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The first case of the Omicron variant of the coronavirus in the United States was confirmed by officials today in an individual in California who had recently traveled to South Africa. He or she was fully vaccinated against COVID-19 and experienced only “mild symptoms that are improving,” officials with the Centers for Disease Control and Prevention said. 

The patient, who was not named in the CDC’s announcement of the first U.S. case of the Omicron variant Dec. 1, is self-quarantining.

“All close contacts have been contacted and have tested negative,” officials said. 

The announcement comes as no surprise to many as the Omicron variant, first identified in South Africa, has been reported in countries around the world in recent days. Hong Kong, the United Kingdom, and Germany each reported this variant, as have Italy and the Netherlands. Over the weekend, the first North American cases were identified in Canada.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, announced over the weekend that this newest variant was likely already in the United States, telling ABC’s This Week its appearance here was “inevitable.”

Similar to previous variants, this new strain likely started circulating in the United States before scientists could do genetic tests to confirm its presence.

The World Health Organization named Omicron a “variant of concern” on Nov. 26, even though much remains unknown about how well it spreads, how severe it can be, and how it may resist vaccines. In the meantime, the United States enacted travel bans from multiple South African countries.

It remains to be seen if Omicron will follow the pattern of the Delta variant, which was first identified in the United States in May and became the dominant strain by July. It’s also possible it will follow the path taken by the Mu variant. Mu emerged in March and April to much concern, only to fizzle out by September because it was unable to compete with the Delta variant.

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

The first case of the Omicron variant of the coronavirus in the United States was confirmed by officials today in an individual in California who had recently traveled to South Africa. He or she was fully vaccinated against COVID-19 and experienced only “mild symptoms that are improving,” officials with the Centers for Disease Control and Prevention said. 

The patient, who was not named in the CDC’s announcement of the first U.S. case of the Omicron variant Dec. 1, is self-quarantining.

“All close contacts have been contacted and have tested negative,” officials said. 

The announcement comes as no surprise to many as the Omicron variant, first identified in South Africa, has been reported in countries around the world in recent days. Hong Kong, the United Kingdom, and Germany each reported this variant, as have Italy and the Netherlands. Over the weekend, the first North American cases were identified in Canada.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, announced over the weekend that this newest variant was likely already in the United States, telling ABC’s This Week its appearance here was “inevitable.”

Similar to previous variants, this new strain likely started circulating in the United States before scientists could do genetic tests to confirm its presence.

The World Health Organization named Omicron a “variant of concern” on Nov. 26, even though much remains unknown about how well it spreads, how severe it can be, and how it may resist vaccines. In the meantime, the United States enacted travel bans from multiple South African countries.

It remains to be seen if Omicron will follow the pattern of the Delta variant, which was first identified in the United States in May and became the dominant strain by July. It’s also possible it will follow the path taken by the Mu variant. Mu emerged in March and April to much concern, only to fizzle out by September because it was unable to compete with the Delta variant.

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

The first case of the Omicron variant of the coronavirus in the United States was confirmed by officials today in an individual in California who had recently traveled to South Africa. He or she was fully vaccinated against COVID-19 and experienced only “mild symptoms that are improving,” officials with the Centers for Disease Control and Prevention said. 

The patient, who was not named in the CDC’s announcement of the first U.S. case of the Omicron variant Dec. 1, is self-quarantining.

“All close contacts have been contacted and have tested negative,” officials said. 

The announcement comes as no surprise to many as the Omicron variant, first identified in South Africa, has been reported in countries around the world in recent days. Hong Kong, the United Kingdom, and Germany each reported this variant, as have Italy and the Netherlands. Over the weekend, the first North American cases were identified in Canada.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, announced over the weekend that this newest variant was likely already in the United States, telling ABC’s This Week its appearance here was “inevitable.”

Similar to previous variants, this new strain likely started circulating in the United States before scientists could do genetic tests to confirm its presence.

The World Health Organization named Omicron a “variant of concern” on Nov. 26, even though much remains unknown about how well it spreads, how severe it can be, and how it may resist vaccines. In the meantime, the United States enacted travel bans from multiple South African countries.

It remains to be seen if Omicron will follow the pattern of the Delta variant, which was first identified in the United States in May and became the dominant strain by July. It’s also possible it will follow the path taken by the Mu variant. Mu emerged in March and April to much concern, only to fizzle out by September because it was unable to compete with the Delta variant.

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

The Moderna CEO says existing COVID-19 vaccines will likely be less effective against the new Omicron variant.

“There is no world, I think, where [the effectiveness] is the same level … we had with Delta,” Stephane Bancel told the Financial Times .

“I think it’s going to be a material drop,” he said. “I just don’t know how much, because we need to wait for the data. But all the scientists I’ve talked to … are like, ‘This is not going to be good.’”

Vaccine companies are now studying whether the new Omicron variant could evade the current shots. Some data is expected in about 2 weeks.

Mr. Bancel said that if a new vaccine is needed, it could take several months to produce at scale. He estimated that Moderna could make billions of vaccine doses in 2022.

“[Moderna] and Pfizer cannot get a billion doses next week. The math doesn’t work,” he said. “But could we get the billion doses out by the summer? Sure.”

The news caused some panic on Nov. 30, prompting financial markets to fall sharply, according to Reuters. But the markets recovered after European officials gave a more reassuring outlook.

“Even if the new variant becomes more widespread, the vaccines we have will continue to provide protection,” Emer Cooke, executive director of the European Medicines Agency, told the European Parliament.

Mr. Cooke said the agency could approve new vaccines that target the Omicron variant within 3 to 4 months, if needed. Moderna and Pfizer have announced they are beginning to tailor a shot to address the Omicron variant in case the data shows they are necessary.

Also on Nov. 30, the European Centre for Disease Prevention and Control announced that 42 Omicron cases had been identified in 10 European Union countries, according to Reuters.

The cases were mild or had no symptoms, although they were found in younger people who may have mild or no symptoms anyway.

“For the assessment of whether [Omicron] escapes immunity, we still have to wait until investigations in the laboratories with [blood samples] from people who have recovered have been carried out,” Andrea Ammon, MD, chair of the agency, said during an online conference.

The University of Oxford, which developed a COVID-19 vaccine with AstraZeneca, said Nov. 30 that there’s no evidence that vaccines won’t prevent severe disease from the Omicron variant, according to Reuters.

“Despite the appearance of new variants over the past year, vaccines have continued to provide very high levels of protection against severe disease and there is no evidence so far that Omicron is any different,” the university said in a statement. “However, we have the necessary tools and processes in place for rapid development of an updated COVID-19 vaccine if it should be necessary.”

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

The Moderna CEO says existing COVID-19 vaccines will likely be less effective against the new Omicron variant.

“There is no world, I think, where [the effectiveness] is the same level … we had with Delta,” Stephane Bancel told the Financial Times .

“I think it’s going to be a material drop,” he said. “I just don’t know how much, because we need to wait for the data. But all the scientists I’ve talked to … are like, ‘This is not going to be good.’”

Vaccine companies are now studying whether the new Omicron variant could evade the current shots. Some data is expected in about 2 weeks.

Mr. Bancel said that if a new vaccine is needed, it could take several months to produce at scale. He estimated that Moderna could make billions of vaccine doses in 2022.

“[Moderna] and Pfizer cannot get a billion doses next week. The math doesn’t work,” he said. “But could we get the billion doses out by the summer? Sure.”

The news caused some panic on Nov. 30, prompting financial markets to fall sharply, according to Reuters. But the markets recovered after European officials gave a more reassuring outlook.

“Even if the new variant becomes more widespread, the vaccines we have will continue to provide protection,” Emer Cooke, executive director of the European Medicines Agency, told the European Parliament.

Mr. Cooke said the agency could approve new vaccines that target the Omicron variant within 3 to 4 months, if needed. Moderna and Pfizer have announced they are beginning to tailor a shot to address the Omicron variant in case the data shows they are necessary.

Also on Nov. 30, the European Centre for Disease Prevention and Control announced that 42 Omicron cases had been identified in 10 European Union countries, according to Reuters.

The cases were mild or had no symptoms, although they were found in younger people who may have mild or no symptoms anyway.

“For the assessment of whether [Omicron] escapes immunity, we still have to wait until investigations in the laboratories with [blood samples] from people who have recovered have been carried out,” Andrea Ammon, MD, chair of the agency, said during an online conference.

The University of Oxford, which developed a COVID-19 vaccine with AstraZeneca, said Nov. 30 that there’s no evidence that vaccines won’t prevent severe disease from the Omicron variant, according to Reuters.

“Despite the appearance of new variants over the past year, vaccines have continued to provide very high levels of protection against severe disease and there is no evidence so far that Omicron is any different,” the university said in a statement. “However, we have the necessary tools and processes in place for rapid development of an updated COVID-19 vaccine if it should be necessary.”

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

The Moderna CEO says existing COVID-19 vaccines will likely be less effective against the new Omicron variant.

“There is no world, I think, where [the effectiveness] is the same level … we had with Delta,” Stephane Bancel told the Financial Times .

“I think it’s going to be a material drop,” he said. “I just don’t know how much, because we need to wait for the data. But all the scientists I’ve talked to … are like, ‘This is not going to be good.’”

Vaccine companies are now studying whether the new Omicron variant could evade the current shots. Some data is expected in about 2 weeks.

Mr. Bancel said that if a new vaccine is needed, it could take several months to produce at scale. He estimated that Moderna could make billions of vaccine doses in 2022.

“[Moderna] and Pfizer cannot get a billion doses next week. The math doesn’t work,” he said. “But could we get the billion doses out by the summer? Sure.”

The news caused some panic on Nov. 30, prompting financial markets to fall sharply, according to Reuters. But the markets recovered after European officials gave a more reassuring outlook.

“Even if the new variant becomes more widespread, the vaccines we have will continue to provide protection,” Emer Cooke, executive director of the European Medicines Agency, told the European Parliament.

Mr. Cooke said the agency could approve new vaccines that target the Omicron variant within 3 to 4 months, if needed. Moderna and Pfizer have announced they are beginning to tailor a shot to address the Omicron variant in case the data shows they are necessary.

Also on Nov. 30, the European Centre for Disease Prevention and Control announced that 42 Omicron cases had been identified in 10 European Union countries, according to Reuters.

The cases were mild or had no symptoms, although they were found in younger people who may have mild or no symptoms anyway.

“For the assessment of whether [Omicron] escapes immunity, we still have to wait until investigations in the laboratories with [blood samples] from people who have recovered have been carried out,” Andrea Ammon, MD, chair of the agency, said during an online conference.

The University of Oxford, which developed a COVID-19 vaccine with AstraZeneca, said Nov. 30 that there’s no evidence that vaccines won’t prevent severe disease from the Omicron variant, according to Reuters.

“Despite the appearance of new variants over the past year, vaccines have continued to provide very high levels of protection against severe disease and there is no evidence so far that Omicron is any different,” the university said in a statement. “However, we have the necessary tools and processes in place for rapid development of an updated COVID-19 vaccine if it should be necessary.”

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

The newly detected Omicron COVID-19 variant may be highly infectious and less responsive to available vaccines than other variants, but it is too early to know how it compares to the Delta variant, top infectious disease official Anthony S. Fauci, MD, said Nov. 30.

Dr. Fauci, speaking at a White House COVID-19 briefing, said there’s a “very unusual constellation of changes” across the COVID-19 genome that indicates it is unlike any variant we have seen so far.

“This mutational profile is very different from other variants of interest and concern, and although some mutations are also found in Delta, this is not Delta,” Dr. Fauci said. “These mutations have been associated with increased transmissibility and immune evasion.”

Omicron is the fifth designated COVID-19 variant of concern.

Detected first in South Africa, Omicron has been found in 20 countries so far. There are no known cases yet in the United States, but it has been detected in Canada.

Omicron has more than 30 mutations to the spike protein, the part of the virus that binds to human cells, Dr. Fauci said.

Cross-protection from boosters

Though the mutations suggest there is increased transmission of this variant, he said it is too soon to know how this compares to the Delta variant. And although the vaccines may not be as effective against Omicron, Dr. Fauci said there will likely be some protection.

“Remember, as with other variants, although partial immune escape may occur, vaccines, particularly boosters, give a level of antibodies that even with variants like Delta give you a degree of cross-protection, particularly against severe disease,” he said.

“When we say that although these mutations suggest a diminution of protection and a degree of immune evasion, we still, from experience with Delta, can make a reasonable conclusion that you would not eliminate all protection against this particular variant,” Dr. Fauci said.

So far, there is no reason to believe Omicron will cause more severe illness than other variants of concern.

“Although some preliminary information from South Africa suggests no unusual symptoms associated with variant, we do not know, and it is too early to tell,” Dr. Fauci said.

He recommended that people continue to wear masks, wash hands, and avoid crowded indoor venues. Most importantly, he recommended that everyone get their vaccines and boosters.

“One thing has become clear over the last 20 months: We can’t predict the future, but we can be prepared for it,” CDC Director Rochelle P. Walensky, MD, said at the briefing. “We have far more tools to fight the variant today than we did at this time last year.”


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

The newly detected Omicron COVID-19 variant may be highly infectious and less responsive to available vaccines than other variants, but it is too early to know how it compares to the Delta variant, top infectious disease official Anthony S. Fauci, MD, said Nov. 30.

Dr. Fauci, speaking at a White House COVID-19 briefing, said there’s a “very unusual constellation of changes” across the COVID-19 genome that indicates it is unlike any variant we have seen so far.

“This mutational profile is very different from other variants of interest and concern, and although some mutations are also found in Delta, this is not Delta,” Dr. Fauci said. “These mutations have been associated with increased transmissibility and immune evasion.”

Omicron is the fifth designated COVID-19 variant of concern.

Detected first in South Africa, Omicron has been found in 20 countries so far. There are no known cases yet in the United States, but it has been detected in Canada.

Omicron has more than 30 mutations to the spike protein, the part of the virus that binds to human cells, Dr. Fauci said.

Cross-protection from boosters

Though the mutations suggest there is increased transmission of this variant, he said it is too soon to know how this compares to the Delta variant. And although the vaccines may not be as effective against Omicron, Dr. Fauci said there will likely be some protection.

“Remember, as with other variants, although partial immune escape may occur, vaccines, particularly boosters, give a level of antibodies that even with variants like Delta give you a degree of cross-protection, particularly against severe disease,” he said.

“When we say that although these mutations suggest a diminution of protection and a degree of immune evasion, we still, from experience with Delta, can make a reasonable conclusion that you would not eliminate all protection against this particular variant,” Dr. Fauci said.

So far, there is no reason to believe Omicron will cause more severe illness than other variants of concern.

“Although some preliminary information from South Africa suggests no unusual symptoms associated with variant, we do not know, and it is too early to tell,” Dr. Fauci said.

He recommended that people continue to wear masks, wash hands, and avoid crowded indoor venues. Most importantly, he recommended that everyone get their vaccines and boosters.

“One thing has become clear over the last 20 months: We can’t predict the future, but we can be prepared for it,” CDC Director Rochelle P. Walensky, MD, said at the briefing. “We have far more tools to fight the variant today than we did at this time last year.”


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

The newly detected Omicron COVID-19 variant may be highly infectious and less responsive to available vaccines than other variants, but it is too early to know how it compares to the Delta variant, top infectious disease official Anthony S. Fauci, MD, said Nov. 30.

Dr. Fauci, speaking at a White House COVID-19 briefing, said there’s a “very unusual constellation of changes” across the COVID-19 genome that indicates it is unlike any variant we have seen so far.

“This mutational profile is very different from other variants of interest and concern, and although some mutations are also found in Delta, this is not Delta,” Dr. Fauci said. “These mutations have been associated with increased transmissibility and immune evasion.”

Omicron is the fifth designated COVID-19 variant of concern.

Detected first in South Africa, Omicron has been found in 20 countries so far. There are no known cases yet in the United States, but it has been detected in Canada.

Omicron has more than 30 mutations to the spike protein, the part of the virus that binds to human cells, Dr. Fauci said.

Cross-protection from boosters

Though the mutations suggest there is increased transmission of this variant, he said it is too soon to know how this compares to the Delta variant. And although the vaccines may not be as effective against Omicron, Dr. Fauci said there will likely be some protection.

“Remember, as with other variants, although partial immune escape may occur, vaccines, particularly boosters, give a level of antibodies that even with variants like Delta give you a degree of cross-protection, particularly against severe disease,” he said.

“When we say that although these mutations suggest a diminution of protection and a degree of immune evasion, we still, from experience with Delta, can make a reasonable conclusion that you would not eliminate all protection against this particular variant,” Dr. Fauci said.

So far, there is no reason to believe Omicron will cause more severe illness than other variants of concern.

“Although some preliminary information from South Africa suggests no unusual symptoms associated with variant, we do not know, and it is too early to tell,” Dr. Fauci said.

He recommended that people continue to wear masks, wash hands, and avoid crowded indoor venues. Most importantly, he recommended that everyone get their vaccines and boosters.

“One thing has become clear over the last 20 months: We can’t predict the future, but we can be prepared for it,” CDC Director Rochelle P. Walensky, MD, said at the briefing. “We have far more tools to fight the variant today than we did at this time last year.”


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

An antiviral pill from Merck may help some high-risk patients survive a COVID-19 infection or help them stay out of the hospital, even though the risks of taking the drug aren’t yet fully known, according to a panel of experts that advises the Food and Drug Administration on its regulatory decisions for these types of drugs.

The FDA’s Antimicrobial Drugs Advisory Committee narrowly voted to authorize the drug molnupiravir, voting 13 to 10 to support emergency use, which requires a medication to meet a lower standard of evidence than does full approval.

The FDA is not bound by the committee’s vote but typically follows its advice.

If authorized by the agency, molnupiravir would be the first antiviral agent available as a pill to treat COVID-19. Other therapies to treat the infection are available — monoclonal antibodies and the drug remdesivir — but they are given by infusion.

The United Kingdom has already authorized the use of Merck’s drug.

“This was clearly a difficult decision,” said committee member Michael Green, MD, a pediatric infectious disease expert at the University of Pittsburg School of Medicine.

Green said he voted yes, and that the drug’s ability to prevent deaths in the study weighed heavily on his decision. He said given uncertainties around the drug both the company and FDA should keep a close eye on patients taking the drug going forward.

“Should an alternative oral agent become available that had a better safety profile and equal or better efficacy profile, the agency might reconsider its authorization,” he said.

Others didn’t agree that the drug should be allowed onto the market.

“I voted no,” said Jennifer Le, PharmD, a professor of clinical pharmacy at the University of California. Dr. Le said the modest benefit of the medication didn’t outweigh all the potential safety issues. “I think I just need more efficacy and safety data,” she said.

Initial results from the first half of people enrolled in the clinical trial found the pill cut the risk of hospitalization or death by 50% in patients at higher risk of severe outcomes from COVID-19.

But later results, released just days before the meeting, showed that the drug’s effectiveness had dropped to about 30%.

In the updated analysis, 48 patients out of the 709 who were taking the drug were hospitalized or died within 29 days compared to 68 out of 699 who randomly got the placebo. There was one death in the group that got molnupiravir compared to nine in the placebo group. Nearly all those deaths occurred during the first phase of the study.

On Nov. 30 Merck explained that the drug’s efficacy appeared to fall, in part, because the placebo group had experienced fewer hospitalizations and deaths than expected during the second half of the study, making the drug look less beneficial by comparison.

The company said it wasn’t sure why patients in the placebo group had fared so much better in later trial enrollments.

“The efficacy of this product is not overwhelmingly good,” said committee member David Hardy, MD, an infectious disease expert at Charles Drew University School of Medicine in Los Angeles. “And I think that makes all of us a little uncomfortable about whether this is an advanced therapeutic because it’s an oral medication rather than an intravenous medication,” he said during the panel’s deliberations.

“I think we have to be very careful about how we’re going to allow people to use this,” Dr. Hardy said.

Many who voted for authorization thought use of the drug should be restricted to unvaccinated people who were at high risk of severe COVID-19 outcomes, the same population enrolled in the clinical trial. People in the trial were considered at higher risk if they were over age 60, had cancer, chronic kidney disease, chronic obstructive pulmonary disease, were obese, or had heart disease or diabetes.

There are some significant limitations of the study that may affect how the drug is used. Vaccinated people couldn’t enroll in the study, so it’s not known if the medication would have any benefit for them. Nearly two-thirds of the U.S. population is fully vaccinated. The study found no additional benefit of the medication compared to the placebo in people who had detectable antibodies, presumably from a prior infection.

Animal studies found that the drug — which kills the virus by forcing it to make errors as it copies its genetic material inside cells — could disrupt bone formation. For that reason, the manufacturer and the FDA agreed that it should not be used in anyone younger than age 18.

Animal studies also indicated that the drug could cause birth defects. For that reason, the company said the drug shouldn’t be given to women who are pregnant or breastfeeding and said doctors should make sure women of childbearing age aren’t pregnant before taking the medication.

Some members of the panel felt that pregnant women and their doctors should be given the choice of whether or not to use the drug, given that pregnant women are at high risk for severe COVID-19 outcomes and infused therapies may not be available in all settings.

Other members of the committee said they were uncomfortable authorizing the drug given its potential to mutate the virus.

The drug, which forces the virus to mutate as it copies its RNA, eventually causes the virus to make so many errors in its genetic material that it can no longer make more of itself and the immune system clears it out of the body.

But it takes a few days to work — the drug is designed to be taken for 5 consecutive days -- and studies of the viral loads of patients taking the drug show that through the first 2 days, viral loads remain detectable as these mutations occur.

Studies by the FDA show some of those mutations in the spike protein are the same ones that have helped the virus become more transmissible and escape the protection of vaccines.

So the question is whether someone taking the medication could develop a dangerous mutation and then infect someone else, sparking the spread of a new variant.

Nicholas Kartsonis, MD, a vice president at Merck, said that the company was still analyzing data.

“Even if the probability is very low — 1 in 10,000 or 1 in 100,000 -- that this drug would induce an escape mutant for which the vaccines we have would not cover, that would be catastrophic for the whole world, actually,” said committee member James Hildreth, MD, an immunologist and president of Meharry Medical College, Nashville. “Do you have sufficient data on the likelihood of that happening?” he asked Dr. Kartsonis of Merck.

“So we don’t,” Dr. Kartsonis said.

He said, in theory, the risk of mutation with molnupiravir is the same as seen with the use of vaccines or monoclonal antibody therapies. Dr. Hildreth wasn’t satisfied with that answer.

“With all respect, the mechanism of your drug is to drive [genetic mutations], so it’s not the same as the vaccine. It’s not the same as monoclonal antibodies,” he said.

Dr. Hildreth later said he didn’t feel comfortable voting for authorization given the uncertainties around escape mutants. He voted no.

“It was an easy vote for me,” he said.

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

An antiviral pill from Merck may help some high-risk patients survive a COVID-19 infection or help them stay out of the hospital, even though the risks of taking the drug aren’t yet fully known, according to a panel of experts that advises the Food and Drug Administration on its regulatory decisions for these types of drugs.

The FDA’s Antimicrobial Drugs Advisory Committee narrowly voted to authorize the drug molnupiravir, voting 13 to 10 to support emergency use, which requires a medication to meet a lower standard of evidence than does full approval.

The FDA is not bound by the committee’s vote but typically follows its advice.

If authorized by the agency, molnupiravir would be the first antiviral agent available as a pill to treat COVID-19. Other therapies to treat the infection are available — monoclonal antibodies and the drug remdesivir — but they are given by infusion.

The United Kingdom has already authorized the use of Merck’s drug.

“This was clearly a difficult decision,” said committee member Michael Green, MD, a pediatric infectious disease expert at the University of Pittsburg School of Medicine.

Green said he voted yes, and that the drug’s ability to prevent deaths in the study weighed heavily on his decision. He said given uncertainties around the drug both the company and FDA should keep a close eye on patients taking the drug going forward.

“Should an alternative oral agent become available that had a better safety profile and equal or better efficacy profile, the agency might reconsider its authorization,” he said.

Others didn’t agree that the drug should be allowed onto the market.

“I voted no,” said Jennifer Le, PharmD, a professor of clinical pharmacy at the University of California. Dr. Le said the modest benefit of the medication didn’t outweigh all the potential safety issues. “I think I just need more efficacy and safety data,” she said.

Initial results from the first half of people enrolled in the clinical trial found the pill cut the risk of hospitalization or death by 50% in patients at higher risk of severe outcomes from COVID-19.

But later results, released just days before the meeting, showed that the drug’s effectiveness had dropped to about 30%.

In the updated analysis, 48 patients out of the 709 who were taking the drug were hospitalized or died within 29 days compared to 68 out of 699 who randomly got the placebo. There was one death in the group that got molnupiravir compared to nine in the placebo group. Nearly all those deaths occurred during the first phase of the study.

On Nov. 30 Merck explained that the drug’s efficacy appeared to fall, in part, because the placebo group had experienced fewer hospitalizations and deaths than expected during the second half of the study, making the drug look less beneficial by comparison.

The company said it wasn’t sure why patients in the placebo group had fared so much better in later trial enrollments.

“The efficacy of this product is not overwhelmingly good,” said committee member David Hardy, MD, an infectious disease expert at Charles Drew University School of Medicine in Los Angeles. “And I think that makes all of us a little uncomfortable about whether this is an advanced therapeutic because it’s an oral medication rather than an intravenous medication,” he said during the panel’s deliberations.

“I think we have to be very careful about how we’re going to allow people to use this,” Dr. Hardy said.

Many who voted for authorization thought use of the drug should be restricted to unvaccinated people who were at high risk of severe COVID-19 outcomes, the same population enrolled in the clinical trial. People in the trial were considered at higher risk if they were over age 60, had cancer, chronic kidney disease, chronic obstructive pulmonary disease, were obese, or had heart disease or diabetes.

There are some significant limitations of the study that may affect how the drug is used. Vaccinated people couldn’t enroll in the study, so it’s not known if the medication would have any benefit for them. Nearly two-thirds of the U.S. population is fully vaccinated. The study found no additional benefit of the medication compared to the placebo in people who had detectable antibodies, presumably from a prior infection.

Animal studies found that the drug — which kills the virus by forcing it to make errors as it copies its genetic material inside cells — could disrupt bone formation. For that reason, the manufacturer and the FDA agreed that it should not be used in anyone younger than age 18.

Animal studies also indicated that the drug could cause birth defects. For that reason, the company said the drug shouldn’t be given to women who are pregnant or breastfeeding and said doctors should make sure women of childbearing age aren’t pregnant before taking the medication.

Some members of the panel felt that pregnant women and their doctors should be given the choice of whether or not to use the drug, given that pregnant women are at high risk for severe COVID-19 outcomes and infused therapies may not be available in all settings.

Other members of the committee said they were uncomfortable authorizing the drug given its potential to mutate the virus.

The drug, which forces the virus to mutate as it copies its RNA, eventually causes the virus to make so many errors in its genetic material that it can no longer make more of itself and the immune system clears it out of the body.

But it takes a few days to work — the drug is designed to be taken for 5 consecutive days -- and studies of the viral loads of patients taking the drug show that through the first 2 days, viral loads remain detectable as these mutations occur.

Studies by the FDA show some of those mutations in the spike protein are the same ones that have helped the virus become more transmissible and escape the protection of vaccines.

So the question is whether someone taking the medication could develop a dangerous mutation and then infect someone else, sparking the spread of a new variant.

Nicholas Kartsonis, MD, a vice president at Merck, said that the company was still analyzing data.

“Even if the probability is very low — 1 in 10,000 or 1 in 100,000 -- that this drug would induce an escape mutant for which the vaccines we have would not cover, that would be catastrophic for the whole world, actually,” said committee member James Hildreth, MD, an immunologist and president of Meharry Medical College, Nashville. “Do you have sufficient data on the likelihood of that happening?” he asked Dr. Kartsonis of Merck.

“So we don’t,” Dr. Kartsonis said.

He said, in theory, the risk of mutation with molnupiravir is the same as seen with the use of vaccines or monoclonal antibody therapies. Dr. Hildreth wasn’t satisfied with that answer.

“With all respect, the mechanism of your drug is to drive [genetic mutations], so it’s not the same as the vaccine. It’s not the same as monoclonal antibodies,” he said.

Dr. Hildreth later said he didn’t feel comfortable voting for authorization given the uncertainties around escape mutants. He voted no.

“It was an easy vote for me,” he said.

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

An antiviral pill from Merck may help some high-risk patients survive a COVID-19 infection or help them stay out of the hospital, even though the risks of taking the drug aren’t yet fully known, according to a panel of experts that advises the Food and Drug Administration on its regulatory decisions for these types of drugs.

The FDA’s Antimicrobial Drugs Advisory Committee narrowly voted to authorize the drug molnupiravir, voting 13 to 10 to support emergency use, which requires a medication to meet a lower standard of evidence than does full approval.

The FDA is not bound by the committee’s vote but typically follows its advice.

If authorized by the agency, molnupiravir would be the first antiviral agent available as a pill to treat COVID-19. Other therapies to treat the infection are available — monoclonal antibodies and the drug remdesivir — but they are given by infusion.

The United Kingdom has already authorized the use of Merck’s drug.

“This was clearly a difficult decision,” said committee member Michael Green, MD, a pediatric infectious disease expert at the University of Pittsburg School of Medicine.

Green said he voted yes, and that the drug’s ability to prevent deaths in the study weighed heavily on his decision. He said given uncertainties around the drug both the company and FDA should keep a close eye on patients taking the drug going forward.

“Should an alternative oral agent become available that had a better safety profile and equal or better efficacy profile, the agency might reconsider its authorization,” he said.

Others didn’t agree that the drug should be allowed onto the market.

“I voted no,” said Jennifer Le, PharmD, a professor of clinical pharmacy at the University of California. Dr. Le said the modest benefit of the medication didn’t outweigh all the potential safety issues. “I think I just need more efficacy and safety data,” she said.

Initial results from the first half of people enrolled in the clinical trial found the pill cut the risk of hospitalization or death by 50% in patients at higher risk of severe outcomes from COVID-19.

But later results, released just days before the meeting, showed that the drug’s effectiveness had dropped to about 30%.

In the updated analysis, 48 patients out of the 709 who were taking the drug were hospitalized or died within 29 days compared to 68 out of 699 who randomly got the placebo. There was one death in the group that got molnupiravir compared to nine in the placebo group. Nearly all those deaths occurred during the first phase of the study.

On Nov. 30 Merck explained that the drug’s efficacy appeared to fall, in part, because the placebo group had experienced fewer hospitalizations and deaths than expected during the second half of the study, making the drug look less beneficial by comparison.

The company said it wasn’t sure why patients in the placebo group had fared so much better in later trial enrollments.

“The efficacy of this product is not overwhelmingly good,” said committee member David Hardy, MD, an infectious disease expert at Charles Drew University School of Medicine in Los Angeles. “And I think that makes all of us a little uncomfortable about whether this is an advanced therapeutic because it’s an oral medication rather than an intravenous medication,” he said during the panel’s deliberations.

“I think we have to be very careful about how we’re going to allow people to use this,” Dr. Hardy said.

Many who voted for authorization thought use of the drug should be restricted to unvaccinated people who were at high risk of severe COVID-19 outcomes, the same population enrolled in the clinical trial. People in the trial were considered at higher risk if they were over age 60, had cancer, chronic kidney disease, chronic obstructive pulmonary disease, were obese, or had heart disease or diabetes.

There are some significant limitations of the study that may affect how the drug is used. Vaccinated people couldn’t enroll in the study, so it’s not known if the medication would have any benefit for them. Nearly two-thirds of the U.S. population is fully vaccinated. The study found no additional benefit of the medication compared to the placebo in people who had detectable antibodies, presumably from a prior infection.

Animal studies found that the drug — which kills the virus by forcing it to make errors as it copies its genetic material inside cells — could disrupt bone formation. For that reason, the manufacturer and the FDA agreed that it should not be used in anyone younger than age 18.

Animal studies also indicated that the drug could cause birth defects. For that reason, the company said the drug shouldn’t be given to women who are pregnant or breastfeeding and said doctors should make sure women of childbearing age aren’t pregnant before taking the medication.

Some members of the panel felt that pregnant women and their doctors should be given the choice of whether or not to use the drug, given that pregnant women are at high risk for severe COVID-19 outcomes and infused therapies may not be available in all settings.

Other members of the committee said they were uncomfortable authorizing the drug given its potential to mutate the virus.

The drug, which forces the virus to mutate as it copies its RNA, eventually causes the virus to make so many errors in its genetic material that it can no longer make more of itself and the immune system clears it out of the body.

But it takes a few days to work — the drug is designed to be taken for 5 consecutive days -- and studies of the viral loads of patients taking the drug show that through the first 2 days, viral loads remain detectable as these mutations occur.

Studies by the FDA show some of those mutations in the spike protein are the same ones that have helped the virus become more transmissible and escape the protection of vaccines.

So the question is whether someone taking the medication could develop a dangerous mutation and then infect someone else, sparking the spread of a new variant.

Nicholas Kartsonis, MD, a vice president at Merck, said that the company was still analyzing data.

“Even if the probability is very low — 1 in 10,000 or 1 in 100,000 -- that this drug would induce an escape mutant for which the vaccines we have would not cover, that would be catastrophic for the whole world, actually,” said committee member James Hildreth, MD, an immunologist and president of Meharry Medical College, Nashville. “Do you have sufficient data on the likelihood of that happening?” he asked Dr. Kartsonis of Merck.

“So we don’t,” Dr. Kartsonis said.

He said, in theory, the risk of mutation with molnupiravir is the same as seen with the use of vaccines or monoclonal antibody therapies. Dr. Hildreth wasn’t satisfied with that answer.

“With all respect, the mechanism of your drug is to drive [genetic mutations], so it’s not the same as the vaccine. It’s not the same as monoclonal antibodies,” he said.

Dr. Hildreth later said he didn’t feel comfortable voting for authorization given the uncertainties around escape mutants. He voted no.

“It was an easy vote for me,” he said.

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

FIRST OF 2 PARTS

A thorough evaluation can identify modifiable factors and guide treatment

Sleep problems are common among children and adolescents,¹ with prevalence rates of 25% to 40%.^2-4 Young children most commonly exhibit what is referred to as bedtime problems and night wakenings, whereas children in middle childhood (age 4 to 12) through adolescence (age 13 to 17) report insomnia. For many children, these problems persist.³ Insufficient sleep in children and adolescents worsens inattention, daytime fatigue, and cognitive and behavioral deficits.⁵ Assessment and treatment of sleep problems in children and adolescents is critical because poor sleep among youth increases the risk for depression, self-harm, and suicide,^6,7 increases family stress, and decreases parental well-being.¹

This 2-part article describes the assessment, diagnosis, and treatment of sleep problems among children and adolescents. In part 1, we focus on:

• sleep architecture (circadian rhythms, stages of sleep)
• sleep in healthy youth (age 6 to 17) and those with attention-deficit/hyperactivity disorder (ADHD), depressive disorders, and anxiety
• how to assess sleep, and the differential diagnosis of behavioral sleep problems in pediatric patients.

In Part 2, we will cover psychotherapeutic and psychopharmacologic interventions for youth with insomnia, and describe an effective approach to consultation with pediatric sleep medicine specialists.

How much sleep do children and adolescents need?

Throughout their development, children spend 40% to 50% of their time asleep. Sleep schedules are based on circadian rhythms, which are physical, mental, and behavioral changes that follow an approximately 24-hour cycle. Human circadian rhythm varies between 24 and 25 hours and is vital in determining our sleep patterns. Exposure to sunlight drives our circadian rhythm, sending signals to our bodies to “turn on” melatonin production at night (ie, 9 pm melatonin secretion starts) and “turn off” melatonin secretion in the morning (ie, 7:30 am) in adults. Exposure to sunlight also drives circadian rhythms for children, and melatonin secretion production occurs earlier in the evening for children. Families are encouraged to expose children to bright light in the morning by taking an early walk, eating breakfast in a sunny room, or having adolescents open up the window shades rather than keeping their eyes shielded from the sun.² How sleepy or alert a child could be is determined by the duration and quality of a child’s previous sleep, and how long they have been awake (“sleep drive”).² The 3 states of sleep architecture are wake; non-rapid eye movement sleep; and rapid eye movement sleep (“dreaming” sleep) (Box²).

Box

Sleep needs also change predictably throughout the lifespan. The National Sleep Foundation guidelines for sleep duration provide clinicians and parents with a range of recommended sleep for each stage of development. Infants require 14 to 17 hours of sleep, whereas adolescents need 8 to 10 hours by age 14 to 17.⁸ The key for clinicians is to determine if the child is within the recommended range, and how they are functioning on the number of hours of sleep they report. This allows for variation in how much sleep an individual child might need while acknowledging that some children within a specific age group might need more or less sleep than other children of the same age.

Sleep in healthy youth: Middle childhood

School-age children (age 6 to 12) typically need 9 to 10 hours of sleep over a 24-hour period.² This developmental period is especially important for children to develop healthy sleep habits; however, developmentally appropriate cognitive and social/emotional factors might interfere with the quality and quantity of sleep. Middle childhood is a time when children can understand the dangers of the outside world (ie, violence, health problems) and resulting anxiety can disrupt sleep. Parents usually are less involved in bedtime as children approach adolescence, which leads to later bedtimes. At this stage, many children begin to take on more serious roles in their academics and extracurricular activities, peer relationships become more important, and use of electronics (eg, television, video games, internet, and handheld devices) increases—all of which compete with sleep.⁹ Frequent sleep issues during middle childhood include:

• irregular sleep-wake schedules
• later bedtimes
• decreased nighttime sleep
• increased caffeine intake
• reduced parental presence at bedtime
• daytime sleepiness.³

In school-age children, regular napping, falling asleep during short car rides, and daytime fatigue at school or home are cause for concern. When these symptoms are present, an evaluation is warranted.

Sleep in healthy youth: Adolescence

The National Sleep Foundation recommends adolescents obtain 8 to 10 hours of sleep per night; for some adolescents, as much as 11 hours of sleep per night might be appropriate.⁸ However, this contrasts with findings from the National Sleep Foundation’s Sleep in America Poll, which revealed that 75% of 12th graders report <8 hours of sleep nightly.¹⁰ Many adolescents experience delayed sleep phase syndrome or delayed sleep-wake phase disorder, which involves a persistent phase shift of >2 hours in the sleep-wake schedule that conflicts with the adolescent’s school, work, or lifestyle demands.¹¹ Such circadian rhythm disorders typically result from a poor match between the sleep-wake schedule and the demands of the adolescent’s life, or a failure to synchronize their internal clock with a 24-hour circadian clock.¹² Children typically become tired after sunset, but puberty is associated with reduced slow-wave sleep and changes in circadian rhythms. As a result, a 3-hour delay (delayed phase preference) is common among adolescents. At approximately age 20, people start to become tired after sunset and awaken earlier in the morning—a pattern driven by sunlight and the timing of melatonin release that will remain stable until the sixth decade of life.

Continue to: Effects of chronic sleep deprivation...

Most older studies of sleep loss examined the impact of total sleep loss (sleep deprivation) rather than the effect of partial sleep loss or sleep restriction, a more commonly experienced phenomenon. More recent research shows that a cumulative sleep deficit could cause the body to override voluntary wakefulness and a sleep-deprived individual can experience brief “microsleeps” where they are unaware and lose attention/wakefulness for several seconds.² This can be deadly if a sleep-deprived adolescent experiences microsleeps while driving.¹³

There is a well-studied correlation between chronic sleep deprivation and increased body mass index in children.¹⁴ This might be caused by reduction in physical activity as well as alterations in the “hunger hormones”—ghrelin and leptin—that have been observed with sleep deprivation.^15-17 Other studies have noted decreased glucose tolerance, reduced insulin sensitivity, and catecholamine and cortisol secretion abnormalities, which place children at higher risk for metabolic syndrome and hypertension.^13,18 Sleep deprivation also is associated with mood and anxiety disorders and is an independent risk factor for substance use and suicidal ideation among adolescents.¹⁹ Sleep deprivation increases impairments in impulse control, concentration, and attention, which could be especially problematic in school-age children.

How sleep is assessed

The sleep history is the first step in evaluating a child or adolescent for a sleep disorder. The sleep history includes exploring the chief complaint, sleep patterns and schedules, bedtime routines, and nocturnal and daytime behaviors (Table).

Chief complaint

Behavioral sleep specialists will assess the primary problem with everyone involved in the child’s bedtime.²⁰ This might include parents (custodial and noncustodial), grandparents, or stepparents as well as the child/adolescent. This important step can reveal a sleep disorder or an inappropriately early bedtime relative to the child’s development. During this assessment, ask detailed questions about how long the sleep problem has persisted, the frequency of sleep problems, and any precipitating stressors. Parents and caregivers can review strategies they have tried, and for how long and to what extent interventions were implemented consistently to result in change.

Sleep patterns and schedules

Review the child/adolescent’s typical sleep patterns and behaviors. Ask parents and caregivers, as well as the patient, about general sleep schedules for the past few weeks or a typical 2-week time period.² A behavioral assessment of sleep should include asking families about how the child/adolescent sleeps during the week and over the weekend, and if school-year sleep differs from summer or holiday sleep schedules. These questions can illuminate how long a sleep problem has been occurring and what sleep habits might be contributing to the problem. Bedtime

Determine if there is a set bedtime or if the child goes to bed when they wish. It is important to ascertain if the bedtime is age-appropriate, if weekday and weekend bedtimes differ, and to what extent extracurricular activities or school demands impact bedtime. Assess the consistency of the bedtime, the nature of bedtime routines (eg, is the child engaging in stimulating activities before bed), where the bedtime routine occurs (eg, sibling’s room, parents’ room, child’s room), and what role (if any) electronic devices play.²

Nocturnal behaviors

Assessment should include a series of questions and age-specific questionnaires to focus on what behaviors occur at night, including awakenings. Parents should be asked how frequent night awakenings occur, how long arousals last, and how the child signals for the parent (eg, calling out, climbing into parents’ bed).² Additionally, ask how parents respond and what is required to help the child fall back asleep (eg, rocking, soothing, feeding). The presence of nightmares, night terrors, parasomnias, and sleep-related breathing disorders also must be assessed.²⁰

Daytime behaviors

A sleep history should include assessment of daytime functioning, including daytime sleepiness, fatigue, morning waking, and functioning during school, extracurriculars, and homework. For children and teens, falling asleep in the car, while in school, or during passive activities (meals, conversation) suggests insufficient sleep, sleep disruption, or excessive daytime sleepiness.²

Continue to: Sleep disruption in youth with psychiatric disorders...

Sleep disruption in youth with psychiatric disorders

Disordered sleep is common across psychiatric disorders. The National Comorbidity Survey Adolescent Supplement—a nationally representative cross-sectional survey of adolescents (N = 10,123)—found that a later weeknight bedtime, shorter weeknight sleep duration, and greater weekend bedtime delay increased the risk of developing a mood, anxiety, or substance use (including nicotine) disorder, and suicidality. These risk factors also were associated with lower “perceived mental and physical health.”²¹ Clinicians should routinely obtain a sleep history in children and adolescents with these disorders. Consider using the sleep screening tool BEARS:

• Bedtime issues
• Excessive daytime sleepiness
• Awakenings
• Regularity and duration of sleep
• Snoring.

ADHD

Up to one-half of children and adolescents with ADHD experience sleep problems,^22,23 including delayed sleep onset, bedtime resistance, daytime fatigue, and feeling groggy in the morning beyond what is typical (>20 minutes). Pharmacotherapy for ADHD contributes to sleep disturbances^24,25 while sleep deprivation exacerbates inattention and hyperactivity. In youth with ADHD, restless leg syndrome, periodic limb movement disorder, and sleep-disordered breathing disorder are more common than in the general population.

Depressive disorders

Up to three-quarters of depressed children and 90% of depressed adolescents report sleep disturbances, including initial, middle, and terminal insomnia as well as hypersomnia.²⁶ Disrupted sleep in pediatric patients with major depressive disorder could be moderated by the patient’s age, with depressive symptoms more common among adolescents (age 12 to 17) than among younger children (age 6 to 11).²⁷ Successful treatment of depression fails to relieve dyssomnia in 10% of children. Sleep problems that persist after successfully treating a depressive episode could increase the risk of another depressive episode.²⁸

Anxiety disorders

Sleep problems are common among children and adolescents with anxiety disorders.²⁹ Longitudinal data from >900 children found that symptoms of sleep disturbance in early childhood were correlated with experiencing an anxiety disorder 20 years later.³⁰ Fears related to the dark or monsters under the bed that are developmentally appropriate for younger children may interfere with sleep. However, in anxious children, fears might also be related to separation, sleeping alone, worry about the loss of a loved one, concerns about personal safety, fear of frightening dreams, or concerns about academics and social relationships. Anxious individuals ruminate about their worries, and this might be especially true for children at bedtime, when there are limited distractions from ruminative fears.³¹ Bedtime resistance, parental involvement in bedtime rituals, and cultural factors related to sleep also could play a role for children with anxiety symptoms and sleep problems.

Having an anxiety disorder is significantly associated with an increased risk of insomnia; however, 73% of the time anxiety symptoms precede an insomnia diagnosis.²⁹ Sleep problems and anxiety symptoms might have a reciprocal influence on one another; tiredness that results from sleep problems could exacerbate anxiety, which further worsens sleep problems.

A large body of research on sleep and anxiety reveals that abuse or exposure to trauma significantly affects sleep.³¹ Common sleep problems for children with posttraumatic stress disorder include difficulty falling asleep, maintaining sleep, and parasomnias of bedwetting and nightmares.^31,32 Compared with depressed and non-abused children, those with history of abuse have prolonged sleep latency, decreased sleep efficiency, and higher levels of activity during the night.³³ In addition to the relationship between anxiety disorders and sleep disorders, many of the selective serotonin reuptake inhibitors—which are the first-line pharmacotherapy for pediatric anxiety disorders^34,35—could affect sleep in anxious youth.³⁶

A bridge to treatment

A thorough assessment can help identify modifiable factors and guide treatment selections. In Part 2 of this article, we will describe healthy sleep practices, cognitive-behavioral therapy for insomnia, when pharmacotherapy might be indicated, and the evidence supporting several medications commonly used to treat pediatric insomnia. We also will discuss factors to consider when seeking consultation with a pediatric behavioral sleep specialist.

FIRST OF 2 PARTS

A thorough evaluation can identify modifiable factors and guide treatment

Sleep problems are common among children and adolescents,¹ with prevalence rates of 25% to 40%.^2-4 Young children most commonly exhibit what is referred to as bedtime problems and night wakenings, whereas children in middle childhood (age 4 to 12) through adolescence (age 13 to 17) report insomnia. For many children, these problems persist.³ Insufficient sleep in children and adolescents worsens inattention, daytime fatigue, and cognitive and behavioral deficits.⁵ Assessment and treatment of sleep problems in children and adolescents is critical because poor sleep among youth increases the risk for depression, self-harm, and suicide,^6,7 increases family stress, and decreases parental well-being.¹

This 2-part article describes the assessment, diagnosis, and treatment of sleep problems among children and adolescents. In part 1, we focus on:

• sleep architecture (circadian rhythms, stages of sleep)
• sleep in healthy youth (age 6 to 17) and those with attention-deficit/hyperactivity disorder (ADHD), depressive disorders, and anxiety
• how to assess sleep, and the differential diagnosis of behavioral sleep problems in pediatric patients.

In Part 2, we will cover psychotherapeutic and psychopharmacologic interventions for youth with insomnia, and describe an effective approach to consultation with pediatric sleep medicine specialists.

How much sleep do children and adolescents need?

Throughout their development, children spend 40% to 50% of their time asleep. Sleep schedules are based on circadian rhythms, which are physical, mental, and behavioral changes that follow an approximately 24-hour cycle. Human circadian rhythm varies between 24 and 25 hours and is vital in determining our sleep patterns. Exposure to sunlight drives our circadian rhythm, sending signals to our bodies to “turn on” melatonin production at night (ie, 9 pm melatonin secretion starts) and “turn off” melatonin secretion in the morning (ie, 7:30 am) in adults. Exposure to sunlight also drives circadian rhythms for children, and melatonin secretion production occurs earlier in the evening for children. Families are encouraged to expose children to bright light in the morning by taking an early walk, eating breakfast in a sunny room, or having adolescents open up the window shades rather than keeping their eyes shielded from the sun.² How sleepy or alert a child could be is determined by the duration and quality of a child’s previous sleep, and how long they have been awake (“sleep drive”).² The 3 states of sleep architecture are wake; non-rapid eye movement sleep; and rapid eye movement sleep (“dreaming” sleep) (Box²).

Box

Sleep needs also change predictably throughout the lifespan. The National Sleep Foundation guidelines for sleep duration provide clinicians and parents with a range of recommended sleep for each stage of development. Infants require 14 to 17 hours of sleep, whereas adolescents need 8 to 10 hours by age 14 to 17.⁸ The key for clinicians is to determine if the child is within the recommended range, and how they are functioning on the number of hours of sleep they report. This allows for variation in how much sleep an individual child might need while acknowledging that some children within a specific age group might need more or less sleep than other children of the same age.

Sleep in healthy youth: Middle childhood

School-age children (age 6 to 12) typically need 9 to 10 hours of sleep over a 24-hour period.² This developmental period is especially important for children to develop healthy sleep habits; however, developmentally appropriate cognitive and social/emotional factors might interfere with the quality and quantity of sleep. Middle childhood is a time when children can understand the dangers of the outside world (ie, violence, health problems) and resulting anxiety can disrupt sleep. Parents usually are less involved in bedtime as children approach adolescence, which leads to later bedtimes. At this stage, many children begin to take on more serious roles in their academics and extracurricular activities, peer relationships become more important, and use of electronics (eg, television, video games, internet, and handheld devices) increases—all of which compete with sleep.⁹ Frequent sleep issues during middle childhood include:

• irregular sleep-wake schedules
• later bedtimes
• decreased nighttime sleep
• increased caffeine intake
• reduced parental presence at bedtime
• daytime sleepiness.³

In school-age children, regular napping, falling asleep during short car rides, and daytime fatigue at school or home are cause for concern. When these symptoms are present, an evaluation is warranted.

Sleep in healthy youth: Adolescence

The National Sleep Foundation recommends adolescents obtain 8 to 10 hours of sleep per night; for some adolescents, as much as 11 hours of sleep per night might be appropriate.⁸ However, this contrasts with findings from the National Sleep Foundation’s Sleep in America Poll, which revealed that 75% of 12th graders report <8 hours of sleep nightly.¹⁰ Many adolescents experience delayed sleep phase syndrome or delayed sleep-wake phase disorder, which involves a persistent phase shift of >2 hours in the sleep-wake schedule that conflicts with the adolescent’s school, work, or lifestyle demands.¹¹ Such circadian rhythm disorders typically result from a poor match between the sleep-wake schedule and the demands of the adolescent’s life, or a failure to synchronize their internal clock with a 24-hour circadian clock.¹² Children typically become tired after sunset, but puberty is associated with reduced slow-wave sleep and changes in circadian rhythms. As a result, a 3-hour delay (delayed phase preference) is common among adolescents. At approximately age 20, people start to become tired after sunset and awaken earlier in the morning—a pattern driven by sunlight and the timing of melatonin release that will remain stable until the sixth decade of life.

Continue to: Effects of chronic sleep deprivation...

Most older studies of sleep loss examined the impact of total sleep loss (sleep deprivation) rather than the effect of partial sleep loss or sleep restriction, a more commonly experienced phenomenon. More recent research shows that a cumulative sleep deficit could cause the body to override voluntary wakefulness and a sleep-deprived individual can experience brief “microsleeps” where they are unaware and lose attention/wakefulness for several seconds.² This can be deadly if a sleep-deprived adolescent experiences microsleeps while driving.¹³

There is a well-studied correlation between chronic sleep deprivation and increased body mass index in children.¹⁴ This might be caused by reduction in physical activity as well as alterations in the “hunger hormones”—ghrelin and leptin—that have been observed with sleep deprivation.^15-17 Other studies have noted decreased glucose tolerance, reduced insulin sensitivity, and catecholamine and cortisol secretion abnormalities, which place children at higher risk for metabolic syndrome and hypertension.^13,18 Sleep deprivation also is associated with mood and anxiety disorders and is an independent risk factor for substance use and suicidal ideation among adolescents.¹⁹ Sleep deprivation increases impairments in impulse control, concentration, and attention, which could be especially problematic in school-age children.

How sleep is assessed

The sleep history is the first step in evaluating a child or adolescent for a sleep disorder. The sleep history includes exploring the chief complaint, sleep patterns and schedules, bedtime routines, and nocturnal and daytime behaviors (Table).

Chief complaint

Behavioral sleep specialists will assess the primary problem with everyone involved in the child’s bedtime.²⁰ This might include parents (custodial and noncustodial), grandparents, or stepparents as well as the child/adolescent. This important step can reveal a sleep disorder or an inappropriately early bedtime relative to the child’s development. During this assessment, ask detailed questions about how long the sleep problem has persisted, the frequency of sleep problems, and any precipitating stressors. Parents and caregivers can review strategies they have tried, and for how long and to what extent interventions were implemented consistently to result in change.

Sleep patterns and schedules

Review the child/adolescent’s typical sleep patterns and behaviors. Ask parents and caregivers, as well as the patient, about general sleep schedules for the past few weeks or a typical 2-week time period.² A behavioral assessment of sleep should include asking families about how the child/adolescent sleeps during the week and over the weekend, and if school-year sleep differs from summer or holiday sleep schedules. These questions can illuminate how long a sleep problem has been occurring and what sleep habits might be contributing to the problem. Bedtime

Determine if there is a set bedtime or if the child goes to bed when they wish. It is important to ascertain if the bedtime is age-appropriate, if weekday and weekend bedtimes differ, and to what extent extracurricular activities or school demands impact bedtime. Assess the consistency of the bedtime, the nature of bedtime routines (eg, is the child engaging in stimulating activities before bed), where the bedtime routine occurs (eg, sibling’s room, parents’ room, child’s room), and what role (if any) electronic devices play.²

Nocturnal behaviors

Assessment should include a series of questions and age-specific questionnaires to focus on what behaviors occur at night, including awakenings. Parents should be asked how frequent night awakenings occur, how long arousals last, and how the child signals for the parent (eg, calling out, climbing into parents’ bed).² Additionally, ask how parents respond and what is required to help the child fall back asleep (eg, rocking, soothing, feeding). The presence of nightmares, night terrors, parasomnias, and sleep-related breathing disorders also must be assessed.²⁰

Daytime behaviors

A sleep history should include assessment of daytime functioning, including daytime sleepiness, fatigue, morning waking, and functioning during school, extracurriculars, and homework. For children and teens, falling asleep in the car, while in school, or during passive activities (meals, conversation) suggests insufficient sleep, sleep disruption, or excessive daytime sleepiness.²

Continue to: Sleep disruption in youth with psychiatric disorders...

Sleep disruption in youth with psychiatric disorders

Disordered sleep is common across psychiatric disorders. The National Comorbidity Survey Adolescent Supplement—a nationally representative cross-sectional survey of adolescents (N = 10,123)—found that a later weeknight bedtime, shorter weeknight sleep duration, and greater weekend bedtime delay increased the risk of developing a mood, anxiety, or substance use (including nicotine) disorder, and suicidality. These risk factors also were associated with lower “perceived mental and physical health.”²¹ Clinicians should routinely obtain a sleep history in children and adolescents with these disorders. Consider using the sleep screening tool BEARS:

• Bedtime issues
• Excessive daytime sleepiness
• Awakenings
• Regularity and duration of sleep
• Snoring.

ADHD

Up to one-half of children and adolescents with ADHD experience sleep problems,^22,23 including delayed sleep onset, bedtime resistance, daytime fatigue, and feeling groggy in the morning beyond what is typical (>20 minutes). Pharmacotherapy for ADHD contributes to sleep disturbances^24,25 while sleep deprivation exacerbates inattention and hyperactivity. In youth with ADHD, restless leg syndrome, periodic limb movement disorder, and sleep-disordered breathing disorder are more common than in the general population.

Depressive disorders

Up to three-quarters of depressed children and 90% of depressed adolescents report sleep disturbances, including initial, middle, and terminal insomnia as well as hypersomnia.²⁶ Disrupted sleep in pediatric patients with major depressive disorder could be moderated by the patient’s age, with depressive symptoms more common among adolescents (age 12 to 17) than among younger children (age 6 to 11).²⁷ Successful treatment of depression fails to relieve dyssomnia in 10% of children. Sleep problems that persist after successfully treating a depressive episode could increase the risk of another depressive episode.²⁸

Anxiety disorders

Sleep problems are common among children and adolescents with anxiety disorders.²⁹ Longitudinal data from >900 children found that symptoms of sleep disturbance in early childhood were correlated with experiencing an anxiety disorder 20 years later.³⁰ Fears related to the dark or monsters under the bed that are developmentally appropriate for younger children may interfere with sleep. However, in anxious children, fears might also be related to separation, sleeping alone, worry about the loss of a loved one, concerns about personal safety, fear of frightening dreams, or concerns about academics and social relationships. Anxious individuals ruminate about their worries, and this might be especially true for children at bedtime, when there are limited distractions from ruminative fears.³¹ Bedtime resistance, parental involvement in bedtime rituals, and cultural factors related to sleep also could play a role for children with anxiety symptoms and sleep problems.

Having an anxiety disorder is significantly associated with an increased risk of insomnia; however, 73% of the time anxiety symptoms precede an insomnia diagnosis.²⁹ Sleep problems and anxiety symptoms might have a reciprocal influence on one another; tiredness that results from sleep problems could exacerbate anxiety, which further worsens sleep problems.

A large body of research on sleep and anxiety reveals that abuse or exposure to trauma significantly affects sleep.³¹ Common sleep problems for children with posttraumatic stress disorder include difficulty falling asleep, maintaining sleep, and parasomnias of bedwetting and nightmares.^31,32 Compared with depressed and non-abused children, those with history of abuse have prolonged sleep latency, decreased sleep efficiency, and higher levels of activity during the night.³³ In addition to the relationship between anxiety disorders and sleep disorders, many of the selective serotonin reuptake inhibitors—which are the first-line pharmacotherapy for pediatric anxiety disorders^34,35—could affect sleep in anxious youth.³⁶

A bridge to treatment

A thorough assessment can help identify modifiable factors and guide treatment selections. In Part 2 of this article, we will describe healthy sleep practices, cognitive-behavioral therapy for insomnia, when pharmacotherapy might be indicated, and the evidence supporting several medications commonly used to treat pediatric insomnia. We also will discuss factors to consider when seeking consultation with a pediatric behavioral sleep specialist.

FIRST OF 2 PARTS

A thorough evaluation can identify modifiable factors and guide treatment

Sleep problems are common among children and adolescents,¹ with prevalence rates of 25% to 40%.^2-4 Young children most commonly exhibit what is referred to as bedtime problems and night wakenings, whereas children in middle childhood (age 4 to 12) through adolescence (age 13 to 17) report insomnia. For many children, these problems persist.³ Insufficient sleep in children and adolescents worsens inattention, daytime fatigue, and cognitive and behavioral deficits.⁵ Assessment and treatment of sleep problems in children and adolescents is critical because poor sleep among youth increases the risk for depression, self-harm, and suicide,^6,7 increases family stress, and decreases parental well-being.¹

This 2-part article describes the assessment, diagnosis, and treatment of sleep problems among children and adolescents. In part 1, we focus on:

• sleep architecture (circadian rhythms, stages of sleep)
• sleep in healthy youth (age 6 to 17) and those with attention-deficit/hyperactivity disorder (ADHD), depressive disorders, and anxiety
• how to assess sleep, and the differential diagnosis of behavioral sleep problems in pediatric patients.

In Part 2, we will cover psychotherapeutic and psychopharmacologic interventions for youth with insomnia, and describe an effective approach to consultation with pediatric sleep medicine specialists.

How much sleep do children and adolescents need?

Throughout their development, children spend 40% to 50% of their time asleep. Sleep schedules are based on circadian rhythms, which are physical, mental, and behavioral changes that follow an approximately 24-hour cycle. Human circadian rhythm varies between 24 and 25 hours and is vital in determining our sleep patterns. Exposure to sunlight drives our circadian rhythm, sending signals to our bodies to “turn on” melatonin production at night (ie, 9 pm melatonin secretion starts) and “turn off” melatonin secretion in the morning (ie, 7:30 am) in adults. Exposure to sunlight also drives circadian rhythms for children, and melatonin secretion production occurs earlier in the evening for children. Families are encouraged to expose children to bright light in the morning by taking an early walk, eating breakfast in a sunny room, or having adolescents open up the window shades rather than keeping their eyes shielded from the sun.² How sleepy or alert a child could be is determined by the duration and quality of a child’s previous sleep, and how long they have been awake (“sleep drive”).² The 3 states of sleep architecture are wake; non-rapid eye movement sleep; and rapid eye movement sleep (“dreaming” sleep) (Box²).

Box

Sleep needs also change predictably throughout the lifespan. The National Sleep Foundation guidelines for sleep duration provide clinicians and parents with a range of recommended sleep for each stage of development. Infants require 14 to 17 hours of sleep, whereas adolescents need 8 to 10 hours by age 14 to 17.⁸ The key for clinicians is to determine if the child is within the recommended range, and how they are functioning on the number of hours of sleep they report. This allows for variation in how much sleep an individual child might need while acknowledging that some children within a specific age group might need more or less sleep than other children of the same age.

Sleep in healthy youth: Middle childhood

School-age children (age 6 to 12) typically need 9 to 10 hours of sleep over a 24-hour period.² This developmental period is especially important for children to develop healthy sleep habits; however, developmentally appropriate cognitive and social/emotional factors might interfere with the quality and quantity of sleep. Middle childhood is a time when children can understand the dangers of the outside world (ie, violence, health problems) and resulting anxiety can disrupt sleep. Parents usually are less involved in bedtime as children approach adolescence, which leads to later bedtimes. At this stage, many children begin to take on more serious roles in their academics and extracurricular activities, peer relationships become more important, and use of electronics (eg, television, video games, internet, and handheld devices) increases—all of which compete with sleep.⁹ Frequent sleep issues during middle childhood include:

• irregular sleep-wake schedules
• later bedtimes
• decreased nighttime sleep
• increased caffeine intake
• reduced parental presence at bedtime
• daytime sleepiness.³

In school-age children, regular napping, falling asleep during short car rides, and daytime fatigue at school or home are cause for concern. When these symptoms are present, an evaluation is warranted.

Sleep in healthy youth: Adolescence

The National Sleep Foundation recommends adolescents obtain 8 to 10 hours of sleep per night; for some adolescents, as much as 11 hours of sleep per night might be appropriate.⁸ However, this contrasts with findings from the National Sleep Foundation’s Sleep in America Poll, which revealed that 75% of 12th graders report <8 hours of sleep nightly.¹⁰ Many adolescents experience delayed sleep phase syndrome or delayed sleep-wake phase disorder, which involves a persistent phase shift of >2 hours in the sleep-wake schedule that conflicts with the adolescent’s school, work, or lifestyle demands.¹¹ Such circadian rhythm disorders typically result from a poor match between the sleep-wake schedule and the demands of the adolescent’s life, or a failure to synchronize their internal clock with a 24-hour circadian clock.¹² Children typically become tired after sunset, but puberty is associated with reduced slow-wave sleep and changes in circadian rhythms. As a result, a 3-hour delay (delayed phase preference) is common among adolescents. At approximately age 20, people start to become tired after sunset and awaken earlier in the morning—a pattern driven by sunlight and the timing of melatonin release that will remain stable until the sixth decade of life.

Continue to: Effects of chronic sleep deprivation...

Most older studies of sleep loss examined the impact of total sleep loss (sleep deprivation) rather than the effect of partial sleep loss or sleep restriction, a more commonly experienced phenomenon. More recent research shows that a cumulative sleep deficit could cause the body to override voluntary wakefulness and a sleep-deprived individual can experience brief “microsleeps” where they are unaware and lose attention/wakefulness for several seconds.² This can be deadly if a sleep-deprived adolescent experiences microsleeps while driving.¹³

There is a well-studied correlation between chronic sleep deprivation and increased body mass index in children.¹⁴ This might be caused by reduction in physical activity as well as alterations in the “hunger hormones”—ghrelin and leptin—that have been observed with sleep deprivation.^15-17 Other studies have noted decreased glucose tolerance, reduced insulin sensitivity, and catecholamine and cortisol secretion abnormalities, which place children at higher risk for metabolic syndrome and hypertension.^13,18 Sleep deprivation also is associated with mood and anxiety disorders and is an independent risk factor for substance use and suicidal ideation among adolescents.¹⁹ Sleep deprivation increases impairments in impulse control, concentration, and attention, which could be especially problematic in school-age children.

How sleep is assessed

The sleep history is the first step in evaluating a child or adolescent for a sleep disorder. The sleep history includes exploring the chief complaint, sleep patterns and schedules, bedtime routines, and nocturnal and daytime behaviors (Table).

Chief complaint

Behavioral sleep specialists will assess the primary problem with everyone involved in the child’s bedtime.²⁰ This might include parents (custodial and noncustodial), grandparents, or stepparents as well as the child/adolescent. This important step can reveal a sleep disorder or an inappropriately early bedtime relative to the child’s development. During this assessment, ask detailed questions about how long the sleep problem has persisted, the frequency of sleep problems, and any precipitating stressors. Parents and caregivers can review strategies they have tried, and for how long and to what extent interventions were implemented consistently to result in change.

Sleep patterns and schedules

Review the child/adolescent’s typical sleep patterns and behaviors. Ask parents and caregivers, as well as the patient, about general sleep schedules for the past few weeks or a typical 2-week time period.² A behavioral assessment of sleep should include asking families about how the child/adolescent sleeps during the week and over the weekend, and if school-year sleep differs from summer or holiday sleep schedules. These questions can illuminate how long a sleep problem has been occurring and what sleep habits might be contributing to the problem. Bedtime

Determine if there is a set bedtime or if the child goes to bed when they wish. It is important to ascertain if the bedtime is age-appropriate, if weekday and weekend bedtimes differ, and to what extent extracurricular activities or school demands impact bedtime. Assess the consistency of the bedtime, the nature of bedtime routines (eg, is the child engaging in stimulating activities before bed), where the bedtime routine occurs (eg, sibling’s room, parents’ room, child’s room), and what role (if any) electronic devices play.²

Nocturnal behaviors

Assessment should include a series of questions and age-specific questionnaires to focus on what behaviors occur at night, including awakenings. Parents should be asked how frequent night awakenings occur, how long arousals last, and how the child signals for the parent (eg, calling out, climbing into parents’ bed).² Additionally, ask how parents respond and what is required to help the child fall back asleep (eg, rocking, soothing, feeding). The presence of nightmares, night terrors, parasomnias, and sleep-related breathing disorders also must be assessed.²⁰

Daytime behaviors

A sleep history should include assessment of daytime functioning, including daytime sleepiness, fatigue, morning waking, and functioning during school, extracurriculars, and homework. For children and teens, falling asleep in the car, while in school, or during passive activities (meals, conversation) suggests insufficient sleep, sleep disruption, or excessive daytime sleepiness.²

Continue to: Sleep disruption in youth with psychiatric disorders...

Sleep disruption in youth with psychiatric disorders

Disordered sleep is common across psychiatric disorders. The National Comorbidity Survey Adolescent Supplement—a nationally representative cross-sectional survey of adolescents (N = 10,123)—found that a later weeknight bedtime, shorter weeknight sleep duration, and greater weekend bedtime delay increased the risk of developing a mood, anxiety, or substance use (including nicotine) disorder, and suicidality. These risk factors also were associated with lower “perceived mental and physical health.”²¹ Clinicians should routinely obtain a sleep history in children and adolescents with these disorders. Consider using the sleep screening tool BEARS:

• Bedtime issues
• Excessive daytime sleepiness
• Awakenings
• Regularity and duration of sleep
• Snoring.

ADHD

Up to one-half of children and adolescents with ADHD experience sleep problems,^22,23 including delayed sleep onset, bedtime resistance, daytime fatigue, and feeling groggy in the morning beyond what is typical (>20 minutes). Pharmacotherapy for ADHD contributes to sleep disturbances^24,25 while sleep deprivation exacerbates inattention and hyperactivity. In youth with ADHD, restless leg syndrome, periodic limb movement disorder, and sleep-disordered breathing disorder are more common than in the general population.

Depressive disorders

Up to three-quarters of depressed children and 90% of depressed adolescents report sleep disturbances, including initial, middle, and terminal insomnia as well as hypersomnia.²⁶ Disrupted sleep in pediatric patients with major depressive disorder could be moderated by the patient’s age, with depressive symptoms more common among adolescents (age 12 to 17) than among younger children (age 6 to 11).²⁷ Successful treatment of depression fails to relieve dyssomnia in 10% of children. Sleep problems that persist after successfully treating a depressive episode could increase the risk of another depressive episode.²⁸

Anxiety disorders

Sleep problems are common among children and adolescents with anxiety disorders.²⁹ Longitudinal data from >900 children found that symptoms of sleep disturbance in early childhood were correlated with experiencing an anxiety disorder 20 years later.³⁰ Fears related to the dark or monsters under the bed that are developmentally appropriate for younger children may interfere with sleep. However, in anxious children, fears might also be related to separation, sleeping alone, worry about the loss of a loved one, concerns about personal safety, fear of frightening dreams, or concerns about academics and social relationships. Anxious individuals ruminate about their worries, and this might be especially true for children at bedtime, when there are limited distractions from ruminative fears.³¹ Bedtime resistance, parental involvement in bedtime rituals, and cultural factors related to sleep also could play a role for children with anxiety symptoms and sleep problems.

Having an anxiety disorder is significantly associated with an increased risk of insomnia; however, 73% of the time anxiety symptoms precede an insomnia diagnosis.²⁹ Sleep problems and anxiety symptoms might have a reciprocal influence on one another; tiredness that results from sleep problems could exacerbate anxiety, which further worsens sleep problems.

A large body of research on sleep and anxiety reveals that abuse or exposure to trauma significantly affects sleep.³¹ Common sleep problems for children with posttraumatic stress disorder include difficulty falling asleep, maintaining sleep, and parasomnias of bedwetting and nightmares.^31,32 Compared with depressed and non-abused children, those with history of abuse have prolonged sleep latency, decreased sleep efficiency, and higher levels of activity during the night.³³ In addition to the relationship between anxiety disorders and sleep disorders, many of the selective serotonin reuptake inhibitors—which are the first-line pharmacotherapy for pediatric anxiety disorders^34,35—could affect sleep in anxious youth.³⁶

A bridge to treatment

A thorough assessment can help identify modifiable factors and guide treatment selections. In Part 2 of this article, we will describe healthy sleep practices, cognitive-behavioral therapy for insomnia, when pharmacotherapy might be indicated, and the evidence supporting several medications commonly used to treat pediatric insomnia. We also will discuss factors to consider when seeking consultation with a pediatric behavioral sleep specialist.

Ms. H, age 42, is being treated by her family physician for her second episode of major depressive disorder (MDD). When she was 35, Ms. H experienced her first episode of MDD, which was successfully treated with fluoxetine, 20 mg/d, for 9 months. The current episode began approximately 3 months ago, and there were no known precipitating factors. Because Ms. H had responded well to fluoxetine, her physician reinitiates fluoxetine, 20 mg/d, for 8 weeks.

At the 8-week follow-up appointment, the physician notes how much better Ms. H seems to be doing. He says that because she has had such a good response, she should continue the fluoxetine and come back in 3 months. Later that evening, Ms. H reflects on her visit. Although she feels better, she still does not feel normal. In fact, she is not sure that she has really felt normal since before her first depressive episode. Ms. H decides to see a psychiatrist.

At her first appointment, the psychiatrist asks Ms. H to complete the Quick Inventory of Depressive Symptoms–Self Rated (QIDS-SR) scale. Her QIDS-SR score is 6, which is consistent with mild residual symptoms of depression.¹ The psychiatrist increases the fluoxetine dosage to 40 mg/d and recommends that she complete a course of cognitive-behavioral therapy (CBT).

Although psychiatry currently does not have tests that provide continuous data such as blood pressure or HbA_1c, well-validated rating scales can help clinicians in getting their patients to achieve symptom remission. Measurement-based care is the “systematic use of measurement tools to monitor progress and guide treatment choices.”¹ Originally, psychometric rating scales were designed for research; typically, they were administered by the clinician, and were too long to be used in routine outpatient clinical practice. Subsequently, it was determined that patients without psychotic symptoms or cognitive deficits can accurately assess their own symptoms, and this led to the development of short self-assessment scales that have a high level of reliability when compared with longer, clinician-administered instruments. Despite the availability of several validated, brief rating scales, it is estimated that only approximately 18% of psychiatrists use them in clinical practice.²

Self-rated scales for depression have been shown to be as valid as clinician-rated scales. For depression, the Patient Health Questionaire-9 (PHQ-9), based on the 9 symptom criteria associated with a diagnosis of MDD, is likely the most commonly used self-assessment scale.¹ However, the QIDS-SR and the Beck Depression Inventory are both well-validated.¹ In particular, QIDS-SR scores and score changes have been shown to be comparable with those on the QIDS-Clinician Rating (QIDS-C) scale.³ A 50% decrease in score typically is defined as a clinical response. Remission of symptoms is often defined as a score ≤4 on the PHQ-9 or ≤5 on the QIDS-SR (Table¹). Similar to laboratory tests, rating scales are not diagnostic, but are a piece of information for the clinician to use in making diagnostic and treatment decisions.

Continue to: Optimizing the use of self-rating scales...

Optimizing the use of self-rating scales

To save time, patients can complete a rating scale before seeing the clinician, and the use of computerized applications can automatically sum scores and plot response graphs.⁴ Some researchers have suggested that some patients may be more honest in completing a self-assessment than in their verbal responses to the clinician.⁴ It is important to discuss the rating scale results with the patient.² With a newly diagnosed patient, goals for treatment and the treatment plan can be outlined. During follow-up visits, clinicians should note areas of improvement and provide encouragement. If the patient’s symptoms are not improving appropriately, the clinician should discuss treatment options and offer the patient hope. This may improve the patient’s engagement in care and their understanding of how symptoms are associated with their illness.² Studies have suggested that the use of validated rating tools (along with other interventions) can result in faster improvement in symptoms and higher response rates, and can assist in achieving remission.^1,2,5

CASE CONTINUED

After 6 weeks of CBT and the increased fluoxetine dose, Ms. H returns to her psychiatrist for a follow-up visit. Her QIDS-SR score is 4, which is down from her initial score of 6. Ms. H is elated when she sees that her symptoms score has decreased since the previous visit. To confirm this finding, the psychiatrist completes the QIDS-C, and records a score of 3. The psychiatrist discusses the appropriate continuation of fluoxetine and CBT.

In this case, the use of a brief clinical rating scale helped Ms. H’s psychiatrist identify residual depressive symptoms and modify treatment so that she achieved remission. Using patient-reported outcomes also helps facilitate meaningful conversations between the patient and clinician and helps identify symptoms suggestive of relapse.² Although this case focused on the use of measurement-based care in depression, brief symptom rating scales for most major psychiatric disorders—many of them self-assessments—also are available, as are brief rating scales to assess medication adverse effects and adherence.⁵

Just as clinicians in other areas of medicine use assessments such as laboratory tests and blood pressure monitoring for initial assessment and in following response to treatment, measurement-based care allows for a quasi-objective evaluation of patients with psychiatric disorders. Improved response rates, time to response, and patient engagement are all positive results of measurement-based care

Related Resources

• Martin-Cook K, Palmer L, Thornton L, et al. Setting measurement-based care in motion: practical lessons in the implementation and integration of measurement-based care in psychiatry clinical practice. Neuropsychiatric Disease & Treatment. 2021;17:1621-1631.
• Aboraya A, Nasrallah HA, Elswick DE, et al. Measurementbased care in psychiatry-past, present, and future. Innov Clin Neurosci. 2018;15(11-12):13-26.

Drug Brand Names

Fluoxetine • Prozac

Ms. H, age 42, is being treated by her family physician for her second episode of major depressive disorder (MDD). When she was 35, Ms. H experienced her first episode of MDD, which was successfully treated with fluoxetine, 20 mg/d, for 9 months. The current episode began approximately 3 months ago, and there were no known precipitating factors. Because Ms. H had responded well to fluoxetine, her physician reinitiates fluoxetine, 20 mg/d, for 8 weeks.

At the 8-week follow-up appointment, the physician notes how much better Ms. H seems to be doing. He says that because she has had such a good response, she should continue the fluoxetine and come back in 3 months. Later that evening, Ms. H reflects on her visit. Although she feels better, she still does not feel normal. In fact, she is not sure that she has really felt normal since before her first depressive episode. Ms. H decides to see a psychiatrist.

At her first appointment, the psychiatrist asks Ms. H to complete the Quick Inventory of Depressive Symptoms–Self Rated (QIDS-SR) scale. Her QIDS-SR score is 6, which is consistent with mild residual symptoms of depression.¹ The psychiatrist increases the fluoxetine dosage to 40 mg/d and recommends that she complete a course of cognitive-behavioral therapy (CBT).

Although psychiatry currently does not have tests that provide continuous data such as blood pressure or HbA_1c, well-validated rating scales can help clinicians in getting their patients to achieve symptom remission. Measurement-based care is the “systematic use of measurement tools to monitor progress and guide treatment choices.”¹ Originally, psychometric rating scales were designed for research; typically, they were administered by the clinician, and were too long to be used in routine outpatient clinical practice. Subsequently, it was determined that patients without psychotic symptoms or cognitive deficits can accurately assess their own symptoms, and this led to the development of short self-assessment scales that have a high level of reliability when compared with longer, clinician-administered instruments. Despite the availability of several validated, brief rating scales, it is estimated that only approximately 18% of psychiatrists use them in clinical practice.²

Self-rated scales for depression have been shown to be as valid as clinician-rated scales. For depression, the Patient Health Questionaire-9 (PHQ-9), based on the 9 symptom criteria associated with a diagnosis of MDD, is likely the most commonly used self-assessment scale.¹ However, the QIDS-SR and the Beck Depression Inventory are both well-validated.¹ In particular, QIDS-SR scores and score changes have been shown to be comparable with those on the QIDS-Clinician Rating (QIDS-C) scale.³ A 50% decrease in score typically is defined as a clinical response. Remission of symptoms is often defined as a score ≤4 on the PHQ-9 or ≤5 on the QIDS-SR (Table¹). Similar to laboratory tests, rating scales are not diagnostic, but are a piece of information for the clinician to use in making diagnostic and treatment decisions.

Continue to: Optimizing the use of self-rating scales...

Optimizing the use of self-rating scales

To save time, patients can complete a rating scale before seeing the clinician, and the use of computerized applications can automatically sum scores and plot response graphs.⁴ Some researchers have suggested that some patients may be more honest in completing a self-assessment than in their verbal responses to the clinician.⁴ It is important to discuss the rating scale results with the patient.² With a newly diagnosed patient, goals for treatment and the treatment plan can be outlined. During follow-up visits, clinicians should note areas of improvement and provide encouragement. If the patient’s symptoms are not improving appropriately, the clinician should discuss treatment options and offer the patient hope. This may improve the patient’s engagement in care and their understanding of how symptoms are associated with their illness.² Studies have suggested that the use of validated rating tools (along with other interventions) can result in faster improvement in symptoms and higher response rates, and can assist in achieving remission.^1,2,5

CASE CONTINUED

After 6 weeks of CBT and the increased fluoxetine dose, Ms. H returns to her psychiatrist for a follow-up visit. Her QIDS-SR score is 4, which is down from her initial score of 6. Ms. H is elated when she sees that her symptoms score has decreased since the previous visit. To confirm this finding, the psychiatrist completes the QIDS-C, and records a score of 3. The psychiatrist discusses the appropriate continuation of fluoxetine and CBT.

In this case, the use of a brief clinical rating scale helped Ms. H’s psychiatrist identify residual depressive symptoms and modify treatment so that she achieved remission. Using patient-reported outcomes also helps facilitate meaningful conversations between the patient and clinician and helps identify symptoms suggestive of relapse.² Although this case focused on the use of measurement-based care in depression, brief symptom rating scales for most major psychiatric disorders—many of them self-assessments—also are available, as are brief rating scales to assess medication adverse effects and adherence.⁵

Just as clinicians in other areas of medicine use assessments such as laboratory tests and blood pressure monitoring for initial assessment and in following response to treatment, measurement-based care allows for a quasi-objective evaluation of patients with psychiatric disorders. Improved response rates, time to response, and patient engagement are all positive results of measurement-based care

Related Resources

• Martin-Cook K, Palmer L, Thornton L, et al. Setting measurement-based care in motion: practical lessons in the implementation and integration of measurement-based care in psychiatry clinical practice. Neuropsychiatric Disease & Treatment. 2021;17:1621-1631.
• Aboraya A, Nasrallah HA, Elswick DE, et al. Measurementbased care in psychiatry-past, present, and future. Innov Clin Neurosci. 2018;15(11-12):13-26.

Drug Brand Names

Fluoxetine • Prozac

Ms. H, age 42, is being treated by her family physician for her second episode of major depressive disorder (MDD). When she was 35, Ms. H experienced her first episode of MDD, which was successfully treated with fluoxetine, 20 mg/d, for 9 months. The current episode began approximately 3 months ago, and there were no known precipitating factors. Because Ms. H had responded well to fluoxetine, her physician reinitiates fluoxetine, 20 mg/d, for 8 weeks.

At the 8-week follow-up appointment, the physician notes how much better Ms. H seems to be doing. He says that because she has had such a good response, she should continue the fluoxetine and come back in 3 months. Later that evening, Ms. H reflects on her visit. Although she feels better, she still does not feel normal. In fact, she is not sure that she has really felt normal since before her first depressive episode. Ms. H decides to see a psychiatrist.

At her first appointment, the psychiatrist asks Ms. H to complete the Quick Inventory of Depressive Symptoms–Self Rated (QIDS-SR) scale. Her QIDS-SR score is 6, which is consistent with mild residual symptoms of depression.¹ The psychiatrist increases the fluoxetine dosage to 40 mg/d and recommends that she complete a course of cognitive-behavioral therapy (CBT).

Although psychiatry currently does not have tests that provide continuous data such as blood pressure or HbA_1c, well-validated rating scales can help clinicians in getting their patients to achieve symptom remission. Measurement-based care is the “systematic use of measurement tools to monitor progress and guide treatment choices.”¹ Originally, psychometric rating scales were designed for research; typically, they were administered by the clinician, and were too long to be used in routine outpatient clinical practice. Subsequently, it was determined that patients without psychotic symptoms or cognitive deficits can accurately assess their own symptoms, and this led to the development of short self-assessment scales that have a high level of reliability when compared with longer, clinician-administered instruments. Despite the availability of several validated, brief rating scales, it is estimated that only approximately 18% of psychiatrists use them in clinical practice.²

Self-rated scales for depression have been shown to be as valid as clinician-rated scales. For depression, the Patient Health Questionaire-9 (PHQ-9), based on the 9 symptom criteria associated with a diagnosis of MDD, is likely the most commonly used self-assessment scale.¹ However, the QIDS-SR and the Beck Depression Inventory are both well-validated.¹ In particular, QIDS-SR scores and score changes have been shown to be comparable with those on the QIDS-Clinician Rating (QIDS-C) scale.³ A 50% decrease in score typically is defined as a clinical response. Remission of symptoms is often defined as a score ≤4 on the PHQ-9 or ≤5 on the QIDS-SR (Table¹). Similar to laboratory tests, rating scales are not diagnostic, but are a piece of information for the clinician to use in making diagnostic and treatment decisions.

Continue to: Optimizing the use of self-rating scales...

Optimizing the use of self-rating scales

To save time, patients can complete a rating scale before seeing the clinician, and the use of computerized applications can automatically sum scores and plot response graphs.⁴ Some researchers have suggested that some patients may be more honest in completing a self-assessment than in their verbal responses to the clinician.⁴ It is important to discuss the rating scale results with the patient.² With a newly diagnosed patient, goals for treatment and the treatment plan can be outlined. During follow-up visits, clinicians should note areas of improvement and provide encouragement. If the patient’s symptoms are not improving appropriately, the clinician should discuss treatment options and offer the patient hope. This may improve the patient’s engagement in care and their understanding of how symptoms are associated with their illness.² Studies have suggested that the use of validated rating tools (along with other interventions) can result in faster improvement in symptoms and higher response rates, and can assist in achieving remission.^1,2,5

CASE CONTINUED

After 6 weeks of CBT and the increased fluoxetine dose, Ms. H returns to her psychiatrist for a follow-up visit. Her QIDS-SR score is 4, which is down from her initial score of 6. Ms. H is elated when she sees that her symptoms score has decreased since the previous visit. To confirm this finding, the psychiatrist completes the QIDS-C, and records a score of 3. The psychiatrist discusses the appropriate continuation of fluoxetine and CBT.

In this case, the use of a brief clinical rating scale helped Ms. H’s psychiatrist identify residual depressive symptoms and modify treatment so that she achieved remission. Using patient-reported outcomes also helps facilitate meaningful conversations between the patient and clinician and helps identify symptoms suggestive of relapse.² Although this case focused on the use of measurement-based care in depression, brief symptom rating scales for most major psychiatric disorders—many of them self-assessments—also are available, as are brief rating scales to assess medication adverse effects and adherence.⁵

Just as clinicians in other areas of medicine use assessments such as laboratory tests and blood pressure monitoring for initial assessment and in following response to treatment, measurement-based care allows for a quasi-objective evaluation of patients with psychiatric disorders. Improved response rates, time to response, and patient engagement are all positive results of measurement-based care

Related Resources

• Martin-Cook K, Palmer L, Thornton L, et al. Setting measurement-based care in motion: practical lessons in the implementation and integration of measurement-based care in psychiatry clinical practice. Neuropsychiatric Disease & Treatment. 2021;17:1621-1631.
• Aboraya A, Nasrallah HA, Elswick DE, et al. Measurementbased care in psychiatry-past, present, and future. Innov Clin Neurosci. 2018;15(11-12):13-26.

Drug Brand Names

Fluoxetine • Prozac

Consider the following patients who have presented to our hospital system:

• A 27-year-old gay man is brought to the emergency department by police after bizarre behavior in a hotel. He is paranoid, disorganized, and responding to internal stimuli. He admits to using methamphetamine before a potential “hookup” at the hotel
• A 35-year-old bisexual man presents to the psychiatric emergency department, worried he will lose his job and relationship after downloading a dating app on his work phone to buy methamphetamine
• A 30-year-old gay man divulges to his psychiatrist that he is insecure about his sexual performance and intimacy with his partner because most of their sexual contact involves using gamma-hydroxybutyric acid (GHB).

These are just some of the many psychiatric presentations we have encountered involving “chemsex” among men who have sex with men (MSM).

What is ‘chemsex?’

“Chemsex” refers to the use of specific drugs—mainly methamphetamine, mephedrone, or GHB—before or during sex to reduce sexual disinhibitions and to facilitate, initiate, prolong, sustain, and intensify the encounter.¹ Chemsex participants report desired enhancements in:

• confidence and ability to engage with partners
• emotional awareness and shared experience with partners
• sexual performance and intensity of sensations.¹

How prevalent is it?

Emerging in urban centers as a part of gay nightlife, chemsex has become increasingly prevalent among young MSM, fueled by a worldwide rise in methamphetamine use.^1,2 In a large 2019 systematic review, Maxwell et al¹ reported a wide range of chemsex prevalence estimates among MSM (3% to 29%). Higher estimates emerged from studies recruiting participants from sexual health clinics and through phone-based dating apps, while lower estimates tended to come from more representative samples of MSM. In studies from the United States, the prevalence of chemsex ranged from 9% to 10% in samples recruited from gay pride events, gay nightlife venues, and internet surveys. Across studies, MSM participating in chemsex were more likely to identify as gay, with mean ages ranging from 32 to 42 years, and were more likely to be HIV-positive.¹

Methamphetamine was the most popular drug used, with GHB having higher prevalence in Western Europe, and mephedrone more common in the United Kingdom.¹ Injection drug use was only examined in studies from the United Kingdom, the Netherlands, and Australia and showed a lower overall prevalence rate—1% to 9%. Methamphetamine was the most commonly injected drug. Other drugs used for chemsex included ketamine, 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”), cocaine, amyl nitrite (“poppers”), and erectile dysfunction medications.¹It is important to remember that chemsex is a socially constructed concept and, as such, is subject to participant preferences and the popularity and availability of specific drugs. These features are likely to vary across geography, subcultures, and time. The above statistics ultimately represent a minority of MSM but highlight the importance of considering this phenomenon when caring for this population.¹

Continue to: What makes chemsex unique?...

What makes chemsex unique?

Apps and access. Individuals who engage in chemsex report easy access to drugs via nightlife settings or through smartphone dating apps. Drugs are often shared during sexual encounters, which removes cost barriers for participants.¹

Environment. Chemsex sometimes takes place in group settings at “sex-on-premises venues,” including clubs, bathhouses, and saunas. The rise of smartphone apps and closure of these venues has shifted much of chemsex to private settings.¹Sexual behavior. Seventeen of the studies included in the Maxwell et al¹ review showed an increased risk of condomless anal intercourse during chemsex. Several studies also reported increased rates of sex with multiple partners and new partners.¹

What are the potential risks?

Physical health. High-risk sexual behaviors associated with chemsex increase the risk of sexually transmitted infections, including HIV and hepatitis C.¹ Use of substances associated with chemsex can lead to overdose, cardiovascular events, and neurotoxicity.^1,2

Mental health. In our clinical experience, the psychiatric implications of chemsex are numerous and exist on a spectrum from acute to chronic (Table 1).

What can clinicians do?

We encourage you to talk about chemsex with your patients. Table 2 provides a “tip sheet” to help you start the conversation, address risks, and provide support. We hope you continue to learn from your patients and keep up-to-date on this evolving topic.

Consider the following patients who have presented to our hospital system:

• A 27-year-old gay man is brought to the emergency department by police after bizarre behavior in a hotel. He is paranoid, disorganized, and responding to internal stimuli. He admits to using methamphetamine before a potential “hookup” at the hotel
• A 35-year-old bisexual man presents to the psychiatric emergency department, worried he will lose his job and relationship after downloading a dating app on his work phone to buy methamphetamine
• A 30-year-old gay man divulges to his psychiatrist that he is insecure about his sexual performance and intimacy with his partner because most of their sexual contact involves using gamma-hydroxybutyric acid (GHB).

These are just some of the many psychiatric presentations we have encountered involving “chemsex” among men who have sex with men (MSM).

What is ‘chemsex?’

“Chemsex” refers to the use of specific drugs—mainly methamphetamine, mephedrone, or GHB—before or during sex to reduce sexual disinhibitions and to facilitate, initiate, prolong, sustain, and intensify the encounter.¹ Chemsex participants report desired enhancements in:

• confidence and ability to engage with partners
• emotional awareness and shared experience with partners
• sexual performance and intensity of sensations.¹

How prevalent is it?

Emerging in urban centers as a part of gay nightlife, chemsex has become increasingly prevalent among young MSM, fueled by a worldwide rise in methamphetamine use.^1,2 In a large 2019 systematic review, Maxwell et al¹ reported a wide range of chemsex prevalence estimates among MSM (3% to 29%). Higher estimates emerged from studies recruiting participants from sexual health clinics and through phone-based dating apps, while lower estimates tended to come from more representative samples of MSM. In studies from the United States, the prevalence of chemsex ranged from 9% to 10% in samples recruited from gay pride events, gay nightlife venues, and internet surveys. Across studies, MSM participating in chemsex were more likely to identify as gay, with mean ages ranging from 32 to 42 years, and were more likely to be HIV-positive.¹

Methamphetamine was the most popular drug used, with GHB having higher prevalence in Western Europe, and mephedrone more common in the United Kingdom.¹ Injection drug use was only examined in studies from the United Kingdom, the Netherlands, and Australia and showed a lower overall prevalence rate—1% to 9%. Methamphetamine was the most commonly injected drug. Other drugs used for chemsex included ketamine, 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”), cocaine, amyl nitrite (“poppers”), and erectile dysfunction medications.¹It is important to remember that chemsex is a socially constructed concept and, as such, is subject to participant preferences and the popularity and availability of specific drugs. These features are likely to vary across geography, subcultures, and time. The above statistics ultimately represent a minority of MSM but highlight the importance of considering this phenomenon when caring for this population.¹

Continue to: What makes chemsex unique?...

What makes chemsex unique?

Apps and access. Individuals who engage in chemsex report easy access to drugs via nightlife settings or through smartphone dating apps. Drugs are often shared during sexual encounters, which removes cost barriers for participants.¹

Environment. Chemsex sometimes takes place in group settings at “sex-on-premises venues,” including clubs, bathhouses, and saunas. The rise of smartphone apps and closure of these venues has shifted much of chemsex to private settings.¹Sexual behavior. Seventeen of the studies included in the Maxwell et al¹ review showed an increased risk of condomless anal intercourse during chemsex. Several studies also reported increased rates of sex with multiple partners and new partners.¹

What are the potential risks?

Physical health. High-risk sexual behaviors associated with chemsex increase the risk of sexually transmitted infections, including HIV and hepatitis C.¹ Use of substances associated with chemsex can lead to overdose, cardiovascular events, and neurotoxicity.^1,2

Mental health. In our clinical experience, the psychiatric implications of chemsex are numerous and exist on a spectrum from acute to chronic (Table 1).

What can clinicians do?

We encourage you to talk about chemsex with your patients. Table 2 provides a “tip sheet” to help you start the conversation, address risks, and provide support. We hope you continue to learn from your patients and keep up-to-date on this evolving topic.

Consider the following patients who have presented to our hospital system:

• A 27-year-old gay man is brought to the emergency department by police after bizarre behavior in a hotel. He is paranoid, disorganized, and responding to internal stimuli. He admits to using methamphetamine before a potential “hookup” at the hotel
• A 35-year-old bisexual man presents to the psychiatric emergency department, worried he will lose his job and relationship after downloading a dating app on his work phone to buy methamphetamine
• A 30-year-old gay man divulges to his psychiatrist that he is insecure about his sexual performance and intimacy with his partner because most of their sexual contact involves using gamma-hydroxybutyric acid (GHB).

These are just some of the many psychiatric presentations we have encountered involving “chemsex” among men who have sex with men (MSM).

What is ‘chemsex?’

“Chemsex” refers to the use of specific drugs—mainly methamphetamine, mephedrone, or GHB—before or during sex to reduce sexual disinhibitions and to facilitate, initiate, prolong, sustain, and intensify the encounter.¹ Chemsex participants report desired enhancements in:

• confidence and ability to engage with partners
• emotional awareness and shared experience with partners
• sexual performance and intensity of sensations.¹

How prevalent is it?

Emerging in urban centers as a part of gay nightlife, chemsex has become increasingly prevalent among young MSM, fueled by a worldwide rise in methamphetamine use.^1,2 In a large 2019 systematic review, Maxwell et al¹ reported a wide range of chemsex prevalence estimates among MSM (3% to 29%). Higher estimates emerged from studies recruiting participants from sexual health clinics and through phone-based dating apps, while lower estimates tended to come from more representative samples of MSM. In studies from the United States, the prevalence of chemsex ranged from 9% to 10% in samples recruited from gay pride events, gay nightlife venues, and internet surveys. Across studies, MSM participating in chemsex were more likely to identify as gay, with mean ages ranging from 32 to 42 years, and were more likely to be HIV-positive.¹

Methamphetamine was the most popular drug used, with GHB having higher prevalence in Western Europe, and mephedrone more common in the United Kingdom.¹ Injection drug use was only examined in studies from the United Kingdom, the Netherlands, and Australia and showed a lower overall prevalence rate—1% to 9%. Methamphetamine was the most commonly injected drug. Other drugs used for chemsex included ketamine, 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”), cocaine, amyl nitrite (“poppers”), and erectile dysfunction medications.¹It is important to remember that chemsex is a socially constructed concept and, as such, is subject to participant preferences and the popularity and availability of specific drugs. These features are likely to vary across geography, subcultures, and time. The above statistics ultimately represent a minority of MSM but highlight the importance of considering this phenomenon when caring for this population.¹

Continue to: What makes chemsex unique?...

What makes chemsex unique?

Apps and access. Individuals who engage in chemsex report easy access to drugs via nightlife settings or through smartphone dating apps. Drugs are often shared during sexual encounters, which removes cost barriers for participants.¹

Environment. Chemsex sometimes takes place in group settings at “sex-on-premises venues,” including clubs, bathhouses, and saunas. The rise of smartphone apps and closure of these venues has shifted much of chemsex to private settings.¹Sexual behavior. Seventeen of the studies included in the Maxwell et al¹ review showed an increased risk of condomless anal intercourse during chemsex. Several studies also reported increased rates of sex with multiple partners and new partners.¹

What are the potential risks?

Physical health. High-risk sexual behaviors associated with chemsex increase the risk of sexually transmitted infections, including HIV and hepatitis C.¹ Use of substances associated with chemsex can lead to overdose, cardiovascular events, and neurotoxicity.^1,2

Mental health. In our clinical experience, the psychiatric implications of chemsex are numerous and exist on a spectrum from acute to chronic (Table 1).

What can clinicians do?

We encourage you to talk about chemsex with your patients. Table 2 provides a “tip sheet” to help you start the conversation, address risks, and provide support. We hope you continue to learn from your patients and keep up-to-date on this evolving topic.

The perils of hubris

Dr. Nasrallah’s fascinating editorial on the psychiatric aspects of prominent individuals’ fall from grace (“From famous to infamous: Psychiatric aspects of the fall from grace,” From the Editor, Current Psychiatry, October 2021, p. 9-10,53) reminded me that the most trenchant insights and antidotes to hubris can more often be found in literature than in a diagnostic code. In Bonfire of the Vanities,¹ Tom’s Wolfe’s satire on 1980s New York, self-proclaimed “Master of the Universe” Sherman McCoy lives in a Park Avenue high rise and works as a bond trader “on Wall Street, fifty floors up … overlooking the world!” As quickly becomes apparent, Sherman’s altitude—both literal and figurative—merely serves as a greater distance from which to fall.

Perhaps fittingly, the phenomenon of self-destruction as a byproduct of success was most prominently “diagnosed” by business school professors, not physicians. The propensity for ethical failure at the apex of achievement was coined the “Bathsheba Syndrome,” in reference to the biblical tale of King David’s degenerative sequence of temptation, infidelity, deceit, and treachery while at the height of his power.² David’s transgressions are enabled by the very success he has achieved.³

One of my valued mentors had an interesting, albeit unscientific, method of mitigating hubris. When he was a senior military lawyer, or judge advocate (JAG), and I was a junior one, my mentor took me to a briefing in which he provided a legal overview to newly minted colonels assuming command billets. One of the functions of JAGs is to provide counsel and advice to commanders. As Dr. Nasrallah noted in his editorial, military leaders are by no means immune from the proverbial fall from grace, and arguably particularly susceptible to it. In beginning his remarks, my mentor offered his heartfelt congratulations to the attendees on their promotion and then proceeded to hand out a pocket mirror for them to pass around. He asked each officer to look in the mirror and personally confirm for him that they were just as unattractive today as they were yesterday.

Charles G. Kels, JD

Defense Health Agency

San Antonio, Texas



The views expressed in this letter are those of the author and do not necessarily reflect those of any government agency.

1. Wolfe T. Bonfire of the vanities. Farrar, Straus and Giroux; 1987.

2. Ludwig DC, Longenecker CO. The Bathsheba syndrome: the ethical failure of successful leaders. J Bus Ethics. 1993;12:265-273.

3. 2 Samuel 11-12.

I enjoyed Dr. Nasrallah’s editorial and his discussion of the dangers of hubris. This brought to mind the role of the auriga in ancient Rome: "the auriga was a slave with gladiator status, whose duty it was to drive a biga, the light vehicle powered by two horses, to transport some important Romans, mainly duces (military commanders). An auriga was a sort of “chauffeur” for important men and was carefully selected from among trustworthy slaves only. It has been supposed also that this name was given to the slave who held a laurel crown, during Roman Triumphs, over the head of the dux, standing at his back but continuously whispering in his ears “Memento Mori” (“remember you are mortal”) to prevent the celebrated commander from losing his sense of proportion in the excesses of the celebrations.”¹  

Continue to: Mark S. Komrad, MD...

Mark S. Komrad, MD

Faculty of Psychiatry

Johns Hopkins Hospital

University of Maryland

Tulane University

Towson, Maryland

Reference

1. Auriga (slave). Accessed November 9, 2021. https://en.wikipedia.org/wiki/Auriga_(slave)

Barriers to care faced by African American patients

According to the US Department of Health and Human Services, the 5 domains of social determinants of health are Economic Stability, Education Access and Quality, Health Care Access and Quality, Neighbor­hood and Built Environment, and Social and Community Context.¹ Patients who are African American face many socioeconomic barriers to access to psychiatric care, including economic inequality, inadequate knowledge about mental health, and deficient social environments. These barriers have a significant impact on the accessibility of psychiatric health care within this community, and they need to be addressed.

Jegede et al² discussed how financial woes and insecurity within the African American community contribute to health care inequalities and adverse health outcomes. According to the US Census Bureau,in 2020, compared to other ethnic groups, African American individuals had the lowest median income.³ Alang⁴ discussed how the stigma of mental health was a barrier among younger, college-educated individuals who are African American, and that those with higher education were more likely to minimize and report low treatment effectiveness. As clinicians, we often fail to discuss the effects the perceived social and cultural stigma of being diagnosed with a substance use or mental health disorder has on seeking care, treatment, and therapy by African American patients. The stigma of being judged by family members or the community and being seen as “weak” for seeking treatment has a detrimental impact on access to psychiatric care.² It is our duty as clinicians to understand these kinds of stigmas and seek ways to mitigate them within this community.

Also, we must not underestimate the importance of patients having access to transportation to treatment. We know that social support is integral to treatment, recovery, and relapse prevention. Chronic cycles of treatment and relapse can occur due to inadequate social support. Having access to a reliable driver—especially one who is a family member or member of the community—can be vital to establishing social support. Jegede et al² found that access to adequate transportation has proven therapeutic benefits and lessens the risk of relapse with decreased exposure to risky environments. We need to devise solutions to help patients find adequate and reliable transportation.

Clinicians should be culturally mindful and aware of the barriers to psychiatric care faced by patients who are African American. They should understand the importance of removing these barriers, and work to improve this population’s access to psychiatric care. Though this may be a daunting task that requires considerable time and resources, as health care providers, we can start the process by communicating and working with local politicians and community leaders. By working together, we can develop a plan to combat these socioeconomic barriers and provide access to psychiatric care within the African American community.

Craig Perry, MD

Elohor Otite, MD

Stacy Doumas, MD
 

Jersey Shore University Medical Center

Neptune, New Jersey

The perils of hubris

Dr. Nasrallah’s fascinating editorial on the psychiatric aspects of prominent individuals’ fall from grace (“From famous to infamous: Psychiatric aspects of the fall from grace,” From the Editor, Current Psychiatry, October 2021, p. 9-10,53) reminded me that the most trenchant insights and antidotes to hubris can more often be found in literature than in a diagnostic code. In Bonfire of the Vanities,¹ Tom’s Wolfe’s satire on 1980s New York, self-proclaimed “Master of the Universe” Sherman McCoy lives in a Park Avenue high rise and works as a bond trader “on Wall Street, fifty floors up … overlooking the world!” As quickly becomes apparent, Sherman’s altitude—both literal and figurative—merely serves as a greater distance from which to fall.

Perhaps fittingly, the phenomenon of self-destruction as a byproduct of success was most prominently “diagnosed” by business school professors, not physicians. The propensity for ethical failure at the apex of achievement was coined the “Bathsheba Syndrome,” in reference to the biblical tale of King David’s degenerative sequence of temptation, infidelity, deceit, and treachery while at the height of his power.² David’s transgressions are enabled by the very success he has achieved.³

One of my valued mentors had an interesting, albeit unscientific, method of mitigating hubris. When he was a senior military lawyer, or judge advocate (JAG), and I was a junior one, my mentor took me to a briefing in which he provided a legal overview to newly minted colonels assuming command billets. One of the functions of JAGs is to provide counsel and advice to commanders. As Dr. Nasrallah noted in his editorial, military leaders are by no means immune from the proverbial fall from grace, and arguably particularly susceptible to it. In beginning his remarks, my mentor offered his heartfelt congratulations to the attendees on their promotion and then proceeded to hand out a pocket mirror for them to pass around. He asked each officer to look in the mirror and personally confirm for him that they were just as unattractive today as they were yesterday.

Charles G. Kels, JD

Defense Health Agency

San Antonio, Texas



The views expressed in this letter are those of the author and do not necessarily reflect those of any government agency.

1. Wolfe T. Bonfire of the vanities. Farrar, Straus and Giroux; 1987.

2. Ludwig DC, Longenecker CO. The Bathsheba syndrome: the ethical failure of successful leaders. J Bus Ethics. 1993;12:265-273.

3. 2 Samuel 11-12.

I enjoyed Dr. Nasrallah’s editorial and his discussion of the dangers of hubris. This brought to mind the role of the auriga in ancient Rome: "the auriga was a slave with gladiator status, whose duty it was to drive a biga, the light vehicle powered by two horses, to transport some important Romans, mainly duces (military commanders). An auriga was a sort of “chauffeur” for important men and was carefully selected from among trustworthy slaves only. It has been supposed also that this name was given to the slave who held a laurel crown, during Roman Triumphs, over the head of the dux, standing at his back but continuously whispering in his ears “Memento Mori” (“remember you are mortal”) to prevent the celebrated commander from losing his sense of proportion in the excesses of the celebrations.”¹  

Continue to: Mark S. Komrad, MD...

Mark S. Komrad, MD

Faculty of Psychiatry

Johns Hopkins Hospital

University of Maryland

Tulane University

Towson, Maryland

Reference

1. Auriga (slave). Accessed November 9, 2021. https://en.wikipedia.org/wiki/Auriga_(slave)

Barriers to care faced by African American patients

According to the US Department of Health and Human Services, the 5 domains of social determinants of health are Economic Stability, Education Access and Quality, Health Care Access and Quality, Neighbor­hood and Built Environment, and Social and Community Context.¹ Patients who are African American face many socioeconomic barriers to access to psychiatric care, including economic inequality, inadequate knowledge about mental health, and deficient social environments. These barriers have a significant impact on the accessibility of psychiatric health care within this community, and they need to be addressed.

Jegede et al² discussed how financial woes and insecurity within the African American community contribute to health care inequalities and adverse health outcomes. According to the US Census Bureau,in 2020, compared to other ethnic groups, African American individuals had the lowest median income.³ Alang⁴ discussed how the stigma of mental health was a barrier among younger, college-educated individuals who are African American, and that those with higher education were more likely to minimize and report low treatment effectiveness. As clinicians, we often fail to discuss the effects the perceived social and cultural stigma of being diagnosed with a substance use or mental health disorder has on seeking care, treatment, and therapy by African American patients. The stigma of being judged by family members or the community and being seen as “weak” for seeking treatment has a detrimental impact on access to psychiatric care.² It is our duty as clinicians to understand these kinds of stigmas and seek ways to mitigate them within this community.

Also, we must not underestimate the importance of patients having access to transportation to treatment. We know that social support is integral to treatment, recovery, and relapse prevention. Chronic cycles of treatment and relapse can occur due to inadequate social support. Having access to a reliable driver—especially one who is a family member or member of the community—can be vital to establishing social support. Jegede et al² found that access to adequate transportation has proven therapeutic benefits and lessens the risk of relapse with decreased exposure to risky environments. We need to devise solutions to help patients find adequate and reliable transportation.

Clinicians should be culturally mindful and aware of the barriers to psychiatric care faced by patients who are African American. They should understand the importance of removing these barriers, and work to improve this population’s access to psychiatric care. Though this may be a daunting task that requires considerable time and resources, as health care providers, we can start the process by communicating and working with local politicians and community leaders. By working together, we can develop a plan to combat these socioeconomic barriers and provide access to psychiatric care within the African American community.

Craig Perry, MD

Elohor Otite, MD

Stacy Doumas, MD
 

Jersey Shore University Medical Center

Neptune, New Jersey

The perils of hubris

Dr. Nasrallah’s fascinating editorial on the psychiatric aspects of prominent individuals’ fall from grace (“From famous to infamous: Psychiatric aspects of the fall from grace,” From the Editor, Current Psychiatry, October 2021, p. 9-10,53) reminded me that the most trenchant insights and antidotes to hubris can more often be found in literature than in a diagnostic code. In Bonfire of the Vanities,¹ Tom’s Wolfe’s satire on 1980s New York, self-proclaimed “Master of the Universe” Sherman McCoy lives in a Park Avenue high rise and works as a bond trader “on Wall Street, fifty floors up … overlooking the world!” As quickly becomes apparent, Sherman’s altitude—both literal and figurative—merely serves as a greater distance from which to fall.

Perhaps fittingly, the phenomenon of self-destruction as a byproduct of success was most prominently “diagnosed” by business school professors, not physicians. The propensity for ethical failure at the apex of achievement was coined the “Bathsheba Syndrome,” in reference to the biblical tale of King David’s degenerative sequence of temptation, infidelity, deceit, and treachery while at the height of his power.² David’s transgressions are enabled by the very success he has achieved.³

One of my valued mentors had an interesting, albeit unscientific, method of mitigating hubris. When he was a senior military lawyer, or judge advocate (JAG), and I was a junior one, my mentor took me to a briefing in which he provided a legal overview to newly minted colonels assuming command billets. One of the functions of JAGs is to provide counsel and advice to commanders. As Dr. Nasrallah noted in his editorial, military leaders are by no means immune from the proverbial fall from grace, and arguably particularly susceptible to it. In beginning his remarks, my mentor offered his heartfelt congratulations to the attendees on their promotion and then proceeded to hand out a pocket mirror for them to pass around. He asked each officer to look in the mirror and personally confirm for him that they were just as unattractive today as they were yesterday.

Charles G. Kels, JD

Defense Health Agency

San Antonio, Texas



The views expressed in this letter are those of the author and do not necessarily reflect those of any government agency.

1. Wolfe T. Bonfire of the vanities. Farrar, Straus and Giroux; 1987.

2. Ludwig DC, Longenecker CO. The Bathsheba syndrome: the ethical failure of successful leaders. J Bus Ethics. 1993;12:265-273.

3. 2 Samuel 11-12.

I enjoyed Dr. Nasrallah’s editorial and his discussion of the dangers of hubris. This brought to mind the role of the auriga in ancient Rome: "the auriga was a slave with gladiator status, whose duty it was to drive a biga, the light vehicle powered by two horses, to transport some important Romans, mainly duces (military commanders). An auriga was a sort of “chauffeur” for important men and was carefully selected from among trustworthy slaves only. It has been supposed also that this name was given to the slave who held a laurel crown, during Roman Triumphs, over the head of the dux, standing at his back but continuously whispering in his ears “Memento Mori” (“remember you are mortal”) to prevent the celebrated commander from losing his sense of proportion in the excesses of the celebrations.”¹  

Continue to: Mark S. Komrad, MD...

Mark S. Komrad, MD

Faculty of Psychiatry

Johns Hopkins Hospital

University of Maryland

Tulane University

Towson, Maryland

Reference

1. Auriga (slave). Accessed November 9, 2021. https://en.wikipedia.org/wiki/Auriga_(slave)

Barriers to care faced by African American patients

According to the US Department of Health and Human Services, the 5 domains of social determinants of health are Economic Stability, Education Access and Quality, Health Care Access and Quality, Neighbor­hood and Built Environment, and Social and Community Context.¹ Patients who are African American face many socioeconomic barriers to access to psychiatric care, including economic inequality, inadequate knowledge about mental health, and deficient social environments. These barriers have a significant impact on the accessibility of psychiatric health care within this community, and they need to be addressed.

Jegede et al² discussed how financial woes and insecurity within the African American community contribute to health care inequalities and adverse health outcomes. According to the US Census Bureau,in 2020, compared to other ethnic groups, African American individuals had the lowest median income.³ Alang⁴ discussed how the stigma of mental health was a barrier among younger, college-educated individuals who are African American, and that those with higher education were more likely to minimize and report low treatment effectiveness. As clinicians, we often fail to discuss the effects the perceived social and cultural stigma of being diagnosed with a substance use or mental health disorder has on seeking care, treatment, and therapy by African American patients. The stigma of being judged by family members or the community and being seen as “weak” for seeking treatment has a detrimental impact on access to psychiatric care.² It is our duty as clinicians to understand these kinds of stigmas and seek ways to mitigate them within this community.

Also, we must not underestimate the importance of patients having access to transportation to treatment. We know that social support is integral to treatment, recovery, and relapse prevention. Chronic cycles of treatment and relapse can occur due to inadequate social support. Having access to a reliable driver—especially one who is a family member or member of the community—can be vital to establishing social support. Jegede et al² found that access to adequate transportation has proven therapeutic benefits and lessens the risk of relapse with decreased exposure to risky environments. We need to devise solutions to help patients find adequate and reliable transportation.

Clinicians should be culturally mindful and aware of the barriers to psychiatric care faced by patients who are African American. They should understand the importance of removing these barriers, and work to improve this population’s access to psychiatric care. Though this may be a daunting task that requires considerable time and resources, as health care providers, we can start the process by communicating and working with local politicians and community leaders. By working together, we can develop a plan to combat these socioeconomic barriers and provide access to psychiatric care within the African American community.

Craig Perry, MD

Elohor Otite, MD

Stacy Doumas, MD
 

Jersey Shore University Medical Center

Neptune, New Jersey

In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.¹ For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box^1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.

Box

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.⁵ Quiroz et al⁶ provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.⁶  

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

• tremor
• renal dysfunction, including renal insufficiency and polyuria or polydipsia
• hypothyroidism
• hyperparathyroidism (with subsequent hypercalcemia)
• weight gain
• gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.⁷ However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.⁷ Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.⁸ A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.⁹ Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.⁹ Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.⁹ Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.⁹

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.⁸ Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...

Lithium use during pregnancy

When considering lithium for a woman who is pregnant, it is important to weigh the potential teratogenic risks against the benefit of successful management of the mood disorder. Ebstein’s anomaly (abnormal tricuspid valve leaflets) is the most well-known teratogenic risk associated with lithium, with an estimated absolute risk of 1 in 1,000 in patients treated with lithium compared with 1 in 20,000 in controls.^10,11 The risk of congenital anomalies is increased in infants exposed to lithium in utero (4% to 12% vs 2% to 4% in controls)¹²; exposure during the first trimester of pregnancy is associated with increased risk. Lithium levels must be adjusted during pregnancy. Pregnant patients are at higher risk of relapse to mania because renal lithium clearance increases by 30% to 50% during pregnancy, and normalizes shortly after delivery.¹³

Lithium exposure during pregnancy has been linked to increased risk of miscarriage and preterm delivery; however, more research is needed to define the true risk of noncardiac teratogenicity associated with lithium.¹¹ Because there is a lack of definitive data regarding teratogenicity, and because of lithium’s well-documented effectiveness in mood disorders, lithium should be considered a first-line therapy for pregnant patients with bipolar disorder.¹⁰

Prescribing trends

Despite data showing the efficacy and benefits of lithium, there has been a paradoxical decrease in lithium prescribing. This is the result of multiple factors, including fear of adverse effects and lithium toxicity and a shift toward newer medications, such as anticonvulsants and antipsychotics, for treatment and prophylaxis of mania.

A 2011 study examined prescribing trends for bipolar disorder in the United Kingdom.¹⁴ Overall, it found increased usage of valproate, carbamazepine, and lamotrigine from 1995 to 2009. During that time, lithium prescribing mostly remained steady at approximately 30%, whereas valproate use increased from 0% to 22.7%. Overall, antipsychotic and valproate prescribing increased relative to lithium.¹⁴ A literature review¹⁵ analyzed 6 studies of lithium prescribing trends from 1950 to 2010. Four of these studies (2 in the United States, 1 in Canada, and 1 in German-Swiss-Austrian hospitals) found lithium use was declining. The increased use found in Italy and Spain was attributed to multiple factors, including a broader definition of bipolar disorders and the unavailability of valproate in Spain, lithium’s low cost, and mental health reforms in both countries that resulted in overall increased psychotropic prescribing. Decreased lithium use was attributed to increased use of valproate and second-generation antipsychotics, lack of clinician training in lithium therapy, and aggressive marketing of brand-name medications.¹⁵
 

Reduced suicides, possible protection against dementia

A 2013 meta-analysis of 48 randomized controlled trials (RCTs) that included a total of 6,674 patients with mood disorders indicated that compared with placebo, lithium was more effective in reducing suicides and deaths from any cause.¹⁶

Large retrospective studies have demonstrated that compared with valproate, lithium has superior anti-suicide properties.¹⁷ Researchers found that risk of suicide attempt or completion was 1.5 to 3 times higher during periods of valproate treatment compared with lithium.¹⁸ Both short- and long-term lithium use was associated with decreased non-suicide mortality compared with valproate.¹⁹ In Denmark, compared with valproate, lithium was associated with fewer psychiatric hospital admissions.¹⁹ One RCT, the BALANCE trial, showed that lithium (alone or in combination with valproate) is more likely to prevent relapse in persons with bipolar I disorder than valproate monotherapy.²⁰

Recent research in Denmark suggests that long-term doses of naturally occurring lithium in drinking water might confer some level of protection against dementia.²¹ Researchers examined the Danish National Patient Register to determine where participants lived and their local water supply. Drinking water lithium levels were assessed, and the mean lithium level for each municipality was calculated. This case-control study selected patients with dementia and 10 age- and sex-matched controls.²¹

Researchers found that the incidence rate ratio of Alzheimer disease, vascular dementia, and dementia overall was significantly lower among individuals whose drinking water contained lithium, 15.1 to 27.0 µg/L, compared with those whose water had lithium levels 2.0 to 5.0 µg/L.²¹ Although this study does not prove causality, it opens the door for continued research on lithium as a neuroprotective agent involved in pathways beyond mood stabilization.

Why should you prescribe lithium?

Lithium, which is available in several formulations (Table), should continue to be first-line pharmacotherapy for treating acute mood episodes, prophylaxis, and suicide prevention in bipolar disorder. Although there are many effective medications for treating bipolar disorder—such as second-generation antipsychotics that are available as a long-acting injectable formulation or can be combined with a mood stabilizer—lithium is a thoroughly researched medication with a long history of effectiveness for managing bipolar disorder. As is the case with all psychotropic medications, lithium has adverse effects and necessary precautions, but these are outweighed by its neuroprotective benefits and efficacy. Research has demonstrated that lithium outperforms medications that have largely replaced it, specifically valproate.

Related Resources

• Ali ZA, El-Mallakh RS. Lithium and kidney disease: Understand the risks. Current Psychiatry. 2021;20(6):34- 38,50. doi:10.12788/cp.0130
• Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217: 266-280. doi:10.1016/j.jad.2017.03.052

Drug Brand Names

Carbamazepine • Tegretol

Lamotrigine • Lamictal

Lithium • Eskalith, Lithobid

Valproate • Depacon, Depakote, Depakene

Bottom Line

Lithium is a well-researched first-line pharmacotherapy for bipolar disorder, with efficacy equivalent to—or superior to—newer pharmacotherapies such as valproate and second-generation antipsychotics. When prescribing lithium, carefully monitor patients for symptoms of adverse effects or toxicity. Despite teratogenic risks, lithium can be considered for pregnant patients with bipolar disorder.

In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.¹ For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box^1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.

Box

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.⁵ Quiroz et al⁶ provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.⁶  

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

• tremor
• renal dysfunction, including renal insufficiency and polyuria or polydipsia
• hypothyroidism
• hyperparathyroidism (with subsequent hypercalcemia)
• weight gain
• gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.⁷ However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.⁷ Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.⁸ A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.⁹ Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.⁹ Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.⁹ Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.⁹

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.⁸ Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...

Lithium use during pregnancy

When considering lithium for a woman who is pregnant, it is important to weigh the potential teratogenic risks against the benefit of successful management of the mood disorder. Ebstein’s anomaly (abnormal tricuspid valve leaflets) is the most well-known teratogenic risk associated with lithium, with an estimated absolute risk of 1 in 1,000 in patients treated with lithium compared with 1 in 20,000 in controls.^10,11 The risk of congenital anomalies is increased in infants exposed to lithium in utero (4% to 12% vs 2% to 4% in controls)¹²; exposure during the first trimester of pregnancy is associated with increased risk. Lithium levels must be adjusted during pregnancy. Pregnant patients are at higher risk of relapse to mania because renal lithium clearance increases by 30% to 50% during pregnancy, and normalizes shortly after delivery.¹³

Lithium exposure during pregnancy has been linked to increased risk of miscarriage and preterm delivery; however, more research is needed to define the true risk of noncardiac teratogenicity associated with lithium.¹¹ Because there is a lack of definitive data regarding teratogenicity, and because of lithium’s well-documented effectiveness in mood disorders, lithium should be considered a first-line therapy for pregnant patients with bipolar disorder.¹⁰

Prescribing trends

Despite data showing the efficacy and benefits of lithium, there has been a paradoxical decrease in lithium prescribing. This is the result of multiple factors, including fear of adverse effects and lithium toxicity and a shift toward newer medications, such as anticonvulsants and antipsychotics, for treatment and prophylaxis of mania.

A 2011 study examined prescribing trends for bipolar disorder in the United Kingdom.¹⁴ Overall, it found increased usage of valproate, carbamazepine, and lamotrigine from 1995 to 2009. During that time, lithium prescribing mostly remained steady at approximately 30%, whereas valproate use increased from 0% to 22.7%. Overall, antipsychotic and valproate prescribing increased relative to lithium.¹⁴ A literature review¹⁵ analyzed 6 studies of lithium prescribing trends from 1950 to 2010. Four of these studies (2 in the United States, 1 in Canada, and 1 in German-Swiss-Austrian hospitals) found lithium use was declining. The increased use found in Italy and Spain was attributed to multiple factors, including a broader definition of bipolar disorders and the unavailability of valproate in Spain, lithium’s low cost, and mental health reforms in both countries that resulted in overall increased psychotropic prescribing. Decreased lithium use was attributed to increased use of valproate and second-generation antipsychotics, lack of clinician training in lithium therapy, and aggressive marketing of brand-name medications.¹⁵
 

Reduced suicides, possible protection against dementia

A 2013 meta-analysis of 48 randomized controlled trials (RCTs) that included a total of 6,674 patients with mood disorders indicated that compared with placebo, lithium was more effective in reducing suicides and deaths from any cause.¹⁶

Large retrospective studies have demonstrated that compared with valproate, lithium has superior anti-suicide properties.¹⁷ Researchers found that risk of suicide attempt or completion was 1.5 to 3 times higher during periods of valproate treatment compared with lithium.¹⁸ Both short- and long-term lithium use was associated with decreased non-suicide mortality compared with valproate.¹⁹ In Denmark, compared with valproate, lithium was associated with fewer psychiatric hospital admissions.¹⁹ One RCT, the BALANCE trial, showed that lithium (alone or in combination with valproate) is more likely to prevent relapse in persons with bipolar I disorder than valproate monotherapy.²⁰

Recent research in Denmark suggests that long-term doses of naturally occurring lithium in drinking water might confer some level of protection against dementia.²¹ Researchers examined the Danish National Patient Register to determine where participants lived and their local water supply. Drinking water lithium levels were assessed, and the mean lithium level for each municipality was calculated. This case-control study selected patients with dementia and 10 age- and sex-matched controls.²¹

Researchers found that the incidence rate ratio of Alzheimer disease, vascular dementia, and dementia overall was significantly lower among individuals whose drinking water contained lithium, 15.1 to 27.0 µg/L, compared with those whose water had lithium levels 2.0 to 5.0 µg/L.²¹ Although this study does not prove causality, it opens the door for continued research on lithium as a neuroprotective agent involved in pathways beyond mood stabilization.

Why should you prescribe lithium?

Lithium, which is available in several formulations (Table), should continue to be first-line pharmacotherapy for treating acute mood episodes, prophylaxis, and suicide prevention in bipolar disorder. Although there are many effective medications for treating bipolar disorder—such as second-generation antipsychotics that are available as a long-acting injectable formulation or can be combined with a mood stabilizer—lithium is a thoroughly researched medication with a long history of effectiveness for managing bipolar disorder. As is the case with all psychotropic medications, lithium has adverse effects and necessary precautions, but these are outweighed by its neuroprotective benefits and efficacy. Research has demonstrated that lithium outperforms medications that have largely replaced it, specifically valproate.

Related Resources

• Ali ZA, El-Mallakh RS. Lithium and kidney disease: Understand the risks. Current Psychiatry. 2021;20(6):34- 38,50. doi:10.12788/cp.0130
• Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217: 266-280. doi:10.1016/j.jad.2017.03.052

Drug Brand Names

Carbamazepine • Tegretol

Lamotrigine • Lamictal

Lithium • Eskalith, Lithobid

Valproate • Depacon, Depakote, Depakene

Bottom Line

Lithium is a well-researched first-line pharmacotherapy for bipolar disorder, with efficacy equivalent to—or superior to—newer pharmacotherapies such as valproate and second-generation antipsychotics. When prescribing lithium, carefully monitor patients for symptoms of adverse effects or toxicity. Despite teratogenic risks, lithium can be considered for pregnant patients with bipolar disorder.

In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.¹ For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box^1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.

Box

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.⁵ Quiroz et al⁶ provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.⁶  

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

• tremor
• renal dysfunction, including renal insufficiency and polyuria or polydipsia
• hypothyroidism
• hyperparathyroidism (with subsequent hypercalcemia)
• weight gain
• gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.⁷ However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.⁷ Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.⁸ A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.⁹ Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.⁹ Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.⁹ Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.⁹

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.⁸ Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...

Lithium use during pregnancy

When considering lithium for a woman who is pregnant, it is important to weigh the potential teratogenic risks against the benefit of successful management of the mood disorder. Ebstein’s anomaly (abnormal tricuspid valve leaflets) is the most well-known teratogenic risk associated with lithium, with an estimated absolute risk of 1 in 1,000 in patients treated with lithium compared with 1 in 20,000 in controls.^10,11 The risk of congenital anomalies is increased in infants exposed to lithium in utero (4% to 12% vs 2% to 4% in controls)¹²; exposure during the first trimester of pregnancy is associated with increased risk. Lithium levels must be adjusted during pregnancy. Pregnant patients are at higher risk of relapse to mania because renal lithium clearance increases by 30% to 50% during pregnancy, and normalizes shortly after delivery.¹³

Lithium exposure during pregnancy has been linked to increased risk of miscarriage and preterm delivery; however, more research is needed to define the true risk of noncardiac teratogenicity associated with lithium.¹¹ Because there is a lack of definitive data regarding teratogenicity, and because of lithium’s well-documented effectiveness in mood disorders, lithium should be considered a first-line therapy for pregnant patients with bipolar disorder.¹⁰

Prescribing trends

Despite data showing the efficacy and benefits of lithium, there has been a paradoxical decrease in lithium prescribing. This is the result of multiple factors, including fear of adverse effects and lithium toxicity and a shift toward newer medications, such as anticonvulsants and antipsychotics, for treatment and prophylaxis of mania.

A 2011 study examined prescribing trends for bipolar disorder in the United Kingdom.¹⁴ Overall, it found increased usage of valproate, carbamazepine, and lamotrigine from 1995 to 2009. During that time, lithium prescribing mostly remained steady at approximately 30%, whereas valproate use increased from 0% to 22.7%. Overall, antipsychotic and valproate prescribing increased relative to lithium.¹⁴ A literature review¹⁵ analyzed 6 studies of lithium prescribing trends from 1950 to 2010. Four of these studies (2 in the United States, 1 in Canada, and 1 in German-Swiss-Austrian hospitals) found lithium use was declining. The increased use found in Italy and Spain was attributed to multiple factors, including a broader definition of bipolar disorders and the unavailability of valproate in Spain, lithium’s low cost, and mental health reforms in both countries that resulted in overall increased psychotropic prescribing. Decreased lithium use was attributed to increased use of valproate and second-generation antipsychotics, lack of clinician training in lithium therapy, and aggressive marketing of brand-name medications.¹⁵
 

Reduced suicides, possible protection against dementia

A 2013 meta-analysis of 48 randomized controlled trials (RCTs) that included a total of 6,674 patients with mood disorders indicated that compared with placebo, lithium was more effective in reducing suicides and deaths from any cause.¹⁶

Large retrospective studies have demonstrated that compared with valproate, lithium has superior anti-suicide properties.¹⁷ Researchers found that risk of suicide attempt or completion was 1.5 to 3 times higher during periods of valproate treatment compared with lithium.¹⁸ Both short- and long-term lithium use was associated with decreased non-suicide mortality compared with valproate.¹⁹ In Denmark, compared with valproate, lithium was associated with fewer psychiatric hospital admissions.¹⁹ One RCT, the BALANCE trial, showed that lithium (alone or in combination with valproate) is more likely to prevent relapse in persons with bipolar I disorder than valproate monotherapy.²⁰

Recent research in Denmark suggests that long-term doses of naturally occurring lithium in drinking water might confer some level of protection against dementia.²¹ Researchers examined the Danish National Patient Register to determine where participants lived and their local water supply. Drinking water lithium levels were assessed, and the mean lithium level for each municipality was calculated. This case-control study selected patients with dementia and 10 age- and sex-matched controls.²¹

Researchers found that the incidence rate ratio of Alzheimer disease, vascular dementia, and dementia overall was significantly lower among individuals whose drinking water contained lithium, 15.1 to 27.0 µg/L, compared with those whose water had lithium levels 2.0 to 5.0 µg/L.²¹ Although this study does not prove causality, it opens the door for continued research on lithium as a neuroprotective agent involved in pathways beyond mood stabilization.

Why should you prescribe lithium?

Lithium, which is available in several formulations (Table), should continue to be first-line pharmacotherapy for treating acute mood episodes, prophylaxis, and suicide prevention in bipolar disorder. Although there are many effective medications for treating bipolar disorder—such as second-generation antipsychotics that are available as a long-acting injectable formulation or can be combined with a mood stabilizer—lithium is a thoroughly researched medication with a long history of effectiveness for managing bipolar disorder. As is the case with all psychotropic medications, lithium has adverse effects and necessary precautions, but these are outweighed by its neuroprotective benefits and efficacy. Research has demonstrated that lithium outperforms medications that have largely replaced it, specifically valproate.

Related Resources

• Ali ZA, El-Mallakh RS. Lithium and kidney disease: Understand the risks. Current Psychiatry. 2021;20(6):34- 38,50. doi:10.12788/cp.0130
• Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord. 2017;217: 266-280. doi:10.1016/j.jad.2017.03.052

Drug Brand Names

Carbamazepine • Tegretol

Lamotrigine • Lamictal

Lithium • Eskalith, Lithobid

Valproate • Depacon, Depakote, Depakene

Bottom Line

Lithium is a well-researched first-line pharmacotherapy for bipolar disorder, with efficacy equivalent to—or superior to—newer pharmacotherapies such as valproate and second-generation antipsychotics. When prescribing lithium, carefully monitor patients for symptoms of adverse effects or toxicity. Despite teratogenic risks, lithium can be considered for pregnant patients with bipolar disorder.

CASE A long history of suicidality

Mr. X, age 26, who has a history of bipolar II disorder and multiple inpatient admissions, presents to a state hospital after a suicide attempt by gunshot. He reports that throughout his lifetime, he has had >20 suicide attempts, often by overdose.

Mr. X is admitted to the hospital under a temporary detention order. He is initially adherent and cooperative with his psychiatric evaluations.

HISTORY Chronic physical and emotional pain

Mr. X is single, unemployed, and lives with his mother and nephew. He was diagnosed with bipolar II disorder during adolescence and receives sertraline, 50 mg twice a day, and lamotrigine, 100 mg twice a day, to which he reports adherence. He also was taking clonazepam and zolpidem, dosages unknown.

His medical history is significant for severe childhood liver disease and inflammatory bowel disease. He dropped out of school during high school due to his multiple medical conditions, which resulted in a significantly diminished overall childhood experience, interrupted developmental trajectory, and chronic physical and emotional pain. He has never been employed and receives financial support through disability benefits. He spends his days on the internet or watching television. He reports daily cigarette and marijuana use and occasional alcohol use, but no other substance use. His mother helps manage his medical conditions and is his main support. His biological father was abusive towards his mother and absent for most of Mr. X’s life. Beyond his mother and therapist, Mr. X has minimal other interpersonal interactions, and reports feeling isolated, lonely, and frustrated.

EVALUATION Agitated and aggressive while hospitalized

Upon learning that he is being involuntarily committed, Mr. X becomes physically aggressive, makes verbal threats, and throws objects across his room. He is given diphenhydramine, 50 mg, haloperidol, 5 mg, and lorazepam, 2 mg, all of which are ordered on an as-needed basis. Mr. X is placed in an emergency restraint chair and put in seclusion. The episode resolves within an hour with reassurance and attention from the treatment team; the rapid escalation from and return to a calmer state is indicative of situational, stress-induced mood lability and impulsivity. Mr. X is counseled on maintaining safety and appropriate behavior, and is advised to ask for medication if he feels agitated or unable to control his behaviors. To maintain safe and appropriate behavior, he requires daily counseling and expectation management regarding his treatment timeline. No further aggressive incidents are noted throughout his hospitalization, and he requires only minimal use of the as-needed medications.

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The authors’ observations

The least appropriate therapy for Mr. X would be exposure and response prevention, which allows patients to face their fears without the need to soothe or relieve related feelings with a compulsive act. It is designed to improve specific behavioral deficits most often associated with obsessive-compulsive disorder, a diagnosis inconsistent with Mr. X’s history and presentation. Trauma-focused CBT could facilitate healing from Mr. X’s childhood trauma/adverse childhood experiences, and DBT might help with his anger, maladaptive coping strategies, and chronic suicidality. Motivational interviewing might help with his substance use and his apparent lack of motivation for other forms of social engagement, including seeking employment.

Based on Mr. X’s history of trauma and chronic physical and emotional pain, the treatment team reevaluated him and reconsidered his original diagnosis.

Continue to: EVALUATION A closer look at the diagnosis...

After meeting with Mr. X, the treatment team begins to piece together a more robust picture of him. They review his childhood trauma involving his biological father, his chronic and limiting medical illnesses, and his restricted and somewhat regressive level of functioning. Further, they consider his >20 suicide attempts, numerous psychiatric hospitalizations, and mood and behavioral lability and reactivity. Based on its review, the treatment team concludes that a diagnosis of bipolar disorder II or major depressive disorder is not fully adequate to describe Mr. X’s clinical picture.

At no point during his hospitalization does Mr. X meet full criteria for a major depressive episode or display mania or hypomania. The treatment team considers posttraumatic stress disorder (PTSD) in the setting of chronic, repetitive trauma given Mr. X’s nightmares, dissociative behavior, anger, negative cognitions, and intrusive symptoms. However, not all his symptoms fall within the diagnostic criteria of PTSD. There are also elements of borderline personality disorder in Mr. X’s history, most notably his multiple suicide attempts, emotional lability, and disrupted interpersonal attachments. In this context, a diagnosis of complex PTSD (CPTSD) seems most appropriate in capturing the array of trauma-related symptoms with which he presents. 

Complex PTSD

Since at least the early to mid-1990s, there has been recognition of a qualitatively distinct clinical picture that can emerge when an individual’s exposure to trauma or adversity is chronic or repetitive, causing not only familiar PTSD symptomatology but also alterations in self-perception, interpersonal functioning, and affective instability. Complex PTSD was first described by Judith Herman, MD, in 1992 as a distinct entity from PTSD.¹ She theorized that PTSD derives primarily from singular traumatic events, while a distinct clinical syndrome might arise after prolonged, repeated trauma.¹ A diagnosis of CPTSD might arise in situations with more chronicity than a classic single circumscribed traumatic event, such as being held in captivity, under the control of perpetrators for extended periods of time, imprisoned, or subject to prolonged sexual abuse. Herman’s description of CPTSD identifies 3 areas of psychopathology that extend beyond PTSD¹:

• symptomatic refers to the complex, diffuse, and tenacious symptom presentation
• characterological focuses on the personality changes in terms of dissociation, ego-fragmentation, and identity complications
• vulnerability describes characteristic repeated harm with respect to self-mutilation or other self-injurious behaviors, and suicidality.

Taxometrics, official recognition, and controversy

Complex PTSD was proposed for inclusion in DSM-IV as “Disorders of Extreme Stress Not Otherwise Specified,” or DESNOS. Reportedly, it was interpreted as a severe presentation of PTSD, and therefore not included in the manual as a separate diagnosis.² In contrast, ICD-10 included a CPTSD-like entity of “Enduring Personality Change After Catastrophic Event” (EPCACE). Although the existence of CPTSD as a categorically distinct diagnosis in the psychiatric mainstream has been debated and discussed for years, with many arguably unaware of its existence, clinicians and researchers specializing in trauma are well-versed in its clinical utility. As such, CPTSD was again discussed during the development of DSM-5. In an apparent attempt to balance this clinical utility with ongoing concerns about its validity as a diagnostically distinct syndrome, DSM-5 did not officially recognize CPTSD, but added several criteria to PTSD referencing changes in self-perception, affective instability, and dysphoria, as well as a dissociative subtype, effectively expanding the scope of a PTSD diagnosis to also include CPTSD symptoms when applicable. ICD-11 has taken a different direction, and officially recognizes CPTSD as a distinct diagnosis.

ICD-11 presents CPTSD as a “sibling” disorder, which it distinguishes from PTSD with high levels of dissociation, depression, and borderline personality disorder traits.³ Within this framework, the diagnosis of CPTSD requires that the PTSD criteria be met in addition to symptoms that fall into a “disturbances of self-organization” category. When parsing the symptoms of the “disturbances of self-organization” category, the overlap with borderline personality disorder symptoms is apparent.⁴ This overlap has given rise to yet another controversy regarding CPTSD’s categorical validity; in addition to its distinctness from PTSD, its distinctness from borderline personality disorder has also been debated. In a study examining the similarity between CPTSD and borderline personality disorder, Jowett et al⁵ concluded that CPTSD was associated with greater exposure to multiple traumas earlier in life and resulted in higher functional impairment than borderline personality disorder, ultimately supporting CPTSD as a separate entity with features that overlap borderline personality disorder.⁵ According to Ford and Courtois⁶ “the evidence ... suggests that a sub-group of BPD patients—who often but not always have comorbid PTSD—may be best understood and treated if CPTSD is explicitly addressed as well—and in some cases, in lieu of—BPD.”

PTSD and CPTSD may therefore both be understood to fall within a spectrum of trauma diagnoses; this paradigm postulates that there exists a wide variety of posttraumatic patient presentations, perhaps on a continuum. On the less severe side of the trauma spectrum, the symptoms traditionally seen and characterized as PTSD (such as hypervigilance, nightmares, and flashbacks) may be found, while, with increasingly severe or prolonged trauma, there may be a tendency to see more complex elements (such as dissociation, personality changes mimicking borderline personality disorder, depression, anxiety, self-injurious behavior, and suicidality).⁷ Nevertheless, controversy about discriminant validity still exists. A review article by Resnick et al⁸ argued that the existing evidence is not strong enough to support CPTSD as a standalone entity. However, Resnick et al⁸ agreed that a singular PTSD diagnosis has limitations, and that there is a need for more research in the field of trauma psychiatry.

Continue to: Utility of the diagnostic conceptualization...

Although the controversy surrounding the distinction of CPTSD demands categorical clarity with respect to PTSD and borderline personality disorder as a means of resolution, the diagnosis has practical applications that should not limit its use in clinical formulation or treatment planning. Comorbid diagnoses do not prevent clinicians from diagnosing and treating patients who present with complicated manifestations of trauma.⁹ In fact, having overlapping diagnoses would highlight the array of patient presentations that can be seen in the posttraumatic condition. Furthermore, in the pursuit of individualized care approaches, the addition of CPTSD as a diagnostic conception would allow for more integrated treatment options using a multi-modular approach.¹⁰

The addition of CPTSD as a diagnosis is helpful in determining the etiology of a patient’s presentation and therefore formulating the most appropriate treatment plan. While the 2-pronged approach of psychopharmacology and therapy is the central dogma of psychiatric care, there are many specific options to consider for each. By viewing such patients through the lens of trauma as opposed to depression and anxiety, there is a clear shift in treatment that has the potential to make more lasting impacts and progress.¹¹

CPTSD may coexist with PTSD, but it extends beyond it to include a pleomorphic symptom picture encompassing personality changes and a high risk for repeated harm. Failure to correctly classify a patient’s presentation as a response to repetitive, prolonged trauma may result in discrimination and inappropriate or ineffective treatment recommendations.

For a comparison of the diagnostic criteria of PTSD, CPTSD, and borderline personality disorder, see Table 1¹², Table 2,^13,14, and Table 3¹².

Patients with CPTSD

One of the authors (NR) has cared for several similar individuals presenting for treatment with vague diagnoses of “chronic depression and anxiety” for years, sometimes with a speculative bipolar disorder diagnosis due to situational mood swings or reactivity, and a generally poor response to both medications and psychotherapy. These patients were frustrated because none of the diagnoses seemed to fully “fit” with their pattern of symptoms or subjective experience, and treatment seemed minimally helpful. Very often, their social history revealed a variety of adversities or traumatic events, such as childhood sexual or physical abuse, a home environment plagued by domestic violence, or being raised by one or both parents with their own history of trauma, or perhaps a personality or substance use disorder. Although many of these patients’ symptom profiles aligned only partially with “typical” PTSD, they were often better captured by CPTSD, with a focus on negative self-perception and impact on close relationships. Helping the patient “connect the dots” to create a more continuous narrative, and consequently reconceptualizing the diagnosis as a complex trauma disorder, has proven effective in a number of these cases, allowing the patient to make sense of their symptoms in the context of their personal history, reducing stigma, and allowing for different avenues with medication, therapy, and self-understanding. It can also help to validate the impact of a patient’s adverse experiences and encourage a patient to view their symptoms as an understandable or even once-adaptive response to traumatic stress, rather than a sign of personal weakness or defectiveness.

TREATMENT A trauma-focused approach

Once the treatment team considersMr. X’s significant childhood trauma and recon­ceptualizes his behaviors through this lens, treatment is adjusted accordingly. His significant reactivity, dissociative symptoms, social impairment, and repeated suicide attempts are better understood and have more significance through a trauma lens, which provides a better explanation than a primary mood disorder.

Therapeutic interventions in the hospital are tailored according to the treatment team’s new insight. Specific DBT skills are practiced, insight-oriented therapy and motivational interviewing are used, and Mr. X and his therapist begin to explore his trauma, both from his biological father and from his intense stressors experienced because of his medical issues.

Mr. X’s mother, who is very involved in his care, is provided with education on this conceptualization and given instruction on trauma-focused therapies in the outpatient setting. While Mr. X’s medication regimen is not changed significantly, for some patients, the reformulation from a primary mood or anxiety disorder to a trauma disorder might require a change in the pharmacotherapy regimen to address behavioral symptoms such as mood reactivity or issues with sleep.

OUTCOME Decreased intensity of suicidal thoughts

By the time of discharge, Mr. X has maintained safety, with no further outbursts, and subjectively reports feeling more understood and validated. Although chronic suicidal ideation can take months or years of treatment to resolve, at the time of discharge Mr. X reports a decreased intensity of these thoughts, and no acute suicidal ideation, plan, or intent. His discharge planning emphasizes ongoing work specifically related to coping with symptoms of traumatic stress, and the involvement of his main social support in facilitating this work.

The authors’ observations

As a caveat, it may be in some cases that chronic negative affect, dysphoria, and self-perception are better understood as a comorbid depressive disorder rather than subsumed into a PTSD/ CPTSD diagnosis. Also, because situational mood instability and impulsivity are often interpreted as bipolar disorder, a history of hypomania and mania should be ruled out. In Mr. X’s case, the diagnostic reformulation did not significantly impact pharmacotherapy because the target symptoms of mood instability, irritability, anxiety, and depression remained, despite the change in diagnosis.

Although the DSM-5 PTSD criteria effectively incorporate many CPTSD elements, we argue that this inclusivity comes at the expense of appreciating CPTSD as a qualitatively distinct condition, and we prefer ICD-11’s recognition of CPTSD as a separate diagnosis that incorporates PTSD criteria but extends the definition to include negative self-concept, affect dysregulation, and interpersonal difficulties.

Related Resources

• US Department of Veterans Affairs. PTSD: National Center for PTSD. Published January 1, 2007. https://www.ptsd.va.gov/ professional/treat/essentials/complex_ptsd.asp
• Jowett S, Karatzias T, Shevlin M, et al. Differentiating symptom profiles of ICD-11 PTSD, complex PTSD, and borderline personality disorder: a latent class analysis in a multiply traumatized sample. Personality disorders: theory, research, and treatment. 2020;11(1):36.

Drug Brand Names

Clonazepam • Klonopin

Haloperidol • Haldol

Lamotrigine • Lamictal

Lorazepam • Ativan

Sertraline • Zoloft

Zolpidem • Ambien

Bottom Line

Consider a diagnosis of complex posttraumatic stress disorder (CPTSD) when providing care for patients with chronic depression and suicidality with a history of trauma or childhood adversity. This reformulation can allow clinicians to understand the contributing factors more holistically; align with the patient more effectively; appreciate past and present interpersonal, psychological, and psychosocial factors that may precipitate and perpetuate symptoms; and allow for treatment recommendations beyond those of mood and anxiety disorders.

CASE A long history of suicidality

Mr. X, age 26, who has a history of bipolar II disorder and multiple inpatient admissions, presents to a state hospital after a suicide attempt by gunshot. He reports that throughout his lifetime, he has had >20 suicide attempts, often by overdose.

Mr. X is admitted to the hospital under a temporary detention order. He is initially adherent and cooperative with his psychiatric evaluations.

HISTORY Chronic physical and emotional pain

Mr. X is single, unemployed, and lives with his mother and nephew. He was diagnosed with bipolar II disorder during adolescence and receives sertraline, 50 mg twice a day, and lamotrigine, 100 mg twice a day, to which he reports adherence. He also was taking clonazepam and zolpidem, dosages unknown.

His medical history is significant for severe childhood liver disease and inflammatory bowel disease. He dropped out of school during high school due to his multiple medical conditions, which resulted in a significantly diminished overall childhood experience, interrupted developmental trajectory, and chronic physical and emotional pain. He has never been employed and receives financial support through disability benefits. He spends his days on the internet or watching television. He reports daily cigarette and marijuana use and occasional alcohol use, but no other substance use. His mother helps manage his medical conditions and is his main support. His biological father was abusive towards his mother and absent for most of Mr. X’s life. Beyond his mother and therapist, Mr. X has minimal other interpersonal interactions, and reports feeling isolated, lonely, and frustrated.

EVALUATION Agitated and aggressive while hospitalized

Upon learning that he is being involuntarily committed, Mr. X becomes physically aggressive, makes verbal threats, and throws objects across his room. He is given diphenhydramine, 50 mg, haloperidol, 5 mg, and lorazepam, 2 mg, all of which are ordered on an as-needed basis. Mr. X is placed in an emergency restraint chair and put in seclusion. The episode resolves within an hour with reassurance and attention from the treatment team; the rapid escalation from and return to a calmer state is indicative of situational, stress-induced mood lability and impulsivity. Mr. X is counseled on maintaining safety and appropriate behavior, and is advised to ask for medication if he feels agitated or unable to control his behaviors. To maintain safe and appropriate behavior, he requires daily counseling and expectation management regarding his treatment timeline. No further aggressive incidents are noted throughout his hospitalization, and he requires only minimal use of the as-needed medications.

[polldaddy:10983392]

The authors’ observations

The least appropriate therapy for Mr. X would be exposure and response prevention, which allows patients to face their fears without the need to soothe or relieve related feelings with a compulsive act. It is designed to improve specific behavioral deficits most often associated with obsessive-compulsive disorder, a diagnosis inconsistent with Mr. X’s history and presentation. Trauma-focused CBT could facilitate healing from Mr. X’s childhood trauma/adverse childhood experiences, and DBT might help with his anger, maladaptive coping strategies, and chronic suicidality. Motivational interviewing might help with his substance use and his apparent lack of motivation for other forms of social engagement, including seeking employment.

Based on Mr. X’s history of trauma and chronic physical and emotional pain, the treatment team reevaluated him and reconsidered his original diagnosis.

Continue to: EVALUATION A closer look at the diagnosis...

After meeting with Mr. X, the treatment team begins to piece together a more robust picture of him. They review his childhood trauma involving his biological father, his chronic and limiting medical illnesses, and his restricted and somewhat regressive level of functioning. Further, they consider his >20 suicide attempts, numerous psychiatric hospitalizations, and mood and behavioral lability and reactivity. Based on its review, the treatment team concludes that a diagnosis of bipolar disorder II or major depressive disorder is not fully adequate to describe Mr. X’s clinical picture.

At no point during his hospitalization does Mr. X meet full criteria for a major depressive episode or display mania or hypomania. The treatment team considers posttraumatic stress disorder (PTSD) in the setting of chronic, repetitive trauma given Mr. X’s nightmares, dissociative behavior, anger, negative cognitions, and intrusive symptoms. However, not all his symptoms fall within the diagnostic criteria of PTSD. There are also elements of borderline personality disorder in Mr. X’s history, most notably his multiple suicide attempts, emotional lability, and disrupted interpersonal attachments. In this context, a diagnosis of complex PTSD (CPTSD) seems most appropriate in capturing the array of trauma-related symptoms with which he presents. 

Complex PTSD

Since at least the early to mid-1990s, there has been recognition of a qualitatively distinct clinical picture that can emerge when an individual’s exposure to trauma or adversity is chronic or repetitive, causing not only familiar PTSD symptomatology but also alterations in self-perception, interpersonal functioning, and affective instability. Complex PTSD was first described by Judith Herman, MD, in 1992 as a distinct entity from PTSD.¹ She theorized that PTSD derives primarily from singular traumatic events, while a distinct clinical syndrome might arise after prolonged, repeated trauma.¹ A diagnosis of CPTSD might arise in situations with more chronicity than a classic single circumscribed traumatic event, such as being held in captivity, under the control of perpetrators for extended periods of time, imprisoned, or subject to prolonged sexual abuse. Herman’s description of CPTSD identifies 3 areas of psychopathology that extend beyond PTSD¹:

• symptomatic refers to the complex, diffuse, and tenacious symptom presentation
• characterological focuses on the personality changes in terms of dissociation, ego-fragmentation, and identity complications
• vulnerability describes characteristic repeated harm with respect to self-mutilation or other self-injurious behaviors, and suicidality.

Taxometrics, official recognition, and controversy

Complex PTSD was proposed for inclusion in DSM-IV as “Disorders of Extreme Stress Not Otherwise Specified,” or DESNOS. Reportedly, it was interpreted as a severe presentation of PTSD, and therefore not included in the manual as a separate diagnosis.² In contrast, ICD-10 included a CPTSD-like entity of “Enduring Personality Change After Catastrophic Event” (EPCACE). Although the existence of CPTSD as a categorically distinct diagnosis in the psychiatric mainstream has been debated and discussed for years, with many arguably unaware of its existence, clinicians and researchers specializing in trauma are well-versed in its clinical utility. As such, CPTSD was again discussed during the development of DSM-5. In an apparent attempt to balance this clinical utility with ongoing concerns about its validity as a diagnostically distinct syndrome, DSM-5 did not officially recognize CPTSD, but added several criteria to PTSD referencing changes in self-perception, affective instability, and dysphoria, as well as a dissociative subtype, effectively expanding the scope of a PTSD diagnosis to also include CPTSD symptoms when applicable. ICD-11 has taken a different direction, and officially recognizes CPTSD as a distinct diagnosis.

ICD-11 presents CPTSD as a “sibling” disorder, which it distinguishes from PTSD with high levels of dissociation, depression, and borderline personality disorder traits.³ Within this framework, the diagnosis of CPTSD requires that the PTSD criteria be met in addition to symptoms that fall into a “disturbances of self-organization” category. When parsing the symptoms of the “disturbances of self-organization” category, the overlap with borderline personality disorder symptoms is apparent.⁴ This overlap has given rise to yet another controversy regarding CPTSD’s categorical validity; in addition to its distinctness from PTSD, its distinctness from borderline personality disorder has also been debated. In a study examining the similarity between CPTSD and borderline personality disorder, Jowett et al⁵ concluded that CPTSD was associated with greater exposure to multiple traumas earlier in life and resulted in higher functional impairment than borderline personality disorder, ultimately supporting CPTSD as a separate entity with features that overlap borderline personality disorder.⁵ According to Ford and Courtois⁶ “the evidence ... suggests that a sub-group of BPD patients—who often but not always have comorbid PTSD—may be best understood and treated if CPTSD is explicitly addressed as well—and in some cases, in lieu of—BPD.”

PTSD and CPTSD may therefore both be understood to fall within a spectrum of trauma diagnoses; this paradigm postulates that there exists a wide variety of posttraumatic patient presentations, perhaps on a continuum. On the less severe side of the trauma spectrum, the symptoms traditionally seen and characterized as PTSD (such as hypervigilance, nightmares, and flashbacks) may be found, while, with increasingly severe or prolonged trauma, there may be a tendency to see more complex elements (such as dissociation, personality changes mimicking borderline personality disorder, depression, anxiety, self-injurious behavior, and suicidality).⁷ Nevertheless, controversy about discriminant validity still exists. A review article by Resnick et al⁸ argued that the existing evidence is not strong enough to support CPTSD as a standalone entity. However, Resnick et al⁸ agreed that a singular PTSD diagnosis has limitations, and that there is a need for more research in the field of trauma psychiatry.

Continue to: Utility of the diagnostic conceptualization...

Although the controversy surrounding the distinction of CPTSD demands categorical clarity with respect to PTSD and borderline personality disorder as a means of resolution, the diagnosis has practical applications that should not limit its use in clinical formulation or treatment planning. Comorbid diagnoses do not prevent clinicians from diagnosing and treating patients who present with complicated manifestations of trauma.⁹ In fact, having overlapping diagnoses would highlight the array of patient presentations that can be seen in the posttraumatic condition. Furthermore, in the pursuit of individualized care approaches, the addition of CPTSD as a diagnostic conception would allow for more integrated treatment options using a multi-modular approach.¹⁰

The addition of CPTSD as a diagnosis is helpful in determining the etiology of a patient’s presentation and therefore formulating the most appropriate treatment plan. While the 2-pronged approach of psychopharmacology and therapy is the central dogma of psychiatric care, there are many specific options to consider for each. By viewing such patients through the lens of trauma as opposed to depression and anxiety, there is a clear shift in treatment that has the potential to make more lasting impacts and progress.¹¹

CPTSD may coexist with PTSD, but it extends beyond it to include a pleomorphic symptom picture encompassing personality changes and a high risk for repeated harm. Failure to correctly classify a patient’s presentation as a response to repetitive, prolonged trauma may result in discrimination and inappropriate or ineffective treatment recommendations.

For a comparison of the diagnostic criteria of PTSD, CPTSD, and borderline personality disorder, see Table 1¹², Table 2,^13,14, and Table 3¹².

Patients with CPTSD

One of the authors (NR) has cared for several similar individuals presenting for treatment with vague diagnoses of “chronic depression and anxiety” for years, sometimes with a speculative bipolar disorder diagnosis due to situational mood swings or reactivity, and a generally poor response to both medications and psychotherapy. These patients were frustrated because none of the diagnoses seemed to fully “fit” with their pattern of symptoms or subjective experience, and treatment seemed minimally helpful. Very often, their social history revealed a variety of adversities or traumatic events, such as childhood sexual or physical abuse, a home environment plagued by domestic violence, or being raised by one or both parents with their own history of trauma, or perhaps a personality or substance use disorder. Although many of these patients’ symptom profiles aligned only partially with “typical” PTSD, they were often better captured by CPTSD, with a focus on negative self-perception and impact on close relationships. Helping the patient “connect the dots” to create a more continuous narrative, and consequently reconceptualizing the diagnosis as a complex trauma disorder, has proven effective in a number of these cases, allowing the patient to make sense of their symptoms in the context of their personal history, reducing stigma, and allowing for different avenues with medication, therapy, and self-understanding. It can also help to validate the impact of a patient’s adverse experiences and encourage a patient to view their symptoms as an understandable or even once-adaptive response to traumatic stress, rather than a sign of personal weakness or defectiveness.

TREATMENT A trauma-focused approach

Once the treatment team considersMr. X’s significant childhood trauma and recon­ceptualizes his behaviors through this lens, treatment is adjusted accordingly. His significant reactivity, dissociative symptoms, social impairment, and repeated suicide attempts are better understood and have more significance through a trauma lens, which provides a better explanation than a primary mood disorder.

Therapeutic interventions in the hospital are tailored according to the treatment team’s new insight. Specific DBT skills are practiced, insight-oriented therapy and motivational interviewing are used, and Mr. X and his therapist begin to explore his trauma, both from his biological father and from his intense stressors experienced because of his medical issues.

Mr. X’s mother, who is very involved in his care, is provided with education on this conceptualization and given instruction on trauma-focused therapies in the outpatient setting. While Mr. X’s medication regimen is not changed significantly, for some patients, the reformulation from a primary mood or anxiety disorder to a trauma disorder might require a change in the pharmacotherapy regimen to address behavioral symptoms such as mood reactivity or issues with sleep.

OUTCOME Decreased intensity of suicidal thoughts

By the time of discharge, Mr. X has maintained safety, with no further outbursts, and subjectively reports feeling more understood and validated. Although chronic suicidal ideation can take months or years of treatment to resolve, at the time of discharge Mr. X reports a decreased intensity of these thoughts, and no acute suicidal ideation, plan, or intent. His discharge planning emphasizes ongoing work specifically related to coping with symptoms of traumatic stress, and the involvement of his main social support in facilitating this work.

The authors’ observations

As a caveat, it may be in some cases that chronic negative affect, dysphoria, and self-perception are better understood as a comorbid depressive disorder rather than subsumed into a PTSD/ CPTSD diagnosis. Also, because situational mood instability and impulsivity are often interpreted as bipolar disorder, a history of hypomania and mania should be ruled out. In Mr. X’s case, the diagnostic reformulation did not significantly impact pharmacotherapy because the target symptoms of mood instability, irritability, anxiety, and depression remained, despite the change in diagnosis.

Although the DSM-5 PTSD criteria effectively incorporate many CPTSD elements, we argue that this inclusivity comes at the expense of appreciating CPTSD as a qualitatively distinct condition, and we prefer ICD-11’s recognition of CPTSD as a separate diagnosis that incorporates PTSD criteria but extends the definition to include negative self-concept, affect dysregulation, and interpersonal difficulties.

Related Resources

• US Department of Veterans Affairs. PTSD: National Center for PTSD. Published January 1, 2007. https://www.ptsd.va.gov/ professional/treat/essentials/complex_ptsd.asp
• Jowett S, Karatzias T, Shevlin M, et al. Differentiating symptom profiles of ICD-11 PTSD, complex PTSD, and borderline personality disorder: a latent class analysis in a multiply traumatized sample. Personality disorders: theory, research, and treatment. 2020;11(1):36.

Drug Brand Names

Clonazepam • Klonopin

Haloperidol • Haldol

Lamotrigine • Lamictal

Lorazepam • Ativan

Sertraline • Zoloft

Zolpidem • Ambien

Bottom Line

Consider a diagnosis of complex posttraumatic stress disorder (CPTSD) when providing care for patients with chronic depression and suicidality with a history of trauma or childhood adversity. This reformulation can allow clinicians to understand the contributing factors more holistically; align with the patient more effectively; appreciate past and present interpersonal, psychological, and psychosocial factors that may precipitate and perpetuate symptoms; and allow for treatment recommendations beyond those of mood and anxiety disorders.

CASE A long history of suicidality

Mr. X, age 26, who has a history of bipolar II disorder and multiple inpatient admissions, presents to a state hospital after a suicide attempt by gunshot. He reports that throughout his lifetime, he has had >20 suicide attempts, often by overdose.

Mr. X is admitted to the hospital under a temporary detention order. He is initially adherent and cooperative with his psychiatric evaluations.

HISTORY Chronic physical and emotional pain

Mr. X is single, unemployed, and lives with his mother and nephew. He was diagnosed with bipolar II disorder during adolescence and receives sertraline, 50 mg twice a day, and lamotrigine, 100 mg twice a day, to which he reports adherence. He also was taking clonazepam and zolpidem, dosages unknown.

His medical history is significant for severe childhood liver disease and inflammatory bowel disease. He dropped out of school during high school due to his multiple medical conditions, which resulted in a significantly diminished overall childhood experience, interrupted developmental trajectory, and chronic physical and emotional pain. He has never been employed and receives financial support through disability benefits. He spends his days on the internet or watching television. He reports daily cigarette and marijuana use and occasional alcohol use, but no other substance use. His mother helps manage his medical conditions and is his main support. His biological father was abusive towards his mother and absent for most of Mr. X’s life. Beyond his mother and therapist, Mr. X has minimal other interpersonal interactions, and reports feeling isolated, lonely, and frustrated.

EVALUATION Agitated and aggressive while hospitalized

Upon learning that he is being involuntarily committed, Mr. X becomes physically aggressive, makes verbal threats, and throws objects across his room. He is given diphenhydramine, 50 mg, haloperidol, 5 mg, and lorazepam, 2 mg, all of which are ordered on an as-needed basis. Mr. X is placed in an emergency restraint chair and put in seclusion. The episode resolves within an hour with reassurance and attention from the treatment team; the rapid escalation from and return to a calmer state is indicative of situational, stress-induced mood lability and impulsivity. Mr. X is counseled on maintaining safety and appropriate behavior, and is advised to ask for medication if he feels agitated or unable to control his behaviors. To maintain safe and appropriate behavior, he requires daily counseling and expectation management regarding his treatment timeline. No further aggressive incidents are noted throughout his hospitalization, and he requires only minimal use of the as-needed medications.

[polldaddy:10983392]

The authors’ observations

The least appropriate therapy for Mr. X would be exposure and response prevention, which allows patients to face their fears without the need to soothe or relieve related feelings with a compulsive act. It is designed to improve specific behavioral deficits most often associated with obsessive-compulsive disorder, a diagnosis inconsistent with Mr. X’s history and presentation. Trauma-focused CBT could facilitate healing from Mr. X’s childhood trauma/adverse childhood experiences, and DBT might help with his anger, maladaptive coping strategies, and chronic suicidality. Motivational interviewing might help with his substance use and his apparent lack of motivation for other forms of social engagement, including seeking employment.

Based on Mr. X’s history of trauma and chronic physical and emotional pain, the treatment team reevaluated him and reconsidered his original diagnosis.

Continue to: EVALUATION A closer look at the diagnosis...

After meeting with Mr. X, the treatment team begins to piece together a more robust picture of him. They review his childhood trauma involving his biological father, his chronic and limiting medical illnesses, and his restricted and somewhat regressive level of functioning. Further, they consider his >20 suicide attempts, numerous psychiatric hospitalizations, and mood and behavioral lability and reactivity. Based on its review, the treatment team concludes that a diagnosis of bipolar disorder II or major depressive disorder is not fully adequate to describe Mr. X’s clinical picture.

At no point during his hospitalization does Mr. X meet full criteria for a major depressive episode or display mania or hypomania. The treatment team considers posttraumatic stress disorder (PTSD) in the setting of chronic, repetitive trauma given Mr. X’s nightmares, dissociative behavior, anger, negative cognitions, and intrusive symptoms. However, not all his symptoms fall within the diagnostic criteria of PTSD. There are also elements of borderline personality disorder in Mr. X’s history, most notably his multiple suicide attempts, emotional lability, and disrupted interpersonal attachments. In this context, a diagnosis of complex PTSD (CPTSD) seems most appropriate in capturing the array of trauma-related symptoms with which he presents. 

Complex PTSD

Since at least the early to mid-1990s, there has been recognition of a qualitatively distinct clinical picture that can emerge when an individual’s exposure to trauma or adversity is chronic or repetitive, causing not only familiar PTSD symptomatology but also alterations in self-perception, interpersonal functioning, and affective instability. Complex PTSD was first described by Judith Herman, MD, in 1992 as a distinct entity from PTSD.¹ She theorized that PTSD derives primarily from singular traumatic events, while a distinct clinical syndrome might arise after prolonged, repeated trauma.¹ A diagnosis of CPTSD might arise in situations with more chronicity than a classic single circumscribed traumatic event, such as being held in captivity, under the control of perpetrators for extended periods of time, imprisoned, or subject to prolonged sexual abuse. Herman’s description of CPTSD identifies 3 areas of psychopathology that extend beyond PTSD¹:

• symptomatic refers to the complex, diffuse, and tenacious symptom presentation
• characterological focuses on the personality changes in terms of dissociation, ego-fragmentation, and identity complications
• vulnerability describes characteristic repeated harm with respect to self-mutilation or other self-injurious behaviors, and suicidality.

Taxometrics, official recognition, and controversy

Complex PTSD was proposed for inclusion in DSM-IV as “Disorders of Extreme Stress Not Otherwise Specified,” or DESNOS. Reportedly, it was interpreted as a severe presentation of PTSD, and therefore not included in the manual as a separate diagnosis.² In contrast, ICD-10 included a CPTSD-like entity of “Enduring Personality Change After Catastrophic Event” (EPCACE). Although the existence of CPTSD as a categorically distinct diagnosis in the psychiatric mainstream has been debated and discussed for years, with many arguably unaware of its existence, clinicians and researchers specializing in trauma are well-versed in its clinical utility. As such, CPTSD was again discussed during the development of DSM-5. In an apparent attempt to balance this clinical utility with ongoing concerns about its validity as a diagnostically distinct syndrome, DSM-5 did not officially recognize CPTSD, but added several criteria to PTSD referencing changes in self-perception, affective instability, and dysphoria, as well as a dissociative subtype, effectively expanding the scope of a PTSD diagnosis to also include CPTSD symptoms when applicable. ICD-11 has taken a different direction, and officially recognizes CPTSD as a distinct diagnosis.

ICD-11 presents CPTSD as a “sibling” disorder, which it distinguishes from PTSD with high levels of dissociation, depression, and borderline personality disorder traits.³ Within this framework, the diagnosis of CPTSD requires that the PTSD criteria be met in addition to symptoms that fall into a “disturbances of self-organization” category. When parsing the symptoms of the “disturbances of self-organization” category, the overlap with borderline personality disorder symptoms is apparent.⁴ This overlap has given rise to yet another controversy regarding CPTSD’s categorical validity; in addition to its distinctness from PTSD, its distinctness from borderline personality disorder has also been debated. In a study examining the similarity between CPTSD and borderline personality disorder, Jowett et al⁵ concluded that CPTSD was associated with greater exposure to multiple traumas earlier in life and resulted in higher functional impairment than borderline personality disorder, ultimately supporting CPTSD as a separate entity with features that overlap borderline personality disorder.⁵ According to Ford and Courtois⁶ “the evidence ... suggests that a sub-group of BPD patients—who often but not always have comorbid PTSD—may be best understood and treated if CPTSD is explicitly addressed as well—and in some cases, in lieu of—BPD.”

PTSD and CPTSD may therefore both be understood to fall within a spectrum of trauma diagnoses; this paradigm postulates that there exists a wide variety of posttraumatic patient presentations, perhaps on a continuum. On the less severe side of the trauma spectrum, the symptoms traditionally seen and characterized as PTSD (such as hypervigilance, nightmares, and flashbacks) may be found, while, with increasingly severe or prolonged trauma, there may be a tendency to see more complex elements (such as dissociation, personality changes mimicking borderline personality disorder, depression, anxiety, self-injurious behavior, and suicidality).⁷ Nevertheless, controversy about discriminant validity still exists. A review article by Resnick et al⁸ argued that the existing evidence is not strong enough to support CPTSD as a standalone entity. However, Resnick et al⁸ agreed that a singular PTSD diagnosis has limitations, and that there is a need for more research in the field of trauma psychiatry.

Continue to: Utility of the diagnostic conceptualization...

Although the controversy surrounding the distinction of CPTSD demands categorical clarity with respect to PTSD and borderline personality disorder as a means of resolution, the diagnosis has practical applications that should not limit its use in clinical formulation or treatment planning. Comorbid diagnoses do not prevent clinicians from diagnosing and treating patients who present with complicated manifestations of trauma.⁹ In fact, having overlapping diagnoses would highlight the array of patient presentations that can be seen in the posttraumatic condition. Furthermore, in the pursuit of individualized care approaches, the addition of CPTSD as a diagnostic conception would allow for more integrated treatment options using a multi-modular approach.¹⁰

The addition of CPTSD as a diagnosis is helpful in determining the etiology of a patient’s presentation and therefore formulating the most appropriate treatment plan. While the 2-pronged approach of psychopharmacology and therapy is the central dogma of psychiatric care, there are many specific options to consider for each. By viewing such patients through the lens of trauma as opposed to depression and anxiety, there is a clear shift in treatment that has the potential to make more lasting impacts and progress.¹¹

CPTSD may coexist with PTSD, but it extends beyond it to include a pleomorphic symptom picture encompassing personality changes and a high risk for repeated harm. Failure to correctly classify a patient’s presentation as a response to repetitive, prolonged trauma may result in discrimination and inappropriate or ineffective treatment recommendations.

For a comparison of the diagnostic criteria of PTSD, CPTSD, and borderline personality disorder, see Table 1¹², Table 2,^13,14, and Table 3¹².

Patients with CPTSD

One of the authors (NR) has cared for several similar individuals presenting for treatment with vague diagnoses of “chronic depression and anxiety” for years, sometimes with a speculative bipolar disorder diagnosis due to situational mood swings or reactivity, and a generally poor response to both medications and psychotherapy. These patients were frustrated because none of the diagnoses seemed to fully “fit” with their pattern of symptoms or subjective experience, and treatment seemed minimally helpful. Very often, their social history revealed a variety of adversities or traumatic events, such as childhood sexual or physical abuse, a home environment plagued by domestic violence, or being raised by one or both parents with their own history of trauma, or perhaps a personality or substance use disorder. Although many of these patients’ symptom profiles aligned only partially with “typical” PTSD, they were often better captured by CPTSD, with a focus on negative self-perception and impact on close relationships. Helping the patient “connect the dots” to create a more continuous narrative, and consequently reconceptualizing the diagnosis as a complex trauma disorder, has proven effective in a number of these cases, allowing the patient to make sense of their symptoms in the context of their personal history, reducing stigma, and allowing for different avenues with medication, therapy, and self-understanding. It can also help to validate the impact of a patient’s adverse experiences and encourage a patient to view their symptoms as an understandable or even once-adaptive response to traumatic stress, rather than a sign of personal weakness or defectiveness.

TREATMENT A trauma-focused approach

Once the treatment team considersMr. X’s significant childhood trauma and recon­ceptualizes his behaviors through this lens, treatment is adjusted accordingly. His significant reactivity, dissociative symptoms, social impairment, and repeated suicide attempts are better understood and have more significance through a trauma lens, which provides a better explanation than a primary mood disorder.

Therapeutic interventions in the hospital are tailored according to the treatment team’s new insight. Specific DBT skills are practiced, insight-oriented therapy and motivational interviewing are used, and Mr. X and his therapist begin to explore his trauma, both from his biological father and from his intense stressors experienced because of his medical issues.

Mr. X’s mother, who is very involved in his care, is provided with education on this conceptualization and given instruction on trauma-focused therapies in the outpatient setting. While Mr. X’s medication regimen is not changed significantly, for some patients, the reformulation from a primary mood or anxiety disorder to a trauma disorder might require a change in the pharmacotherapy regimen to address behavioral symptoms such as mood reactivity or issues with sleep.

OUTCOME Decreased intensity of suicidal thoughts

By the time of discharge, Mr. X has maintained safety, with no further outbursts, and subjectively reports feeling more understood and validated. Although chronic suicidal ideation can take months or years of treatment to resolve, at the time of discharge Mr. X reports a decreased intensity of these thoughts, and no acute suicidal ideation, plan, or intent. His discharge planning emphasizes ongoing work specifically related to coping with symptoms of traumatic stress, and the involvement of his main social support in facilitating this work.

The authors’ observations

As a caveat, it may be in some cases that chronic negative affect, dysphoria, and self-perception are better understood as a comorbid depressive disorder rather than subsumed into a PTSD/ CPTSD diagnosis. Also, because situational mood instability and impulsivity are often interpreted as bipolar disorder, a history of hypomania and mania should be ruled out. In Mr. X’s case, the diagnostic reformulation did not significantly impact pharmacotherapy because the target symptoms of mood instability, irritability, anxiety, and depression remained, despite the change in diagnosis.

Although the DSM-5 PTSD criteria effectively incorporate many CPTSD elements, we argue that this inclusivity comes at the expense of appreciating CPTSD as a qualitatively distinct condition, and we prefer ICD-11’s recognition of CPTSD as a separate diagnosis that incorporates PTSD criteria but extends the definition to include negative self-concept, affect dysregulation, and interpersonal difficulties.

Related Resources

• US Department of Veterans Affairs. PTSD: National Center for PTSD. Published January 1, 2007. https://www.ptsd.va.gov/ professional/treat/essentials/complex_ptsd.asp
• Jowett S, Karatzias T, Shevlin M, et al. Differentiating symptom profiles of ICD-11 PTSD, complex PTSD, and borderline personality disorder: a latent class analysis in a multiply traumatized sample. Personality disorders: theory, research, and treatment. 2020;11(1):36.

Drug Brand Names

Clonazepam • Klonopin

Haloperidol • Haldol

Lamotrigine • Lamictal

Lorazepam • Ativan

Sertraline • Zoloft

Zolpidem • Ambien

Bottom Line

Consider a diagnosis of complex posttraumatic stress disorder (CPTSD) when providing care for patients with chronic depression and suicidality with a history of trauma or childhood adversity. This reformulation can allow clinicians to understand the contributing factors more holistically; align with the patient more effectively; appreciate past and present interpersonal, psychological, and psychosocial factors that may precipitate and perpetuate symptoms; and allow for treatment recommendations beyond those of mood and anxiety disorders.