective symptoms and objective signs that can be easily feigned or manipulated. In the setting of malingering or factitious disorder, when a patient is feigning symptoms of alcohol withdrawal, the CIWA-Ar scale may be rendered clinically useless. This can lead to dangerous iatrogenic adverse effects, lengthy and nontherapeutic hospital stays, and an increasing financial burden on health care systems.

The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is a well-established protocol that attempts to measure the degree of alcohol and benzodiazepine withdrawal. The CIWA-Ar scale measures 10 domains and indexes the severity of withdrawal on a scale from 0 to 67; scores >8 are generally considered to be indicative of at least mild-to-moderate withdrawal, and scores >20 represent significant withdrawal.¹ Despite its common use in many medical settings, the CIWA-Ar scale has been impugned as a less-than-reliable index of true alcohol withdrawal² and has the potential for misuse among ordering physicians.³ In this case report, I describe a malingering patient who intentionally and successfully feigned symptoms of alcohol withdrawal, which demonstrates that the purposeful reproduction of symptoms measured by the CIWA-Ar scale can render the protocol clinically useless.

CASE REPORT

Mr. G, a 63-year-old African-American man, was admitted to the general medical floor with a chief complaint of alcohol withdrawal. He had a history of alcohol use disorder, severe, and unspecified depression. He said he had been drinking a gallon of wine plus “a fifth” of vodka every day for the past 1.5 months. More than 1 year ago, he had been admitted for alcohol withdrawal with subsequent delirium tremens, but he denied having any other psychiatric history.

In the emergency department, Mr. G was given IV lorazepam, 6 mg total, for alcohol withdrawal. He was reported to be “scoring” on the CIWA-Ar scale with apparently uncontrollable tremulousness, visual hallucinations, and confusion. His vitals were within normal limits, his mean corpuscular volume and lipase level were within normal limits, and the rest of his presentation was largely unremarkable.

Once admitted to the general medical floor, he continued to receive benzodiazepines for what was documented as severe alcohol withdrawal. When clinical staff were not in the room, the patient was observed to be resting comfortably without tremulousness. When the patient was seen by the psychiatry consultation service, he produced full body tremulousness with marked shoulder and hip thrusting. His account of how much he had been drinking contradicted the amount he reported to other teams in the hospital. When the consulting psychiatrist appeared unimpressed by his full body jerking, the patient abruptly pointed to the corner of the room and yelled “What is that?” when nothing was there. When the primary medical team suggested to the patient that his vitals were within normal limits and he did not appear to be in true alcohol withdrawal, the patient escalated the degree of his full body jerking.

Over the next few days, the patient routinely would tell clinical staff “I’m having DTs.” He also specifically requested lorazepam. After consultation, the medical and psychiatry teams determined the patient was feigning symptoms of alcohol withdrawal. The lorazepam was discontinued, and the patient was discharged home with outpatient psychiatric follow-up.

Limitations of the CIWA-Ar scale

The CIWA-Ar scale is intended to guide the need for medications, such as benzodiazepines, to help mitigate symptoms of alcohol withdrawal. Symptom-triggered benzodiazepine treatment has been shown to be superior to fixed-schedule dosing.⁴ However, symptom-triggered treatment is problematic in the setting of feigned symptoms.

When psychiatrists and nurses calculate a CIWA-Ar score, they rely on both subjective accounts of a patient’s withdrawal severity as well as objective signs, such as vitals and a physical examination. Many of the elements included in the CIWA-Ar scale can be easily feigned (Table). Feigned alcohol withdrawal may fall into 2 categories: (1) the false reporting of subjective symptoms, and (2) the false portrayal of objective signs.

Continue to: The false reporting...

The false reporting of subjective symptoms can include the reported presence of nausea or vomiting, anxiety, tactile hallucinations, auditory hallucinations, headache or head fullness, and visual hallucinations. The false portrayal of objective signs can include the feigning of tremulousness, agitation, and confusion (eg, incorrectly answering orienting questions). In both categories, the simple presence of these signs or symptoms, whether falsely reported or falsely portrayed, would cause the patient to “score” on the CIWA-Ar scale.

Thus, the need to effectively rule out feigned symptoms is essential because inappropriate dosing of benzodiazepines can be dangerous, costly, and utilize limited hospital resources that could otherwise be diverted to a patient with a true medical or psychiatric illness. In these instances, it is crucial to pay close attention to vital signs because these are more reliable indices of withdrawal. A patient’s ability to purposefully feign symptoms of alcohol withdrawal highlights the limitations of the CIWA-Ar scale as a validated measure of alcohol withdrawal, and renders it effectively useless in the setting of either malingering or factitious disorder.

Resnick⁵ describes malingering as either pure malingering, partial malingering, or false imputation. Pure malingering refers to the feigning of a nonexistent disorder or illness. Partial malingering refers to the exaggeration of symptoms that are present, but to a lesser degree. False imputation refers to the attribution of symptoms from a separate disorder to one the patient knows is unrelated (eg, attributing chronic low back pain from a prior sports injury to a recent motor vehicle accident). In Mr. G’s case, he had multiple prior admissions for true, non-feigned alcohol withdrawal with subsequent delirium tremens. His knowledge of the signs and symptoms of alcohol withdrawal therefore helped him make calculated efforts to manipulate clinical staff in his quest to obtain benzodiazepines. Whether this was pure or partial malingering remained unclear because Mr. G’s true level of withdrawal could not be adequately assessed.

Potentially serious consequences

The CIWA-Ar scale is among the most widely used scales to determine the level of alcohol withdrawal and need for subsequent benzodiazepine treatment. However, its effective use is limited because it relies on subjective symptoms and objective signs that can be easily feigned or manipulated. In the setting of malingering or factitious disorder, when a patient is feigning symptoms of alcohol withdrawal, the CIWA-Ar scale may be rendered clinically useless. This can lead to dangerous iatrogenic adverse effects, lengthy and nontherapeutic hospital stays, and an increasing financial burden on health care systems.

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien