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Indoor masking needed in almost 70% of U.S. counties: CDC data
In announcing new guidance on July 27, the CDC said vaccinated people should wear face masks in indoor public places with “high” or “substantial” community transmission rates of COVID-19.
Data from the CDC shows that designation covers 69.3% of all counties in the United States – 52.2% (1,680 counties) with high community transmission rates and 17.1% (551 counties) with substantial rates.
A county has “high transmission” if it reports 100 or more weekly cases per 100,000 residents or a 10% or higher test positivity rate in the last 7 days, the CDC said. “Substantial transmission” means a county reports 50-99 weekly cases per 100,000 residents or has a positivity rate between 8% and 9.9% in the last 7 days.
About 23% of U.S. counties had moderate rates of community transmission, and 7.67% had low rates.
To find out the transmission rate in your county, go to the CDC COVID data tracker.
Smithsonian requiring masks again
The Smithsonian now requires all visitors over age 2, regardless of vaccination status, to wear face masks indoors and in all museum spaces.
The Smithsonian said in a news release that fully vaccinated visitors won’t have to wear masks at the National Zoo or outdoor gardens for museums.
The new rule goes into effect Aug. 6. It reverses a rule that said fully vaccinated visitors didn’t have to wear masks indoors beginning June 28.
Indoor face masks will be required throughout the District of Columbia beginning July 31., D.C. Mayor Muriel Bowser.
House Republicans protest face mask policy
About 40 maskless Republican members of the U.S. House of Representatives filed onto the Senate floor on July 29 to protest a new rule requiring House members to wear face masks, the Hill reported.
Congress’s attending doctor said in a memo that the 435 members of the House, plus workers, must wear masks indoors, but not the 100 members of the Senate. The Senate is a smaller body and has had better mask compliance than the House.
Rep. Ronny Jackson (R-Tex.), told the Hill that Republicans wanted to show “what it was like on the floor of the Senate versus the floor of the House. Obviously, it’s vastly different.”
Among the group of Republicans who filed onto the Senate floor were Rep. Lauren Boebert of Colorado, Rep. Matt Gaetz and Rep. Byron Donalds of Florida, Rep. Marjorie Taylor Greene of Georgia, Rep. Chip Roy and Rep. Louie Gohmert of Texas, Rep. Madison Cawthorn of North Carolina, Rep. Warren Davidson of Ohio, and Rep. Andy Biggs of Arizona.
A version of this article first appeared on WebMD.com.
In announcing new guidance on July 27, the CDC said vaccinated people should wear face masks in indoor public places with “high” or “substantial” community transmission rates of COVID-19.
Data from the CDC shows that designation covers 69.3% of all counties in the United States – 52.2% (1,680 counties) with high community transmission rates and 17.1% (551 counties) with substantial rates.
A county has “high transmission” if it reports 100 or more weekly cases per 100,000 residents or a 10% or higher test positivity rate in the last 7 days, the CDC said. “Substantial transmission” means a county reports 50-99 weekly cases per 100,000 residents or has a positivity rate between 8% and 9.9% in the last 7 days.
About 23% of U.S. counties had moderate rates of community transmission, and 7.67% had low rates.
To find out the transmission rate in your county, go to the CDC COVID data tracker.
Smithsonian requiring masks again
The Smithsonian now requires all visitors over age 2, regardless of vaccination status, to wear face masks indoors and in all museum spaces.
The Smithsonian said in a news release that fully vaccinated visitors won’t have to wear masks at the National Zoo or outdoor gardens for museums.
The new rule goes into effect Aug. 6. It reverses a rule that said fully vaccinated visitors didn’t have to wear masks indoors beginning June 28.
Indoor face masks will be required throughout the District of Columbia beginning July 31., D.C. Mayor Muriel Bowser.
House Republicans protest face mask policy
About 40 maskless Republican members of the U.S. House of Representatives filed onto the Senate floor on July 29 to protest a new rule requiring House members to wear face masks, the Hill reported.
Congress’s attending doctor said in a memo that the 435 members of the House, plus workers, must wear masks indoors, but not the 100 members of the Senate. The Senate is a smaller body and has had better mask compliance than the House.
Rep. Ronny Jackson (R-Tex.), told the Hill that Republicans wanted to show “what it was like on the floor of the Senate versus the floor of the House. Obviously, it’s vastly different.”
Among the group of Republicans who filed onto the Senate floor were Rep. Lauren Boebert of Colorado, Rep. Matt Gaetz and Rep. Byron Donalds of Florida, Rep. Marjorie Taylor Greene of Georgia, Rep. Chip Roy and Rep. Louie Gohmert of Texas, Rep. Madison Cawthorn of North Carolina, Rep. Warren Davidson of Ohio, and Rep. Andy Biggs of Arizona.
A version of this article first appeared on WebMD.com.
In announcing new guidance on July 27, the CDC said vaccinated people should wear face masks in indoor public places with “high” or “substantial” community transmission rates of COVID-19.
Data from the CDC shows that designation covers 69.3% of all counties in the United States – 52.2% (1,680 counties) with high community transmission rates and 17.1% (551 counties) with substantial rates.
A county has “high transmission” if it reports 100 or more weekly cases per 100,000 residents or a 10% or higher test positivity rate in the last 7 days, the CDC said. “Substantial transmission” means a county reports 50-99 weekly cases per 100,000 residents or has a positivity rate between 8% and 9.9% in the last 7 days.
About 23% of U.S. counties had moderate rates of community transmission, and 7.67% had low rates.
To find out the transmission rate in your county, go to the CDC COVID data tracker.
Smithsonian requiring masks again
The Smithsonian now requires all visitors over age 2, regardless of vaccination status, to wear face masks indoors and in all museum spaces.
The Smithsonian said in a news release that fully vaccinated visitors won’t have to wear masks at the National Zoo or outdoor gardens for museums.
The new rule goes into effect Aug. 6. It reverses a rule that said fully vaccinated visitors didn’t have to wear masks indoors beginning June 28.
Indoor face masks will be required throughout the District of Columbia beginning July 31., D.C. Mayor Muriel Bowser.
House Republicans protest face mask policy
About 40 maskless Republican members of the U.S. House of Representatives filed onto the Senate floor on July 29 to protest a new rule requiring House members to wear face masks, the Hill reported.
Congress’s attending doctor said in a memo that the 435 members of the House, plus workers, must wear masks indoors, but not the 100 members of the Senate. The Senate is a smaller body and has had better mask compliance than the House.
Rep. Ronny Jackson (R-Tex.), told the Hill that Republicans wanted to show “what it was like on the floor of the Senate versus the floor of the House. Obviously, it’s vastly different.”
Among the group of Republicans who filed onto the Senate floor were Rep. Lauren Boebert of Colorado, Rep. Matt Gaetz and Rep. Byron Donalds of Florida, Rep. Marjorie Taylor Greene of Georgia, Rep. Chip Roy and Rep. Louie Gohmert of Texas, Rep. Madison Cawthorn of North Carolina, Rep. Warren Davidson of Ohio, and Rep. Andy Biggs of Arizona.
A version of this article first appeared on WebMD.com.
‘War has changed’: CDC says Delta as contagious as chicken pox
Internal Centers for Disease Control and Prevention documents support the high transmission rate of the Delta variant and put the risk in easier to understand terms.
In addition, the agency released a new study that shows that breakthrough infections in the vaccinated make people about as contagious as those who are unvaccinated. The new report, published July 30 in Morbidity and Mortality Weekly Report (MMWR), also reveals that the Delta variant likely causes more severe COVID-19 illness.
Given these recent findings, the internal CDC slide show advises that the agency should “acknowledge the war has changed.”
A ‘pivotal discovery’
CDC Director Rochelle Walensky, MD, MPH, said in a statement that the MMWR report demonstrates “that [D]elta infection resulted in similarly high SARS-CoV-2 viral loads in vaccinated and unvaccinated people.
“High viral loads suggest an increased risk of transmission and raised concern that, unlike with other variants, vaccinated people infected with [D]elta can transmit the virus,” she added. “This finding is concerning and was a pivotal discovery leading to CDC’s updated mask recommendation.”
The investigators analyzed 469 COVID-19 cases reported in Massachusetts residents July 3 through 17, 2021. The infections were associated with an outbreak following multiple events and large gatherings in Provincetown in that state’s easternmost Barnstable County, also known as Cape Cod.
Notably, 346 infections, or 74%, of the cases occurred in fully vaccinated individuals. This group had a median age of 42, and 87% were male. Also, 79% of the breakthrough infections were symptomatic.
Researchers also identified the Delta variant in 90% of 133 specimens collected for analysis. Furthermore, viral loads were about the same between samples taken from people who were fully vaccinated and those who were not.
Four of the five people hospitalized were fully vaccinated. No deaths were reported.
The publication of these results was highly anticipated following the CDC’s updated mask recommendations on July 27.
Outside the scope of the MMWR report is the total number of cases associated with the outbreak, including visitors from outside Massachusetts, which now approach 900 infections, NBC Boston reported.
‘Very sobering’ data
“The new information from the CDC around the [D]elta variant is very sobering,” David Hirschwerk, MD, infectious disease specialist at Northwell Health in New Hyde Park, N.Y., said in an interview.
“The CDC is trying to convey and present this uncertain situation clearly to the public based on new, accumulated data,” he said. For example, given the evidence for higher contagiousness of the Delta variant, Dr. Hirschwerk added, “there will be situations where vaccinated people get infected, because the amount of the virus overwhelms the immune protection.
“What is new that is concerning is that people who are vaccinated still have the potential to transmit the virus to the same degree,” he said.
The MMWR study “helps us better understand the question related to whether or not a person who has completed a COVID-19 series can spread the infection,” agreed Michelle Barron, MD, a professor in the division of infectious disease at the University of Colorado, Aurora.
“The message is that, because the [D]elta variant is much more contagious than the original strain, unvaccinated persons need to get vaccinated because it is nearly impossible to avoid the virus indefinitely,” Michael Lin, MD, MPH, infectious diseases specialist and epidemiologist at Rush University Medical Center, Chicago, said when asked to comment.
The new data highlight “that vaccinated persons, if they become sick, should still seek COVID-19 testing and should still isolate, as they are likely contagious,” Dr. Lin added.
More contagious than other infections
The internal CDC slide presentation also puts the new transmission risk in simple terms. Saying that the Delta variant is about as contagious as chicken pox, for example, immediately brings back vivid memories for some of staying indoors and away from friends during childhood or teenage outbreaks.
“A lot of people will remember getting chicken pox and then having their siblings get it shortly thereafter,” Dr. Barron said. “The only key thing to note is that this does not mean that the COVID-19 [D]elta variant mechanism of spread is the same as chicken pox and Ebola. The primary means of spread of COVID-19, even the Delta variant, is via droplets.”
This also means each person infected with the Delta variant could infect an average of eight or nine others.
In contrast, the original strain of the SARS-CoV-2 virus was about as infectious as the common cold. In other words, someone was likely to infect about two other people on average.
In addition to the cold, the CDC notes that the Delta variant is now more contagious than Ebola, the seasonal flu, or small pox.
These Delta variant comparisons are one tangible way of explaining why the CDC on July 27 recommended a return to masking in schools and other indoor spaces for people – vaccinated and unvaccinated – in about 70% of the counties across the United States.
In comparing the Delta variant with other infections, “I think the CDC is trying to help people understand a little bit better the situation we now face since the information is so new. We are in a very different position now than just a few weeks ago, and it is hard for people to accept this,” Dr. Hirschwerk said.
The Delta variant is so different that the CDC considers it almost acting like a new virus altogether.
The CDC’s internal documents were first released by The Washington Post on July 29. The slides cite communication challenges for the agency to continue promoting vaccination while also acknowledging that breakthrough cases are occurring and therefore the fully vaccinated, in some instances, are likely infecting others.
Moving back to science talk, the CDC used the recent outbreak in Barnstable County as an example. The cycle threshold, or Ct values, a measure of viral load, were about the same between 80 vaccinated people linked to the outbreak who had a mean Ct value of 21.9, compared with 65 other unvaccinated people with a Ct of 21.5.
Many experts are quick to note that vaccination remains essential, in part because a vaccinated person also walks around with a much lower risk for severe outcomes, hospitalization, and death. In the internal slide show, the CDC points out that vaccination reduces the risk for infection threefold.
“Even with this high amount of virus, [the Delta variant] did not necessarily make the vaccinated individuals as sick,” Dr. Barron said.
In her statement, Dr. Walensky credited collaboration with the Commonwealth of Massachusetts Department of Public Health and the CDC for the new data. She also thanked the residents of Barnstable County for participating in interviews done by contact tracers and their willingness to get tested and adhere to safety protocols after learning of their exposure.
Next moves by CDC?
The agency notes that next steps include consideration of prevention measures such as vaccine mandates for healthcare professionals to protect vulnerable populations, universal masking for source control and prevention, and reconsidering other community mitigation strategies.
Asked if this potential policy is appropriate and feasible, Dr. Lin said, “Yes, I believe that every person working in health care should be vaccinated for COVID-19, and it is feasible.”
Dr. Barron agreed as well. “We as health care providers choose to work in health care, and we should be doing everything feasible to ensure that we are protecting our patients and keeping our coworkers safe.”
“Whether you are a health care professional or not, I would urge everyone to get the COVID-19 vaccine, especially as cases across the country continue to rise,” Dr. Hirschwerk said. “Unequivocally vaccines protect you from the virus.”
A version of this article first appeared on Medscape.com.
Internal Centers for Disease Control and Prevention documents support the high transmission rate of the Delta variant and put the risk in easier to understand terms.
In addition, the agency released a new study that shows that breakthrough infections in the vaccinated make people about as contagious as those who are unvaccinated. The new report, published July 30 in Morbidity and Mortality Weekly Report (MMWR), also reveals that the Delta variant likely causes more severe COVID-19 illness.
Given these recent findings, the internal CDC slide show advises that the agency should “acknowledge the war has changed.”
A ‘pivotal discovery’
CDC Director Rochelle Walensky, MD, MPH, said in a statement that the MMWR report demonstrates “that [D]elta infection resulted in similarly high SARS-CoV-2 viral loads in vaccinated and unvaccinated people.
“High viral loads suggest an increased risk of transmission and raised concern that, unlike with other variants, vaccinated people infected with [D]elta can transmit the virus,” she added. “This finding is concerning and was a pivotal discovery leading to CDC’s updated mask recommendation.”
The investigators analyzed 469 COVID-19 cases reported in Massachusetts residents July 3 through 17, 2021. The infections were associated with an outbreak following multiple events and large gatherings in Provincetown in that state’s easternmost Barnstable County, also known as Cape Cod.
Notably, 346 infections, or 74%, of the cases occurred in fully vaccinated individuals. This group had a median age of 42, and 87% were male. Also, 79% of the breakthrough infections were symptomatic.
Researchers also identified the Delta variant in 90% of 133 specimens collected for analysis. Furthermore, viral loads were about the same between samples taken from people who were fully vaccinated and those who were not.
Four of the five people hospitalized were fully vaccinated. No deaths were reported.
The publication of these results was highly anticipated following the CDC’s updated mask recommendations on July 27.
Outside the scope of the MMWR report is the total number of cases associated with the outbreak, including visitors from outside Massachusetts, which now approach 900 infections, NBC Boston reported.
‘Very sobering’ data
“The new information from the CDC around the [D]elta variant is very sobering,” David Hirschwerk, MD, infectious disease specialist at Northwell Health in New Hyde Park, N.Y., said in an interview.
“The CDC is trying to convey and present this uncertain situation clearly to the public based on new, accumulated data,” he said. For example, given the evidence for higher contagiousness of the Delta variant, Dr. Hirschwerk added, “there will be situations where vaccinated people get infected, because the amount of the virus overwhelms the immune protection.
“What is new that is concerning is that people who are vaccinated still have the potential to transmit the virus to the same degree,” he said.
The MMWR study “helps us better understand the question related to whether or not a person who has completed a COVID-19 series can spread the infection,” agreed Michelle Barron, MD, a professor in the division of infectious disease at the University of Colorado, Aurora.
“The message is that, because the [D]elta variant is much more contagious than the original strain, unvaccinated persons need to get vaccinated because it is nearly impossible to avoid the virus indefinitely,” Michael Lin, MD, MPH, infectious diseases specialist and epidemiologist at Rush University Medical Center, Chicago, said when asked to comment.
The new data highlight “that vaccinated persons, if they become sick, should still seek COVID-19 testing and should still isolate, as they are likely contagious,” Dr. Lin added.
More contagious than other infections
The internal CDC slide presentation also puts the new transmission risk in simple terms. Saying that the Delta variant is about as contagious as chicken pox, for example, immediately brings back vivid memories for some of staying indoors and away from friends during childhood or teenage outbreaks.
“A lot of people will remember getting chicken pox and then having their siblings get it shortly thereafter,” Dr. Barron said. “The only key thing to note is that this does not mean that the COVID-19 [D]elta variant mechanism of spread is the same as chicken pox and Ebola. The primary means of spread of COVID-19, even the Delta variant, is via droplets.”
This also means each person infected with the Delta variant could infect an average of eight or nine others.
In contrast, the original strain of the SARS-CoV-2 virus was about as infectious as the common cold. In other words, someone was likely to infect about two other people on average.
In addition to the cold, the CDC notes that the Delta variant is now more contagious than Ebola, the seasonal flu, or small pox.
These Delta variant comparisons are one tangible way of explaining why the CDC on July 27 recommended a return to masking in schools and other indoor spaces for people – vaccinated and unvaccinated – in about 70% of the counties across the United States.
In comparing the Delta variant with other infections, “I think the CDC is trying to help people understand a little bit better the situation we now face since the information is so new. We are in a very different position now than just a few weeks ago, and it is hard for people to accept this,” Dr. Hirschwerk said.
The Delta variant is so different that the CDC considers it almost acting like a new virus altogether.
The CDC’s internal documents were first released by The Washington Post on July 29. The slides cite communication challenges for the agency to continue promoting vaccination while also acknowledging that breakthrough cases are occurring and therefore the fully vaccinated, in some instances, are likely infecting others.
Moving back to science talk, the CDC used the recent outbreak in Barnstable County as an example. The cycle threshold, or Ct values, a measure of viral load, were about the same between 80 vaccinated people linked to the outbreak who had a mean Ct value of 21.9, compared with 65 other unvaccinated people with a Ct of 21.5.
Many experts are quick to note that vaccination remains essential, in part because a vaccinated person also walks around with a much lower risk for severe outcomes, hospitalization, and death. In the internal slide show, the CDC points out that vaccination reduces the risk for infection threefold.
“Even with this high amount of virus, [the Delta variant] did not necessarily make the vaccinated individuals as sick,” Dr. Barron said.
In her statement, Dr. Walensky credited collaboration with the Commonwealth of Massachusetts Department of Public Health and the CDC for the new data. She also thanked the residents of Barnstable County for participating in interviews done by contact tracers and their willingness to get tested and adhere to safety protocols after learning of their exposure.
Next moves by CDC?
The agency notes that next steps include consideration of prevention measures such as vaccine mandates for healthcare professionals to protect vulnerable populations, universal masking for source control and prevention, and reconsidering other community mitigation strategies.
Asked if this potential policy is appropriate and feasible, Dr. Lin said, “Yes, I believe that every person working in health care should be vaccinated for COVID-19, and it is feasible.”
Dr. Barron agreed as well. “We as health care providers choose to work in health care, and we should be doing everything feasible to ensure that we are protecting our patients and keeping our coworkers safe.”
“Whether you are a health care professional or not, I would urge everyone to get the COVID-19 vaccine, especially as cases across the country continue to rise,” Dr. Hirschwerk said. “Unequivocally vaccines protect you from the virus.”
A version of this article first appeared on Medscape.com.
Internal Centers for Disease Control and Prevention documents support the high transmission rate of the Delta variant and put the risk in easier to understand terms.
In addition, the agency released a new study that shows that breakthrough infections in the vaccinated make people about as contagious as those who are unvaccinated. The new report, published July 30 in Morbidity and Mortality Weekly Report (MMWR), also reveals that the Delta variant likely causes more severe COVID-19 illness.
Given these recent findings, the internal CDC slide show advises that the agency should “acknowledge the war has changed.”
A ‘pivotal discovery’
CDC Director Rochelle Walensky, MD, MPH, said in a statement that the MMWR report demonstrates “that [D]elta infection resulted in similarly high SARS-CoV-2 viral loads in vaccinated and unvaccinated people.
“High viral loads suggest an increased risk of transmission and raised concern that, unlike with other variants, vaccinated people infected with [D]elta can transmit the virus,” she added. “This finding is concerning and was a pivotal discovery leading to CDC’s updated mask recommendation.”
The investigators analyzed 469 COVID-19 cases reported in Massachusetts residents July 3 through 17, 2021. The infections were associated with an outbreak following multiple events and large gatherings in Provincetown in that state’s easternmost Barnstable County, also known as Cape Cod.
Notably, 346 infections, or 74%, of the cases occurred in fully vaccinated individuals. This group had a median age of 42, and 87% were male. Also, 79% of the breakthrough infections were symptomatic.
Researchers also identified the Delta variant in 90% of 133 specimens collected for analysis. Furthermore, viral loads were about the same between samples taken from people who were fully vaccinated and those who were not.
Four of the five people hospitalized were fully vaccinated. No deaths were reported.
The publication of these results was highly anticipated following the CDC’s updated mask recommendations on July 27.
Outside the scope of the MMWR report is the total number of cases associated with the outbreak, including visitors from outside Massachusetts, which now approach 900 infections, NBC Boston reported.
‘Very sobering’ data
“The new information from the CDC around the [D]elta variant is very sobering,” David Hirschwerk, MD, infectious disease specialist at Northwell Health in New Hyde Park, N.Y., said in an interview.
“The CDC is trying to convey and present this uncertain situation clearly to the public based on new, accumulated data,” he said. For example, given the evidence for higher contagiousness of the Delta variant, Dr. Hirschwerk added, “there will be situations where vaccinated people get infected, because the amount of the virus overwhelms the immune protection.
“What is new that is concerning is that people who are vaccinated still have the potential to transmit the virus to the same degree,” he said.
The MMWR study “helps us better understand the question related to whether or not a person who has completed a COVID-19 series can spread the infection,” agreed Michelle Barron, MD, a professor in the division of infectious disease at the University of Colorado, Aurora.
“The message is that, because the [D]elta variant is much more contagious than the original strain, unvaccinated persons need to get vaccinated because it is nearly impossible to avoid the virus indefinitely,” Michael Lin, MD, MPH, infectious diseases specialist and epidemiologist at Rush University Medical Center, Chicago, said when asked to comment.
The new data highlight “that vaccinated persons, if they become sick, should still seek COVID-19 testing and should still isolate, as they are likely contagious,” Dr. Lin added.
More contagious than other infections
The internal CDC slide presentation also puts the new transmission risk in simple terms. Saying that the Delta variant is about as contagious as chicken pox, for example, immediately brings back vivid memories for some of staying indoors and away from friends during childhood or teenage outbreaks.
“A lot of people will remember getting chicken pox and then having their siblings get it shortly thereafter,” Dr. Barron said. “The only key thing to note is that this does not mean that the COVID-19 [D]elta variant mechanism of spread is the same as chicken pox and Ebola. The primary means of spread of COVID-19, even the Delta variant, is via droplets.”
This also means each person infected with the Delta variant could infect an average of eight or nine others.
In contrast, the original strain of the SARS-CoV-2 virus was about as infectious as the common cold. In other words, someone was likely to infect about two other people on average.
In addition to the cold, the CDC notes that the Delta variant is now more contagious than Ebola, the seasonal flu, or small pox.
These Delta variant comparisons are one tangible way of explaining why the CDC on July 27 recommended a return to masking in schools and other indoor spaces for people – vaccinated and unvaccinated – in about 70% of the counties across the United States.
In comparing the Delta variant with other infections, “I think the CDC is trying to help people understand a little bit better the situation we now face since the information is so new. We are in a very different position now than just a few weeks ago, and it is hard for people to accept this,” Dr. Hirschwerk said.
The Delta variant is so different that the CDC considers it almost acting like a new virus altogether.
The CDC’s internal documents were first released by The Washington Post on July 29. The slides cite communication challenges for the agency to continue promoting vaccination while also acknowledging that breakthrough cases are occurring and therefore the fully vaccinated, in some instances, are likely infecting others.
Moving back to science talk, the CDC used the recent outbreak in Barnstable County as an example. The cycle threshold, or Ct values, a measure of viral load, were about the same between 80 vaccinated people linked to the outbreak who had a mean Ct value of 21.9, compared with 65 other unvaccinated people with a Ct of 21.5.
Many experts are quick to note that vaccination remains essential, in part because a vaccinated person also walks around with a much lower risk for severe outcomes, hospitalization, and death. In the internal slide show, the CDC points out that vaccination reduces the risk for infection threefold.
“Even with this high amount of virus, [the Delta variant] did not necessarily make the vaccinated individuals as sick,” Dr. Barron said.
In her statement, Dr. Walensky credited collaboration with the Commonwealth of Massachusetts Department of Public Health and the CDC for the new data. She also thanked the residents of Barnstable County for participating in interviews done by contact tracers and their willingness to get tested and adhere to safety protocols after learning of their exposure.
Next moves by CDC?
The agency notes that next steps include consideration of prevention measures such as vaccine mandates for healthcare professionals to protect vulnerable populations, universal masking for source control and prevention, and reconsidering other community mitigation strategies.
Asked if this potential policy is appropriate and feasible, Dr. Lin said, “Yes, I believe that every person working in health care should be vaccinated for COVID-19, and it is feasible.”
Dr. Barron agreed as well. “We as health care providers choose to work in health care, and we should be doing everything feasible to ensure that we are protecting our patients and keeping our coworkers safe.”
“Whether you are a health care professional or not, I would urge everyone to get the COVID-19 vaccine, especially as cases across the country continue to rise,” Dr. Hirschwerk said. “Unequivocally vaccines protect you from the virus.”
A version of this article first appeared on Medscape.com.
COVID brings evolutionary virologists out of the shadows, into the fight
It has been a strange, exhausting year for many evolutionary virologists.
“Scientists are not used to having attention and are not used to being in the press and are not used to being attacked on Twitter,” Martha Nelson, PhD, a staff scientist who studies viral evolution at the National Institutes of Health, said in an interview.
Over the past year and a half, the theory of evolution has been thrust into the spotlight – more now than ever, perhaps, as the world is stalked by the Delta variant and fears arise of a mutation that’s even worse.
The origins of SARS-CoV-2 and the rise of the Delta variant have been debated, and vaccine efficacy and the possible need for booster shots have been speculated upon. In all these instances, consciously or not, there is engagement with the field of evolutionary virology.
It has been central to deepening the understanding of the ongoing pandemic, even as SARS-CoV-2 has exposed gaps in what we understand about how viruses behave and evolve.
Evolutionary virology experts believe that, after the pandemic, their expertise and tools could be applied to and integrated with clinical medicine to improve outcomes and understanding of disease.
“From our perspective, evolutionary biology has been a side dish and something that hasn’t been integrated into the core practice of medicine,” said Dr. Nelson. “I’m really curious to see how that changes over time.”
Pandemic evolution
Novel pathogens, antibiotic-resistant bacteria, and cancer cells are all products of ongoing evolution. “Just like cellular organisms, viruses have genomes, and all genomes evolve,” Eugene Koonin, PhD, evolutionary genomics group leader at the NIH, said in an interview.
Compared with cellular organisms, viruses evolve quite fast, he said.
A study published in the Proceedings of the National Academy of Sciences exemplifies evolutionary virology in action. In the study, Dr. Koonin and fellow researchers analyzed more than 300,000 genome sequences of SARS-CoV-2 variants that were publicly available as of January 2021 and mapped all the mutations in each sequence.
The researchers identified a small subset of mutations that arose independently more than once and that likely aided viral adaptation, said Nash Rochman, PhD, a research fellow at the NIH and coauthor of the PNAS study.
Many of these mutations were concentrated in two areas of the genome – the receptor binding domain of the spike protein, and a region of the nucleocapsid protein – and were often grouped together, possibly creating greater advantages for the virus than would have occurred individually, he said.
The researchers also found that, from the beginning of the pandemic, the SARS-CoV-2 genome has been evolving and diversifying in different regions around the world, allowing for the rise of new lineages and, possibly, even new species, Dr. Koonin said.
During the pandemic, researchers have used evolutionary virology tools to tackle many other questions. For example, Dr. Nelson tracked the spread of SARS-CoV-2 across Europe and North America. In a study that is currently undergoing peer review, the investigators found recently vaccinated individuals, who are only partially immune, are at the highest risk for incubating antibody-resistant variants.
C. Brandon Ogbunu, PhD, an evolutionary geneticist at Yale University, New Haven, Conn., whose work is focused on disease evolution, studied whether SARS-CoV-2 would evolve to become more transmissible, and if so, would it also become more or less virulent. His lab also investigated the transmission and spread of the virus.
“I think the last year, on one end, has been this opportunity to apply concepts and perspectives that we’ve been developing for the last several decades,” Dr. Ogbunu said in an interview. “At the same time, this pandemic has also been this wake-up call for many of us with regards to revealing the things we do not understand about the ways viruses infect, spread, and how evolution works within viruses.”
He emphasizes the need for evolutionary biology to partner with other fields – including information theory and biophysics – to help unlock viral mysteries: “We need to think very, very carefully about the way those fields intersect.”
Dr. Nelson also pointed to the need for better, more centralized data gathering in the United States.
The sheer volume of information scientists have collected about SARS-CoV-2 will aid in the study of virus evolution for years to come, said Dr. Koonin.
Evolution in medicine
Evolutionary virology and related research can be applied to medicine outside of the context of a global pandemic. “The principles and technical portions of evolutionary virology are very applicable to other diseases, including cancer,” Dr. Koonin said.
Viruses, bacteria, and cancer cells are all evolving systems. Viruses and bacteria are constantly evolving to thwart drugs and vaccines. How physicians and health care professionals practice medicine shapes the selection pressures driving how these pathogens evolve, Dr. Nelson said.
The rise of antibiotic-resistant bacteria is a particularly relevant example of how evolution affects the way physicians treat patients. Having an evolutionary perspective can help inform how to treat patients most effectively, both for individual patients as well as for broader public health, she said.
“For a long time, there’s been a lot of interest in pathogen evolution that hasn’t translated so much into clinical practice,” said Dr. Nelson. “There’s been kind of a gulf between the research side of evolutionary virology and pathogen emergence and actual practice of medicine.”
As genomic sequencing has become faster and cheaper, that gulf has started to narrow, she said. As this technology continues to prove itself by, for example, tracking the evolution of one virus in real time, Dr. Nelson hopes there will be a positive snowball effect, leading to more attention, investment, and improvements in genomic data and that its use in epidemiology and medicine will expand going forward.
Bringing viral evolution studies more into medicine will require a mindset shift, Dr. Ogbunu said. Clinical practice is, by design, very focused on the individual patient. Evolutionary biology, on the other hand, deals with populations and probabilities.
Being able to engage with evolutionary biology would help physicians better understand disease and explain it to their patients, he said.
To start, Dr. Nelson recommended requiring at least one course in evolutionary biology or evolutionary medicine in medical school and crafting continuing education in this area for physicians. (Presentations at conferences could be one way to do this.)
Dr. Nelson also recommended deeper engagement and collaboration between physicians who collect samples from patients and evolutionary biologists who analyze genetic data. This would improve the quality of the data, the analysis, and the eventual findings that could be relevant to patients and clinical practice.
Still, “my first and inevitable reaction is I would so much rather prefer to exist in relative obscurity,” said Dr. Koonin, noting that the tragedy of the pandemic outweighs the advancements in the field.
Although there’s no going back to prepandemic times, there is an enormous opportunity in the aftermath of COVID to increase dialogue between physicians and evolutionary virologists to improve medical practice as well as public health.
Dr. Nelson summed it up: “Everything we uncover about these pathogens may help us prevent something like this again.”
A version of this article first appeared on Medscape.com.
It has been a strange, exhausting year for many evolutionary virologists.
“Scientists are not used to having attention and are not used to being in the press and are not used to being attacked on Twitter,” Martha Nelson, PhD, a staff scientist who studies viral evolution at the National Institutes of Health, said in an interview.
Over the past year and a half, the theory of evolution has been thrust into the spotlight – more now than ever, perhaps, as the world is stalked by the Delta variant and fears arise of a mutation that’s even worse.
The origins of SARS-CoV-2 and the rise of the Delta variant have been debated, and vaccine efficacy and the possible need for booster shots have been speculated upon. In all these instances, consciously or not, there is engagement with the field of evolutionary virology.
It has been central to deepening the understanding of the ongoing pandemic, even as SARS-CoV-2 has exposed gaps in what we understand about how viruses behave and evolve.
Evolutionary virology experts believe that, after the pandemic, their expertise and tools could be applied to and integrated with clinical medicine to improve outcomes and understanding of disease.
“From our perspective, evolutionary biology has been a side dish and something that hasn’t been integrated into the core practice of medicine,” said Dr. Nelson. “I’m really curious to see how that changes over time.”
Pandemic evolution
Novel pathogens, antibiotic-resistant bacteria, and cancer cells are all products of ongoing evolution. “Just like cellular organisms, viruses have genomes, and all genomes evolve,” Eugene Koonin, PhD, evolutionary genomics group leader at the NIH, said in an interview.
Compared with cellular organisms, viruses evolve quite fast, he said.
A study published in the Proceedings of the National Academy of Sciences exemplifies evolutionary virology in action. In the study, Dr. Koonin and fellow researchers analyzed more than 300,000 genome sequences of SARS-CoV-2 variants that were publicly available as of January 2021 and mapped all the mutations in each sequence.
The researchers identified a small subset of mutations that arose independently more than once and that likely aided viral adaptation, said Nash Rochman, PhD, a research fellow at the NIH and coauthor of the PNAS study.
Many of these mutations were concentrated in two areas of the genome – the receptor binding domain of the spike protein, and a region of the nucleocapsid protein – and were often grouped together, possibly creating greater advantages for the virus than would have occurred individually, he said.
The researchers also found that, from the beginning of the pandemic, the SARS-CoV-2 genome has been evolving and diversifying in different regions around the world, allowing for the rise of new lineages and, possibly, even new species, Dr. Koonin said.
During the pandemic, researchers have used evolutionary virology tools to tackle many other questions. For example, Dr. Nelson tracked the spread of SARS-CoV-2 across Europe and North America. In a study that is currently undergoing peer review, the investigators found recently vaccinated individuals, who are only partially immune, are at the highest risk for incubating antibody-resistant variants.
C. Brandon Ogbunu, PhD, an evolutionary geneticist at Yale University, New Haven, Conn., whose work is focused on disease evolution, studied whether SARS-CoV-2 would evolve to become more transmissible, and if so, would it also become more or less virulent. His lab also investigated the transmission and spread of the virus.
“I think the last year, on one end, has been this opportunity to apply concepts and perspectives that we’ve been developing for the last several decades,” Dr. Ogbunu said in an interview. “At the same time, this pandemic has also been this wake-up call for many of us with regards to revealing the things we do not understand about the ways viruses infect, spread, and how evolution works within viruses.”
He emphasizes the need for evolutionary biology to partner with other fields – including information theory and biophysics – to help unlock viral mysteries: “We need to think very, very carefully about the way those fields intersect.”
Dr. Nelson also pointed to the need for better, more centralized data gathering in the United States.
The sheer volume of information scientists have collected about SARS-CoV-2 will aid in the study of virus evolution for years to come, said Dr. Koonin.
Evolution in medicine
Evolutionary virology and related research can be applied to medicine outside of the context of a global pandemic. “The principles and technical portions of evolutionary virology are very applicable to other diseases, including cancer,” Dr. Koonin said.
Viruses, bacteria, and cancer cells are all evolving systems. Viruses and bacteria are constantly evolving to thwart drugs and vaccines. How physicians and health care professionals practice medicine shapes the selection pressures driving how these pathogens evolve, Dr. Nelson said.
The rise of antibiotic-resistant bacteria is a particularly relevant example of how evolution affects the way physicians treat patients. Having an evolutionary perspective can help inform how to treat patients most effectively, both for individual patients as well as for broader public health, she said.
“For a long time, there’s been a lot of interest in pathogen evolution that hasn’t translated so much into clinical practice,” said Dr. Nelson. “There’s been kind of a gulf between the research side of evolutionary virology and pathogen emergence and actual practice of medicine.”
As genomic sequencing has become faster and cheaper, that gulf has started to narrow, she said. As this technology continues to prove itself by, for example, tracking the evolution of one virus in real time, Dr. Nelson hopes there will be a positive snowball effect, leading to more attention, investment, and improvements in genomic data and that its use in epidemiology and medicine will expand going forward.
Bringing viral evolution studies more into medicine will require a mindset shift, Dr. Ogbunu said. Clinical practice is, by design, very focused on the individual patient. Evolutionary biology, on the other hand, deals with populations and probabilities.
Being able to engage with evolutionary biology would help physicians better understand disease and explain it to their patients, he said.
To start, Dr. Nelson recommended requiring at least one course in evolutionary biology or evolutionary medicine in medical school and crafting continuing education in this area for physicians. (Presentations at conferences could be one way to do this.)
Dr. Nelson also recommended deeper engagement and collaboration between physicians who collect samples from patients and evolutionary biologists who analyze genetic data. This would improve the quality of the data, the analysis, and the eventual findings that could be relevant to patients and clinical practice.
Still, “my first and inevitable reaction is I would so much rather prefer to exist in relative obscurity,” said Dr. Koonin, noting that the tragedy of the pandemic outweighs the advancements in the field.
Although there’s no going back to prepandemic times, there is an enormous opportunity in the aftermath of COVID to increase dialogue between physicians and evolutionary virologists to improve medical practice as well as public health.
Dr. Nelson summed it up: “Everything we uncover about these pathogens may help us prevent something like this again.”
A version of this article first appeared on Medscape.com.
It has been a strange, exhausting year for many evolutionary virologists.
“Scientists are not used to having attention and are not used to being in the press and are not used to being attacked on Twitter,” Martha Nelson, PhD, a staff scientist who studies viral evolution at the National Institutes of Health, said in an interview.
Over the past year and a half, the theory of evolution has been thrust into the spotlight – more now than ever, perhaps, as the world is stalked by the Delta variant and fears arise of a mutation that’s even worse.
The origins of SARS-CoV-2 and the rise of the Delta variant have been debated, and vaccine efficacy and the possible need for booster shots have been speculated upon. In all these instances, consciously or not, there is engagement with the field of evolutionary virology.
It has been central to deepening the understanding of the ongoing pandemic, even as SARS-CoV-2 has exposed gaps in what we understand about how viruses behave and evolve.
Evolutionary virology experts believe that, after the pandemic, their expertise and tools could be applied to and integrated with clinical medicine to improve outcomes and understanding of disease.
“From our perspective, evolutionary biology has been a side dish and something that hasn’t been integrated into the core practice of medicine,” said Dr. Nelson. “I’m really curious to see how that changes over time.”
Pandemic evolution
Novel pathogens, antibiotic-resistant bacteria, and cancer cells are all products of ongoing evolution. “Just like cellular organisms, viruses have genomes, and all genomes evolve,” Eugene Koonin, PhD, evolutionary genomics group leader at the NIH, said in an interview.
Compared with cellular organisms, viruses evolve quite fast, he said.
A study published in the Proceedings of the National Academy of Sciences exemplifies evolutionary virology in action. In the study, Dr. Koonin and fellow researchers analyzed more than 300,000 genome sequences of SARS-CoV-2 variants that were publicly available as of January 2021 and mapped all the mutations in each sequence.
The researchers identified a small subset of mutations that arose independently more than once and that likely aided viral adaptation, said Nash Rochman, PhD, a research fellow at the NIH and coauthor of the PNAS study.
Many of these mutations were concentrated in two areas of the genome – the receptor binding domain of the spike protein, and a region of the nucleocapsid protein – and were often grouped together, possibly creating greater advantages for the virus than would have occurred individually, he said.
The researchers also found that, from the beginning of the pandemic, the SARS-CoV-2 genome has been evolving and diversifying in different regions around the world, allowing for the rise of new lineages and, possibly, even new species, Dr. Koonin said.
During the pandemic, researchers have used evolutionary virology tools to tackle many other questions. For example, Dr. Nelson tracked the spread of SARS-CoV-2 across Europe and North America. In a study that is currently undergoing peer review, the investigators found recently vaccinated individuals, who are only partially immune, are at the highest risk for incubating antibody-resistant variants.
C. Brandon Ogbunu, PhD, an evolutionary geneticist at Yale University, New Haven, Conn., whose work is focused on disease evolution, studied whether SARS-CoV-2 would evolve to become more transmissible, and if so, would it also become more or less virulent. His lab also investigated the transmission and spread of the virus.
“I think the last year, on one end, has been this opportunity to apply concepts and perspectives that we’ve been developing for the last several decades,” Dr. Ogbunu said in an interview. “At the same time, this pandemic has also been this wake-up call for many of us with regards to revealing the things we do not understand about the ways viruses infect, spread, and how evolution works within viruses.”
He emphasizes the need for evolutionary biology to partner with other fields – including information theory and biophysics – to help unlock viral mysteries: “We need to think very, very carefully about the way those fields intersect.”
Dr. Nelson also pointed to the need for better, more centralized data gathering in the United States.
The sheer volume of information scientists have collected about SARS-CoV-2 will aid in the study of virus evolution for years to come, said Dr. Koonin.
Evolution in medicine
Evolutionary virology and related research can be applied to medicine outside of the context of a global pandemic. “The principles and technical portions of evolutionary virology are very applicable to other diseases, including cancer,” Dr. Koonin said.
Viruses, bacteria, and cancer cells are all evolving systems. Viruses and bacteria are constantly evolving to thwart drugs and vaccines. How physicians and health care professionals practice medicine shapes the selection pressures driving how these pathogens evolve, Dr. Nelson said.
The rise of antibiotic-resistant bacteria is a particularly relevant example of how evolution affects the way physicians treat patients. Having an evolutionary perspective can help inform how to treat patients most effectively, both for individual patients as well as for broader public health, she said.
“For a long time, there’s been a lot of interest in pathogen evolution that hasn’t translated so much into clinical practice,” said Dr. Nelson. “There’s been kind of a gulf between the research side of evolutionary virology and pathogen emergence and actual practice of medicine.”
As genomic sequencing has become faster and cheaper, that gulf has started to narrow, she said. As this technology continues to prove itself by, for example, tracking the evolution of one virus in real time, Dr. Nelson hopes there will be a positive snowball effect, leading to more attention, investment, and improvements in genomic data and that its use in epidemiology and medicine will expand going forward.
Bringing viral evolution studies more into medicine will require a mindset shift, Dr. Ogbunu said. Clinical practice is, by design, very focused on the individual patient. Evolutionary biology, on the other hand, deals with populations and probabilities.
Being able to engage with evolutionary biology would help physicians better understand disease and explain it to their patients, he said.
To start, Dr. Nelson recommended requiring at least one course in evolutionary biology or evolutionary medicine in medical school and crafting continuing education in this area for physicians. (Presentations at conferences could be one way to do this.)
Dr. Nelson also recommended deeper engagement and collaboration between physicians who collect samples from patients and evolutionary biologists who analyze genetic data. This would improve the quality of the data, the analysis, and the eventual findings that could be relevant to patients and clinical practice.
Still, “my first and inevitable reaction is I would so much rather prefer to exist in relative obscurity,” said Dr. Koonin, noting that the tragedy of the pandemic outweighs the advancements in the field.
Although there’s no going back to prepandemic times, there is an enormous opportunity in the aftermath of COVID to increase dialogue between physicians and evolutionary virologists to improve medical practice as well as public health.
Dr. Nelson summed it up: “Everything we uncover about these pathogens may help us prevent something like this again.”
A version of this article first appeared on Medscape.com.
Needed: More studies of CSF molecular biomarkers in psychiatric disorders
Psychiatry and neurology are the brain’s twin medical disciplines. Unlike neurologic brain disorders, where localizing the “lesion” is a primary objective, psychiatric brain disorders are much more subtle, with no “gross” lesions but numerous cellular and molecular pathologies within neural circuits.
Measuring the molecular components of the cerebrospinal fluid (CSF), the glorious “sewage system” of the brain, may help reveal granular clues to the neurobiology of psychiatric disorders.
Mental illnesses involve the disruption of brain structures and functions in a diffuse manner across the cortex. Abnormal neuroplasticity has been implicated in several major psychiatric disorders. Examples include hypoplasia of the hippocampus in major depressive disorder and cortical thinning/dysplasia in schizophrenia. Reductions of neurotropic factors such as nerve growth factor or brain-derived neurotropic factor have been reported in mood and psychotic disorders, and appear to correlate with neuroplasticity changes.
Recent advances in psychiatric neuroscience have provided many clues to the pathophysiology of psychopathological conditions, including neuroinflammation, oxidative stress, apoptosis, impaired energy metabolism, abnormal metabolomics and lipidomics, and hypo- and hyperfunction of various neurotransmitters systems (especially glutamate N-methyl-
Thus, psychiatric research should focus on exploring and detecting molecular signatures (ie, biomarkers) of psychiatric disorders, including biomarkers of axonal and synaptic damage, glial activation, and oxidative stress. This is especially critical given the extensive heterogeneity of schizophrenia and mood and anxiety disorders. The CSF is a vastly unexploited substrate for discovering molecular biomarkers that will pave the way to precision psychiatry, and possibly open the door for completely new therapeutic strategies to tackle the most challenging neuropsychiatric disorders.
A role for CSF analysis
It’s quite puzzling why acute psychiatric episodes of schizophrenia, bipolar disorder, major depressive disorder, or panic attacks are not routinely assessed with a spinal tap, in conjunction with other brain measures such as neuroimaging (morphology, spectroscopy, cerebral blood flow, and diffusion tensor imaging) as well as a comprehensive neurocognitive examination and neurophysiological tests such as pre-pulse inhibition, mismatch negativity, and P-50, N-10, and P-300 evoked potentials. Combining CSF analysis with all those measures may help us stratify the spectra of psychosis, depression, and anxiety, as well as posttraumatic stress disorder and obsessive-compulsive disorder, into unique biotypes with overlapping clinical phenotypes and specific treatment approaches.
There are relatively few published CSF studies in psychiatric patients (mostly schizophrenia and bipolar and depressive disorders). The Table1-9 shows some of those findings. More than 365 biomarkers have been reported in schizophrenia, most of them in serum and tissue.10 However, none of them can be used for diagnostic purposes because schizophrenia is a syndrome comprised of several hundred different diseases (biotypes) that have similar clinical symptoms. Many of the serum and tissue biomarkers have not been studied in CSF, and they must if advances in the neurobiology and treatment of the psychotic and mood spectra are to be achieved. And adapting the CSF biomarkers described in neurologic disorders such as multiple sclerosis11 to schizophrenia and bipolar disorder (which also have well-established myelin pathologies) may yield a trove of neurobiologic findings.
If CSF studies eventually prove to be very useful for identifying subtypes for diagnosis and treatment, psychiatrists do not have to do the lumbar puncture themselves, but may refer patients to a “spinal tap” laboratory, just as they refer patients to a phlebotomy laboratory for routine blood tests. The adoption of CSF assessment in psychiatry will solidify its status as a clinical neuroscience, like its sister, neurology.
1. Vasic N, Connemann BJ, Wolf RC, et al. Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand? Eur Arch Psychiatry Clin Neurosci. 2012;262(5):375-391.
2. Pollak TA, Drndarski S, Stone JM, et al. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79-92.
3. Katisko K, Cajanus A, Jääskeläinen O, et al. Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders. J Neurol. 2020;267(1):162-167.
4. Bechter K, Reiber H, Herzog S, et al. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321-330.
5. Hidese S, Hattori K, Sasayama D, et al. Cerebrospinal fluid neural cell adhesion molecule levels and their correlation with clinical variables in patients with schizophrenia, bipolar disorder, and major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2017;76:12-18.
6. Tunca Z, Kıvırcık Akdede B, Özerdem A, et al. Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. Eur Psychiatry. 2015;30(2):198-204.
7. Al Shweiki MR, Oeckl P, Steinacker P, et al. Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies. Expert Rev Proteomics. 2017;14(6):499-514.
8. Kroksmark H, Vinberg M. Does S100B have a potential role in affective disorders? A literature review. Nord J Psychiatry. 2018;72(7):462-470.
9. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(6):869-887.
10. Nasrallah HA. Lab tests for psychiatric disorders: few clinicians are aware of them. Current Psychiatry. 2013;12(2):5-7.
11. Porter L, Shoushtarizadeh A, Jelinek GA, et al. Metabolomic biomarkers of multiple sclerosis: a systematic review. Front Mol Biosci. 2020;7:574133. doi: 10.3389/fmolb.2020.574133
Psychiatry and neurology are the brain’s twin medical disciplines. Unlike neurologic brain disorders, where localizing the “lesion” is a primary objective, psychiatric brain disorders are much more subtle, with no “gross” lesions but numerous cellular and molecular pathologies within neural circuits.
Measuring the molecular components of the cerebrospinal fluid (CSF), the glorious “sewage system” of the brain, may help reveal granular clues to the neurobiology of psychiatric disorders.
Mental illnesses involve the disruption of brain structures and functions in a diffuse manner across the cortex. Abnormal neuroplasticity has been implicated in several major psychiatric disorders. Examples include hypoplasia of the hippocampus in major depressive disorder and cortical thinning/dysplasia in schizophrenia. Reductions of neurotropic factors such as nerve growth factor or brain-derived neurotropic factor have been reported in mood and psychotic disorders, and appear to correlate with neuroplasticity changes.
Recent advances in psychiatric neuroscience have provided many clues to the pathophysiology of psychopathological conditions, including neuroinflammation, oxidative stress, apoptosis, impaired energy metabolism, abnormal metabolomics and lipidomics, and hypo- and hyperfunction of various neurotransmitters systems (especially glutamate N-methyl-
Thus, psychiatric research should focus on exploring and detecting molecular signatures (ie, biomarkers) of psychiatric disorders, including biomarkers of axonal and synaptic damage, glial activation, and oxidative stress. This is especially critical given the extensive heterogeneity of schizophrenia and mood and anxiety disorders. The CSF is a vastly unexploited substrate for discovering molecular biomarkers that will pave the way to precision psychiatry, and possibly open the door for completely new therapeutic strategies to tackle the most challenging neuropsychiatric disorders.
A role for CSF analysis
It’s quite puzzling why acute psychiatric episodes of schizophrenia, bipolar disorder, major depressive disorder, or panic attacks are not routinely assessed with a spinal tap, in conjunction with other brain measures such as neuroimaging (morphology, spectroscopy, cerebral blood flow, and diffusion tensor imaging) as well as a comprehensive neurocognitive examination and neurophysiological tests such as pre-pulse inhibition, mismatch negativity, and P-50, N-10, and P-300 evoked potentials. Combining CSF analysis with all those measures may help us stratify the spectra of psychosis, depression, and anxiety, as well as posttraumatic stress disorder and obsessive-compulsive disorder, into unique biotypes with overlapping clinical phenotypes and specific treatment approaches.
There are relatively few published CSF studies in psychiatric patients (mostly schizophrenia and bipolar and depressive disorders). The Table1-9 shows some of those findings. More than 365 biomarkers have been reported in schizophrenia, most of them in serum and tissue.10 However, none of them can be used for diagnostic purposes because schizophrenia is a syndrome comprised of several hundred different diseases (biotypes) that have similar clinical symptoms. Many of the serum and tissue biomarkers have not been studied in CSF, and they must if advances in the neurobiology and treatment of the psychotic and mood spectra are to be achieved. And adapting the CSF biomarkers described in neurologic disorders such as multiple sclerosis11 to schizophrenia and bipolar disorder (which also have well-established myelin pathologies) may yield a trove of neurobiologic findings.
If CSF studies eventually prove to be very useful for identifying subtypes for diagnosis and treatment, psychiatrists do not have to do the lumbar puncture themselves, but may refer patients to a “spinal tap” laboratory, just as they refer patients to a phlebotomy laboratory for routine blood tests. The adoption of CSF assessment in psychiatry will solidify its status as a clinical neuroscience, like its sister, neurology.
Psychiatry and neurology are the brain’s twin medical disciplines. Unlike neurologic brain disorders, where localizing the “lesion” is a primary objective, psychiatric brain disorders are much more subtle, with no “gross” lesions but numerous cellular and molecular pathologies within neural circuits.
Measuring the molecular components of the cerebrospinal fluid (CSF), the glorious “sewage system” of the brain, may help reveal granular clues to the neurobiology of psychiatric disorders.
Mental illnesses involve the disruption of brain structures and functions in a diffuse manner across the cortex. Abnormal neuroplasticity has been implicated in several major psychiatric disorders. Examples include hypoplasia of the hippocampus in major depressive disorder and cortical thinning/dysplasia in schizophrenia. Reductions of neurotropic factors such as nerve growth factor or brain-derived neurotropic factor have been reported in mood and psychotic disorders, and appear to correlate with neuroplasticity changes.
Recent advances in psychiatric neuroscience have provided many clues to the pathophysiology of psychopathological conditions, including neuroinflammation, oxidative stress, apoptosis, impaired energy metabolism, abnormal metabolomics and lipidomics, and hypo- and hyperfunction of various neurotransmitters systems (especially glutamate N-methyl-
Thus, psychiatric research should focus on exploring and detecting molecular signatures (ie, biomarkers) of psychiatric disorders, including biomarkers of axonal and synaptic damage, glial activation, and oxidative stress. This is especially critical given the extensive heterogeneity of schizophrenia and mood and anxiety disorders. The CSF is a vastly unexploited substrate for discovering molecular biomarkers that will pave the way to precision psychiatry, and possibly open the door for completely new therapeutic strategies to tackle the most challenging neuropsychiatric disorders.
A role for CSF analysis
It’s quite puzzling why acute psychiatric episodes of schizophrenia, bipolar disorder, major depressive disorder, or panic attacks are not routinely assessed with a spinal tap, in conjunction with other brain measures such as neuroimaging (morphology, spectroscopy, cerebral blood flow, and diffusion tensor imaging) as well as a comprehensive neurocognitive examination and neurophysiological tests such as pre-pulse inhibition, mismatch negativity, and P-50, N-10, and P-300 evoked potentials. Combining CSF analysis with all those measures may help us stratify the spectra of psychosis, depression, and anxiety, as well as posttraumatic stress disorder and obsessive-compulsive disorder, into unique biotypes with overlapping clinical phenotypes and specific treatment approaches.
There are relatively few published CSF studies in psychiatric patients (mostly schizophrenia and bipolar and depressive disorders). The Table1-9 shows some of those findings. More than 365 biomarkers have been reported in schizophrenia, most of them in serum and tissue.10 However, none of them can be used for diagnostic purposes because schizophrenia is a syndrome comprised of several hundred different diseases (biotypes) that have similar clinical symptoms. Many of the serum and tissue biomarkers have not been studied in CSF, and they must if advances in the neurobiology and treatment of the psychotic and mood spectra are to be achieved. And adapting the CSF biomarkers described in neurologic disorders such as multiple sclerosis11 to schizophrenia and bipolar disorder (which also have well-established myelin pathologies) may yield a trove of neurobiologic findings.
If CSF studies eventually prove to be very useful for identifying subtypes for diagnosis and treatment, psychiatrists do not have to do the lumbar puncture themselves, but may refer patients to a “spinal tap” laboratory, just as they refer patients to a phlebotomy laboratory for routine blood tests. The adoption of CSF assessment in psychiatry will solidify its status as a clinical neuroscience, like its sister, neurology.
1. Vasic N, Connemann BJ, Wolf RC, et al. Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand? Eur Arch Psychiatry Clin Neurosci. 2012;262(5):375-391.
2. Pollak TA, Drndarski S, Stone JM, et al. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79-92.
3. Katisko K, Cajanus A, Jääskeläinen O, et al. Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders. J Neurol. 2020;267(1):162-167.
4. Bechter K, Reiber H, Herzog S, et al. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321-330.
5. Hidese S, Hattori K, Sasayama D, et al. Cerebrospinal fluid neural cell adhesion molecule levels and their correlation with clinical variables in patients with schizophrenia, bipolar disorder, and major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2017;76:12-18.
6. Tunca Z, Kıvırcık Akdede B, Özerdem A, et al. Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. Eur Psychiatry. 2015;30(2):198-204.
7. Al Shweiki MR, Oeckl P, Steinacker P, et al. Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies. Expert Rev Proteomics. 2017;14(6):499-514.
8. Kroksmark H, Vinberg M. Does S100B have a potential role in affective disorders? A literature review. Nord J Psychiatry. 2018;72(7):462-470.
9. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(6):869-887.
10. Nasrallah HA. Lab tests for psychiatric disorders: few clinicians are aware of them. Current Psychiatry. 2013;12(2):5-7.
11. Porter L, Shoushtarizadeh A, Jelinek GA, et al. Metabolomic biomarkers of multiple sclerosis: a systematic review. Front Mol Biosci. 2020;7:574133. doi: 10.3389/fmolb.2020.574133
1. Vasic N, Connemann BJ, Wolf RC, et al. Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand? Eur Arch Psychiatry Clin Neurosci. 2012;262(5):375-391.
2. Pollak TA, Drndarski S, Stone JM, et al. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79-92.
3. Katisko K, Cajanus A, Jääskeläinen O, et al. Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders. J Neurol. 2020;267(1):162-167.
4. Bechter K, Reiber H, Herzog S, et al. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321-330.
5. Hidese S, Hattori K, Sasayama D, et al. Cerebrospinal fluid neural cell adhesion molecule levels and their correlation with clinical variables in patients with schizophrenia, bipolar disorder, and major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2017;76:12-18.
6. Tunca Z, Kıvırcık Akdede B, Özerdem A, et al. Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. Eur Psychiatry. 2015;30(2):198-204.
7. Al Shweiki MR, Oeckl P, Steinacker P, et al. Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies. Expert Rev Proteomics. 2017;14(6):499-514.
8. Kroksmark H, Vinberg M. Does S100B have a potential role in affective disorders? A literature review. Nord J Psychiatry. 2018;72(7):462-470.
9. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(6):869-887.
10. Nasrallah HA. Lab tests for psychiatric disorders: few clinicians are aware of them. Current Psychiatry. 2013;12(2):5-7.
11. Porter L, Shoushtarizadeh A, Jelinek GA, et al. Metabolomic biomarkers of multiple sclerosis: a systematic review. Front Mol Biosci. 2020;7:574133. doi: 10.3389/fmolb.2020.574133
Late-onset, treatment-resistant anxiety and depression
CASE Anxious and can’t sleep
Mr. A, age 41, presents to his primary care physician (PCP) with anxiety and insomnia. He describes having generalized anxiety with initial and middle insomnia, and says he is sleeping an average of 2 hours per night. He denies any other psychiatric symptoms. Mr. A has no significant psychiatric or medical history.
Mr. A is initiated on zolpidem tartrate, 12.5 mg every night at bedtime, and paroxetine, 20 mg every night at bedtime, for anxiety and insomnia, but these medications result in little to no improvement.
During a 4-month period, he is treated with trials of alprazolam, 0.5 mg every 8 hours as needed; diazepam 5 mg twice a day as needed; diphenhydramine, 50 mg at bedtime; and eszopiclone, 3 mg at bedtime. Despite these treatments, he experiences increased anxiety and insomnia, and develops depressive symptoms, including depressed mood, poor concentration, general malaise, extreme fatigue, a 15-pound unintentional weight loss, erectile dysfunction, and decreased libido. Mr. A denies having suicidal or homicidal ideations. Additionally, he typically goes to the gym approximately 3 times per week, and has noticed that the amount of weight he is able to lift has decreased, which is distressing. Previously, he had been able to lift 300 pounds, but now he can only lift 200 pounds.
[polldaddy:10891920]
The authors’ observations
Insomnia, anxiety, and depression are common chief complaints in medical settings. However, some psychiatric presentations may have an underlying medical etiology.
DSM-5 requires that medical conditions be ruled out in order for a patient to meet criteria for a psychiatric diagnosis.1 Medical differential diagnoses for patients with psychiatric symptoms can include autoimmune, drug/toxin, metabolic, infectious, neoplastic, neurologic, and nutritional etiologies (Table 12). To rule out the possibility of an underlying medical etiology, general screening guidelines include complete blood count, complete metabolic panel, urinalysis, and urine drug screen with alcohol. Human immunodeficiency virus testing and thyroid hormone testing are also commonly ordered.3 Further laboratory testing and imaging is typically not warranted in the absence of historical or physical findings because they are not advocated as cost-effective, so health care professionals must use their clinical judgment to determine appropriate further evaluation. The onset of anxiety most commonly occurs in late adolescence early and adulthood, but Mr. A experienced his first symptoms of anxiety at age 41.2 Mr. A’s age, lack of psychiatric or family history of mental illness, acute onset of symptoms, and failure of symptoms to abate with standard psychiatric treatments warrant a more extensive workup.
EVALUATION Imaging reveals an important finding
Because Mr. A’s symptoms do not improve with standard psychiatric treatments, his PCP orders standard laboratory bloodwork to investigate a possible medical etiology; however, his results are all within normal range.
After the PCP’s niece is coincidentally diagnosed with a pituitary macroadenoma, the PCP orders brain imaging for Mr. A. Results of an MRI show that Mr. A has a 1.6-cm macroadenoma of the pituitary. He is referred to an endocrinologist, who orders additional laboratory tests that show an elevated 24-hour free urine cortisol level of 73 μg/24 h (normal range: 3.5 to 45 μg/24 h), suggesting that Mr. A’s anxiety may be due to Cushing’s disease or that his anxiety caused falsely elevated urinary cortisol levels. Four weeks later, bloodwork is repeated and shows an abnormal dexamethasone suppression test, and 2 more elevated 24-hour free urine cortisol levels of 76 μg/24 h and 150 μg/24 h. A repeat MRI shows a 1.8-cm, mostly cystic sellar mass, indicating the need for surgical intervention. Although the tumor is large and shows optic nerve compression, Mr. A does not complain of headaches or changes in vision.
Continue to: Two months later...
Two months later, Mr. A undergoes a transsphenoidal tumor resection of the pituitary adenoma, and biopsy results confirm an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma, which is consistent with Cushing’s disease. Following surgery, steroid treatment with dexamethasone is discontinued due to a persistently elevated
[polldaddy:10891923]
The authors’ observations
Chronic excess glucocorticoid production is the underlying pathophysiology of Cushing’s disease, which is most commonly caused by an ACTH-producing adenoma.4,5 When these hormones become dysregulated, the result can be over- or underproduction of cortisol, which can lead to physical and psychiatric manifestations.6
Cushing’s disease most commonly manifests with the physical symptoms of centripetal fat deposition, abdominal striae, facial plethora, muscle atrophy, bone density loss, immunosuppression, and cardiovascular complications.5
Hypercortisolism can precipitate anxiety (12% to 79%), mood disorders (50% to 70%), and (less commonly) psychotic disorders; however, in a clinical setting, if a patient presented with one of these as a chief complaint, they would likely first be treated psychiatrically rather than worked up medically for a rare medical condition.5,7-13
Mr. A’s initial bloodwork was unremarkable, but cortisol levels were not obtained at that time because testing for cortisol levels to rule out an underlying medical condition is not routine in patients with depression and anxiety. In Mr. A’s case, a neuroendocrine workup was only ordered once his PCP’s niece coincidentally was diagnosed with a pituitary adenoma.
Continue to: For Mr. A...
For Mr. A, Cushing’s disease presented as a psychiatric disorder with anxiety and insomnia that were resistant to numerous psychiatric medications during an 8-month period. If Mr. A’s PCP had not ordered a brain MRI, he may have continued to receive ineffective psychiatric treatment for some time. Many of Mr. A’s physical symptoms were consistent with Cushing’s disease and mental illness, including erectile dysfunction, fatigue, and muscle weakness; however, his 15-pound weight loss pointed more toward psychiatric illness and further disguised his underlying medical diagnosis, because sudden weight gain is commonly seen in Cushing’s disease (Table 24,5,7,9).
TREATMENT Persistent psychiatric symptoms, then finally relief
Four weeks after surgery, Mr. A’s psychiatric symptoms gradually intensify, which prompts him to see a psychiatrist. A mental status examination (MSE) shows that he is well-nourished, with normal activity, appropriate behavior, and coherent thought process, but depressed mood and flat affect. He denies suicidal or homicidal ideation. He reports that despite being advised to have realistic expectations, he had high hopes that the surgery would lead to remission of all his symptoms, and expresses disappointment that he does not feel “back to normal.”
Six days later, Mr. A’s wife takes him to the hospital. His MSE shows that he has a tense appearance, fidgety activity, depressed and anxious mood, restricted affect, circumstantial thought process, and paranoid delusions that his wife was plotting against him. He says he still is experiencing insomnia. He also discloses having suicidal ideations with a plan and intent to overdose on medication, as well as homicidal ideations about killing his wife and children. Mr. A provides reasons for why he would want to hurt his family, and does not appear to be bothered by these thoughts.
Mr. A is admitted to the inpatient psychiatric unit and is prescribed quetiapine, 100 mg every night at bedtime. During the next 2 days, quetiapine is titrated to 300 mg every night at bedtime. On hospital Day 3, Mr. A says he is feeling worse than the previous days. He is still having vague suicidal thoughts and feels agitated, guilty, and depressed. To treat these persistent symptoms, quetiapine is further increased to 400 mg every night at bedtime, and he is initiated on bupropion XL, 150 mg, to treat persistent symptoms.
After 1 week of hospitalization, the treatment team meets with Mr. A and his wife, who has been supportive throughout her husband’s hospitalization. During the meeting, they both agree that Mr. A has experienced some improvement because he is no longer having suicidal or homicidal thoughts, but he is still feeling depressed and frustrated by his continued insomnia. Following the meeting, Mr. A’s quetiapine is further increased to 450 mg every night at bedtime to address continued insomnia, and bupropion XL is increased to 300 mg/d to address continued depressive symptoms. During the next few days, his affective symptoms improve; however, his initial insomnia continues, and quetiapine is further increased to 500 mg every night at bedtime.
Continue to: On hospital Day 20...
On hospital Day 20, Mr. A is discharged back to his outpatient psychiatrist and receives quetiapine, 500 mg every night at bedtime, and bupropion XL, 300 mg/d. Although Mr. A’s depression and anxiety continue to be well controlled, his insomnia persists. Sleep hygiene is addressed, and alprazolam, 0.5 mg every night at bedtime, is added to his regimen, which proves to be effective.
OUTCOME A slow remission
After a year of treatment, Mr. A is slowly tapered off of all medications. Two years later, he is in complete remission of all psychiatric symptoms and no longer requires any psychotropic medications.
The authors’ observations
Treatment for hypercortisolism in patients with psychiatric symptoms triggered by glucocorticoid imbalance has typically resulted in a decrease in the severity of their psychiatric symptoms.9,11 A prospective longitudinal study examining 33 patients found that correction of hypercortisolism in patients with Cushing’s syndrome often led to resolution of their psychiatric symptoms, with 87.9% of patients back to baseline within 1 year.14 However, to our knowledge, few reports have described the management of patients whose symptoms are resistant to treatment of hypercortisolism.
In our case, after transsphenoidal resection of an adenoma, Mr. A became suicidal and paranoid, and his anxiety and insomnia also persisted. A possible explanation for the worsening of Mr. A’s symptoms after surgery could be the slow recovery of the hypothalamic-pituitary-adrenal (HPA) axis and therefore a temporary deficiency in glucocorticoid, which caused an increase in catecholamines, leading to an increase in stress.14 This concept of a “slow recovery” is supported by the fact that Mr. A was successfully weaned off all medication after 1 year of treatment, and achieved complete remission of psychiatric symptoms for >2 years. Furthermore, the severity of Mr. A’s symptoms appeared to correlate with his 24-hour urine cortisol and
Future research should evaluate the utility of screening all patients with treatment-resistant anxiety and/or insomnia for hypercortisolism. Even without other clues to endocrinopathies, serum cortisol levels can be used as a screening tool for diagnosing underlying medical causes in patients with anxiety and depression.2 A greater understanding of the relationship between medical and psychiatric manifestations will allow clinicians to better care for patients. Further research is needed to elucidate the quantitative relationship between cortisol levels and anxiety to evaluate severity, guide treatment planning, and follow treatment response for patients with anxiety. It may be useful to determine the threshold between elevated cortisol levels due to anxiety vs elevated cortisol due to an underlying medical pathology such as Cushing’s disease. Additionally, little research has been conducted to compare how psychiatric symptoms respond to pituitary macroadenoma resection alone, pharmaceutical intervention alone, or a combination of these approaches. It would be beneficial to evaluate these treatment strategies to elucidate the most effective method to reduce psychiatric symptoms in patients with hypercortisolism, and perhaps to reduce the incidence of post-resection worsening of psychiatric symptoms.
Continue to: This case was challenging...
This case was challenging because Mr. A did not initially respond to psychiatric intervention, his psychiatric symptoms worsened after transsphenoidal resection of the pituitary adenoma, and his symptoms were alleviated only after psychiatric medications were re-initiated following surgery. This case highlights the importance of considering an underlying medically diagnosable and treatable cause of psychiatric illness, and illustrates the complex ongoing management that may be necessary to help a patient with this condition achieve their baseline. Further, Mr. A’s case shows that the absence of response to standard psychiatric therapies should warrant earlier laboratory and/or imaging evaluation prior to or in conjunction with psychiatric referral. Additionally, testing for cortisol levels is not typically done for a patient with treatment-resistant anxiety, and this case highlights the importance of considering hypercortisolism in such circumstances.
Bottom Line
Consider testing cortisol levels in patients with treatment-resistant anxiety and insomnia, because cortisol plays a role in Cushing’s disease and anxiety. The severity of psychiatric manifestations of Cushing’s disease may correlate with cortisol levels. Treatment should focus on symptomatic management and underlying etiology.
Related Resources
- Roberts LW, Hales RE, Yudofsky SC, ed. The American Psychiatric Association Publishing Textbook of Psychiatry. 7th ed. American Psychiatric Association Publishing; 2019.
- Rotham J. Cushing’s syndrome: a tale of frequent misdiagnosis. National Center for Health Research. 2020. www.center4research.org/cushings-syndrome-frequent-misdiagnosis/
- Middleman D. Psychiatric issues of Cushing’s patients: coping with Cushing’s. Cushing’s Support and Research Foundation. www.csrf.net/coping-with-cushings/psychiatric-issues-of-cushings-patients/
Drug Brand Names
Alprazolam • Xanax
Bupropion • Wellbutrin
Dexamethasone • Decadron
Diazepam • Valium
Eszopiclone • Lunesta
Paroxetine • Paxil
Quetiapine • Seroquel
Zolpidem tartrate • Ambien CR
1. Diagnostic and statistical manual of mental disorders, 5th ed. American Psychiatric Association; 2013.
2. Sadock BJ, Sadock VA, Ruiz P, et al. Neural sciences. In: Sadock BJ, Sadock VA, Ruiz P, et al. Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences/clinical psychiatry. 11th ed. Wolters Kluwer; 2015.
3. Anfinson TJ, Kathol RG. Screening laboratory evaluation in psychiatric patients: a review. Gen Hosp Psychiatry. 1992;14(4):248-257.
4. Fehm HL, Voigt KH. Pathophysiology of Cushing’s disease. Pathobiol Annu. 1979;9:225-255.
5. Fujii Y, Mizoguchi Y, Masuoka J, et al. Cushing’s syndrome and psychosis: a case report and literature review. Prim Care Companion CNS Disord. 2018;20(5):18.
6. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2011;4(2):739-769.
7. Santos A, Resimini E, Pascual JC, et al. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence diagnosis, and management. Drugs. 2017;77(8):829-842.
8. Arnaldi G, Angeli A, Atkinson B, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602.
9. Sonino N, Fava GA. Psychosomatic aspects of Cushing’s disease. Psychother Psychosom. 1998;67(3):140-146.
10. Loosen PT, Chambliss B, DeBold CR, et al. Psychiatric phenomenology in Cushing’s disease. Pharmacopsychiatry. 1992;25(4):192-198.
11. Kelly WF, Kelly MJ, Faragher B. A prospective study of psychiatric and psychological aspects of Cushing’s syndrome. Clin Endocrinol. 1996;45(6):715-720.
12. Katho RG, Delahunt JW, Hannah L. Transition from bipolar affective disorder to intermittent Cushing’s syndrome: case report. J Clin Psychiatry. 1985;46(5):194-196.
13. Hirsh D, Orr G, Kantarovich V, et al. Cushing’s syndrome presenting as a schizophrenia-like psychotic state. Isr J Psychiatry Relat Sci. 2000;37(1):46-50.
14. Dorn LD, Burgess ES, Friedman TC, et al. The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J Clin Endocrinol Metab. 1997;82(3):912-919.
15. Starkman MN, Schteingart DE, Schork MA. Cushing’s syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome. Psychiatry Res. 1986;19(3):177-178.
CASE Anxious and can’t sleep
Mr. A, age 41, presents to his primary care physician (PCP) with anxiety and insomnia. He describes having generalized anxiety with initial and middle insomnia, and says he is sleeping an average of 2 hours per night. He denies any other psychiatric symptoms. Mr. A has no significant psychiatric or medical history.
Mr. A is initiated on zolpidem tartrate, 12.5 mg every night at bedtime, and paroxetine, 20 mg every night at bedtime, for anxiety and insomnia, but these medications result in little to no improvement.
During a 4-month period, he is treated with trials of alprazolam, 0.5 mg every 8 hours as needed; diazepam 5 mg twice a day as needed; diphenhydramine, 50 mg at bedtime; and eszopiclone, 3 mg at bedtime. Despite these treatments, he experiences increased anxiety and insomnia, and develops depressive symptoms, including depressed mood, poor concentration, general malaise, extreme fatigue, a 15-pound unintentional weight loss, erectile dysfunction, and decreased libido. Mr. A denies having suicidal or homicidal ideations. Additionally, he typically goes to the gym approximately 3 times per week, and has noticed that the amount of weight he is able to lift has decreased, which is distressing. Previously, he had been able to lift 300 pounds, but now he can only lift 200 pounds.
[polldaddy:10891920]
The authors’ observations
Insomnia, anxiety, and depression are common chief complaints in medical settings. However, some psychiatric presentations may have an underlying medical etiology.
DSM-5 requires that medical conditions be ruled out in order for a patient to meet criteria for a psychiatric diagnosis.1 Medical differential diagnoses for patients with psychiatric symptoms can include autoimmune, drug/toxin, metabolic, infectious, neoplastic, neurologic, and nutritional etiologies (Table 12). To rule out the possibility of an underlying medical etiology, general screening guidelines include complete blood count, complete metabolic panel, urinalysis, and urine drug screen with alcohol. Human immunodeficiency virus testing and thyroid hormone testing are also commonly ordered.3 Further laboratory testing and imaging is typically not warranted in the absence of historical or physical findings because they are not advocated as cost-effective, so health care professionals must use their clinical judgment to determine appropriate further evaluation. The onset of anxiety most commonly occurs in late adolescence early and adulthood, but Mr. A experienced his first symptoms of anxiety at age 41.2 Mr. A’s age, lack of psychiatric or family history of mental illness, acute onset of symptoms, and failure of symptoms to abate with standard psychiatric treatments warrant a more extensive workup.
EVALUATION Imaging reveals an important finding
Because Mr. A’s symptoms do not improve with standard psychiatric treatments, his PCP orders standard laboratory bloodwork to investigate a possible medical etiology; however, his results are all within normal range.
After the PCP’s niece is coincidentally diagnosed with a pituitary macroadenoma, the PCP orders brain imaging for Mr. A. Results of an MRI show that Mr. A has a 1.6-cm macroadenoma of the pituitary. He is referred to an endocrinologist, who orders additional laboratory tests that show an elevated 24-hour free urine cortisol level of 73 μg/24 h (normal range: 3.5 to 45 μg/24 h), suggesting that Mr. A’s anxiety may be due to Cushing’s disease or that his anxiety caused falsely elevated urinary cortisol levels. Four weeks later, bloodwork is repeated and shows an abnormal dexamethasone suppression test, and 2 more elevated 24-hour free urine cortisol levels of 76 μg/24 h and 150 μg/24 h. A repeat MRI shows a 1.8-cm, mostly cystic sellar mass, indicating the need for surgical intervention. Although the tumor is large and shows optic nerve compression, Mr. A does not complain of headaches or changes in vision.
Continue to: Two months later...
Two months later, Mr. A undergoes a transsphenoidal tumor resection of the pituitary adenoma, and biopsy results confirm an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma, which is consistent with Cushing’s disease. Following surgery, steroid treatment with dexamethasone is discontinued due to a persistently elevated
[polldaddy:10891923]
The authors’ observations
Chronic excess glucocorticoid production is the underlying pathophysiology of Cushing’s disease, which is most commonly caused by an ACTH-producing adenoma.4,5 When these hormones become dysregulated, the result can be over- or underproduction of cortisol, which can lead to physical and psychiatric manifestations.6
Cushing’s disease most commonly manifests with the physical symptoms of centripetal fat deposition, abdominal striae, facial plethora, muscle atrophy, bone density loss, immunosuppression, and cardiovascular complications.5
Hypercortisolism can precipitate anxiety (12% to 79%), mood disorders (50% to 70%), and (less commonly) psychotic disorders; however, in a clinical setting, if a patient presented with one of these as a chief complaint, they would likely first be treated psychiatrically rather than worked up medically for a rare medical condition.5,7-13
Mr. A’s initial bloodwork was unremarkable, but cortisol levels were not obtained at that time because testing for cortisol levels to rule out an underlying medical condition is not routine in patients with depression and anxiety. In Mr. A’s case, a neuroendocrine workup was only ordered once his PCP’s niece coincidentally was diagnosed with a pituitary adenoma.
Continue to: For Mr. A...
For Mr. A, Cushing’s disease presented as a psychiatric disorder with anxiety and insomnia that were resistant to numerous psychiatric medications during an 8-month period. If Mr. A’s PCP had not ordered a brain MRI, he may have continued to receive ineffective psychiatric treatment for some time. Many of Mr. A’s physical symptoms were consistent with Cushing’s disease and mental illness, including erectile dysfunction, fatigue, and muscle weakness; however, his 15-pound weight loss pointed more toward psychiatric illness and further disguised his underlying medical diagnosis, because sudden weight gain is commonly seen in Cushing’s disease (Table 24,5,7,9).
TREATMENT Persistent psychiatric symptoms, then finally relief
Four weeks after surgery, Mr. A’s psychiatric symptoms gradually intensify, which prompts him to see a psychiatrist. A mental status examination (MSE) shows that he is well-nourished, with normal activity, appropriate behavior, and coherent thought process, but depressed mood and flat affect. He denies suicidal or homicidal ideation. He reports that despite being advised to have realistic expectations, he had high hopes that the surgery would lead to remission of all his symptoms, and expresses disappointment that he does not feel “back to normal.”
Six days later, Mr. A’s wife takes him to the hospital. His MSE shows that he has a tense appearance, fidgety activity, depressed and anxious mood, restricted affect, circumstantial thought process, and paranoid delusions that his wife was plotting against him. He says he still is experiencing insomnia. He also discloses having suicidal ideations with a plan and intent to overdose on medication, as well as homicidal ideations about killing his wife and children. Mr. A provides reasons for why he would want to hurt his family, and does not appear to be bothered by these thoughts.
Mr. A is admitted to the inpatient psychiatric unit and is prescribed quetiapine, 100 mg every night at bedtime. During the next 2 days, quetiapine is titrated to 300 mg every night at bedtime. On hospital Day 3, Mr. A says he is feeling worse than the previous days. He is still having vague suicidal thoughts and feels agitated, guilty, and depressed. To treat these persistent symptoms, quetiapine is further increased to 400 mg every night at bedtime, and he is initiated on bupropion XL, 150 mg, to treat persistent symptoms.
After 1 week of hospitalization, the treatment team meets with Mr. A and his wife, who has been supportive throughout her husband’s hospitalization. During the meeting, they both agree that Mr. A has experienced some improvement because he is no longer having suicidal or homicidal thoughts, but he is still feeling depressed and frustrated by his continued insomnia. Following the meeting, Mr. A’s quetiapine is further increased to 450 mg every night at bedtime to address continued insomnia, and bupropion XL is increased to 300 mg/d to address continued depressive symptoms. During the next few days, his affective symptoms improve; however, his initial insomnia continues, and quetiapine is further increased to 500 mg every night at bedtime.
Continue to: On hospital Day 20...
On hospital Day 20, Mr. A is discharged back to his outpatient psychiatrist and receives quetiapine, 500 mg every night at bedtime, and bupropion XL, 300 mg/d. Although Mr. A’s depression and anxiety continue to be well controlled, his insomnia persists. Sleep hygiene is addressed, and alprazolam, 0.5 mg every night at bedtime, is added to his regimen, which proves to be effective.
OUTCOME A slow remission
After a year of treatment, Mr. A is slowly tapered off of all medications. Two years later, he is in complete remission of all psychiatric symptoms and no longer requires any psychotropic medications.
The authors’ observations
Treatment for hypercortisolism in patients with psychiatric symptoms triggered by glucocorticoid imbalance has typically resulted in a decrease in the severity of their psychiatric symptoms.9,11 A prospective longitudinal study examining 33 patients found that correction of hypercortisolism in patients with Cushing’s syndrome often led to resolution of their psychiatric symptoms, with 87.9% of patients back to baseline within 1 year.14 However, to our knowledge, few reports have described the management of patients whose symptoms are resistant to treatment of hypercortisolism.
In our case, after transsphenoidal resection of an adenoma, Mr. A became suicidal and paranoid, and his anxiety and insomnia also persisted. A possible explanation for the worsening of Mr. A’s symptoms after surgery could be the slow recovery of the hypothalamic-pituitary-adrenal (HPA) axis and therefore a temporary deficiency in glucocorticoid, which caused an increase in catecholamines, leading to an increase in stress.14 This concept of a “slow recovery” is supported by the fact that Mr. A was successfully weaned off all medication after 1 year of treatment, and achieved complete remission of psychiatric symptoms for >2 years. Furthermore, the severity of Mr. A’s symptoms appeared to correlate with his 24-hour urine cortisol and
Future research should evaluate the utility of screening all patients with treatment-resistant anxiety and/or insomnia for hypercortisolism. Even without other clues to endocrinopathies, serum cortisol levels can be used as a screening tool for diagnosing underlying medical causes in patients with anxiety and depression.2 A greater understanding of the relationship between medical and psychiatric manifestations will allow clinicians to better care for patients. Further research is needed to elucidate the quantitative relationship between cortisol levels and anxiety to evaluate severity, guide treatment planning, and follow treatment response for patients with anxiety. It may be useful to determine the threshold between elevated cortisol levels due to anxiety vs elevated cortisol due to an underlying medical pathology such as Cushing’s disease. Additionally, little research has been conducted to compare how psychiatric symptoms respond to pituitary macroadenoma resection alone, pharmaceutical intervention alone, or a combination of these approaches. It would be beneficial to evaluate these treatment strategies to elucidate the most effective method to reduce psychiatric symptoms in patients with hypercortisolism, and perhaps to reduce the incidence of post-resection worsening of psychiatric symptoms.
Continue to: This case was challenging...
This case was challenging because Mr. A did not initially respond to psychiatric intervention, his psychiatric symptoms worsened after transsphenoidal resection of the pituitary adenoma, and his symptoms were alleviated only after psychiatric medications were re-initiated following surgery. This case highlights the importance of considering an underlying medically diagnosable and treatable cause of psychiatric illness, and illustrates the complex ongoing management that may be necessary to help a patient with this condition achieve their baseline. Further, Mr. A’s case shows that the absence of response to standard psychiatric therapies should warrant earlier laboratory and/or imaging evaluation prior to or in conjunction with psychiatric referral. Additionally, testing for cortisol levels is not typically done for a patient with treatment-resistant anxiety, and this case highlights the importance of considering hypercortisolism in such circumstances.
Bottom Line
Consider testing cortisol levels in patients with treatment-resistant anxiety and insomnia, because cortisol plays a role in Cushing’s disease and anxiety. The severity of psychiatric manifestations of Cushing’s disease may correlate with cortisol levels. Treatment should focus on symptomatic management and underlying etiology.
Related Resources
- Roberts LW, Hales RE, Yudofsky SC, ed. The American Psychiatric Association Publishing Textbook of Psychiatry. 7th ed. American Psychiatric Association Publishing; 2019.
- Rotham J. Cushing’s syndrome: a tale of frequent misdiagnosis. National Center for Health Research. 2020. www.center4research.org/cushings-syndrome-frequent-misdiagnosis/
- Middleman D. Psychiatric issues of Cushing’s patients: coping with Cushing’s. Cushing’s Support and Research Foundation. www.csrf.net/coping-with-cushings/psychiatric-issues-of-cushings-patients/
Drug Brand Names
Alprazolam • Xanax
Bupropion • Wellbutrin
Dexamethasone • Decadron
Diazepam • Valium
Eszopiclone • Lunesta
Paroxetine • Paxil
Quetiapine • Seroquel
Zolpidem tartrate • Ambien CR
CASE Anxious and can’t sleep
Mr. A, age 41, presents to his primary care physician (PCP) with anxiety and insomnia. He describes having generalized anxiety with initial and middle insomnia, and says he is sleeping an average of 2 hours per night. He denies any other psychiatric symptoms. Mr. A has no significant psychiatric or medical history.
Mr. A is initiated on zolpidem tartrate, 12.5 mg every night at bedtime, and paroxetine, 20 mg every night at bedtime, for anxiety and insomnia, but these medications result in little to no improvement.
During a 4-month period, he is treated with trials of alprazolam, 0.5 mg every 8 hours as needed; diazepam 5 mg twice a day as needed; diphenhydramine, 50 mg at bedtime; and eszopiclone, 3 mg at bedtime. Despite these treatments, he experiences increased anxiety and insomnia, and develops depressive symptoms, including depressed mood, poor concentration, general malaise, extreme fatigue, a 15-pound unintentional weight loss, erectile dysfunction, and decreased libido. Mr. A denies having suicidal or homicidal ideations. Additionally, he typically goes to the gym approximately 3 times per week, and has noticed that the amount of weight he is able to lift has decreased, which is distressing. Previously, he had been able to lift 300 pounds, but now he can only lift 200 pounds.
[polldaddy:10891920]
The authors’ observations
Insomnia, anxiety, and depression are common chief complaints in medical settings. However, some psychiatric presentations may have an underlying medical etiology.
DSM-5 requires that medical conditions be ruled out in order for a patient to meet criteria for a psychiatric diagnosis.1 Medical differential diagnoses for patients with psychiatric symptoms can include autoimmune, drug/toxin, metabolic, infectious, neoplastic, neurologic, and nutritional etiologies (Table 12). To rule out the possibility of an underlying medical etiology, general screening guidelines include complete blood count, complete metabolic panel, urinalysis, and urine drug screen with alcohol. Human immunodeficiency virus testing and thyroid hormone testing are also commonly ordered.3 Further laboratory testing and imaging is typically not warranted in the absence of historical or physical findings because they are not advocated as cost-effective, so health care professionals must use their clinical judgment to determine appropriate further evaluation. The onset of anxiety most commonly occurs in late adolescence early and adulthood, but Mr. A experienced his first symptoms of anxiety at age 41.2 Mr. A’s age, lack of psychiatric or family history of mental illness, acute onset of symptoms, and failure of symptoms to abate with standard psychiatric treatments warrant a more extensive workup.
EVALUATION Imaging reveals an important finding
Because Mr. A’s symptoms do not improve with standard psychiatric treatments, his PCP orders standard laboratory bloodwork to investigate a possible medical etiology; however, his results are all within normal range.
After the PCP’s niece is coincidentally diagnosed with a pituitary macroadenoma, the PCP orders brain imaging for Mr. A. Results of an MRI show that Mr. A has a 1.6-cm macroadenoma of the pituitary. He is referred to an endocrinologist, who orders additional laboratory tests that show an elevated 24-hour free urine cortisol level of 73 μg/24 h (normal range: 3.5 to 45 μg/24 h), suggesting that Mr. A’s anxiety may be due to Cushing’s disease or that his anxiety caused falsely elevated urinary cortisol levels. Four weeks later, bloodwork is repeated and shows an abnormal dexamethasone suppression test, and 2 more elevated 24-hour free urine cortisol levels of 76 μg/24 h and 150 μg/24 h. A repeat MRI shows a 1.8-cm, mostly cystic sellar mass, indicating the need for surgical intervention. Although the tumor is large and shows optic nerve compression, Mr. A does not complain of headaches or changes in vision.
Continue to: Two months later...
Two months later, Mr. A undergoes a transsphenoidal tumor resection of the pituitary adenoma, and biopsy results confirm an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma, which is consistent with Cushing’s disease. Following surgery, steroid treatment with dexamethasone is discontinued due to a persistently elevated
[polldaddy:10891923]
The authors’ observations
Chronic excess glucocorticoid production is the underlying pathophysiology of Cushing’s disease, which is most commonly caused by an ACTH-producing adenoma.4,5 When these hormones become dysregulated, the result can be over- or underproduction of cortisol, which can lead to physical and psychiatric manifestations.6
Cushing’s disease most commonly manifests with the physical symptoms of centripetal fat deposition, abdominal striae, facial plethora, muscle atrophy, bone density loss, immunosuppression, and cardiovascular complications.5
Hypercortisolism can precipitate anxiety (12% to 79%), mood disorders (50% to 70%), and (less commonly) psychotic disorders; however, in a clinical setting, if a patient presented with one of these as a chief complaint, they would likely first be treated psychiatrically rather than worked up medically for a rare medical condition.5,7-13
Mr. A’s initial bloodwork was unremarkable, but cortisol levels were not obtained at that time because testing for cortisol levels to rule out an underlying medical condition is not routine in patients with depression and anxiety. In Mr. A’s case, a neuroendocrine workup was only ordered once his PCP’s niece coincidentally was diagnosed with a pituitary adenoma.
Continue to: For Mr. A...
For Mr. A, Cushing’s disease presented as a psychiatric disorder with anxiety and insomnia that were resistant to numerous psychiatric medications during an 8-month period. If Mr. A’s PCP had not ordered a brain MRI, he may have continued to receive ineffective psychiatric treatment for some time. Many of Mr. A’s physical symptoms were consistent with Cushing’s disease and mental illness, including erectile dysfunction, fatigue, and muscle weakness; however, his 15-pound weight loss pointed more toward psychiatric illness and further disguised his underlying medical diagnosis, because sudden weight gain is commonly seen in Cushing’s disease (Table 24,5,7,9).
TREATMENT Persistent psychiatric symptoms, then finally relief
Four weeks after surgery, Mr. A’s psychiatric symptoms gradually intensify, which prompts him to see a psychiatrist. A mental status examination (MSE) shows that he is well-nourished, with normal activity, appropriate behavior, and coherent thought process, but depressed mood and flat affect. He denies suicidal or homicidal ideation. He reports that despite being advised to have realistic expectations, he had high hopes that the surgery would lead to remission of all his symptoms, and expresses disappointment that he does not feel “back to normal.”
Six days later, Mr. A’s wife takes him to the hospital. His MSE shows that he has a tense appearance, fidgety activity, depressed and anxious mood, restricted affect, circumstantial thought process, and paranoid delusions that his wife was plotting against him. He says he still is experiencing insomnia. He also discloses having suicidal ideations with a plan and intent to overdose on medication, as well as homicidal ideations about killing his wife and children. Mr. A provides reasons for why he would want to hurt his family, and does not appear to be bothered by these thoughts.
Mr. A is admitted to the inpatient psychiatric unit and is prescribed quetiapine, 100 mg every night at bedtime. During the next 2 days, quetiapine is titrated to 300 mg every night at bedtime. On hospital Day 3, Mr. A says he is feeling worse than the previous days. He is still having vague suicidal thoughts and feels agitated, guilty, and depressed. To treat these persistent symptoms, quetiapine is further increased to 400 mg every night at bedtime, and he is initiated on bupropion XL, 150 mg, to treat persistent symptoms.
After 1 week of hospitalization, the treatment team meets with Mr. A and his wife, who has been supportive throughout her husband’s hospitalization. During the meeting, they both agree that Mr. A has experienced some improvement because he is no longer having suicidal or homicidal thoughts, but he is still feeling depressed and frustrated by his continued insomnia. Following the meeting, Mr. A’s quetiapine is further increased to 450 mg every night at bedtime to address continued insomnia, and bupropion XL is increased to 300 mg/d to address continued depressive symptoms. During the next few days, his affective symptoms improve; however, his initial insomnia continues, and quetiapine is further increased to 500 mg every night at bedtime.
Continue to: On hospital Day 20...
On hospital Day 20, Mr. A is discharged back to his outpatient psychiatrist and receives quetiapine, 500 mg every night at bedtime, and bupropion XL, 300 mg/d. Although Mr. A’s depression and anxiety continue to be well controlled, his insomnia persists. Sleep hygiene is addressed, and alprazolam, 0.5 mg every night at bedtime, is added to his regimen, which proves to be effective.
OUTCOME A slow remission
After a year of treatment, Mr. A is slowly tapered off of all medications. Two years later, he is in complete remission of all psychiatric symptoms and no longer requires any psychotropic medications.
The authors’ observations
Treatment for hypercortisolism in patients with psychiatric symptoms triggered by glucocorticoid imbalance has typically resulted in a decrease in the severity of their psychiatric symptoms.9,11 A prospective longitudinal study examining 33 patients found that correction of hypercortisolism in patients with Cushing’s syndrome often led to resolution of their psychiatric symptoms, with 87.9% of patients back to baseline within 1 year.14 However, to our knowledge, few reports have described the management of patients whose symptoms are resistant to treatment of hypercortisolism.
In our case, after transsphenoidal resection of an adenoma, Mr. A became suicidal and paranoid, and his anxiety and insomnia also persisted. A possible explanation for the worsening of Mr. A’s symptoms after surgery could be the slow recovery of the hypothalamic-pituitary-adrenal (HPA) axis and therefore a temporary deficiency in glucocorticoid, which caused an increase in catecholamines, leading to an increase in stress.14 This concept of a “slow recovery” is supported by the fact that Mr. A was successfully weaned off all medication after 1 year of treatment, and achieved complete remission of psychiatric symptoms for >2 years. Furthermore, the severity of Mr. A’s symptoms appeared to correlate with his 24-hour urine cortisol and
Future research should evaluate the utility of screening all patients with treatment-resistant anxiety and/or insomnia for hypercortisolism. Even without other clues to endocrinopathies, serum cortisol levels can be used as a screening tool for diagnosing underlying medical causes in patients with anxiety and depression.2 A greater understanding of the relationship between medical and psychiatric manifestations will allow clinicians to better care for patients. Further research is needed to elucidate the quantitative relationship between cortisol levels and anxiety to evaluate severity, guide treatment planning, and follow treatment response for patients with anxiety. It may be useful to determine the threshold between elevated cortisol levels due to anxiety vs elevated cortisol due to an underlying medical pathology such as Cushing’s disease. Additionally, little research has been conducted to compare how psychiatric symptoms respond to pituitary macroadenoma resection alone, pharmaceutical intervention alone, or a combination of these approaches. It would be beneficial to evaluate these treatment strategies to elucidate the most effective method to reduce psychiatric symptoms in patients with hypercortisolism, and perhaps to reduce the incidence of post-resection worsening of psychiatric symptoms.
Continue to: This case was challenging...
This case was challenging because Mr. A did not initially respond to psychiatric intervention, his psychiatric symptoms worsened after transsphenoidal resection of the pituitary adenoma, and his symptoms were alleviated only after psychiatric medications were re-initiated following surgery. This case highlights the importance of considering an underlying medically diagnosable and treatable cause of psychiatric illness, and illustrates the complex ongoing management that may be necessary to help a patient with this condition achieve their baseline. Further, Mr. A’s case shows that the absence of response to standard psychiatric therapies should warrant earlier laboratory and/or imaging evaluation prior to or in conjunction with psychiatric referral. Additionally, testing for cortisol levels is not typically done for a patient with treatment-resistant anxiety, and this case highlights the importance of considering hypercortisolism in such circumstances.
Bottom Line
Consider testing cortisol levels in patients with treatment-resistant anxiety and insomnia, because cortisol plays a role in Cushing’s disease and anxiety. The severity of psychiatric manifestations of Cushing’s disease may correlate with cortisol levels. Treatment should focus on symptomatic management and underlying etiology.
Related Resources
- Roberts LW, Hales RE, Yudofsky SC, ed. The American Psychiatric Association Publishing Textbook of Psychiatry. 7th ed. American Psychiatric Association Publishing; 2019.
- Rotham J. Cushing’s syndrome: a tale of frequent misdiagnosis. National Center for Health Research. 2020. www.center4research.org/cushings-syndrome-frequent-misdiagnosis/
- Middleman D. Psychiatric issues of Cushing’s patients: coping with Cushing’s. Cushing’s Support and Research Foundation. www.csrf.net/coping-with-cushings/psychiatric-issues-of-cushings-patients/
Drug Brand Names
Alprazolam • Xanax
Bupropion • Wellbutrin
Dexamethasone • Decadron
Diazepam • Valium
Eszopiclone • Lunesta
Paroxetine • Paxil
Quetiapine • Seroquel
Zolpidem tartrate • Ambien CR
1. Diagnostic and statistical manual of mental disorders, 5th ed. American Psychiatric Association; 2013.
2. Sadock BJ, Sadock VA, Ruiz P, et al. Neural sciences. In: Sadock BJ, Sadock VA, Ruiz P, et al. Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences/clinical psychiatry. 11th ed. Wolters Kluwer; 2015.
3. Anfinson TJ, Kathol RG. Screening laboratory evaluation in psychiatric patients: a review. Gen Hosp Psychiatry. 1992;14(4):248-257.
4. Fehm HL, Voigt KH. Pathophysiology of Cushing’s disease. Pathobiol Annu. 1979;9:225-255.
5. Fujii Y, Mizoguchi Y, Masuoka J, et al. Cushing’s syndrome and psychosis: a case report and literature review. Prim Care Companion CNS Disord. 2018;20(5):18.
6. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2011;4(2):739-769.
7. Santos A, Resimini E, Pascual JC, et al. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence diagnosis, and management. Drugs. 2017;77(8):829-842.
8. Arnaldi G, Angeli A, Atkinson B, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602.
9. Sonino N, Fava GA. Psychosomatic aspects of Cushing’s disease. Psychother Psychosom. 1998;67(3):140-146.
10. Loosen PT, Chambliss B, DeBold CR, et al. Psychiatric phenomenology in Cushing’s disease. Pharmacopsychiatry. 1992;25(4):192-198.
11. Kelly WF, Kelly MJ, Faragher B. A prospective study of psychiatric and psychological aspects of Cushing’s syndrome. Clin Endocrinol. 1996;45(6):715-720.
12. Katho RG, Delahunt JW, Hannah L. Transition from bipolar affective disorder to intermittent Cushing’s syndrome: case report. J Clin Psychiatry. 1985;46(5):194-196.
13. Hirsh D, Orr G, Kantarovich V, et al. Cushing’s syndrome presenting as a schizophrenia-like psychotic state. Isr J Psychiatry Relat Sci. 2000;37(1):46-50.
14. Dorn LD, Burgess ES, Friedman TC, et al. The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J Clin Endocrinol Metab. 1997;82(3):912-919.
15. Starkman MN, Schteingart DE, Schork MA. Cushing’s syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome. Psychiatry Res. 1986;19(3):177-178.
1. Diagnostic and statistical manual of mental disorders, 5th ed. American Psychiatric Association; 2013.
2. Sadock BJ, Sadock VA, Ruiz P, et al. Neural sciences. In: Sadock BJ, Sadock VA, Ruiz P, et al. Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences/clinical psychiatry. 11th ed. Wolters Kluwer; 2015.
3. Anfinson TJ, Kathol RG. Screening laboratory evaluation in psychiatric patients: a review. Gen Hosp Psychiatry. 1992;14(4):248-257.
4. Fehm HL, Voigt KH. Pathophysiology of Cushing’s disease. Pathobiol Annu. 1979;9:225-255.
5. Fujii Y, Mizoguchi Y, Masuoka J, et al. Cushing’s syndrome and psychosis: a case report and literature review. Prim Care Companion CNS Disord. 2018;20(5):18.
6. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2011;4(2):739-769.
7. Santos A, Resimini E, Pascual JC, et al. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence diagnosis, and management. Drugs. 2017;77(8):829-842.
8. Arnaldi G, Angeli A, Atkinson B, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602.
9. Sonino N, Fava GA. Psychosomatic aspects of Cushing’s disease. Psychother Psychosom. 1998;67(3):140-146.
10. Loosen PT, Chambliss B, DeBold CR, et al. Psychiatric phenomenology in Cushing’s disease. Pharmacopsychiatry. 1992;25(4):192-198.
11. Kelly WF, Kelly MJ, Faragher B. A prospective study of psychiatric and psychological aspects of Cushing’s syndrome. Clin Endocrinol. 1996;45(6):715-720.
12. Katho RG, Delahunt JW, Hannah L. Transition from bipolar affective disorder to intermittent Cushing’s syndrome: case report. J Clin Psychiatry. 1985;46(5):194-196.
13. Hirsh D, Orr G, Kantarovich V, et al. Cushing’s syndrome presenting as a schizophrenia-like psychotic state. Isr J Psychiatry Relat Sci. 2000;37(1):46-50.
14. Dorn LD, Burgess ES, Friedman TC, et al. The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J Clin Endocrinol Metab. 1997;82(3):912-919.
15. Starkman MN, Schteingart DE, Schork MA. Cushing’s syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome. Psychiatry Res. 1986;19(3):177-178.
Medicine’s ‘Big Lie’
While today “The Big Lie” mainly refers to the actions of the prior President, an older and bigger lie that has a real effect on every American is one perpetrated by our very own health care conglomerate. Americans pay the highest rates for health care on the planet; health care consumes about 17% of our gross domestic product.1 If we got higher-quality care, faster services, longer lives, or even greater consumer happiness, paying those rates might be worth it. But we don’t.
Worse yet is the idea that “board certification” assures the public that the doctor from whom they receive/purchase care is of a higher quality than one who is not so credentialed. That is our “Big Lie!” For decades, the public has been told that they should seek out board-certified doctors. Doctors in training have been told they must get board-certified. Hospitals brag about employing only board-certified doctors, insurers sometimes mandate board certification for a doctor to get paid, and employers use board certification as a benchmark for hiring and as a factor in compensation.
The sacred secret is that board certification makes no difference. There is no substantial evidence in any branch of medicine that doctors who are board-certified are better. There is no evidence that board-certified doctors get their patients healthier with more frequency, faster, less expensively, or with fewer medical errors than other doctors. The reality is that board certification is a sham. It’s a certificate granted after taking a very expensive test, and it is now part of an industry that is misleading the public and harming the trust the medical profession had once earned. Board certification is the equivalent of a diploma mill or an online certificate in any other field.
Why has this been kept under wraps for so long? Follow the money. The American Board of Medical Specialties (ABMS) oversees 24 specialty boards and reported revenue of $22.2M and expenses of $19.3M on its 2019 IRS Form 990.2 They make profit every year. But, looking further, these “not-for-profit” educational entities are sitting on hundreds of millions of dollars in their “foundations.” Take the American Board of Psychiatry and Neurology, for instance. They had more than $140M in assets in 2019.3 How is this possible? Easy. They have misled the American public and been remarkably successful convincing other organizations, such as the Joint Commission, the Accreditation Council for Graduate Medical Education, and the National Committee for Quality Assurance, that board certification is an assurance of quality. They charge high fees to “candidates” for taking the computer-based test and have developed a system called maintenance of certification (MOC) that is onerous, expensive, and serves as an annuity that forces doctors to pay annually to keep their board certification.
Medicine is a science. In the practice of our discipline, we are expected to follow the science and to adhere to scientific principles. Yet there is neither scientific proof nor good evidence that board certification means anything in terms of competence, safety to the public, or quality of care. Doctors favor life-long learning, and continuing education has long been the standard and should remain so, not board certification or MOC. The mandatory continuing education required in every state to maintain a medical license is sufficient to prove doctors are current in their field of practice and to protect the public.
It is time for the medical community to admit that the emperor wears no clothes, and demand that the money grab of the ABMS and its affiliates be halted. This would result in greater access to care for patients and would reduce the cost of medical care, as the hundreds of millions being “stolen” from doctors today—costs that get passed on to patients—could be recouped and used for treating patients who clearly are in need and are being forgotten as the medical-industrial complex continues to flex its muscles and ensnare more of our national budget in its tentacles.
Neil S. Kaye, MD, DLFAPA
Hockessin, Delaware
1. The World Bank. Current health expenditure (% of GDP). Accessed July 12, 2021. https://data.worldbank.org/indicator/SH.XPD.CHEX.GD.ZS
2. American Board of Medical Specialties. 2019 Form 990. Return of Organization Exempt From Income Tax. Accessed July 12, 2021. https://www.abms.org/wp-content/uploads/2021/01/2019-american-board-of-medical-specialties-form-990.pdf
3. ProPublica. American Board of Psychiatry and Neurology. Accessed July 13, 2021. https://projects.propublica.org/nonprofits/organizations/410654864
While today “The Big Lie” mainly refers to the actions of the prior President, an older and bigger lie that has a real effect on every American is one perpetrated by our very own health care conglomerate. Americans pay the highest rates for health care on the planet; health care consumes about 17% of our gross domestic product.1 If we got higher-quality care, faster services, longer lives, or even greater consumer happiness, paying those rates might be worth it. But we don’t.
Worse yet is the idea that “board certification” assures the public that the doctor from whom they receive/purchase care is of a higher quality than one who is not so credentialed. That is our “Big Lie!” For decades, the public has been told that they should seek out board-certified doctors. Doctors in training have been told they must get board-certified. Hospitals brag about employing only board-certified doctors, insurers sometimes mandate board certification for a doctor to get paid, and employers use board certification as a benchmark for hiring and as a factor in compensation.
The sacred secret is that board certification makes no difference. There is no substantial evidence in any branch of medicine that doctors who are board-certified are better. There is no evidence that board-certified doctors get their patients healthier with more frequency, faster, less expensively, or with fewer medical errors than other doctors. The reality is that board certification is a sham. It’s a certificate granted after taking a very expensive test, and it is now part of an industry that is misleading the public and harming the trust the medical profession had once earned. Board certification is the equivalent of a diploma mill or an online certificate in any other field.
Why has this been kept under wraps for so long? Follow the money. The American Board of Medical Specialties (ABMS) oversees 24 specialty boards and reported revenue of $22.2M and expenses of $19.3M on its 2019 IRS Form 990.2 They make profit every year. But, looking further, these “not-for-profit” educational entities are sitting on hundreds of millions of dollars in their “foundations.” Take the American Board of Psychiatry and Neurology, for instance. They had more than $140M in assets in 2019.3 How is this possible? Easy. They have misled the American public and been remarkably successful convincing other organizations, such as the Joint Commission, the Accreditation Council for Graduate Medical Education, and the National Committee for Quality Assurance, that board certification is an assurance of quality. They charge high fees to “candidates” for taking the computer-based test and have developed a system called maintenance of certification (MOC) that is onerous, expensive, and serves as an annuity that forces doctors to pay annually to keep their board certification.
Medicine is a science. In the practice of our discipline, we are expected to follow the science and to adhere to scientific principles. Yet there is neither scientific proof nor good evidence that board certification means anything in terms of competence, safety to the public, or quality of care. Doctors favor life-long learning, and continuing education has long been the standard and should remain so, not board certification or MOC. The mandatory continuing education required in every state to maintain a medical license is sufficient to prove doctors are current in their field of practice and to protect the public.
It is time for the medical community to admit that the emperor wears no clothes, and demand that the money grab of the ABMS and its affiliates be halted. This would result in greater access to care for patients and would reduce the cost of medical care, as the hundreds of millions being “stolen” from doctors today—costs that get passed on to patients—could be recouped and used for treating patients who clearly are in need and are being forgotten as the medical-industrial complex continues to flex its muscles and ensnare more of our national budget in its tentacles.
Neil S. Kaye, MD, DLFAPA
Hockessin, Delaware
While today “The Big Lie” mainly refers to the actions of the prior President, an older and bigger lie that has a real effect on every American is one perpetrated by our very own health care conglomerate. Americans pay the highest rates for health care on the planet; health care consumes about 17% of our gross domestic product.1 If we got higher-quality care, faster services, longer lives, or even greater consumer happiness, paying those rates might be worth it. But we don’t.
Worse yet is the idea that “board certification” assures the public that the doctor from whom they receive/purchase care is of a higher quality than one who is not so credentialed. That is our “Big Lie!” For decades, the public has been told that they should seek out board-certified doctors. Doctors in training have been told they must get board-certified. Hospitals brag about employing only board-certified doctors, insurers sometimes mandate board certification for a doctor to get paid, and employers use board certification as a benchmark for hiring and as a factor in compensation.
The sacred secret is that board certification makes no difference. There is no substantial evidence in any branch of medicine that doctors who are board-certified are better. There is no evidence that board-certified doctors get their patients healthier with more frequency, faster, less expensively, or with fewer medical errors than other doctors. The reality is that board certification is a sham. It’s a certificate granted after taking a very expensive test, and it is now part of an industry that is misleading the public and harming the trust the medical profession had once earned. Board certification is the equivalent of a diploma mill or an online certificate in any other field.
Why has this been kept under wraps for so long? Follow the money. The American Board of Medical Specialties (ABMS) oversees 24 specialty boards and reported revenue of $22.2M and expenses of $19.3M on its 2019 IRS Form 990.2 They make profit every year. But, looking further, these “not-for-profit” educational entities are sitting on hundreds of millions of dollars in their “foundations.” Take the American Board of Psychiatry and Neurology, for instance. They had more than $140M in assets in 2019.3 How is this possible? Easy. They have misled the American public and been remarkably successful convincing other organizations, such as the Joint Commission, the Accreditation Council for Graduate Medical Education, and the National Committee for Quality Assurance, that board certification is an assurance of quality. They charge high fees to “candidates” for taking the computer-based test and have developed a system called maintenance of certification (MOC) that is onerous, expensive, and serves as an annuity that forces doctors to pay annually to keep their board certification.
Medicine is a science. In the practice of our discipline, we are expected to follow the science and to adhere to scientific principles. Yet there is neither scientific proof nor good evidence that board certification means anything in terms of competence, safety to the public, or quality of care. Doctors favor life-long learning, and continuing education has long been the standard and should remain so, not board certification or MOC. The mandatory continuing education required in every state to maintain a medical license is sufficient to prove doctors are current in their field of practice and to protect the public.
It is time for the medical community to admit that the emperor wears no clothes, and demand that the money grab of the ABMS and its affiliates be halted. This would result in greater access to care for patients and would reduce the cost of medical care, as the hundreds of millions being “stolen” from doctors today—costs that get passed on to patients—could be recouped and used for treating patients who clearly are in need and are being forgotten as the medical-industrial complex continues to flex its muscles and ensnare more of our national budget in its tentacles.
Neil S. Kaye, MD, DLFAPA
Hockessin, Delaware
1. The World Bank. Current health expenditure (% of GDP). Accessed July 12, 2021. https://data.worldbank.org/indicator/SH.XPD.CHEX.GD.ZS
2. American Board of Medical Specialties. 2019 Form 990. Return of Organization Exempt From Income Tax. Accessed July 12, 2021. https://www.abms.org/wp-content/uploads/2021/01/2019-american-board-of-medical-specialties-form-990.pdf
3. ProPublica. American Board of Psychiatry and Neurology. Accessed July 13, 2021. https://projects.propublica.org/nonprofits/organizations/410654864
1. The World Bank. Current health expenditure (% of GDP). Accessed July 12, 2021. https://data.worldbank.org/indicator/SH.XPD.CHEX.GD.ZS
2. American Board of Medical Specialties. 2019 Form 990. Return of Organization Exempt From Income Tax. Accessed July 12, 2021. https://www.abms.org/wp-content/uploads/2021/01/2019-american-board-of-medical-specialties-form-990.pdf
3. ProPublica. American Board of Psychiatry and Neurology. Accessed July 13, 2021. https://projects.propublica.org/nonprofits/organizations/410654864
Workplace violence: Enhance your safety in outpatient settings
In the health care setting, workplace violence directed by patients against clinicians or other staff (eg, verbal or physical assaults) is common.1-3 Factors that contribute to violent incidents within mental health settings include communication problems, substance use, patients’ noncompliance with medications, procedural failures (administrative and legal), and a lack of resources.4
Being verbally or physically assaulted, stalked, or threatened by a patient is a reality for mental health professionals, especially in outpatient settings with limited resources and a lack of onsite security.5 Addressing the concerns outlined in this article can enhance your safety in outpatient settings. These steps should be customized for your practice with the possible assistance of legal counsel, risk management, and/or law enforcement.5
Plans and policies to mitigate the risk of violence. Assess for hazards within and around the workplace.5 Learn to assess your patient’s violence risk level in pre-screening interviews before their first appointment. Create a violence prevention and response plan, which may involve calling law enforcement if you fear for your safety or the safety of others.5 The confidentiality clauses of the Health Insurance Portability and Accountability Act make an exception to allow for disclosure to prevent or reduce a serious and substantial threat to the health or safety of an individual or society (you should limit your disclosure to pertinent nonclinical information).5,6 Develop policies and procedures to identify, communicate, track, and document patients’ concerning behaviors as well as policies and procedures to terminate care of patients who display these concerning behaviors.5 These plans and policies should include informing patients that neither violence nor threats of any kind will be tolerated. Frequently review these plans and policies with clinic personnel; these documents should be easily accessible to everyone (eg, posted on a board).
Communication and education. Keep open lines of communication with all clinic personnel, and encourage them to promptly report incidents and any concerning patient behaviors. Frequently check in with them about any safety concerns they have, and encourage them to suggest ways to reduce risks.7 Include discussions about safety during clinic meetings. Educate clinic personnel about the nonverbal warning signs of behavior escalation, and provide de-escalation and response training.5 Hold simulation drills so clinic personnel can become more familiar with the violence prevention and response plan.
Office safety. Install a security barrier between the waiting room and office spaces so that patients cannot easily barge into the office spaces. Ensure access to the office areas is restricted to clinic personnel using access card readers, electronic locks, locks with deadbolts, etc.5 Escort patients within the office and ensure that individuals who are not associated with the clinic are not permitted to enter any area of the office alone.5 Install video surveillance cameras at entrances, exits, and other strategic locations and post signs signaling their presence.5 Post signs stating that concealed weapons are not allowed on the premises. Install panic buttons in each office, at the reception desk, and other areas (eg, restrooms).5 Develop a code word or phrase that will allow front desk staff to know that you are in trouble when they call your office. Have a designated room in which staff can gather and lock themselves if they are not able to escape.5 Provide law enforcement with floor plans of the clinic to help expedite their response.2
Personal safety. During patient visits, position yourself so you can exit a room quickly if needed, and avoid having your back to the exit.5,7 Ensure the patient is not blocking the exit. Avoid wearing attire that can be used as a weapon against you, such as a tie or necklace, or can impede your escape, such as high heels.7 Avoid wearing valuable accessories that can be damaged or destroyed during a “take down.”7 Wear an audible alarm.5 Avoid posting personal information that is publicly accessible (eg, in the office or online) and may reveal your habits.5 Insist upon a “buddy system” in which no one works alone, including outside normal business hours, or goes to their car alone.5
1. Phillips JP. Workplace violence against health care workers in the United States. N Engl J Med. 2016;374(17):1661-1669.
2. Workplace violence: issues in response. Rugala EA, Issacs AR (eds). Critical Incident Response Group, National Center for Analysis of Violent Crime, FBI Academy. 2003. Accessed November 27, 2020. https://www.fbi.gov/file-repository/stats-services-publications-workplace-violence-workplace-violence/view
3. Velani KH. 2019 Healthcare Crime Survey. International Association for Healthcare Security and Safety – Foundation (IAHSS – Foundation). Accessed November 27, 2020. https://iahssf.org/crime-surveys/2019-healthcare-crime-survey/3/
4. O’Rourke M, Wrigley C, Hammond S. Violence within mental health services: how to enhance risk management. Risk Manag Healthc Policy. 2018;11:159-167.
5. Neal D. Seven actions to ensure safety in psychiatric office settings. Psychiatric News. 2020;55(7):15.
6. Health Insurance Portability and Accountability Act of 1996. Public Law No. 104–191, 110 Stat. 1936 (1996).
7. Xiong GL, Newman WJ. Take CAUTION in emergency and inpatient psychiatric settings. Current Psychiatry. 2013;12(7):9-10.
In the health care setting, workplace violence directed by patients against clinicians or other staff (eg, verbal or physical assaults) is common.1-3 Factors that contribute to violent incidents within mental health settings include communication problems, substance use, patients’ noncompliance with medications, procedural failures (administrative and legal), and a lack of resources.4
Being verbally or physically assaulted, stalked, or threatened by a patient is a reality for mental health professionals, especially in outpatient settings with limited resources and a lack of onsite security.5 Addressing the concerns outlined in this article can enhance your safety in outpatient settings. These steps should be customized for your practice with the possible assistance of legal counsel, risk management, and/or law enforcement.5
Plans and policies to mitigate the risk of violence. Assess for hazards within and around the workplace.5 Learn to assess your patient’s violence risk level in pre-screening interviews before their first appointment. Create a violence prevention and response plan, which may involve calling law enforcement if you fear for your safety or the safety of others.5 The confidentiality clauses of the Health Insurance Portability and Accountability Act make an exception to allow for disclosure to prevent or reduce a serious and substantial threat to the health or safety of an individual or society (you should limit your disclosure to pertinent nonclinical information).5,6 Develop policies and procedures to identify, communicate, track, and document patients’ concerning behaviors as well as policies and procedures to terminate care of patients who display these concerning behaviors.5 These plans and policies should include informing patients that neither violence nor threats of any kind will be tolerated. Frequently review these plans and policies with clinic personnel; these documents should be easily accessible to everyone (eg, posted on a board).
Communication and education. Keep open lines of communication with all clinic personnel, and encourage them to promptly report incidents and any concerning patient behaviors. Frequently check in with them about any safety concerns they have, and encourage them to suggest ways to reduce risks.7 Include discussions about safety during clinic meetings. Educate clinic personnel about the nonverbal warning signs of behavior escalation, and provide de-escalation and response training.5 Hold simulation drills so clinic personnel can become more familiar with the violence prevention and response plan.
Office safety. Install a security barrier between the waiting room and office spaces so that patients cannot easily barge into the office spaces. Ensure access to the office areas is restricted to clinic personnel using access card readers, electronic locks, locks with deadbolts, etc.5 Escort patients within the office and ensure that individuals who are not associated with the clinic are not permitted to enter any area of the office alone.5 Install video surveillance cameras at entrances, exits, and other strategic locations and post signs signaling their presence.5 Post signs stating that concealed weapons are not allowed on the premises. Install panic buttons in each office, at the reception desk, and other areas (eg, restrooms).5 Develop a code word or phrase that will allow front desk staff to know that you are in trouble when they call your office. Have a designated room in which staff can gather and lock themselves if they are not able to escape.5 Provide law enforcement with floor plans of the clinic to help expedite their response.2
Personal safety. During patient visits, position yourself so you can exit a room quickly if needed, and avoid having your back to the exit.5,7 Ensure the patient is not blocking the exit. Avoid wearing attire that can be used as a weapon against you, such as a tie or necklace, or can impede your escape, such as high heels.7 Avoid wearing valuable accessories that can be damaged or destroyed during a “take down.”7 Wear an audible alarm.5 Avoid posting personal information that is publicly accessible (eg, in the office or online) and may reveal your habits.5 Insist upon a “buddy system” in which no one works alone, including outside normal business hours, or goes to their car alone.5
In the health care setting, workplace violence directed by patients against clinicians or other staff (eg, verbal or physical assaults) is common.1-3 Factors that contribute to violent incidents within mental health settings include communication problems, substance use, patients’ noncompliance with medications, procedural failures (administrative and legal), and a lack of resources.4
Being verbally or physically assaulted, stalked, or threatened by a patient is a reality for mental health professionals, especially in outpatient settings with limited resources and a lack of onsite security.5 Addressing the concerns outlined in this article can enhance your safety in outpatient settings. These steps should be customized for your practice with the possible assistance of legal counsel, risk management, and/or law enforcement.5
Plans and policies to mitigate the risk of violence. Assess for hazards within and around the workplace.5 Learn to assess your patient’s violence risk level in pre-screening interviews before their first appointment. Create a violence prevention and response plan, which may involve calling law enforcement if you fear for your safety or the safety of others.5 The confidentiality clauses of the Health Insurance Portability and Accountability Act make an exception to allow for disclosure to prevent or reduce a serious and substantial threat to the health or safety of an individual or society (you should limit your disclosure to pertinent nonclinical information).5,6 Develop policies and procedures to identify, communicate, track, and document patients’ concerning behaviors as well as policies and procedures to terminate care of patients who display these concerning behaviors.5 These plans and policies should include informing patients that neither violence nor threats of any kind will be tolerated. Frequently review these plans and policies with clinic personnel; these documents should be easily accessible to everyone (eg, posted on a board).
Communication and education. Keep open lines of communication with all clinic personnel, and encourage them to promptly report incidents and any concerning patient behaviors. Frequently check in with them about any safety concerns they have, and encourage them to suggest ways to reduce risks.7 Include discussions about safety during clinic meetings. Educate clinic personnel about the nonverbal warning signs of behavior escalation, and provide de-escalation and response training.5 Hold simulation drills so clinic personnel can become more familiar with the violence prevention and response plan.
Office safety. Install a security barrier between the waiting room and office spaces so that patients cannot easily barge into the office spaces. Ensure access to the office areas is restricted to clinic personnel using access card readers, electronic locks, locks with deadbolts, etc.5 Escort patients within the office and ensure that individuals who are not associated with the clinic are not permitted to enter any area of the office alone.5 Install video surveillance cameras at entrances, exits, and other strategic locations and post signs signaling their presence.5 Post signs stating that concealed weapons are not allowed on the premises. Install panic buttons in each office, at the reception desk, and other areas (eg, restrooms).5 Develop a code word or phrase that will allow front desk staff to know that you are in trouble when they call your office. Have a designated room in which staff can gather and lock themselves if they are not able to escape.5 Provide law enforcement with floor plans of the clinic to help expedite their response.2
Personal safety. During patient visits, position yourself so you can exit a room quickly if needed, and avoid having your back to the exit.5,7 Ensure the patient is not blocking the exit. Avoid wearing attire that can be used as a weapon against you, such as a tie or necklace, or can impede your escape, such as high heels.7 Avoid wearing valuable accessories that can be damaged or destroyed during a “take down.”7 Wear an audible alarm.5 Avoid posting personal information that is publicly accessible (eg, in the office or online) and may reveal your habits.5 Insist upon a “buddy system” in which no one works alone, including outside normal business hours, or goes to their car alone.5
1. Phillips JP. Workplace violence against health care workers in the United States. N Engl J Med. 2016;374(17):1661-1669.
2. Workplace violence: issues in response. Rugala EA, Issacs AR (eds). Critical Incident Response Group, National Center for Analysis of Violent Crime, FBI Academy. 2003. Accessed November 27, 2020. https://www.fbi.gov/file-repository/stats-services-publications-workplace-violence-workplace-violence/view
3. Velani KH. 2019 Healthcare Crime Survey. International Association for Healthcare Security and Safety – Foundation (IAHSS – Foundation). Accessed November 27, 2020. https://iahssf.org/crime-surveys/2019-healthcare-crime-survey/3/
4. O’Rourke M, Wrigley C, Hammond S. Violence within mental health services: how to enhance risk management. Risk Manag Healthc Policy. 2018;11:159-167.
5. Neal D. Seven actions to ensure safety in psychiatric office settings. Psychiatric News. 2020;55(7):15.
6. Health Insurance Portability and Accountability Act of 1996. Public Law No. 104–191, 110 Stat. 1936 (1996).
7. Xiong GL, Newman WJ. Take CAUTION in emergency and inpatient psychiatric settings. Current Psychiatry. 2013;12(7):9-10.
1. Phillips JP. Workplace violence against health care workers in the United States. N Engl J Med. 2016;374(17):1661-1669.
2. Workplace violence: issues in response. Rugala EA, Issacs AR (eds). Critical Incident Response Group, National Center for Analysis of Violent Crime, FBI Academy. 2003. Accessed November 27, 2020. https://www.fbi.gov/file-repository/stats-services-publications-workplace-violence-workplace-violence/view
3. Velani KH. 2019 Healthcare Crime Survey. International Association for Healthcare Security and Safety – Foundation (IAHSS – Foundation). Accessed November 27, 2020. https://iahssf.org/crime-surveys/2019-healthcare-crime-survey/3/
4. O’Rourke M, Wrigley C, Hammond S. Violence within mental health services: how to enhance risk management. Risk Manag Healthc Policy. 2018;11:159-167.
5. Neal D. Seven actions to ensure safety in psychiatric office settings. Psychiatric News. 2020;55(7):15.
6. Health Insurance Portability and Accountability Act of 1996. Public Law No. 104–191, 110 Stat. 1936 (1996).
7. Xiong GL, Newman WJ. Take CAUTION in emergency and inpatient psychiatric settings. Current Psychiatry. 2013;12(7):9-10.
Writing letters for transgender patients undergoing medical transition
Transgender and nonconforming people are estimated to make up 0.3% to 1.4% of the population, and these estimates are likely undercounts.1 Knowingly or unknowingly, psychiatric and mental health clinicians are caring for transgender patients, and need to become familiar with ways to provide proper clinical care for this often-marginalized population. Being knowledgeable about the requirements for letter writing for patients who are transgender and desire to transition medically is one way that we can assist and affirm these individuals.
The World Professional Association for Transgender Health (WPATH) publishes standards of care (SOC) that discuss the role of mental health professionals during a patient’s gender transition.2 The initial mental health evaluation should establish if gender dysphoria exists, and not just assume that it does. It is also important to assess whether the patient has had past negative experiences in the treatment setting or a history of trauma, and to evaluate for stressors in social life. Some transgender people may present to mental health professionals solely for the purpose of pursuing gender-related services, and others do not. The transgender person may or may not choose to undergo hormone replacement therapy or surgical transition.
Within the United States, a small percentage of clinicians use the informed consent model and, instead of requiring letters for medical intervention, will conduct an assessment to determine if the patient can provide informed consent about the procedures. But because the WPATH SOC are considered the primary standards and insurance companies will not cover the surgeries without these letters, most surgeons will not accept a patient without this documentation.3
Letters for hormone therapy and upper body surgery
Adults need 1 letter of recommendation from a qualified mental health professional, and the following WPATH criteria must be met: 1) persistent, well-documented gender dysphoria, 2) capacity to make a fully informed decision to consent for treatment, 3) age of majority, and 4) if significant medical or mental health conditions are present, they must be reasonably well-controlled.4
The letter should contain identifying characteristics; diagnoses and psychosocial assessment; duration of clinical relationship; type of evaluation or therapy; an explanation that the criteria for hormone therapy have been met/clinical rationale (gender dysphoria, capacity to consent, age of majority, that other mental health conditions are reasonably well-controlled); a statement that informed consent had been obtained; and a statement that the referring clinician is available for coordination of care.
Letters for lower body surgery
WPATH recommends letters from 2 mental health clinicians who evaluated the patient. In addition to the criteria set for hormone therapy described above, the SOC recommend 12 months of continuous living in the gender role that is congruent with a patient’s gender identity before genital surgery. It is also suggested that the patient undergoes 12 months of hormone therapy before hysterectomy/oophorectomy in transgender men or before orchiectomy in transgender women.4
The letter should contain identifying characteristics; diagnoses and psychosocial assessment; duration of clinical relationship; type of evaluation or therapy; criteria for surgery/clinical rationale (gender dysphoria, capacity to consent, age of majority, other health concerns are well-controlled, hormone therapy, real-life experience), informed consent; and availability for coordination of care.
Transgender individuals need clinicians who can provide competent, sensitive health care, and gender affirmation can enhance psychological health.
1. Winter S, Diamond M, Green J, et al. Transgender people: health at the margins of society. Lancet. 2016;388(10042):390-400.
2. World Professional Association for Transgender Health. Standards of care for the health of transsexual, transgender, and gender nonconforming people. 7th version. Published 2012. Accessed July 14, 2021. https://www.wpath.org/publications/soc
3. Budge SL, Dickey LM. Barriers, challenges, and decision-making in the letter writing process for gender transition. Psychiatr Clin N Am. 2016;40(1):65-78.
4. Coleman E, Bocking W, Botzer M, et al. Standards of care for the health of transsexual, transgender and gender-nonconforming people. Version 7. International Journal of Transgenderism. 2011;13:165-232.
Transgender and nonconforming people are estimated to make up 0.3% to 1.4% of the population, and these estimates are likely undercounts.1 Knowingly or unknowingly, psychiatric and mental health clinicians are caring for transgender patients, and need to become familiar with ways to provide proper clinical care for this often-marginalized population. Being knowledgeable about the requirements for letter writing for patients who are transgender and desire to transition medically is one way that we can assist and affirm these individuals.
The World Professional Association for Transgender Health (WPATH) publishes standards of care (SOC) that discuss the role of mental health professionals during a patient’s gender transition.2 The initial mental health evaluation should establish if gender dysphoria exists, and not just assume that it does. It is also important to assess whether the patient has had past negative experiences in the treatment setting or a history of trauma, and to evaluate for stressors in social life. Some transgender people may present to mental health professionals solely for the purpose of pursuing gender-related services, and others do not. The transgender person may or may not choose to undergo hormone replacement therapy or surgical transition.
Within the United States, a small percentage of clinicians use the informed consent model and, instead of requiring letters for medical intervention, will conduct an assessment to determine if the patient can provide informed consent about the procedures. But because the WPATH SOC are considered the primary standards and insurance companies will not cover the surgeries without these letters, most surgeons will not accept a patient without this documentation.3
Letters for hormone therapy and upper body surgery
Adults need 1 letter of recommendation from a qualified mental health professional, and the following WPATH criteria must be met: 1) persistent, well-documented gender dysphoria, 2) capacity to make a fully informed decision to consent for treatment, 3) age of majority, and 4) if significant medical or mental health conditions are present, they must be reasonably well-controlled.4
The letter should contain identifying characteristics; diagnoses and psychosocial assessment; duration of clinical relationship; type of evaluation or therapy; an explanation that the criteria for hormone therapy have been met/clinical rationale (gender dysphoria, capacity to consent, age of majority, that other mental health conditions are reasonably well-controlled); a statement that informed consent had been obtained; and a statement that the referring clinician is available for coordination of care.
Letters for lower body surgery
WPATH recommends letters from 2 mental health clinicians who evaluated the patient. In addition to the criteria set for hormone therapy described above, the SOC recommend 12 months of continuous living in the gender role that is congruent with a patient’s gender identity before genital surgery. It is also suggested that the patient undergoes 12 months of hormone therapy before hysterectomy/oophorectomy in transgender men or before orchiectomy in transgender women.4
The letter should contain identifying characteristics; diagnoses and psychosocial assessment; duration of clinical relationship; type of evaluation or therapy; criteria for surgery/clinical rationale (gender dysphoria, capacity to consent, age of majority, other health concerns are well-controlled, hormone therapy, real-life experience), informed consent; and availability for coordination of care.
Transgender individuals need clinicians who can provide competent, sensitive health care, and gender affirmation can enhance psychological health.
Transgender and nonconforming people are estimated to make up 0.3% to 1.4% of the population, and these estimates are likely undercounts.1 Knowingly or unknowingly, psychiatric and mental health clinicians are caring for transgender patients, and need to become familiar with ways to provide proper clinical care for this often-marginalized population. Being knowledgeable about the requirements for letter writing for patients who are transgender and desire to transition medically is one way that we can assist and affirm these individuals.
The World Professional Association for Transgender Health (WPATH) publishes standards of care (SOC) that discuss the role of mental health professionals during a patient’s gender transition.2 The initial mental health evaluation should establish if gender dysphoria exists, and not just assume that it does. It is also important to assess whether the patient has had past negative experiences in the treatment setting or a history of trauma, and to evaluate for stressors in social life. Some transgender people may present to mental health professionals solely for the purpose of pursuing gender-related services, and others do not. The transgender person may or may not choose to undergo hormone replacement therapy or surgical transition.
Within the United States, a small percentage of clinicians use the informed consent model and, instead of requiring letters for medical intervention, will conduct an assessment to determine if the patient can provide informed consent about the procedures. But because the WPATH SOC are considered the primary standards and insurance companies will not cover the surgeries without these letters, most surgeons will not accept a patient without this documentation.3
Letters for hormone therapy and upper body surgery
Adults need 1 letter of recommendation from a qualified mental health professional, and the following WPATH criteria must be met: 1) persistent, well-documented gender dysphoria, 2) capacity to make a fully informed decision to consent for treatment, 3) age of majority, and 4) if significant medical or mental health conditions are present, they must be reasonably well-controlled.4
The letter should contain identifying characteristics; diagnoses and psychosocial assessment; duration of clinical relationship; type of evaluation or therapy; an explanation that the criteria for hormone therapy have been met/clinical rationale (gender dysphoria, capacity to consent, age of majority, that other mental health conditions are reasonably well-controlled); a statement that informed consent had been obtained; and a statement that the referring clinician is available for coordination of care.
Letters for lower body surgery
WPATH recommends letters from 2 mental health clinicians who evaluated the patient. In addition to the criteria set for hormone therapy described above, the SOC recommend 12 months of continuous living in the gender role that is congruent with a patient’s gender identity before genital surgery. It is also suggested that the patient undergoes 12 months of hormone therapy before hysterectomy/oophorectomy in transgender men or before orchiectomy in transgender women.4
The letter should contain identifying characteristics; diagnoses and psychosocial assessment; duration of clinical relationship; type of evaluation or therapy; criteria for surgery/clinical rationale (gender dysphoria, capacity to consent, age of majority, other health concerns are well-controlled, hormone therapy, real-life experience), informed consent; and availability for coordination of care.
Transgender individuals need clinicians who can provide competent, sensitive health care, and gender affirmation can enhance psychological health.
1. Winter S, Diamond M, Green J, et al. Transgender people: health at the margins of society. Lancet. 2016;388(10042):390-400.
2. World Professional Association for Transgender Health. Standards of care for the health of transsexual, transgender, and gender nonconforming people. 7th version. Published 2012. Accessed July 14, 2021. https://www.wpath.org/publications/soc
3. Budge SL, Dickey LM. Barriers, challenges, and decision-making in the letter writing process for gender transition. Psychiatr Clin N Am. 2016;40(1):65-78.
4. Coleman E, Bocking W, Botzer M, et al. Standards of care for the health of transsexual, transgender and gender-nonconforming people. Version 7. International Journal of Transgenderism. 2011;13:165-232.
1. Winter S, Diamond M, Green J, et al. Transgender people: health at the margins of society. Lancet. 2016;388(10042):390-400.
2. World Professional Association for Transgender Health. Standards of care for the health of transsexual, transgender, and gender nonconforming people. 7th version. Published 2012. Accessed July 14, 2021. https://www.wpath.org/publications/soc
3. Budge SL, Dickey LM. Barriers, challenges, and decision-making in the letter writing process for gender transition. Psychiatr Clin N Am. 2016;40(1):65-78.
4. Coleman E, Bocking W, Botzer M, et al. Standards of care for the health of transsexual, transgender and gender-nonconforming people. Version 7. International Journal of Transgenderism. 2011;13:165-232.
Building a better work/life balance
Physician burnout is a common and serious problem. In a 2017 survey of >14,000 US physicians across 27 specialties, 42% reported burnout,1 which typically is defined as a long-term stress reaction marked by emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment.2
Creating a focused, yet comfortable professional life is essential for preventing burnout. For our patients’ sake and for our own personal fulfillment, there is much we can do to maintain a healthy professional and home life balance. This article describes the factors that contribute to physician burnout, and outlines steps you can take to improve your work/life balance.
The multifactorial roots of stress
Many physicians frequently blend their professional and personal lives. Most are absorbed in their practices, which leaves limited time for family interactions, daily life, or wellness.
Work hours are often long, and schedules are filled with obligations. In recent years, changes to medical practice have resulted in many additional responsibilities for physicians, such as administrative tasks and adapting to electronic health care, particularly to the use of electronic health records (EHRs). This has escalated workload and worries while diminishing patient interaction, creating more distant clinical relationships and providing less financial remuneration. Monetary pressures to see more patients limit the quality of care. Overload often forces physicians to stay at work late and/or labor excessive hours at home with less family interaction. The introduction of EHRs escalated this trend, while detracting from a healthy family, personal, and professional life. Addressing cumbersome documentation requirements while striving to maintain contact with patients is frustrating.3
Physician job dissatisfaction has worsened over time. Burnout escalates errors, diminishes patient rapport and safety, and produces suboptimal outcomes, all resulting in declining professional satisfaction.
Improving your work/life balance
The following strategies can help you make changes to better balance your professional and personal lives.
Assess priorities and goals. Before taking steps to achieve an optimal work-home balance, first review medical, spousal, and parental expectations. Social support is key.
Continue to: Identify stressors
Identify stressors. Use self-report questionnaires and collegial discussions to assess for the presence and/or severity of burnout. Prevention and/or intervention at personal and organizational levels can positively impact physician well-being.4
Focus on self-care. Prioritize your personal health care, sleep hygiene, exercise routines, quality of diet, and recreational activities. Do not self-prescribe medications, and avoid excessive alcohol use.5
Make changes to your practice. In your office, make efforts to maximize social connectiveness. Consider assigning routine tasks to other staff members. Upgrading your typing skills, employing medical records scribes, and/or using voice recording systems can reduce your workload.5
Advocate for better legislation. Both through professional medical organizations and at government levels, work to modify regulations that require physicians to spend their time on nonclinical tasks. This might include advocating to simplify EHRs and insurance company reimbursement requirements to decrease paperwork and reduce barriers to prescribing. Stress management seminars, which typically are offered at state and national conferences, can foster interpersonal and professional competencies throughout one’s medical career.6 Medical licensure boards should make efforts to reduce the stigma of reporting mental health issues; they should assure confidentiality protection and help for those who seek assistance.5
1. Peckham C. Medscape psychiatrist lifestyle report: race and ethnicity, bias and burnout. Medscape. Published January 11, 2017. Accessed July 12, 2021. http://www.medscape.com/features/slideshow/lifestyle/2017/psychiatry#page=1
2. Agency for Healthcare Research and Quality. Physician burnout. Published July 2017. Accessed July 13, 2021. https://www.ahrq.gov/prevention/clinician/ahrq-works/burnout/index.html
3. Lippmann S. Can shrinks “shrink” the electronic health record? Internet and Psychiatry. December 19, 2019. Accessed on August 15, 2020. https://www.internetandpsychiatry.com/wp/editorials/can-shrinks-shrink-the-electronic-health-record/
4. West CP, Dyrbye LN, Erwin PJ, et al. Interventions to prevent and reduce physician burnout: a systematic review and meta-analysis. Lancet. 2016;388(10057):2272-2281.
5. Mohanty D, Prabhu A, Lippmann S. Physician burnout: signs and solutions. J Fam Pract. 2019;68(8):442-446.
6. McCue JD, Sachs CL. A stress management workshop improves residents’ coping skills. Arch Intern Med. 1991;151(11):2273-2277.
Physician burnout is a common and serious problem. In a 2017 survey of >14,000 US physicians across 27 specialties, 42% reported burnout,1 which typically is defined as a long-term stress reaction marked by emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment.2
Creating a focused, yet comfortable professional life is essential for preventing burnout. For our patients’ sake and for our own personal fulfillment, there is much we can do to maintain a healthy professional and home life balance. This article describes the factors that contribute to physician burnout, and outlines steps you can take to improve your work/life balance.
The multifactorial roots of stress
Many physicians frequently blend their professional and personal lives. Most are absorbed in their practices, which leaves limited time for family interactions, daily life, or wellness.
Work hours are often long, and schedules are filled with obligations. In recent years, changes to medical practice have resulted in many additional responsibilities for physicians, such as administrative tasks and adapting to electronic health care, particularly to the use of electronic health records (EHRs). This has escalated workload and worries while diminishing patient interaction, creating more distant clinical relationships and providing less financial remuneration. Monetary pressures to see more patients limit the quality of care. Overload often forces physicians to stay at work late and/or labor excessive hours at home with less family interaction. The introduction of EHRs escalated this trend, while detracting from a healthy family, personal, and professional life. Addressing cumbersome documentation requirements while striving to maintain contact with patients is frustrating.3
Physician job dissatisfaction has worsened over time. Burnout escalates errors, diminishes patient rapport and safety, and produces suboptimal outcomes, all resulting in declining professional satisfaction.
Improving your work/life balance
The following strategies can help you make changes to better balance your professional and personal lives.
Assess priorities and goals. Before taking steps to achieve an optimal work-home balance, first review medical, spousal, and parental expectations. Social support is key.
Continue to: Identify stressors
Identify stressors. Use self-report questionnaires and collegial discussions to assess for the presence and/or severity of burnout. Prevention and/or intervention at personal and organizational levels can positively impact physician well-being.4
Focus on self-care. Prioritize your personal health care, sleep hygiene, exercise routines, quality of diet, and recreational activities. Do not self-prescribe medications, and avoid excessive alcohol use.5
Make changes to your practice. In your office, make efforts to maximize social connectiveness. Consider assigning routine tasks to other staff members. Upgrading your typing skills, employing medical records scribes, and/or using voice recording systems can reduce your workload.5
Advocate for better legislation. Both through professional medical organizations and at government levels, work to modify regulations that require physicians to spend their time on nonclinical tasks. This might include advocating to simplify EHRs and insurance company reimbursement requirements to decrease paperwork and reduce barriers to prescribing. Stress management seminars, which typically are offered at state and national conferences, can foster interpersonal and professional competencies throughout one’s medical career.6 Medical licensure boards should make efforts to reduce the stigma of reporting mental health issues; they should assure confidentiality protection and help for those who seek assistance.5
Physician burnout is a common and serious problem. In a 2017 survey of >14,000 US physicians across 27 specialties, 42% reported burnout,1 which typically is defined as a long-term stress reaction marked by emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment.2
Creating a focused, yet comfortable professional life is essential for preventing burnout. For our patients’ sake and for our own personal fulfillment, there is much we can do to maintain a healthy professional and home life balance. This article describes the factors that contribute to physician burnout, and outlines steps you can take to improve your work/life balance.
The multifactorial roots of stress
Many physicians frequently blend their professional and personal lives. Most are absorbed in their practices, which leaves limited time for family interactions, daily life, or wellness.
Work hours are often long, and schedules are filled with obligations. In recent years, changes to medical practice have resulted in many additional responsibilities for physicians, such as administrative tasks and adapting to electronic health care, particularly to the use of electronic health records (EHRs). This has escalated workload and worries while diminishing patient interaction, creating more distant clinical relationships and providing less financial remuneration. Monetary pressures to see more patients limit the quality of care. Overload often forces physicians to stay at work late and/or labor excessive hours at home with less family interaction. The introduction of EHRs escalated this trend, while detracting from a healthy family, personal, and professional life. Addressing cumbersome documentation requirements while striving to maintain contact with patients is frustrating.3
Physician job dissatisfaction has worsened over time. Burnout escalates errors, diminishes patient rapport and safety, and produces suboptimal outcomes, all resulting in declining professional satisfaction.
Improving your work/life balance
The following strategies can help you make changes to better balance your professional and personal lives.
Assess priorities and goals. Before taking steps to achieve an optimal work-home balance, first review medical, spousal, and parental expectations. Social support is key.
Continue to: Identify stressors
Identify stressors. Use self-report questionnaires and collegial discussions to assess for the presence and/or severity of burnout. Prevention and/or intervention at personal and organizational levels can positively impact physician well-being.4
Focus on self-care. Prioritize your personal health care, sleep hygiene, exercise routines, quality of diet, and recreational activities. Do not self-prescribe medications, and avoid excessive alcohol use.5
Make changes to your practice. In your office, make efforts to maximize social connectiveness. Consider assigning routine tasks to other staff members. Upgrading your typing skills, employing medical records scribes, and/or using voice recording systems can reduce your workload.5
Advocate for better legislation. Both through professional medical organizations and at government levels, work to modify regulations that require physicians to spend their time on nonclinical tasks. This might include advocating to simplify EHRs and insurance company reimbursement requirements to decrease paperwork and reduce barriers to prescribing. Stress management seminars, which typically are offered at state and national conferences, can foster interpersonal and professional competencies throughout one’s medical career.6 Medical licensure boards should make efforts to reduce the stigma of reporting mental health issues; they should assure confidentiality protection and help for those who seek assistance.5
1. Peckham C. Medscape psychiatrist lifestyle report: race and ethnicity, bias and burnout. Medscape. Published January 11, 2017. Accessed July 12, 2021. http://www.medscape.com/features/slideshow/lifestyle/2017/psychiatry#page=1
2. Agency for Healthcare Research and Quality. Physician burnout. Published July 2017. Accessed July 13, 2021. https://www.ahrq.gov/prevention/clinician/ahrq-works/burnout/index.html
3. Lippmann S. Can shrinks “shrink” the electronic health record? Internet and Psychiatry. December 19, 2019. Accessed on August 15, 2020. https://www.internetandpsychiatry.com/wp/editorials/can-shrinks-shrink-the-electronic-health-record/
4. West CP, Dyrbye LN, Erwin PJ, et al. Interventions to prevent and reduce physician burnout: a systematic review and meta-analysis. Lancet. 2016;388(10057):2272-2281.
5. Mohanty D, Prabhu A, Lippmann S. Physician burnout: signs and solutions. J Fam Pract. 2019;68(8):442-446.
6. McCue JD, Sachs CL. A stress management workshop improves residents’ coping skills. Arch Intern Med. 1991;151(11):2273-2277.
1. Peckham C. Medscape psychiatrist lifestyle report: race and ethnicity, bias and burnout. Medscape. Published January 11, 2017. Accessed July 12, 2021. http://www.medscape.com/features/slideshow/lifestyle/2017/psychiatry#page=1
2. Agency for Healthcare Research and Quality. Physician burnout. Published July 2017. Accessed July 13, 2021. https://www.ahrq.gov/prevention/clinician/ahrq-works/burnout/index.html
3. Lippmann S. Can shrinks “shrink” the electronic health record? Internet and Psychiatry. December 19, 2019. Accessed on August 15, 2020. https://www.internetandpsychiatry.com/wp/editorials/can-shrinks-shrink-the-electronic-health-record/
4. West CP, Dyrbye LN, Erwin PJ, et al. Interventions to prevent and reduce physician burnout: a systematic review and meta-analysis. Lancet. 2016;388(10057):2272-2281.
5. Mohanty D, Prabhu A, Lippmann S. Physician burnout: signs and solutions. J Fam Pract. 2019;68(8):442-446.
6. McCue JD, Sachs CL. A stress management workshop improves residents’ coping skills. Arch Intern Med. 1991;151(11):2273-2277.
Avoiding malpractice while treating depression in pregnant women
Many physicians have seen advertisements that encourage women who took an antidepressant while they were pregnant and had a negative outcome to contact a law firm. These ads could make patients more reluctant to take prescribed antidepressants, and psychiatrists more hesitant to prescribe necessary medications during pregnancy—which is a disservice to the mother and child.
More recently, several headline-grabbing studies appeared to suggest that there is an increased risk to infants who are exposed to antidepressants prenatally. Unfortunately, many patients do not understand that replication of these studies is often lacking, and methodological and confounding issues abound. All of this makes it difficult for patients and their families to know if they should take an antidepressant during pregnancy, and for psychiatrists to know what to discuss about the risks and benefits of various antidepressants during pregnancy. This article reviews the rationale for treatment of depression in pregnancy; the risks of untreated depression in pregnancy, as well as the potential risks of medication; ethical issues in the treatment of depression in pregnancy; the limitations of available research; and best approaches for practice.
Risks of untreated depression in pregnancy
Pregnant women may have misconceptions about treatment during pregnancy, and psychiatrists often are hesitant to treat pregnant women. However, the risks of untreated depression during pregnancy are even greater than the risks of untreated depression at other points in a woman’s life. In addition to general psychiatric risks seen in depression, pregnant women may experience other issues, such as preeclampsia and liver metabolism changes.1-2 Risks to the fetus related to untreated or partially treated mental health concerns include poor prenatal care related to poor self-care, an increased risk of exposure to illicit substances or alcohol related to “self-medication,” preterm delivery, and low birthweight (Table 13-8). Further risks for an infant of a mother with untreated depression include decreased cognitive performance and poor bonding with poor stress adaptation.5,6 Thus, appropriate treatment of depression is even more important during pregnancy than at other times of life.
Potential risks of treating depression in pregnancy
When prescribing psychotropic medications to a pregnant woman, there are several naturally occurring adverse outcomes to consider. For example, miscarriages, stillbirths, and congenital malformations can occur without explanation in the general population. In addition, also consider the specific health history of the mother and the available research literature regarding the specific psychotropic agent (keeping in mind that there are ethical issues associated with conducting prospective research in pregnant women, such as it being unethical to withhold treatment to pregnant women who are depressed in order to have a control group, and that retrospective research is often confounded by recall bias). Potential risks to be aware of include miscarriage (spontaneous abortion), malformation (teratogenesis, birth defects), preterm delivery, neonatal adaptation syndrome, and behavioral teratogenesis (Table 13-8).
Selective serotonin reuptake inhibitors (SSRIs), the usual medication treatment of choice for depression, have at times been implicated in adverse pregnancy outcomes, but no strong evidence suggests they increase the miscarriage rate. Overall data are reassuring regarding the risk of malformation associated with SSRI use. Of note, the FDA had switched paroxetine from a Class C drug to a Class D drug after early reports of a potential 1.5% to 2% risk of fetal cardiac malformations compared with a 1% baseline risk in the general population (these FDA pregnancy risk letter categories have since been phased out).9,10 Nevertheless, the absolute risk remains small. Another large study found that there was no substantial increased risk of cardiac malformations attributable to antidepressant use during the first trimester.11
Lessons from a class action suit
Since we last reviewed pregnancy and antidepressants in 2013,8 several class action lawsuits against the manufacturers of psychotropic medications have been heard. Product liability actions brought against manufacturers are different from medical malpractice suits brought against individual physicians, which may result from lack of informed consent, suicide, or homicide.
One of the largest class action suits was against Zoloft (specifically Zoloft and Pfizer, since the brand manufacturer is responsible for the product insert information.)12,13 At the time, sertraline was already commonly prescribed due to the relatively safe reproductive profile.
Continue to: Many of the more than 300...
Many of the more than 300 federal claims were united in a multi-district litigation (MDL) suit under the United States District Court of Eastern Pennsylvania (MDL 2342). Pfizer issued Daubert challenges (efforts to exclude the introduction of “junk science” into the courtroom) against the plaintiffs’ experts’ scientific methods and results.12,13 The plaintiffs (those suing Pfizer) had to prove that the medications caused the negative outcome, not that they were merely temporally associated. Subsequently, 2 plaintiff experts—a PharmD and a biostatistician—were removed. Pfizer successfully challenged the methodological soundness of the plaintiffs’ experts’ testimony (Table 212,13), and the case was dismissed. In general, the courts identified the Bradford Hill criteria as often being important (though not definitive) methodology for determining causation (Table 312,13).
A concept raised in prior psychotropic lawsuits was the “learned intermediary doctrine,” in which pharmaceutical companies stated that once a risk is known, it is the responsibility of the prescribing physician to assess risks vs benefits and inform the patient.8 Many aspects of the larger class action lawsuits related to failure of the company to do adequate research to identify risks and appropriately inform the public and the medical community of these risks.14
Challenges in interpreting the literature
Some of the difficulties in interpreting the literature on the association of antidepressants and birth defects can be seen in a 2020 study by Anderson et al.15 This study was published in JAMA Psychiatry, received widespread coverage in the media, and was discussed on the CDC’s website.16 Anderson et al15 compared a large cohort of 30,630 infants with birth defects from the multicenter case-control National Birth Defects Prevention Study with 11,478 randomly selected controls with no defects. Three primary study groups were women whose pregnancies resulted in:
- birth defects with no antidepressant exposure (n = 28,719)
- birth defects with exposure to an antidepressant (n = 1,911)
- no birth defect control group (n = 10,886 no antidepressant exposure, n = 592 antidepressant exposure).
This study reported there were “some associations between maternal antidepressant use and specific birth defects” and “Venlafaxine was associated with more birth defects than other antidepressants, which needs confirmation.”15 However, in an accompanying editorial, Wisner et al17 discussed potential problems and limitations with this study and research of this nature in general (Table 417). In addition, Anderson et al15 used certain “controversial” statistical practices.18 For example, “[T]o align with American Statistical Association guidelines to consider effect sizes when interpreting results instead of statistical significance, we noted associations as meaningfully elevated if [adjusted odds ratios] were 2.0 or greater and lower confidence interval bounds were 0.8 or greater.”15
Those who read only abstracts or news stories may believe this study of >40,000 participants included a large number of women who were receiving venlafaxine. However, the number of pregnant women who were prescribed venlafaxine was actually very small—112 who took venlafaxine experienced a birth defect. In addition, the authors noted “Venlafaxine was associated with many of the same defects across the samples (data not shown).”15 As discussed above, historically one of the areas the courts have considered was whether or not appropriate methodology was applied, and whether the results could be replicated with the data provided.
Continue to: Further, new studies...
Further, new studies need to be considered in context of the literature as a whole and collective clinical experience. A recent systematic review found that among 3,186 infants exposed to venlafaxine during the first trimester, there were 107 major malformations.19 This indicated a relative risk estimate of 1.12, with a 95% CI of 0.92 to 1.35. The authors concluded that venlafaxine exposure in the first trimester was not associated with an increased risk of malformations.
Expectant parents may come across a headline that implies a specific antidepressant causes problems, but have not read the study or know how to interpret it. Often it is best for a physician to find out what the basis of the concern is, and if possible, review the study with the patient to make sure it is in the right context, and if it applies to the individual patient’s situation.
Consider the ethical issues
In addition to preventive ethics, other critical ethical issues in pregnancy include omission bias, beneficence, and autonomy.4,20-24 Omission bias occurs when physicians are more concerned about acts of commission (in which treatment leads to a negative outcome) than they are about acts of omission, which involve not treating the patient’s illness. To address this, it is important to discuss with the patient both the risks of treating and the risks of not treating maternal depression, so that the mother can make the best decision for her own specific set of circumstances.
Regarding beneficence (promoting the patient’s best interest), consider both the mother’s and the infant’s best interest, which usually are quite closely related. Women may feel guilty about taking a medication that they perceive is harmful for the fetus but good for their own mental health. Physicians can help with this by providing education about the benefits of treating depression for the fetus’ benefit as well. The fetus is completely dependent on the environment that the mother places them in, not merely the medication effects (eg, psychologic/physiologic stress effects, poor diet, lack of exercise, risk of “self-medication”).
Regarding autonomy (a woman’s own decision-making), Coverdale et al21 discussed strategies that can enhance a pregnant patient’s autonomy—including discussing treatment options and counselling about the effects of depression itself in pregnancy, as well as considering the effects of depression on the process of decision-making. For example, a woman with depression may see the world through a negative lens or may have difficulty concentrating. Patients may also require education about the concept of relative risk in comparison to absolute risk—especially in light of attention-grabbing headlines.
Continue to: Finally, as part of...
Finally, as part of preventative ethics, anticipate the ethical dilemmas before the common situation of pregnancy. Almost one-half of pregnancies are unplanned.25 Many women thus expose their fetus to medication during the critical early period of organogenesis, before noticing they were pregnant. Therefore, even if a patient of childbearing age insists that she is not sexually active, the prudent psychiatrist should still begin discussions about medications in pregnancy.
An outline of best practices
Best practice includes preventive ethics, and when treating any woman of childbearing age, psychiatrists should consider prescribing medications that are known to be relatively safe in pregnancy rather than risky in pregnancy. Therefore, any psychiatrist whose practice includes women of childbearing age should have a working knowledge of which agents are relatively safe in pregnancy. After a woman is pregnant, careful decision-making about medication should continue. Consult with reproductive psychiatry colleagues where necessary.
A patient with depression would usually merit closer follow-up during the pregnancy. In some cases, psychotherapy alone can be effective in depression. However, approximately 6% to 13% of women are prescribed antidepressants during pregnancy, and this has been increasing.26 Women who discontinue their antidepressant while pregnant are more likely to relapse than those who continue their medication,27 thus exposing their fetus to negative effects of depression as well as medication (prior to discontinuation).
When possible, monotherapy (one agent) in the lowest effective dose is often the judicious approach to treatment. For a patient prescribed pre-existing polypharmacy at time of pregnancy, a risk-benefit analysis of which medications should remain, which should be stopped, and a plan for taper, if needed, should be discussed and documented. Using too little of an antidepressant dose would expose the fetus to both depression and medication, whereas using a maximum dose when not needed would expose the fetus to more medication than is necessary to treat the mother’s symptoms. This discussion with the mother (and her partner, if available) should be documented in the chart. The mother should understand both the risk of untreated illness and the potential risks of medications, as well as the benefits of medications and alternatives. It is important for the mother to realize that there is no risk-free option, and that malformations can occur in the general population as well as in individuals with untreated depression, separate from any medication exposure. In fact, most malformations do not have a known cause, and overall approximately 3% of pregnancies result in a birth defect.28
If possible, discuss the treatment plan with the patient’s obstetrician, or ask the mother to discuss the plan with her obstetrician, so that everyone is on the same page. This discussion can help attenuate patient anxiety that results from hearing different things from different clinicians. Communication with other treating professionals (eg, OB/GYNs, pediatricians) can be beneficial and reduce liability if multiple physicians have agreed on a treatment plan—even if there is a negative outcome. With malpractice, a clinician is not necessarily at fault for a bad outcome or adverse effect, but is at fault for lack of informed consent or negligence (deviation from standard of care), which is harder for an attorney to demonstrate if there is deliberation, communication, and a plan that multiple doctors agree upon.
Continue to: Be aware that informed consent...
Be aware that informed consent is an ongoing process, and a woman may need to be reminded or informed of potential risks at varying stages of her life (eg, when starting a new relationship, getting married, etc.). Documentation can include that the clinician has discussed the risks, benefits, adverse effects, and alternatives of various medications, and a description of any patient-specific or medication-specific issues. In addition to verbal discussions, giving patients printed information can be helpful, as can directing them to appropriate websites (see Related Resources). Some physicians require patients to sign a form to indicate that they are aware of known risks.
Similar to being proactive before your patient becomes pregnant, think proactively regarding the postpartum period. Is your patient planning to breastfeed? Is the medication compatible with breastfeeding, or is bottle feeding the best option considering the mother’s specific circumstances? For example, developing severe symptoms, experiencing insomnia, needing to take a contraindicated medication, or having a vulnerable infant might sway a mother towards not breastfeeding. The expectant mother (and her partner, where possible) should be educated about postpartum risks and the importance of sleep in preventing postpartum depression.
Bottom Line
Concerns about being sued should not prevent appropriate care of depression in a woman who is pregnant. Discuss with your patient both the risk of untreated mental illness and the risk of medications to ensure she understands that avoiding antidepressants does not guarantee a safe or healthy pregnancy.
Related Resources
- MotherToBaby. www.mothertobaby.org/
- Centers for Disease Control and Prevention. Treating for two: medicine and pregnancy. www.cdc.gov/pregnancy/meds/treatingfortwo/index.html
- MGH Center for Women’s Mental Health. Reproductive psychiatry resource and information center. www.womensmentalhealth.org/
Drug Brand Names
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
1. Palmsten K, Setoguchi S, Margulis AV, et al. Elevated risk of preeclampsia in pregnant women with depression: depression or antidepressants? Am J Epidemiol. 2012;175(10):988-997.
2. Sit DK, Perel JM, Helsel JC, et al. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry. 2008;69(4):652-658.
3. Grote NK, Bridge JA, Gavin AR, et al. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry. 2010;67(10):1012-1024.
4. Friedman SH. The ethics of treating depression in pregnancy. J Prim Health Care. 2015;7(1):81-83.
5. Friedman SH, Resnick PJ. Postpartum depression: an update. Women’s Health. 2009;5(3):287-295.
6. Liu Y, Kaaya S, Chai J, et al. Maternal depressive symptoms and early childhood cognitive development: a meta-analysis. Psychol Med. 2017;47(4):680-689.
7. Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009; 166(5):557-566.
8. Friedman SH, Hall RCW. Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls. Current Psychiatry. 2013;12(2):21-25.
9. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther. 2007;29(5):918-926.
10. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6):749-752.
11. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-2407.
12. In re: Zoloft (sertraline hydrochloride) products liability litigation. MDL No. 2342. No. 12-md-2342. United States District Court, E.D. Pennsylvania. June 27, 2014.
13. In re: Zoloft (sertraline hydrocloride) products liability litigation. MDL No. 2342. United States District Court, E.D. Pennsylvania. December 2, 2015.
14. Kirsch N, Pacheco LD, Hossain A, et al. Medicolegal review: perinatal Effexor lawsuits and legal strategies adverse to prescribing obstetric providers. AJP Rep. 2019;9(1):e88-e91.
15. Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020;77(12):1246-1255.
16. Centers for Disease Control and Prevention. Use of the antidepressant venlafaxine during early pregnancy may be linked to specific birth defects. Published October 28, 2020. Accessed October 29, 2020. https://www.cdc.gov/ncbddd/birthdefects/features/venlafaxine-during-pregnancy.html
17. Wisner KL, Oberlander TF, Huybrechts KF. The association between antidepressant exposure and birth defects--are we there yet? JAMA Psychiatry. 2020;77(12):1215-1216.
18. Wasserstein RL, Lazar NA. The ASA statement on p-values: context, process, and purpose. American Statistician. 2016;70(2):129-133.
19. Lassen D, Ennis ZN, Damkier P. First-trimester pregnancy exposure to venlafaxine or duloxetine and risk of major congenital malformations: a systematic review. Basic Clin Pharmacol Toxicol. 2016;118(1):32-36.
20. Miller LJ. Ethical issues in perinatal mental health. Psychiatr Clin North Am. 2009;32(2):259-270.
21. Coverdale JH, McCullough JB, Chervenak FA. Enhancing decision-making by depressed pregnant patients. J Perinat Med. 2002;30(4):349-351.
22. Coverdale JH, McCullough LB, Chervenak FA, et al. Clinical implications of respect for autonomy in the psychiatric treatment of pregnant patients with depression. Psychiatr Serv. 1997;48:209-212.
23. Coverdale JH, Chervenak FA, McCullough LB, et al. Ethically justified clinically comprehensive guidelines for the management of the depressed pregnant patient. Am J Obstet Gynecol. 1996;174(1):169-173.
24. Wisner KL, Zarin DA, Holmboe ES, et al. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry. 2000;157(12):1933-1940.
25. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception. 2011;84(5):478-485.
26. Cooper WO, Willy ME, Pont SJ, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol. 2007;196(6):544.e1-5.
27. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507.
28. Centers for Disease Control and Prevention. Update on overall prevalence of major birth defects--Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep. 2008;57(1):1-5.
Many physicians have seen advertisements that encourage women who took an antidepressant while they were pregnant and had a negative outcome to contact a law firm. These ads could make patients more reluctant to take prescribed antidepressants, and psychiatrists more hesitant to prescribe necessary medications during pregnancy—which is a disservice to the mother and child.
More recently, several headline-grabbing studies appeared to suggest that there is an increased risk to infants who are exposed to antidepressants prenatally. Unfortunately, many patients do not understand that replication of these studies is often lacking, and methodological and confounding issues abound. All of this makes it difficult for patients and their families to know if they should take an antidepressant during pregnancy, and for psychiatrists to know what to discuss about the risks and benefits of various antidepressants during pregnancy. This article reviews the rationale for treatment of depression in pregnancy; the risks of untreated depression in pregnancy, as well as the potential risks of medication; ethical issues in the treatment of depression in pregnancy; the limitations of available research; and best approaches for practice.
Risks of untreated depression in pregnancy
Pregnant women may have misconceptions about treatment during pregnancy, and psychiatrists often are hesitant to treat pregnant women. However, the risks of untreated depression during pregnancy are even greater than the risks of untreated depression at other points in a woman’s life. In addition to general psychiatric risks seen in depression, pregnant women may experience other issues, such as preeclampsia and liver metabolism changes.1-2 Risks to the fetus related to untreated or partially treated mental health concerns include poor prenatal care related to poor self-care, an increased risk of exposure to illicit substances or alcohol related to “self-medication,” preterm delivery, and low birthweight (Table 13-8). Further risks for an infant of a mother with untreated depression include decreased cognitive performance and poor bonding with poor stress adaptation.5,6 Thus, appropriate treatment of depression is even more important during pregnancy than at other times of life.
Potential risks of treating depression in pregnancy
When prescribing psychotropic medications to a pregnant woman, there are several naturally occurring adverse outcomes to consider. For example, miscarriages, stillbirths, and congenital malformations can occur without explanation in the general population. In addition, also consider the specific health history of the mother and the available research literature regarding the specific psychotropic agent (keeping in mind that there are ethical issues associated with conducting prospective research in pregnant women, such as it being unethical to withhold treatment to pregnant women who are depressed in order to have a control group, and that retrospective research is often confounded by recall bias). Potential risks to be aware of include miscarriage (spontaneous abortion), malformation (teratogenesis, birth defects), preterm delivery, neonatal adaptation syndrome, and behavioral teratogenesis (Table 13-8).
Selective serotonin reuptake inhibitors (SSRIs), the usual medication treatment of choice for depression, have at times been implicated in adverse pregnancy outcomes, but no strong evidence suggests they increase the miscarriage rate. Overall data are reassuring regarding the risk of malformation associated with SSRI use. Of note, the FDA had switched paroxetine from a Class C drug to a Class D drug after early reports of a potential 1.5% to 2% risk of fetal cardiac malformations compared with a 1% baseline risk in the general population (these FDA pregnancy risk letter categories have since been phased out).9,10 Nevertheless, the absolute risk remains small. Another large study found that there was no substantial increased risk of cardiac malformations attributable to antidepressant use during the first trimester.11
Lessons from a class action suit
Since we last reviewed pregnancy and antidepressants in 2013,8 several class action lawsuits against the manufacturers of psychotropic medications have been heard. Product liability actions brought against manufacturers are different from medical malpractice suits brought against individual physicians, which may result from lack of informed consent, suicide, or homicide.
One of the largest class action suits was against Zoloft (specifically Zoloft and Pfizer, since the brand manufacturer is responsible for the product insert information.)12,13 At the time, sertraline was already commonly prescribed due to the relatively safe reproductive profile.
Continue to: Many of the more than 300...
Many of the more than 300 federal claims were united in a multi-district litigation (MDL) suit under the United States District Court of Eastern Pennsylvania (MDL 2342). Pfizer issued Daubert challenges (efforts to exclude the introduction of “junk science” into the courtroom) against the plaintiffs’ experts’ scientific methods and results.12,13 The plaintiffs (those suing Pfizer) had to prove that the medications caused the negative outcome, not that they were merely temporally associated. Subsequently, 2 plaintiff experts—a PharmD and a biostatistician—were removed. Pfizer successfully challenged the methodological soundness of the plaintiffs’ experts’ testimony (Table 212,13), and the case was dismissed. In general, the courts identified the Bradford Hill criteria as often being important (though not definitive) methodology for determining causation (Table 312,13).
A concept raised in prior psychotropic lawsuits was the “learned intermediary doctrine,” in which pharmaceutical companies stated that once a risk is known, it is the responsibility of the prescribing physician to assess risks vs benefits and inform the patient.8 Many aspects of the larger class action lawsuits related to failure of the company to do adequate research to identify risks and appropriately inform the public and the medical community of these risks.14
Challenges in interpreting the literature
Some of the difficulties in interpreting the literature on the association of antidepressants and birth defects can be seen in a 2020 study by Anderson et al.15 This study was published in JAMA Psychiatry, received widespread coverage in the media, and was discussed on the CDC’s website.16 Anderson et al15 compared a large cohort of 30,630 infants with birth defects from the multicenter case-control National Birth Defects Prevention Study with 11,478 randomly selected controls with no defects. Three primary study groups were women whose pregnancies resulted in:
- birth defects with no antidepressant exposure (n = 28,719)
- birth defects with exposure to an antidepressant (n = 1,911)
- no birth defect control group (n = 10,886 no antidepressant exposure, n = 592 antidepressant exposure).
This study reported there were “some associations between maternal antidepressant use and specific birth defects” and “Venlafaxine was associated with more birth defects than other antidepressants, which needs confirmation.”15 However, in an accompanying editorial, Wisner et al17 discussed potential problems and limitations with this study and research of this nature in general (Table 417). In addition, Anderson et al15 used certain “controversial” statistical practices.18 For example, “[T]o align with American Statistical Association guidelines to consider effect sizes when interpreting results instead of statistical significance, we noted associations as meaningfully elevated if [adjusted odds ratios] were 2.0 or greater and lower confidence interval bounds were 0.8 or greater.”15
Those who read only abstracts or news stories may believe this study of >40,000 participants included a large number of women who were receiving venlafaxine. However, the number of pregnant women who were prescribed venlafaxine was actually very small—112 who took venlafaxine experienced a birth defect. In addition, the authors noted “Venlafaxine was associated with many of the same defects across the samples (data not shown).”15 As discussed above, historically one of the areas the courts have considered was whether or not appropriate methodology was applied, and whether the results could be replicated with the data provided.
Continue to: Further, new studies...
Further, new studies need to be considered in context of the literature as a whole and collective clinical experience. A recent systematic review found that among 3,186 infants exposed to venlafaxine during the first trimester, there were 107 major malformations.19 This indicated a relative risk estimate of 1.12, with a 95% CI of 0.92 to 1.35. The authors concluded that venlafaxine exposure in the first trimester was not associated with an increased risk of malformations.
Expectant parents may come across a headline that implies a specific antidepressant causes problems, but have not read the study or know how to interpret it. Often it is best for a physician to find out what the basis of the concern is, and if possible, review the study with the patient to make sure it is in the right context, and if it applies to the individual patient’s situation.
Consider the ethical issues
In addition to preventive ethics, other critical ethical issues in pregnancy include omission bias, beneficence, and autonomy.4,20-24 Omission bias occurs when physicians are more concerned about acts of commission (in which treatment leads to a negative outcome) than they are about acts of omission, which involve not treating the patient’s illness. To address this, it is important to discuss with the patient both the risks of treating and the risks of not treating maternal depression, so that the mother can make the best decision for her own specific set of circumstances.
Regarding beneficence (promoting the patient’s best interest), consider both the mother’s and the infant’s best interest, which usually are quite closely related. Women may feel guilty about taking a medication that they perceive is harmful for the fetus but good for their own mental health. Physicians can help with this by providing education about the benefits of treating depression for the fetus’ benefit as well. The fetus is completely dependent on the environment that the mother places them in, not merely the medication effects (eg, psychologic/physiologic stress effects, poor diet, lack of exercise, risk of “self-medication”).
Regarding autonomy (a woman’s own decision-making), Coverdale et al21 discussed strategies that can enhance a pregnant patient’s autonomy—including discussing treatment options and counselling about the effects of depression itself in pregnancy, as well as considering the effects of depression on the process of decision-making. For example, a woman with depression may see the world through a negative lens or may have difficulty concentrating. Patients may also require education about the concept of relative risk in comparison to absolute risk—especially in light of attention-grabbing headlines.
Continue to: Finally, as part of...
Finally, as part of preventative ethics, anticipate the ethical dilemmas before the common situation of pregnancy. Almost one-half of pregnancies are unplanned.25 Many women thus expose their fetus to medication during the critical early period of organogenesis, before noticing they were pregnant. Therefore, even if a patient of childbearing age insists that she is not sexually active, the prudent psychiatrist should still begin discussions about medications in pregnancy.
An outline of best practices
Best practice includes preventive ethics, and when treating any woman of childbearing age, psychiatrists should consider prescribing medications that are known to be relatively safe in pregnancy rather than risky in pregnancy. Therefore, any psychiatrist whose practice includes women of childbearing age should have a working knowledge of which agents are relatively safe in pregnancy. After a woman is pregnant, careful decision-making about medication should continue. Consult with reproductive psychiatry colleagues where necessary.
A patient with depression would usually merit closer follow-up during the pregnancy. In some cases, psychotherapy alone can be effective in depression. However, approximately 6% to 13% of women are prescribed antidepressants during pregnancy, and this has been increasing.26 Women who discontinue their antidepressant while pregnant are more likely to relapse than those who continue their medication,27 thus exposing their fetus to negative effects of depression as well as medication (prior to discontinuation).
When possible, monotherapy (one agent) in the lowest effective dose is often the judicious approach to treatment. For a patient prescribed pre-existing polypharmacy at time of pregnancy, a risk-benefit analysis of which medications should remain, which should be stopped, and a plan for taper, if needed, should be discussed and documented. Using too little of an antidepressant dose would expose the fetus to both depression and medication, whereas using a maximum dose when not needed would expose the fetus to more medication than is necessary to treat the mother’s symptoms. This discussion with the mother (and her partner, if available) should be documented in the chart. The mother should understand both the risk of untreated illness and the potential risks of medications, as well as the benefits of medications and alternatives. It is important for the mother to realize that there is no risk-free option, and that malformations can occur in the general population as well as in individuals with untreated depression, separate from any medication exposure. In fact, most malformations do not have a known cause, and overall approximately 3% of pregnancies result in a birth defect.28
If possible, discuss the treatment plan with the patient’s obstetrician, or ask the mother to discuss the plan with her obstetrician, so that everyone is on the same page. This discussion can help attenuate patient anxiety that results from hearing different things from different clinicians. Communication with other treating professionals (eg, OB/GYNs, pediatricians) can be beneficial and reduce liability if multiple physicians have agreed on a treatment plan—even if there is a negative outcome. With malpractice, a clinician is not necessarily at fault for a bad outcome or adverse effect, but is at fault for lack of informed consent or negligence (deviation from standard of care), which is harder for an attorney to demonstrate if there is deliberation, communication, and a plan that multiple doctors agree upon.
Continue to: Be aware that informed consent...
Be aware that informed consent is an ongoing process, and a woman may need to be reminded or informed of potential risks at varying stages of her life (eg, when starting a new relationship, getting married, etc.). Documentation can include that the clinician has discussed the risks, benefits, adverse effects, and alternatives of various medications, and a description of any patient-specific or medication-specific issues. In addition to verbal discussions, giving patients printed information can be helpful, as can directing them to appropriate websites (see Related Resources). Some physicians require patients to sign a form to indicate that they are aware of known risks.
Similar to being proactive before your patient becomes pregnant, think proactively regarding the postpartum period. Is your patient planning to breastfeed? Is the medication compatible with breastfeeding, or is bottle feeding the best option considering the mother’s specific circumstances? For example, developing severe symptoms, experiencing insomnia, needing to take a contraindicated medication, or having a vulnerable infant might sway a mother towards not breastfeeding. The expectant mother (and her partner, where possible) should be educated about postpartum risks and the importance of sleep in preventing postpartum depression.
Bottom Line
Concerns about being sued should not prevent appropriate care of depression in a woman who is pregnant. Discuss with your patient both the risk of untreated mental illness and the risk of medications to ensure she understands that avoiding antidepressants does not guarantee a safe or healthy pregnancy.
Related Resources
- MotherToBaby. www.mothertobaby.org/
- Centers for Disease Control and Prevention. Treating for two: medicine and pregnancy. www.cdc.gov/pregnancy/meds/treatingfortwo/index.html
- MGH Center for Women’s Mental Health. Reproductive psychiatry resource and information center. www.womensmentalhealth.org/
Drug Brand Names
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Many physicians have seen advertisements that encourage women who took an antidepressant while they were pregnant and had a negative outcome to contact a law firm. These ads could make patients more reluctant to take prescribed antidepressants, and psychiatrists more hesitant to prescribe necessary medications during pregnancy—which is a disservice to the mother and child.
More recently, several headline-grabbing studies appeared to suggest that there is an increased risk to infants who are exposed to antidepressants prenatally. Unfortunately, many patients do not understand that replication of these studies is often lacking, and methodological and confounding issues abound. All of this makes it difficult for patients and their families to know if they should take an antidepressant during pregnancy, and for psychiatrists to know what to discuss about the risks and benefits of various antidepressants during pregnancy. This article reviews the rationale for treatment of depression in pregnancy; the risks of untreated depression in pregnancy, as well as the potential risks of medication; ethical issues in the treatment of depression in pregnancy; the limitations of available research; and best approaches for practice.
Risks of untreated depression in pregnancy
Pregnant women may have misconceptions about treatment during pregnancy, and psychiatrists often are hesitant to treat pregnant women. However, the risks of untreated depression during pregnancy are even greater than the risks of untreated depression at other points in a woman’s life. In addition to general psychiatric risks seen in depression, pregnant women may experience other issues, such as preeclampsia and liver metabolism changes.1-2 Risks to the fetus related to untreated or partially treated mental health concerns include poor prenatal care related to poor self-care, an increased risk of exposure to illicit substances or alcohol related to “self-medication,” preterm delivery, and low birthweight (Table 13-8). Further risks for an infant of a mother with untreated depression include decreased cognitive performance and poor bonding with poor stress adaptation.5,6 Thus, appropriate treatment of depression is even more important during pregnancy than at other times of life.
Potential risks of treating depression in pregnancy
When prescribing psychotropic medications to a pregnant woman, there are several naturally occurring adverse outcomes to consider. For example, miscarriages, stillbirths, and congenital malformations can occur without explanation in the general population. In addition, also consider the specific health history of the mother and the available research literature regarding the specific psychotropic agent (keeping in mind that there are ethical issues associated with conducting prospective research in pregnant women, such as it being unethical to withhold treatment to pregnant women who are depressed in order to have a control group, and that retrospective research is often confounded by recall bias). Potential risks to be aware of include miscarriage (spontaneous abortion), malformation (teratogenesis, birth defects), preterm delivery, neonatal adaptation syndrome, and behavioral teratogenesis (Table 13-8).
Selective serotonin reuptake inhibitors (SSRIs), the usual medication treatment of choice for depression, have at times been implicated in adverse pregnancy outcomes, but no strong evidence suggests they increase the miscarriage rate. Overall data are reassuring regarding the risk of malformation associated with SSRI use. Of note, the FDA had switched paroxetine from a Class C drug to a Class D drug after early reports of a potential 1.5% to 2% risk of fetal cardiac malformations compared with a 1% baseline risk in the general population (these FDA pregnancy risk letter categories have since been phased out).9,10 Nevertheless, the absolute risk remains small. Another large study found that there was no substantial increased risk of cardiac malformations attributable to antidepressant use during the first trimester.11
Lessons from a class action suit
Since we last reviewed pregnancy and antidepressants in 2013,8 several class action lawsuits against the manufacturers of psychotropic medications have been heard. Product liability actions brought against manufacturers are different from medical malpractice suits brought against individual physicians, which may result from lack of informed consent, suicide, or homicide.
One of the largest class action suits was against Zoloft (specifically Zoloft and Pfizer, since the brand manufacturer is responsible for the product insert information.)12,13 At the time, sertraline was already commonly prescribed due to the relatively safe reproductive profile.
Continue to: Many of the more than 300...
Many of the more than 300 federal claims were united in a multi-district litigation (MDL) suit under the United States District Court of Eastern Pennsylvania (MDL 2342). Pfizer issued Daubert challenges (efforts to exclude the introduction of “junk science” into the courtroom) against the plaintiffs’ experts’ scientific methods and results.12,13 The plaintiffs (those suing Pfizer) had to prove that the medications caused the negative outcome, not that they were merely temporally associated. Subsequently, 2 plaintiff experts—a PharmD and a biostatistician—were removed. Pfizer successfully challenged the methodological soundness of the plaintiffs’ experts’ testimony (Table 212,13), and the case was dismissed. In general, the courts identified the Bradford Hill criteria as often being important (though not definitive) methodology for determining causation (Table 312,13).
A concept raised in prior psychotropic lawsuits was the “learned intermediary doctrine,” in which pharmaceutical companies stated that once a risk is known, it is the responsibility of the prescribing physician to assess risks vs benefits and inform the patient.8 Many aspects of the larger class action lawsuits related to failure of the company to do adequate research to identify risks and appropriately inform the public and the medical community of these risks.14
Challenges in interpreting the literature
Some of the difficulties in interpreting the literature on the association of antidepressants and birth defects can be seen in a 2020 study by Anderson et al.15 This study was published in JAMA Psychiatry, received widespread coverage in the media, and was discussed on the CDC’s website.16 Anderson et al15 compared a large cohort of 30,630 infants with birth defects from the multicenter case-control National Birth Defects Prevention Study with 11,478 randomly selected controls with no defects. Three primary study groups were women whose pregnancies resulted in:
- birth defects with no antidepressant exposure (n = 28,719)
- birth defects with exposure to an antidepressant (n = 1,911)
- no birth defect control group (n = 10,886 no antidepressant exposure, n = 592 antidepressant exposure).
This study reported there were “some associations between maternal antidepressant use and specific birth defects” and “Venlafaxine was associated with more birth defects than other antidepressants, which needs confirmation.”15 However, in an accompanying editorial, Wisner et al17 discussed potential problems and limitations with this study and research of this nature in general (Table 417). In addition, Anderson et al15 used certain “controversial” statistical practices.18 For example, “[T]o align with American Statistical Association guidelines to consider effect sizes when interpreting results instead of statistical significance, we noted associations as meaningfully elevated if [adjusted odds ratios] were 2.0 or greater and lower confidence interval bounds were 0.8 or greater.”15
Those who read only abstracts or news stories may believe this study of >40,000 participants included a large number of women who were receiving venlafaxine. However, the number of pregnant women who were prescribed venlafaxine was actually very small—112 who took venlafaxine experienced a birth defect. In addition, the authors noted “Venlafaxine was associated with many of the same defects across the samples (data not shown).”15 As discussed above, historically one of the areas the courts have considered was whether or not appropriate methodology was applied, and whether the results could be replicated with the data provided.
Continue to: Further, new studies...
Further, new studies need to be considered in context of the literature as a whole and collective clinical experience. A recent systematic review found that among 3,186 infants exposed to venlafaxine during the first trimester, there were 107 major malformations.19 This indicated a relative risk estimate of 1.12, with a 95% CI of 0.92 to 1.35. The authors concluded that venlafaxine exposure in the first trimester was not associated with an increased risk of malformations.
Expectant parents may come across a headline that implies a specific antidepressant causes problems, but have not read the study or know how to interpret it. Often it is best for a physician to find out what the basis of the concern is, and if possible, review the study with the patient to make sure it is in the right context, and if it applies to the individual patient’s situation.
Consider the ethical issues
In addition to preventive ethics, other critical ethical issues in pregnancy include omission bias, beneficence, and autonomy.4,20-24 Omission bias occurs when physicians are more concerned about acts of commission (in which treatment leads to a negative outcome) than they are about acts of omission, which involve not treating the patient’s illness. To address this, it is important to discuss with the patient both the risks of treating and the risks of not treating maternal depression, so that the mother can make the best decision for her own specific set of circumstances.
Regarding beneficence (promoting the patient’s best interest), consider both the mother’s and the infant’s best interest, which usually are quite closely related. Women may feel guilty about taking a medication that they perceive is harmful for the fetus but good for their own mental health. Physicians can help with this by providing education about the benefits of treating depression for the fetus’ benefit as well. The fetus is completely dependent on the environment that the mother places them in, not merely the medication effects (eg, psychologic/physiologic stress effects, poor diet, lack of exercise, risk of “self-medication”).
Regarding autonomy (a woman’s own decision-making), Coverdale et al21 discussed strategies that can enhance a pregnant patient’s autonomy—including discussing treatment options and counselling about the effects of depression itself in pregnancy, as well as considering the effects of depression on the process of decision-making. For example, a woman with depression may see the world through a negative lens or may have difficulty concentrating. Patients may also require education about the concept of relative risk in comparison to absolute risk—especially in light of attention-grabbing headlines.
Continue to: Finally, as part of...
Finally, as part of preventative ethics, anticipate the ethical dilemmas before the common situation of pregnancy. Almost one-half of pregnancies are unplanned.25 Many women thus expose their fetus to medication during the critical early period of organogenesis, before noticing they were pregnant. Therefore, even if a patient of childbearing age insists that she is not sexually active, the prudent psychiatrist should still begin discussions about medications in pregnancy.
An outline of best practices
Best practice includes preventive ethics, and when treating any woman of childbearing age, psychiatrists should consider prescribing medications that are known to be relatively safe in pregnancy rather than risky in pregnancy. Therefore, any psychiatrist whose practice includes women of childbearing age should have a working knowledge of which agents are relatively safe in pregnancy. After a woman is pregnant, careful decision-making about medication should continue. Consult with reproductive psychiatry colleagues where necessary.
A patient with depression would usually merit closer follow-up during the pregnancy. In some cases, psychotherapy alone can be effective in depression. However, approximately 6% to 13% of women are prescribed antidepressants during pregnancy, and this has been increasing.26 Women who discontinue their antidepressant while pregnant are more likely to relapse than those who continue their medication,27 thus exposing their fetus to negative effects of depression as well as medication (prior to discontinuation).
When possible, monotherapy (one agent) in the lowest effective dose is often the judicious approach to treatment. For a patient prescribed pre-existing polypharmacy at time of pregnancy, a risk-benefit analysis of which medications should remain, which should be stopped, and a plan for taper, if needed, should be discussed and documented. Using too little of an antidepressant dose would expose the fetus to both depression and medication, whereas using a maximum dose when not needed would expose the fetus to more medication than is necessary to treat the mother’s symptoms. This discussion with the mother (and her partner, if available) should be documented in the chart. The mother should understand both the risk of untreated illness and the potential risks of medications, as well as the benefits of medications and alternatives. It is important for the mother to realize that there is no risk-free option, and that malformations can occur in the general population as well as in individuals with untreated depression, separate from any medication exposure. In fact, most malformations do not have a known cause, and overall approximately 3% of pregnancies result in a birth defect.28
If possible, discuss the treatment plan with the patient’s obstetrician, or ask the mother to discuss the plan with her obstetrician, so that everyone is on the same page. This discussion can help attenuate patient anxiety that results from hearing different things from different clinicians. Communication with other treating professionals (eg, OB/GYNs, pediatricians) can be beneficial and reduce liability if multiple physicians have agreed on a treatment plan—even if there is a negative outcome. With malpractice, a clinician is not necessarily at fault for a bad outcome or adverse effect, but is at fault for lack of informed consent or negligence (deviation from standard of care), which is harder for an attorney to demonstrate if there is deliberation, communication, and a plan that multiple doctors agree upon.
Continue to: Be aware that informed consent...
Be aware that informed consent is an ongoing process, and a woman may need to be reminded or informed of potential risks at varying stages of her life (eg, when starting a new relationship, getting married, etc.). Documentation can include that the clinician has discussed the risks, benefits, adverse effects, and alternatives of various medications, and a description of any patient-specific or medication-specific issues. In addition to verbal discussions, giving patients printed information can be helpful, as can directing them to appropriate websites (see Related Resources). Some physicians require patients to sign a form to indicate that they are aware of known risks.
Similar to being proactive before your patient becomes pregnant, think proactively regarding the postpartum period. Is your patient planning to breastfeed? Is the medication compatible with breastfeeding, or is bottle feeding the best option considering the mother’s specific circumstances? For example, developing severe symptoms, experiencing insomnia, needing to take a contraindicated medication, or having a vulnerable infant might sway a mother towards not breastfeeding. The expectant mother (and her partner, where possible) should be educated about postpartum risks and the importance of sleep in preventing postpartum depression.
Bottom Line
Concerns about being sued should not prevent appropriate care of depression in a woman who is pregnant. Discuss with your patient both the risk of untreated mental illness and the risk of medications to ensure she understands that avoiding antidepressants does not guarantee a safe or healthy pregnancy.
Related Resources
- MotherToBaby. www.mothertobaby.org/
- Centers for Disease Control and Prevention. Treating for two: medicine and pregnancy. www.cdc.gov/pregnancy/meds/treatingfortwo/index.html
- MGH Center for Women’s Mental Health. Reproductive psychiatry resource and information center. www.womensmentalhealth.org/
Drug Brand Names
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
1. Palmsten K, Setoguchi S, Margulis AV, et al. Elevated risk of preeclampsia in pregnant women with depression: depression or antidepressants? Am J Epidemiol. 2012;175(10):988-997.
2. Sit DK, Perel JM, Helsel JC, et al. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry. 2008;69(4):652-658.
3. Grote NK, Bridge JA, Gavin AR, et al. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry. 2010;67(10):1012-1024.
4. Friedman SH. The ethics of treating depression in pregnancy. J Prim Health Care. 2015;7(1):81-83.
5. Friedman SH, Resnick PJ. Postpartum depression: an update. Women’s Health. 2009;5(3):287-295.
6. Liu Y, Kaaya S, Chai J, et al. Maternal depressive symptoms and early childhood cognitive development: a meta-analysis. Psychol Med. 2017;47(4):680-689.
7. Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009; 166(5):557-566.
8. Friedman SH, Hall RCW. Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls. Current Psychiatry. 2013;12(2):21-25.
9. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther. 2007;29(5):918-926.
10. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6):749-752.
11. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-2407.
12. In re: Zoloft (sertraline hydrochloride) products liability litigation. MDL No. 2342. No. 12-md-2342. United States District Court, E.D. Pennsylvania. June 27, 2014.
13. In re: Zoloft (sertraline hydrocloride) products liability litigation. MDL No. 2342. United States District Court, E.D. Pennsylvania. December 2, 2015.
14. Kirsch N, Pacheco LD, Hossain A, et al. Medicolegal review: perinatal Effexor lawsuits and legal strategies adverse to prescribing obstetric providers. AJP Rep. 2019;9(1):e88-e91.
15. Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020;77(12):1246-1255.
16. Centers for Disease Control and Prevention. Use of the antidepressant venlafaxine during early pregnancy may be linked to specific birth defects. Published October 28, 2020. Accessed October 29, 2020. https://www.cdc.gov/ncbddd/birthdefects/features/venlafaxine-during-pregnancy.html
17. Wisner KL, Oberlander TF, Huybrechts KF. The association between antidepressant exposure and birth defects--are we there yet? JAMA Psychiatry. 2020;77(12):1215-1216.
18. Wasserstein RL, Lazar NA. The ASA statement on p-values: context, process, and purpose. American Statistician. 2016;70(2):129-133.
19. Lassen D, Ennis ZN, Damkier P. First-trimester pregnancy exposure to venlafaxine or duloxetine and risk of major congenital malformations: a systematic review. Basic Clin Pharmacol Toxicol. 2016;118(1):32-36.
20. Miller LJ. Ethical issues in perinatal mental health. Psychiatr Clin North Am. 2009;32(2):259-270.
21. Coverdale JH, McCullough JB, Chervenak FA. Enhancing decision-making by depressed pregnant patients. J Perinat Med. 2002;30(4):349-351.
22. Coverdale JH, McCullough LB, Chervenak FA, et al. Clinical implications of respect for autonomy in the psychiatric treatment of pregnant patients with depression. Psychiatr Serv. 1997;48:209-212.
23. Coverdale JH, Chervenak FA, McCullough LB, et al. Ethically justified clinically comprehensive guidelines for the management of the depressed pregnant patient. Am J Obstet Gynecol. 1996;174(1):169-173.
24. Wisner KL, Zarin DA, Holmboe ES, et al. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry. 2000;157(12):1933-1940.
25. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception. 2011;84(5):478-485.
26. Cooper WO, Willy ME, Pont SJ, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol. 2007;196(6):544.e1-5.
27. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507.
28. Centers for Disease Control and Prevention. Update on overall prevalence of major birth defects--Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep. 2008;57(1):1-5.
1. Palmsten K, Setoguchi S, Margulis AV, et al. Elevated risk of preeclampsia in pregnant women with depression: depression or antidepressants? Am J Epidemiol. 2012;175(10):988-997.
2. Sit DK, Perel JM, Helsel JC, et al. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry. 2008;69(4):652-658.
3. Grote NK, Bridge JA, Gavin AR, et al. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry. 2010;67(10):1012-1024.
4. Friedman SH. The ethics of treating depression in pregnancy. J Prim Health Care. 2015;7(1):81-83.
5. Friedman SH, Resnick PJ. Postpartum depression: an update. Women’s Health. 2009;5(3):287-295.
6. Liu Y, Kaaya S, Chai J, et al. Maternal depressive symptoms and early childhood cognitive development: a meta-analysis. Psychol Med. 2017;47(4):680-689.
7. Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009; 166(5):557-566.
8. Friedman SH, Hall RCW. Antidepressant use during pregnancy: How to avoid clinical and legal pitfalls. Current Psychiatry. 2013;12(2):21-25.
9. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther. 2007;29(5):918-926.
10. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6):749-752.
11. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-2407.
12. In re: Zoloft (sertraline hydrochloride) products liability litigation. MDL No. 2342. No. 12-md-2342. United States District Court, E.D. Pennsylvania. June 27, 2014.
13. In re: Zoloft (sertraline hydrocloride) products liability litigation. MDL No. 2342. United States District Court, E.D. Pennsylvania. December 2, 2015.
14. Kirsch N, Pacheco LD, Hossain A, et al. Medicolegal review: perinatal Effexor lawsuits and legal strategies adverse to prescribing obstetric providers. AJP Rep. 2019;9(1):e88-e91.
15. Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020;77(12):1246-1255.
16. Centers for Disease Control and Prevention. Use of the antidepressant venlafaxine during early pregnancy may be linked to specific birth defects. Published October 28, 2020. Accessed October 29, 2020. https://www.cdc.gov/ncbddd/birthdefects/features/venlafaxine-during-pregnancy.html
17. Wisner KL, Oberlander TF, Huybrechts KF. The association between antidepressant exposure and birth defects--are we there yet? JAMA Psychiatry. 2020;77(12):1215-1216.
18. Wasserstein RL, Lazar NA. The ASA statement on p-values: context, process, and purpose. American Statistician. 2016;70(2):129-133.
19. Lassen D, Ennis ZN, Damkier P. First-trimester pregnancy exposure to venlafaxine or duloxetine and risk of major congenital malformations: a systematic review. Basic Clin Pharmacol Toxicol. 2016;118(1):32-36.
20. Miller LJ. Ethical issues in perinatal mental health. Psychiatr Clin North Am. 2009;32(2):259-270.
21. Coverdale JH, McCullough JB, Chervenak FA. Enhancing decision-making by depressed pregnant patients. J Perinat Med. 2002;30(4):349-351.
22. Coverdale JH, McCullough LB, Chervenak FA, et al. Clinical implications of respect for autonomy in the psychiatric treatment of pregnant patients with depression. Psychiatr Serv. 1997;48:209-212.
23. Coverdale JH, Chervenak FA, McCullough LB, et al. Ethically justified clinically comprehensive guidelines for the management of the depressed pregnant patient. Am J Obstet Gynecol. 1996;174(1):169-173.
24. Wisner KL, Zarin DA, Holmboe ES, et al. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry. 2000;157(12):1933-1940.
25. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. Contraception. 2011;84(5):478-485.
26. Cooper WO, Willy ME, Pont SJ, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol. 2007;196(6):544.e1-5.
27. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507.
28. Centers for Disease Control and Prevention. Update on overall prevalence of major birth defects--Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep. 2008;57(1):1-5.
