MDedge Psychiatry

TOPLINE:

A meta-analysis supports the use of mobile mental health apps, both as a standalone and added to conventional treatment, for adults with moderate to severe depression.

METHODOLOGY:

Mobile mental health apps have proliferated but data on their effectiveness in different patient populations is lacking.

To investigate, researchers conducted a systematic review and meta-analysis of 13 randomized clinical trials assessing treatment efficacy of mobile mental health apps in 1470 adults with moderate to severe depression.

The primary outcome was change in depression symptoms from pre- to post-treatment; secondary outcomes included patient-level factors associated with app efficacy.

TAKEAWAY: 

Mobile app interventions were associated with significantly reduced depressive symptoms vs both active and inactive control groups, with a medium effect size (standardized mean difference [SMD] 0.50).

App interventions delivered for < 8 weeks had a significantly greater effect size than those delivered for 8+ weeks (SMD 0.77 vs 0.43). Apps were more effective in patients not on medication or in therapy. Apps offering rewards or incentives also appeared to be more effective.

Interventions with in-app notifications were associated with significantly lower treatment outcomes (SMD 0.45) than interventions without (SMD 0.45 vs 0.71).

IN PRACTICE:

“The significant treatment efficacy of app-based interventions compared with active and inactive controls suggests the potential of mobile app interventions as an alternative to conventional psychotherapy, with further merits in accessibility, financial affordability, and safety from stigma,” the authors write.

SOURCE:

The study, with first author Hayoung Bae, BA, with Korea University School of Psychology, Seoul, South Korea, was published online November 20 in JAMA Network Open .

LIMITATIONS:

The findings are based on a small number of trials, with significant heterogeneity among the included trials. The analysis included only English-language publications. Using summary data for the subgroup analyses might have prevented a detailed understanding of the moderating associations of individual participant characteristics.

DISCLOSURES:

The study was supported by a grant from the National Research Foundation funded by the Korean government. The authors report no relevant financial relationships.

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

TOPLINE:

A meta-analysis supports the use of mobile mental health apps, both as a standalone and added to conventional treatment, for adults with moderate to severe depression.

METHODOLOGY:

Mobile mental health apps have proliferated but data on their effectiveness in different patient populations is lacking.

To investigate, researchers conducted a systematic review and meta-analysis of 13 randomized clinical trials assessing treatment efficacy of mobile mental health apps in 1470 adults with moderate to severe depression.

The primary outcome was change in depression symptoms from pre- to post-treatment; secondary outcomes included patient-level factors associated with app efficacy.

TAKEAWAY: 

Mobile app interventions were associated with significantly reduced depressive symptoms vs both active and inactive control groups, with a medium effect size (standardized mean difference [SMD] 0.50).

App interventions delivered for < 8 weeks had a significantly greater effect size than those delivered for 8+ weeks (SMD 0.77 vs 0.43). Apps were more effective in patients not on medication or in therapy. Apps offering rewards or incentives also appeared to be more effective.

Interventions with in-app notifications were associated with significantly lower treatment outcomes (SMD 0.45) than interventions without (SMD 0.45 vs 0.71).

IN PRACTICE:

“The significant treatment efficacy of app-based interventions compared with active and inactive controls suggests the potential of mobile app interventions as an alternative to conventional psychotherapy, with further merits in accessibility, financial affordability, and safety from stigma,” the authors write.

SOURCE:

The study, with first author Hayoung Bae, BA, with Korea University School of Psychology, Seoul, South Korea, was published online November 20 in JAMA Network Open .

LIMITATIONS:

The findings are based on a small number of trials, with significant heterogeneity among the included trials. The analysis included only English-language publications. Using summary data for the subgroup analyses might have prevented a detailed understanding of the moderating associations of individual participant characteristics.

DISCLOSURES:

The study was supported by a grant from the National Research Foundation funded by the Korean government. The authors report no relevant financial relationships.

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

TOPLINE:

A meta-analysis supports the use of mobile mental health apps, both as a standalone and added to conventional treatment, for adults with moderate to severe depression.

METHODOLOGY:

Mobile mental health apps have proliferated but data on their effectiveness in different patient populations is lacking.

To investigate, researchers conducted a systematic review and meta-analysis of 13 randomized clinical trials assessing treatment efficacy of mobile mental health apps in 1470 adults with moderate to severe depression.

The primary outcome was change in depression symptoms from pre- to post-treatment; secondary outcomes included patient-level factors associated with app efficacy.

TAKEAWAY: 

Mobile app interventions were associated with significantly reduced depressive symptoms vs both active and inactive control groups, with a medium effect size (standardized mean difference [SMD] 0.50).

App interventions delivered for < 8 weeks had a significantly greater effect size than those delivered for 8+ weeks (SMD 0.77 vs 0.43). Apps were more effective in patients not on medication or in therapy. Apps offering rewards or incentives also appeared to be more effective.

Interventions with in-app notifications were associated with significantly lower treatment outcomes (SMD 0.45) than interventions without (SMD 0.45 vs 0.71).

IN PRACTICE:

“The significant treatment efficacy of app-based interventions compared with active and inactive controls suggests the potential of mobile app interventions as an alternative to conventional psychotherapy, with further merits in accessibility, financial affordability, and safety from stigma,” the authors write.

SOURCE:

The study, with first author Hayoung Bae, BA, with Korea University School of Psychology, Seoul, South Korea, was published online November 20 in JAMA Network Open .

LIMITATIONS:

The findings are based on a small number of trials, with significant heterogeneity among the included trials. The analysis included only English-language publications. Using summary data for the subgroup analyses might have prevented a detailed understanding of the moderating associations of individual participant characteristics.

DISCLOSURES:

The study was supported by a grant from the National Research Foundation funded by the Korean government. The authors report no relevant financial relationships.

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

The average physician makes $352,000, and some earn well into the $500,000s. So, doctors don’t have to worry about money, right?

You know the answer to that.

One thing all physicians have in common about money, says James M. Dahle, MD, FACEP, founder of The White Coat Investor, is that they don’t receive any training in business, personal finance, or investing throughout their schooling or careers unless they seek it out. This leaves many unprepared to make the best investing and money-saving decisions, while others get too frustrated about their lack of knowledge to even dip their toe into the investing pool.

Exhibit A: Four out of 10 physicians have a net worth below $1 million, according to the Medscape Physician Wealth & Debt Report 2023. Elizabeth Chiang, MD, PhD, an oculoplastic surgeon and a physician money coach at Grow Your Wealthy Mindset, notes that many of those doctors are over age 65, “which means they essentially can’t retire.”

And that’s just one pain point.

Physicians have money concerns specific to their profession and background. Luckily, some fellow doctors also serve as financial and wealth advisors just for other doctors. We sought out a few to get their advice--and fixes--for common physician blind spots.

Blind Spot #1

The early lean years skew doctors’ money outlook. “We have an extended training period, which commonly consists of taking on a large amount of debt, followed by 3 to 8 years of being paid a modest salary, and then finally a large boost in income,” explains Dr. Chiang. This can lay a shaky foundation for the earning years to come, and as a result, a lot of doctors just don’t think about money in healthy ways. Once their incomes increase, physicians may be surprised, for example, that making a multiple six-figure salary means paying six figures in taxes.

The Fix

Treat financial health like physical health. That means money cannot be a taboo subject. “The misguided mindset is that we didn’t become physicians to make money, we did it to help people,” explains Jordan Frey, MD, creator of the blog, The Prudent Plastic Surgeon.

Dr. Frey acknowledges that the desire to help is certainly true. But the result is a false idea that “to think about our personal finances makes us a worse doctor.”

Blind Spot #2

Because doctors know a lot about one thing (medicine), they might assume they know a lot about everything (such as investing). “Totally different fields with a different language and different way to think about it,” Dahle explains. This overconfidence could lead to some negligent or risky financial decisions.

The Fix

Educate yourself. There are several books on personal finance and investing written by physicians for physicians. Dr. Chiang recommends The Physician Philosopher’s Guide to Personal Finance, by James Turner, MD; Financial Freedom Rx, by Chirag Shah, MD, and Jayanth Sridhar, MD; and The Physician’s Guide to Finance, by Nicholas Christian and Amanda Christian, MD. There are also podcasts, blogs, and courses to help educate doctors on finance, such as the Fire Your Financial Advisor course by The White Coat Investor.

Blind Spot #3

Undersaving. Retirement saving is one thing, but 24% of doctors say they don’t even put money away in a taxable savings account, according to the Wealth & Debt Report.

Cobin Soelberg, MD, JD, a board-certified anesthesiologist and founder and principal advisor with Greeley Wealth Management, is the treasurer of his anesthesiology group. “I get to see every month how much people are saving, and even on an anesthesiologist salary, where everyone’s making about $400,000 a year, a lot of people are not saving anything, which is crazy.”

Undersaving can be both a time issue and a mindset one.

Time: Doctors often start investing in their retirement accounts later than the average professional, says Dr. Chiang. “A lot of physicians will max out their 401k or 403b,” she explains. “But if you’re putting in $20,000 a year and only starting when you’re in your early 30s, that’s not enough to get you to retirement.”

Mindset: Doctors also see people of all ages who are sick, dying, and injured. “They all know someone who worked hard and saved and then dropped dead at 55,” explains Dr. Dahle. This, he says, can lead to a bit of a “you only live once” attitude that prioritizes spending over saving.

The Fix

Shoot for 20%. If you can’t save 20% of your gross now, strive to get to that point. Think of it as telling a patient they have to change their behavior or trouble will come - not if, but when. “Develop a written investing plan and then stick with it through thick and thin,” says Dr. Dahle. “Once you have a reasonable plan, all you have to do is fund it adequately by saving 20% of your gross income, and a doctor will easily retire as a multimillionaire.”

Blind Spot #4

Bad investment strategies. Thirty-six percent of doctors experience their largest financial losses from lousy investments, according to the Wealth & Debt Report. Meanwhile, 17% of PCPs and 12% of specialists say they haven’t made any investments at all. That’s a terrible mix of doing the wrong thing and doing a worse thing.

The Fix

Don’t overthink investing, but don’t underthink it either. “As high-income earners, doctors just don’t need to take this high level of risk to reach their financial goals,” Dr. Frey says. A good investment plan doesn’t require you to time the stock market or predict individual stock winners. Consider what Vanguard founder Jack Bogle once said about investing: “Be bored by the process but elated by the outcome.”

Dr. Frey suggests going super-simple: index funds. Ignore investing strategies with actively managed mutual funds or individual stocks, as well as risky alternative investments such as cryptocurrency and angel investments. Everyone assumes doctors have money to burn, and they will push sketchy investment ideas at them. Avoid.

Blind Spot #5

Not taking debt seriously enough. The average medical student debt is $250,000 and can exceed $500,000, says Dr. Soelberg. Many doctors spend the first 10 to 20 years of their careers paying this off. Today’s graduates are paying more than 7% on their loans.

And it’s not just student debt: 39% of physicians carry five or more credit cards, and 34% have mortgages larger than $300,000 (with half of those are more than than $500K), per the Wealth & Debt Report.

The Fix

Treat debt like cancer. It’s a lethal enemy you can’t get rid of right away, but a steady, aggressive, long-term attack will have the best results. Dr. Soelberg suggests allocating the most you can afford per month, whether that’s $1000 or $5000, toward debt. Raise the amount as your income grows. Do the same with your 401k or retirement plan. Whatever is left, you can spend. Five to 10 years later, you will realize, “Wow. I’m debt free.”

Blind Spot #6

Not putting in the work to improve your situation. Seventy-one percent of doctors admit they haven’t done anything to reduce major expenses, according to the Wealth & Debt Report. Are you leaving major money on the table?

The Fix

Audit yourself in major areas like housing and taxes. While the average professional may need to put 10% to 20% down on a home, physicians can qualify for physician mortgage loans and can often put down 3% or less, says Dr. Chiang. If you can afford the higher mortgage payment, excess savings earmarked for a larger down payment can be put toward debt or invested.

Another trick, if you’re able, is to seek an area that is less in demand at a higher salary. “Physicians in places like New York City or San Francisco tend to make less than physicians in the Midwest or the South,” Dr. Chiang explains. A colleague of hers moved to rural Pennsylvania, where he made a high salary and had a low cost of living for 3½ years, paid off his student debt, and then relocated to an area where he wanted to live long term.

As for taxes, become familiar with tax law. Research things like, “What is considered a business expense for doctors?” says Brett Mollard, MD, a diagnostic radiologist who provides financial advice to younger physicians. “What will your estimated total tax burden be at the end of the year? Will you need to make extra payments to prevent owing a large sum of money from underpaying or to avoid tax penalties?”

Blind Spot #7

Living like a rock star on a doctor’s income. Getting caught up in trying to live the same lifestyle as your colleagues is a classic bear trap. “Sitting in the doctor’s lounge, it’s so crazy,” Dr. Soelberg says. He describes conversations like, “‘Where did you go on your trip?’ ‘What new toys are you buying?’” There’s pressure to live up to an image of what a doctor’s life is supposed to look like before you’ve sorted the basic things like paying off debt.

The Fix

Live like a resident even if you haven’t been one for years, at least until you’re in a better financial position. “You’re already used to living a life of lower means, and you’re an expert when it comes to delaying gratification,” says Dr. Mollard. “Do it a little longer.” Live frugally and spend only on things that bring you joy. “A lot of physicians are trying to be really rich in all areas of their life instead of the ones that actually matter to them,” Dr. Soelberg says. Identify what’s important to you and only splurge on that.

Blind Spot #8

Never asking for help. The right financial planner can provide expert help. Emphasis on right. “Doctors can be very trusting of other professionals, even when they should not be,” says Dr. Dahle. He notes that in financial services, many people masquerade as knowledgeable advisors who are really just salespeople. While legitimate financial advisors strive to make their clients money, they are also ultimately out to line their pockets and love to work with physician salaries. Thus, doctors can end up working with financial planners that don’t specifically understand their situations or end up taking too much from their clients.

The Fix

Find a planner who specializes in, or at least understands, physicians. Ask them how they make money, says Dr. Chiang. If someone hesitates to tell you about their fee structure or if it sounds like a lot, shop around and ask colleagues for recommendations.

“Ultimately, the path to wealth is to create and grow the margin between what you make and what you spend,” says Dr. Frey. Throw some investing into the mix and physicians can set themselves up on a path for a stress-free financial life.


A version of this article appeared on Medscape.com.

The average physician makes $352,000, and some earn well into the $500,000s. So, doctors don’t have to worry about money, right?

You know the answer to that.

One thing all physicians have in common about money, says James M. Dahle, MD, FACEP, founder of The White Coat Investor, is that they don’t receive any training in business, personal finance, or investing throughout their schooling or careers unless they seek it out. This leaves many unprepared to make the best investing and money-saving decisions, while others get too frustrated about their lack of knowledge to even dip their toe into the investing pool.

Exhibit A: Four out of 10 physicians have a net worth below $1 million, according to the Medscape Physician Wealth & Debt Report 2023. Elizabeth Chiang, MD, PhD, an oculoplastic surgeon and a physician money coach at Grow Your Wealthy Mindset, notes that many of those doctors are over age 65, “which means they essentially can’t retire.”

And that’s just one pain point.

Physicians have money concerns specific to their profession and background. Luckily, some fellow doctors also serve as financial and wealth advisors just for other doctors. We sought out a few to get their advice--and fixes--for common physician blind spots.

Blind Spot #1

The early lean years skew doctors’ money outlook. “We have an extended training period, which commonly consists of taking on a large amount of debt, followed by 3 to 8 years of being paid a modest salary, and then finally a large boost in income,” explains Dr. Chiang. This can lay a shaky foundation for the earning years to come, and as a result, a lot of doctors just don’t think about money in healthy ways. Once their incomes increase, physicians may be surprised, for example, that making a multiple six-figure salary means paying six figures in taxes.

The Fix

Treat financial health like physical health. That means money cannot be a taboo subject. “The misguided mindset is that we didn’t become physicians to make money, we did it to help people,” explains Jordan Frey, MD, creator of the blog, The Prudent Plastic Surgeon.

Dr. Frey acknowledges that the desire to help is certainly true. But the result is a false idea that “to think about our personal finances makes us a worse doctor.”

Blind Spot #2

Because doctors know a lot about one thing (medicine), they might assume they know a lot about everything (such as investing). “Totally different fields with a different language and different way to think about it,” Dahle explains. This overconfidence could lead to some negligent or risky financial decisions.

The Fix

Educate yourself. There are several books on personal finance and investing written by physicians for physicians. Dr. Chiang recommends The Physician Philosopher’s Guide to Personal Finance, by James Turner, MD; Financial Freedom Rx, by Chirag Shah, MD, and Jayanth Sridhar, MD; and The Physician’s Guide to Finance, by Nicholas Christian and Amanda Christian, MD. There are also podcasts, blogs, and courses to help educate doctors on finance, such as the Fire Your Financial Advisor course by The White Coat Investor.

Blind Spot #3

Undersaving. Retirement saving is one thing, but 24% of doctors say they don’t even put money away in a taxable savings account, according to the Wealth & Debt Report.

Cobin Soelberg, MD, JD, a board-certified anesthesiologist and founder and principal advisor with Greeley Wealth Management, is the treasurer of his anesthesiology group. “I get to see every month how much people are saving, and even on an anesthesiologist salary, where everyone’s making about $400,000 a year, a lot of people are not saving anything, which is crazy.”

Undersaving can be both a time issue and a mindset one.

Time: Doctors often start investing in their retirement accounts later than the average professional, says Dr. Chiang. “A lot of physicians will max out their 401k or 403b,” she explains. “But if you’re putting in $20,000 a year and only starting when you’re in your early 30s, that’s not enough to get you to retirement.”

Mindset: Doctors also see people of all ages who are sick, dying, and injured. “They all know someone who worked hard and saved and then dropped dead at 55,” explains Dr. Dahle. This, he says, can lead to a bit of a “you only live once” attitude that prioritizes spending over saving.

The Fix

Shoot for 20%. If you can’t save 20% of your gross now, strive to get to that point. Think of it as telling a patient they have to change their behavior or trouble will come - not if, but when. “Develop a written investing plan and then stick with it through thick and thin,” says Dr. Dahle. “Once you have a reasonable plan, all you have to do is fund it adequately by saving 20% of your gross income, and a doctor will easily retire as a multimillionaire.”

Blind Spot #4

Bad investment strategies. Thirty-six percent of doctors experience their largest financial losses from lousy investments, according to the Wealth & Debt Report. Meanwhile, 17% of PCPs and 12% of specialists say they haven’t made any investments at all. That’s a terrible mix of doing the wrong thing and doing a worse thing.

The Fix

Don’t overthink investing, but don’t underthink it either. “As high-income earners, doctors just don’t need to take this high level of risk to reach their financial goals,” Dr. Frey says. A good investment plan doesn’t require you to time the stock market or predict individual stock winners. Consider what Vanguard founder Jack Bogle once said about investing: “Be bored by the process but elated by the outcome.”

Dr. Frey suggests going super-simple: index funds. Ignore investing strategies with actively managed mutual funds or individual stocks, as well as risky alternative investments such as cryptocurrency and angel investments. Everyone assumes doctors have money to burn, and they will push sketchy investment ideas at them. Avoid.

Blind Spot #5

Not taking debt seriously enough. The average medical student debt is $250,000 and can exceed $500,000, says Dr. Soelberg. Many doctors spend the first 10 to 20 years of their careers paying this off. Today’s graduates are paying more than 7% on their loans.

And it’s not just student debt: 39% of physicians carry five or more credit cards, and 34% have mortgages larger than $300,000 (with half of those are more than than $500K), per the Wealth & Debt Report.

The Fix

Treat debt like cancer. It’s a lethal enemy you can’t get rid of right away, but a steady, aggressive, long-term attack will have the best results. Dr. Soelberg suggests allocating the most you can afford per month, whether that’s $1000 or $5000, toward debt. Raise the amount as your income grows. Do the same with your 401k or retirement plan. Whatever is left, you can spend. Five to 10 years later, you will realize, “Wow. I’m debt free.”

Blind Spot #6

Not putting in the work to improve your situation. Seventy-one percent of doctors admit they haven’t done anything to reduce major expenses, according to the Wealth & Debt Report. Are you leaving major money on the table?

The Fix

Audit yourself in major areas like housing and taxes. While the average professional may need to put 10% to 20% down on a home, physicians can qualify for physician mortgage loans and can often put down 3% or less, says Dr. Chiang. If you can afford the higher mortgage payment, excess savings earmarked for a larger down payment can be put toward debt or invested.

Another trick, if you’re able, is to seek an area that is less in demand at a higher salary. “Physicians in places like New York City or San Francisco tend to make less than physicians in the Midwest or the South,” Dr. Chiang explains. A colleague of hers moved to rural Pennsylvania, where he made a high salary and had a low cost of living for 3½ years, paid off his student debt, and then relocated to an area where he wanted to live long term.

As for taxes, become familiar with tax law. Research things like, “What is considered a business expense for doctors?” says Brett Mollard, MD, a diagnostic radiologist who provides financial advice to younger physicians. “What will your estimated total tax burden be at the end of the year? Will you need to make extra payments to prevent owing a large sum of money from underpaying or to avoid tax penalties?”

Blind Spot #7

Living like a rock star on a doctor’s income. Getting caught up in trying to live the same lifestyle as your colleagues is a classic bear trap. “Sitting in the doctor’s lounge, it’s so crazy,” Dr. Soelberg says. He describes conversations like, “‘Where did you go on your trip?’ ‘What new toys are you buying?’” There’s pressure to live up to an image of what a doctor’s life is supposed to look like before you’ve sorted the basic things like paying off debt.

The Fix

Live like a resident even if you haven’t been one for years, at least until you’re in a better financial position. “You’re already used to living a life of lower means, and you’re an expert when it comes to delaying gratification,” says Dr. Mollard. “Do it a little longer.” Live frugally and spend only on things that bring you joy. “A lot of physicians are trying to be really rich in all areas of their life instead of the ones that actually matter to them,” Dr. Soelberg says. Identify what’s important to you and only splurge on that.

Blind Spot #8

Never asking for help. The right financial planner can provide expert help. Emphasis on right. “Doctors can be very trusting of other professionals, even when they should not be,” says Dr. Dahle. He notes that in financial services, many people masquerade as knowledgeable advisors who are really just salespeople. While legitimate financial advisors strive to make their clients money, they are also ultimately out to line their pockets and love to work with physician salaries. Thus, doctors can end up working with financial planners that don’t specifically understand their situations or end up taking too much from their clients.

The Fix

Find a planner who specializes in, or at least understands, physicians. Ask them how they make money, says Dr. Chiang. If someone hesitates to tell you about their fee structure or if it sounds like a lot, shop around and ask colleagues for recommendations.

“Ultimately, the path to wealth is to create and grow the margin between what you make and what you spend,” says Dr. Frey. Throw some investing into the mix and physicians can set themselves up on a path for a stress-free financial life.


A version of this article appeared on Medscape.com.

The average physician makes $352,000, and some earn well into the $500,000s. So, doctors don’t have to worry about money, right?

You know the answer to that.

One thing all physicians have in common about money, says James M. Dahle, MD, FACEP, founder of The White Coat Investor, is that they don’t receive any training in business, personal finance, or investing throughout their schooling or careers unless they seek it out. This leaves many unprepared to make the best investing and money-saving decisions, while others get too frustrated about their lack of knowledge to even dip their toe into the investing pool.

Exhibit A: Four out of 10 physicians have a net worth below $1 million, according to the Medscape Physician Wealth & Debt Report 2023. Elizabeth Chiang, MD, PhD, an oculoplastic surgeon and a physician money coach at Grow Your Wealthy Mindset, notes that many of those doctors are over age 65, “which means they essentially can’t retire.”

And that’s just one pain point.

Physicians have money concerns specific to their profession and background. Luckily, some fellow doctors also serve as financial and wealth advisors just for other doctors. We sought out a few to get their advice--and fixes--for common physician blind spots.

Blind Spot #1

The early lean years skew doctors’ money outlook. “We have an extended training period, which commonly consists of taking on a large amount of debt, followed by 3 to 8 years of being paid a modest salary, and then finally a large boost in income,” explains Dr. Chiang. This can lay a shaky foundation for the earning years to come, and as a result, a lot of doctors just don’t think about money in healthy ways. Once their incomes increase, physicians may be surprised, for example, that making a multiple six-figure salary means paying six figures in taxes.

The Fix

Treat financial health like physical health. That means money cannot be a taboo subject. “The misguided mindset is that we didn’t become physicians to make money, we did it to help people,” explains Jordan Frey, MD, creator of the blog, The Prudent Plastic Surgeon.

Dr. Frey acknowledges that the desire to help is certainly true. But the result is a false idea that “to think about our personal finances makes us a worse doctor.”

Blind Spot #2

Because doctors know a lot about one thing (medicine), they might assume they know a lot about everything (such as investing). “Totally different fields with a different language and different way to think about it,” Dahle explains. This overconfidence could lead to some negligent or risky financial decisions.

The Fix

Educate yourself. There are several books on personal finance and investing written by physicians for physicians. Dr. Chiang recommends The Physician Philosopher’s Guide to Personal Finance, by James Turner, MD; Financial Freedom Rx, by Chirag Shah, MD, and Jayanth Sridhar, MD; and The Physician’s Guide to Finance, by Nicholas Christian and Amanda Christian, MD. There are also podcasts, blogs, and courses to help educate doctors on finance, such as the Fire Your Financial Advisor course by The White Coat Investor.

Blind Spot #3

Undersaving. Retirement saving is one thing, but 24% of doctors say they don’t even put money away in a taxable savings account, according to the Wealth & Debt Report.

Cobin Soelberg, MD, JD, a board-certified anesthesiologist and founder and principal advisor with Greeley Wealth Management, is the treasurer of his anesthesiology group. “I get to see every month how much people are saving, and even on an anesthesiologist salary, where everyone’s making about $400,000 a year, a lot of people are not saving anything, which is crazy.”

Undersaving can be both a time issue and a mindset one.

Time: Doctors often start investing in their retirement accounts later than the average professional, says Dr. Chiang. “A lot of physicians will max out their 401k or 403b,” she explains. “But if you’re putting in $20,000 a year and only starting when you’re in your early 30s, that’s not enough to get you to retirement.”

Mindset: Doctors also see people of all ages who are sick, dying, and injured. “They all know someone who worked hard and saved and then dropped dead at 55,” explains Dr. Dahle. This, he says, can lead to a bit of a “you only live once” attitude that prioritizes spending over saving.

The Fix

Shoot for 20%. If you can’t save 20% of your gross now, strive to get to that point. Think of it as telling a patient they have to change their behavior or trouble will come - not if, but when. “Develop a written investing plan and then stick with it through thick and thin,” says Dr. Dahle. “Once you have a reasonable plan, all you have to do is fund it adequately by saving 20% of your gross income, and a doctor will easily retire as a multimillionaire.”

Blind Spot #4

Bad investment strategies. Thirty-six percent of doctors experience their largest financial losses from lousy investments, according to the Wealth & Debt Report. Meanwhile, 17% of PCPs and 12% of specialists say they haven’t made any investments at all. That’s a terrible mix of doing the wrong thing and doing a worse thing.

The Fix

Don’t overthink investing, but don’t underthink it either. “As high-income earners, doctors just don’t need to take this high level of risk to reach their financial goals,” Dr. Frey says. A good investment plan doesn’t require you to time the stock market or predict individual stock winners. Consider what Vanguard founder Jack Bogle once said about investing: “Be bored by the process but elated by the outcome.”

Dr. Frey suggests going super-simple: index funds. Ignore investing strategies with actively managed mutual funds or individual stocks, as well as risky alternative investments such as cryptocurrency and angel investments. Everyone assumes doctors have money to burn, and they will push sketchy investment ideas at them. Avoid.

Blind Spot #5

Not taking debt seriously enough. The average medical student debt is $250,000 and can exceed $500,000, says Dr. Soelberg. Many doctors spend the first 10 to 20 years of their careers paying this off. Today’s graduates are paying more than 7% on their loans.

And it’s not just student debt: 39% of physicians carry five or more credit cards, and 34% have mortgages larger than $300,000 (with half of those are more than than $500K), per the Wealth & Debt Report.

The Fix

Treat debt like cancer. It’s a lethal enemy you can’t get rid of right away, but a steady, aggressive, long-term attack will have the best results. Dr. Soelberg suggests allocating the most you can afford per month, whether that’s $1000 or $5000, toward debt. Raise the amount as your income grows. Do the same with your 401k or retirement plan. Whatever is left, you can spend. Five to 10 years later, you will realize, “Wow. I’m debt free.”

Blind Spot #6

Not putting in the work to improve your situation. Seventy-one percent of doctors admit they haven’t done anything to reduce major expenses, according to the Wealth & Debt Report. Are you leaving major money on the table?

The Fix

Audit yourself in major areas like housing and taxes. While the average professional may need to put 10% to 20% down on a home, physicians can qualify for physician mortgage loans and can often put down 3% or less, says Dr. Chiang. If you can afford the higher mortgage payment, excess savings earmarked for a larger down payment can be put toward debt or invested.

Another trick, if you’re able, is to seek an area that is less in demand at a higher salary. “Physicians in places like New York City or San Francisco tend to make less than physicians in the Midwest or the South,” Dr. Chiang explains. A colleague of hers moved to rural Pennsylvania, where he made a high salary and had a low cost of living for 3½ years, paid off his student debt, and then relocated to an area where he wanted to live long term.

As for taxes, become familiar with tax law. Research things like, “What is considered a business expense for doctors?” says Brett Mollard, MD, a diagnostic radiologist who provides financial advice to younger physicians. “What will your estimated total tax burden be at the end of the year? Will you need to make extra payments to prevent owing a large sum of money from underpaying or to avoid tax penalties?”

Blind Spot #7

Living like a rock star on a doctor’s income. Getting caught up in trying to live the same lifestyle as your colleagues is a classic bear trap. “Sitting in the doctor’s lounge, it’s so crazy,” Dr. Soelberg says. He describes conversations like, “‘Where did you go on your trip?’ ‘What new toys are you buying?’” There’s pressure to live up to an image of what a doctor’s life is supposed to look like before you’ve sorted the basic things like paying off debt.

The Fix

Live like a resident even if you haven’t been one for years, at least until you’re in a better financial position. “You’re already used to living a life of lower means, and you’re an expert when it comes to delaying gratification,” says Dr. Mollard. “Do it a little longer.” Live frugally and spend only on things that bring you joy. “A lot of physicians are trying to be really rich in all areas of their life instead of the ones that actually matter to them,” Dr. Soelberg says. Identify what’s important to you and only splurge on that.

Blind Spot #8

Never asking for help. The right financial planner can provide expert help. Emphasis on right. “Doctors can be very trusting of other professionals, even when they should not be,” says Dr. Dahle. He notes that in financial services, many people masquerade as knowledgeable advisors who are really just salespeople. While legitimate financial advisors strive to make their clients money, they are also ultimately out to line their pockets and love to work with physician salaries. Thus, doctors can end up working with financial planners that don’t specifically understand their situations or end up taking too much from their clients.

The Fix

Find a planner who specializes in, or at least understands, physicians. Ask them how they make money, says Dr. Chiang. If someone hesitates to tell you about their fee structure or if it sounds like a lot, shop around and ask colleagues for recommendations.

“Ultimately, the path to wealth is to create and grow the margin between what you make and what you spend,” says Dr. Frey. Throw some investing into the mix and physicians can set themselves up on a path for a stress-free financial life.


A version of this article appeared on Medscape.com.

Delirious mania is a syndrome characterized by the acute onset of severe hyperactivity, psychosis, catatonia, and intermittent confusion. While there have been growing reports of this phenomenon over the last 2 decades, it remains poorly recognized and understood.^1,2 There is no widely accepted nosology for delirious mania and the condition is absent from DSM-5, which magnifies the difficulties in making a timely diagnosis and initiating appropriate treatment. Delayed diagnosis and treatment may result in a detrimental outcome.^2,3 Delirious mania has also been labeled as lethal catatonia, specific febrile delirium, hyperactive or exhaustive mania, and Bell’s mania.^2,4,5 The characterization and diagnosis of this condition have a long and inconsistent history (Box^1,6-11).

Box

Delirious mania continues to be met with incertitude in clinical practice, and numerous inconsistencies have been reported in the literature. For example, some cases that have been reported as delirious mania had more evidence of primary delirium due to another medical condition or primary mania.^12,13 Other cases have demonstrated swift improvement of symptoms after monotherapy with antipsychotics without a trial of benzodiazepines or electroconvulsive therapy (ECT); the exclusion of a sudden onset questions the validity of the diagnosis and promotes the use of less efficacious treatments.^14,15 Other reports have confirmed that the diagnosis is missed when certain symptoms are more predominant, such as a thought disorder (acute schizophrenia), grandiosity and delusional ideation (bipolar disorder [BD]), and less commonly assessed catatonic signs (ambitendency, automatic obedience). These symptoms are mistakenly attributed to the respective disease.^1,16 This especially holds true when delirious mania is initially diagnosed as a primary psychosis, which leads to the administration of antipsychotics.¹⁷ Other cases have reported that delirious mania was resistant to treatment, but ECT was never pursued.¹⁸

In this review, we provide a more comprehensive perspective of the clinical presentation, pathogenesis, and management of delirious mania. We searched PubMed and Google Scholar using the keywords “delirious mania,” “delirious mania AND catatonia,” or “manic delirium.” Most articles we found were case reports, case series, or retrospective chart reviews. There were no systematic reviews, meta analyses, or randomized control trials (RCTs). The 12 articles included in this review consist of 7 individual case reports, 4 case series, and 1 retrospective chart review that describe a total of 36 cases (Table^{1,2,5,17,19-26}).

Clinical presentation: What to look for

Patients with delirious mania typically develop symptoms extremely rapidly. In virtually all published literature, symptoms were reported to emerge within hours to days and consisted of severe forms of mania, psychosis, and delirium; 100% of the cases in our review had these symptoms. Commonly reported symptoms were:

• intense excitement
• emotional lability
• grandiose delusions
• profound insomnia
• pressured and rapid speech
• auditory and visual hallucinations
• hypersexuality
• thought disorganization.

Exquisite paranoia can also result in violent aggression (and may require the use of physical restraints). Patients may confine themselves to very small spaces (such as a closet) in response to the intense paranoia. Impairments in various neurocognitive domains—including inability to focus; disorientation; language and visuospatial disturbances; difficulty with shifting and sustaining attention; and short-term memory impairments—have been reported. Patients often cannot recall the events during the episode.^1,2,5,27,28

Catatonia has been closely associated with delirious mania.²⁹ Features of excited catatonia—such as excessive motor activity, negativism, grimacing, posturing, echolalia, echopraxia, stereotypy, automatic obedience, verbigeration, combativeness, impulsivity, and rigidity—typically accompany delirious mania.^1,5,10,19,27

In addition to these symptoms, patients may engage in specific behaviors. They may exhibit inappropriate toileting such as smearing feces on walls or in bags, fecal or urinary incontinence, disrobing or running naked in public places, or pouring liquid on the floor or on one’s head.^1,2

Continue to: Of the 36 cases...

Of the 36 cases reported in the literature we reviewed, 20 (55%) were female. Most patients had an underlining psychiatric condition, including BD (72%), major depressive disorder (8%), and schizophrenia (2%). Three patients had no psychiatric history.

Physical examination

On initial presentation, a patient with delirious mania may be dehydrated, with dry mucous membranes, pale conjunctiva, tongue dryness, and poor skin turgor.^28,30 Due to excessive motor activity, diaphoresis with tachycardia, fluctuating blood pressure, and fever may be present.³¹

Certain basic cognitive tasks should be assessed to determine the patient’s orientation to place, date, and time. Assess if the patient can recall recent events, names of objects, or perform serial 7s; clock drawing capabilities also should be ascertained.^1,2,5 A Mini-Mental State Examination is useful.³²

The Bush-Francis Catatonia Rating Scale should be used to elicit features of catatonia, such as waxy flexibility, negativism, gegenhalten, mitgehen, catalepsy, ambitendency, automatic obedience, and grasp reflex.¹⁰

Laboratory findings are nonspecific

Although no specific laboratory findings are associated with delirious mania, bloodwork and imaging are routinely investigated, especially if delirium characteristics are most striking. A complete blood count, chemistries, hepatic panel, thyroid functioning, blood and/or urine cultures, creatinine phosphokinase (CPK), and urinalysis can be ordered. Head imaging such as MRI and CT to rule out intracranial pathology are typically performed.¹⁹ However, the diagnosis of delirious mania is based on the presence of the phenotypic features, by verification of catatonia, and by the responsiveness to the treatment delivered.²⁹

Continue to: Pathogenisis: Several hypotheses

The pathogenesis of delirious mania is not well understood. There are several postulations but no salient theory. Most patients with delirious mania have an underlying systemic medical or psychiatric condition.

Mood disorders. Patients with BD or schizoaffective disorder are especially susceptible to delirious mania. The percentage of manic patients who present with delirious mania varies by study. One study suggested approximately 19% have features of the phenomenon,³³ while others estimated 15% to 25%.³⁴ Elias et al³⁵ calculated that 15% of patients with mania succumb to manic exhaustion; from this it can be reasonably concluded that these were cases of misdiagnosed delirious mania.

Delirium hypothesis. Patients with delirious mania typically have features of delirium, including fluctuation of consciousness, disorientation, and/or poor sleep-wake cycle.³⁶ During rapid eye movement (REM) and non-REM sleep, memory circuits are fortified. When there is a substantial loss of REM and non-REM sleep, these circuits become faulty, even after 1 night. Pathological brain waves on EEG reflect the inability to reinforce the memory circuits. Patients with these waves may develop hallucinations, bizarre delusions, and altered sensorium. ECT reduces the pathological slow wave morphologies, thus restoring the synaptic maintenance and correcting the incompetent circuitry. This can explain the robust and rapid response of ECT in a patient with delirious mania.^37,38

Neurotransmitter hypothesis. It has been shown that in patients with delirious mania there is dysregulation of dopamine transport, which leads to dopamine overflow in the synapse. In contrast to a drug effect (ie, cocaine or methamphetamine) that acts by inhibiting dopamine reuptake, dopamine overflow in delirious mania is caused by the loss of dopamine transporter regulation. This results in a dysfunctional dopaminergic state that precipitates an acute state of delirium and agitation.^39,40

Serotonin plays a role in mood disorders, including mania and depression.^41,42 More specifically, serotonin has been implicated in impulsivity and aggression as shown by reduced levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and depletion of 5-hydroxytryptophan (5-HTP).⁴³

Continue to: Alterations in gamma-aminobutyric acid (GABA) transmission...

Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.⁴⁴ Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.⁴⁵ Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbito­frontal, prefrontal, parietal, and motor cortical regions.⁴⁶ A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.⁴⁷

Other neurotransmitters, such as glutamate, at the N-methyl-D-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.⁴⁸ However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.

Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study⁴⁹ that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al⁵⁰ found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.

COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.^51,52 There also have been cases of COVID-19–induced catatonia.^53-55 One case of delirious mania in a patient with COVID-19 has been reported.²¹ The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.⁵⁶ These cytokines have been linked to psychosis and other psychiatric disorders.⁵⁷ The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.²¹

Management: Benzodiazepines and ECT

A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports^27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.

Continue to: Knowing which medications...

Knowing which medications to avoid is as important as knowing which agents to administer. Be vigilant in avoiding high-potency antipsychotics, as these medications can worsen extrapyramidal symptoms and may precipitate seizures or neuroleptic malignant syndrome (NMS).²⁸ Anticholinergic agents should also be avoided because they worsen confusion. Although lithium is effective in BD, in delirious mania, high doses of lithium and haloperidol may cause severe encephalopathic syndromes, with symptoms that can include lethargy, tremors, cerebellar dysfunction, and worsened confusion; it may also cause widespread and irreversible brain damage.⁵⁹While positive outcomes have been documented when using a combination of antipsychotics and lithium,^8,60 this approach should be considered carefully and tailored to individual cases, taking into account the severity of manic and psychotic symptoms in addition to the level of catatonia.

Due to long periods of hyperactivity, withdrawal, and diaphoresis, patients with delirious mania may be severely dehydrated with metabolic derangements, including elevated CPK due to rhabdomyolysis from prolonged exertion, IM antipsychotics, or rigidity. To prevent acute renal failure, this must be immediately addressed with rapid fluid resuscitation and electrolyte repletion.⁶¹

Benzodiazepines. The rapid use of lorazepam should be initiated when delirious mania is suspected. Doses of 6 to 20 mg have been reported to be effective if tolerated.^5,20 Typically, high-dose lorazepam will not have the sedative effect that would normally occur in a patient who does not have delirious mania.² Lorazepam should be titrated until full resolution of symptoms. Doses up to 30 mg have been reported as effective and tolerable.⁶² In our literature review, 50% of patients (18/36) responded or partially responded to lorazepam. However, only 3 case reports documented a complete remission with lorazepam, and many patients needed ECT for remission of symptoms.

ECT is generally reserved for patients who are not helped by benzodiazepine therapy, which is estimated to be up to 20%.⁵ ECT is highly effective in delirious mania, with remission rates ranging from 80% to 100%.¹ ECT is also effective in acute non­delirious mania (comparable to depression); however, it is only used in a small minority of cases (0.2% to 12%).³⁵ In our review, 58% of cases (21/36) reported using ECT, and in all cases it resulted in complete remission.

A dramatic improvement can be seen even after a single ECT session, though most patients show improvement after 4 sessions or 3 to 7 days.^1,2,5 In our review, most patients received 4 to 12 sessions until achieving complete remission.

Continue to: No RCTs have evaluated...

No RCTs have evaluated ECT electrode placement in patients with delirious mania. However, several RCTs have investigated electrode placement in patients with acute nondelirious mania. Hiremani et al⁶³ found that bitemporal placement had a more rapid response rate than bifrontal placement, but there was no overall difference in response rate. Barekatain et al⁶⁴ found no difference between these 2 bilateral approaches. Many of the delirious mania cases report using a bilateral placement (including 42% of the ECT cases in our review) due to the emergent need for rapid relief of symptoms, which is especially necessary if the patient is experiencing hemodynamic instability, excessive violence, risk for self-harm, worsening delirium, or resistance to lorazepam.

Prognosis: Often fatal if left untreated

Patients with delirious mania are at high risk to progress to a more severe form of NMS or malignant catatonia. Therefore, high-potency antipsychotics should be avoided; mortality can be elevated from 60% without antipsychotics to 78% with antipsychotics.⁴ Some researchers estimate 75% to 78% of cases of delirious mania can be fatal if left untreated.^3,6

Bottom Line

Delirious mania is routinely mistaken for more conventional manic or psychotic disorders. Clinicians need to be able to rapidly recognize the symptoms of this syndrome, which include mania, psychosis, delirium, and possible catatonia, so they can avoid administering toxic agents and instead initiate effective treatments such as benzodiazepines and electroconvulsive therapy.

Related Resources

• Arsan C, Baker C, Wong J, et al. Delirious mania: an approach to diagnosis and treatment. Prim Care Companion CNS Disord. 2021;23(1):20f02744. doi:10.4088/PCC.20f02744
• Lamba G, Kennedy EA, Vu CP. Case report: ECT for delirious mania. Clinical Psychiatry News. December 14, 2021. https://www.mdedge.com/psychiatry/article/249909/bipolar-disorder/case-report-ect-delirious-mania

Drug Brand Names

Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan

Delirious mania is a syndrome characterized by the acute onset of severe hyperactivity, psychosis, catatonia, and intermittent confusion. While there have been growing reports of this phenomenon over the last 2 decades, it remains poorly recognized and understood.^1,2 There is no widely accepted nosology for delirious mania and the condition is absent from DSM-5, which magnifies the difficulties in making a timely diagnosis and initiating appropriate treatment. Delayed diagnosis and treatment may result in a detrimental outcome.^2,3 Delirious mania has also been labeled as lethal catatonia, specific febrile delirium, hyperactive or exhaustive mania, and Bell’s mania.^2,4,5 The characterization and diagnosis of this condition have a long and inconsistent history (Box^1,6-11).

Box

Delirious mania continues to be met with incertitude in clinical practice, and numerous inconsistencies have been reported in the literature. For example, some cases that have been reported as delirious mania had more evidence of primary delirium due to another medical condition or primary mania.^12,13 Other cases have demonstrated swift improvement of symptoms after monotherapy with antipsychotics without a trial of benzodiazepines or electroconvulsive therapy (ECT); the exclusion of a sudden onset questions the validity of the diagnosis and promotes the use of less efficacious treatments.^14,15 Other reports have confirmed that the diagnosis is missed when certain symptoms are more predominant, such as a thought disorder (acute schizophrenia), grandiosity and delusional ideation (bipolar disorder [BD]), and less commonly assessed catatonic signs (ambitendency, automatic obedience). These symptoms are mistakenly attributed to the respective disease.^1,16 This especially holds true when delirious mania is initially diagnosed as a primary psychosis, which leads to the administration of antipsychotics.¹⁷ Other cases have reported that delirious mania was resistant to treatment, but ECT was never pursued.¹⁸

In this review, we provide a more comprehensive perspective of the clinical presentation, pathogenesis, and management of delirious mania. We searched PubMed and Google Scholar using the keywords “delirious mania,” “delirious mania AND catatonia,” or “manic delirium.” Most articles we found were case reports, case series, or retrospective chart reviews. There were no systematic reviews, meta analyses, or randomized control trials (RCTs). The 12 articles included in this review consist of 7 individual case reports, 4 case series, and 1 retrospective chart review that describe a total of 36 cases (Table^{1,2,5,17,19-26}).

Clinical presentation: What to look for

Patients with delirious mania typically develop symptoms extremely rapidly. In virtually all published literature, symptoms were reported to emerge within hours to days and consisted of severe forms of mania, psychosis, and delirium; 100% of the cases in our review had these symptoms. Commonly reported symptoms were:

• intense excitement
• emotional lability
• grandiose delusions
• profound insomnia
• pressured and rapid speech
• auditory and visual hallucinations
• hypersexuality
• thought disorganization.

Exquisite paranoia can also result in violent aggression (and may require the use of physical restraints). Patients may confine themselves to very small spaces (such as a closet) in response to the intense paranoia. Impairments in various neurocognitive domains—including inability to focus; disorientation; language and visuospatial disturbances; difficulty with shifting and sustaining attention; and short-term memory impairments—have been reported. Patients often cannot recall the events during the episode.^1,2,5,27,28

Catatonia has been closely associated with delirious mania.²⁹ Features of excited catatonia—such as excessive motor activity, negativism, grimacing, posturing, echolalia, echopraxia, stereotypy, automatic obedience, verbigeration, combativeness, impulsivity, and rigidity—typically accompany delirious mania.^1,5,10,19,27

In addition to these symptoms, patients may engage in specific behaviors. They may exhibit inappropriate toileting such as smearing feces on walls or in bags, fecal or urinary incontinence, disrobing or running naked in public places, or pouring liquid on the floor or on one’s head.^1,2

Continue to: Of the 36 cases...

Of the 36 cases reported in the literature we reviewed, 20 (55%) were female. Most patients had an underlining psychiatric condition, including BD (72%), major depressive disorder (8%), and schizophrenia (2%). Three patients had no psychiatric history.

Physical examination

On initial presentation, a patient with delirious mania may be dehydrated, with dry mucous membranes, pale conjunctiva, tongue dryness, and poor skin turgor.^28,30 Due to excessive motor activity, diaphoresis with tachycardia, fluctuating blood pressure, and fever may be present.³¹

Certain basic cognitive tasks should be assessed to determine the patient’s orientation to place, date, and time. Assess if the patient can recall recent events, names of objects, or perform serial 7s; clock drawing capabilities also should be ascertained.^1,2,5 A Mini-Mental State Examination is useful.³²

The Bush-Francis Catatonia Rating Scale should be used to elicit features of catatonia, such as waxy flexibility, negativism, gegenhalten, mitgehen, catalepsy, ambitendency, automatic obedience, and grasp reflex.¹⁰

Laboratory findings are nonspecific

Although no specific laboratory findings are associated with delirious mania, bloodwork and imaging are routinely investigated, especially if delirium characteristics are most striking. A complete blood count, chemistries, hepatic panel, thyroid functioning, blood and/or urine cultures, creatinine phosphokinase (CPK), and urinalysis can be ordered. Head imaging such as MRI and CT to rule out intracranial pathology are typically performed.¹⁹ However, the diagnosis of delirious mania is based on the presence of the phenotypic features, by verification of catatonia, and by the responsiveness to the treatment delivered.²⁹

Continue to: Pathogenisis: Several hypotheses

The pathogenesis of delirious mania is not well understood. There are several postulations but no salient theory. Most patients with delirious mania have an underlying systemic medical or psychiatric condition.

Mood disorders. Patients with BD or schizoaffective disorder are especially susceptible to delirious mania. The percentage of manic patients who present with delirious mania varies by study. One study suggested approximately 19% have features of the phenomenon,³³ while others estimated 15% to 25%.³⁴ Elias et al³⁵ calculated that 15% of patients with mania succumb to manic exhaustion; from this it can be reasonably concluded that these were cases of misdiagnosed delirious mania.

Delirium hypothesis. Patients with delirious mania typically have features of delirium, including fluctuation of consciousness, disorientation, and/or poor sleep-wake cycle.³⁶ During rapid eye movement (REM) and non-REM sleep, memory circuits are fortified. When there is a substantial loss of REM and non-REM sleep, these circuits become faulty, even after 1 night. Pathological brain waves on EEG reflect the inability to reinforce the memory circuits. Patients with these waves may develop hallucinations, bizarre delusions, and altered sensorium. ECT reduces the pathological slow wave morphologies, thus restoring the synaptic maintenance and correcting the incompetent circuitry. This can explain the robust and rapid response of ECT in a patient with delirious mania.^37,38

Neurotransmitter hypothesis. It has been shown that in patients with delirious mania there is dysregulation of dopamine transport, which leads to dopamine overflow in the synapse. In contrast to a drug effect (ie, cocaine or methamphetamine) that acts by inhibiting dopamine reuptake, dopamine overflow in delirious mania is caused by the loss of dopamine transporter regulation. This results in a dysfunctional dopaminergic state that precipitates an acute state of delirium and agitation.^39,40

Serotonin plays a role in mood disorders, including mania and depression.^41,42 More specifically, serotonin has been implicated in impulsivity and aggression as shown by reduced levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and depletion of 5-hydroxytryptophan (5-HTP).⁴³

Continue to: Alterations in gamma-aminobutyric acid (GABA) transmission...

Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.⁴⁴ Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.⁴⁵ Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbito­frontal, prefrontal, parietal, and motor cortical regions.⁴⁶ A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.⁴⁷

Other neurotransmitters, such as glutamate, at the N-methyl-D-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.⁴⁸ However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.

Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study⁴⁹ that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al⁵⁰ found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.

COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.^51,52 There also have been cases of COVID-19–induced catatonia.^53-55 One case of delirious mania in a patient with COVID-19 has been reported.²¹ The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.⁵⁶ These cytokines have been linked to psychosis and other psychiatric disorders.⁵⁷ The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.²¹

Management: Benzodiazepines and ECT

A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports^27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.

Continue to: Knowing which medications...

Knowing which medications to avoid is as important as knowing which agents to administer. Be vigilant in avoiding high-potency antipsychotics, as these medications can worsen extrapyramidal symptoms and may precipitate seizures or neuroleptic malignant syndrome (NMS).²⁸ Anticholinergic agents should also be avoided because they worsen confusion. Although lithium is effective in BD, in delirious mania, high doses of lithium and haloperidol may cause severe encephalopathic syndromes, with symptoms that can include lethargy, tremors, cerebellar dysfunction, and worsened confusion; it may also cause widespread and irreversible brain damage.⁵⁹While positive outcomes have been documented when using a combination of antipsychotics and lithium,^8,60 this approach should be considered carefully and tailored to individual cases, taking into account the severity of manic and psychotic symptoms in addition to the level of catatonia.

Due to long periods of hyperactivity, withdrawal, and diaphoresis, patients with delirious mania may be severely dehydrated with metabolic derangements, including elevated CPK due to rhabdomyolysis from prolonged exertion, IM antipsychotics, or rigidity. To prevent acute renal failure, this must be immediately addressed with rapid fluid resuscitation and electrolyte repletion.⁶¹

Benzodiazepines. The rapid use of lorazepam should be initiated when delirious mania is suspected. Doses of 6 to 20 mg have been reported to be effective if tolerated.^5,20 Typically, high-dose lorazepam will not have the sedative effect that would normally occur in a patient who does not have delirious mania.² Lorazepam should be titrated until full resolution of symptoms. Doses up to 30 mg have been reported as effective and tolerable.⁶² In our literature review, 50% of patients (18/36) responded or partially responded to lorazepam. However, only 3 case reports documented a complete remission with lorazepam, and many patients needed ECT for remission of symptoms.

ECT is generally reserved for patients who are not helped by benzodiazepine therapy, which is estimated to be up to 20%.⁵ ECT is highly effective in delirious mania, with remission rates ranging from 80% to 100%.¹ ECT is also effective in acute non­delirious mania (comparable to depression); however, it is only used in a small minority of cases (0.2% to 12%).³⁵ In our review, 58% of cases (21/36) reported using ECT, and in all cases it resulted in complete remission.

A dramatic improvement can be seen even after a single ECT session, though most patients show improvement after 4 sessions or 3 to 7 days.^1,2,5 In our review, most patients received 4 to 12 sessions until achieving complete remission.

Continue to: No RCTs have evaluated...

No RCTs have evaluated ECT electrode placement in patients with delirious mania. However, several RCTs have investigated electrode placement in patients with acute nondelirious mania. Hiremani et al⁶³ found that bitemporal placement had a more rapid response rate than bifrontal placement, but there was no overall difference in response rate. Barekatain et al⁶⁴ found no difference between these 2 bilateral approaches. Many of the delirious mania cases report using a bilateral placement (including 42% of the ECT cases in our review) due to the emergent need for rapid relief of symptoms, which is especially necessary if the patient is experiencing hemodynamic instability, excessive violence, risk for self-harm, worsening delirium, or resistance to lorazepam.

Prognosis: Often fatal if left untreated

Patients with delirious mania are at high risk to progress to a more severe form of NMS or malignant catatonia. Therefore, high-potency antipsychotics should be avoided; mortality can be elevated from 60% without antipsychotics to 78% with antipsychotics.⁴ Some researchers estimate 75% to 78% of cases of delirious mania can be fatal if left untreated.^3,6

Bottom Line

Delirious mania is routinely mistaken for more conventional manic or psychotic disorders. Clinicians need to be able to rapidly recognize the symptoms of this syndrome, which include mania, psychosis, delirium, and possible catatonia, so they can avoid administering toxic agents and instead initiate effective treatments such as benzodiazepines and electroconvulsive therapy.

Related Resources

• Arsan C, Baker C, Wong J, et al. Delirious mania: an approach to diagnosis and treatment. Prim Care Companion CNS Disord. 2021;23(1):20f02744. doi:10.4088/PCC.20f02744
• Lamba G, Kennedy EA, Vu CP. Case report: ECT for delirious mania. Clinical Psychiatry News. December 14, 2021. https://www.mdedge.com/psychiatry/article/249909/bipolar-disorder/case-report-ect-delirious-mania

Drug Brand Names

Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan

Delirious mania is a syndrome characterized by the acute onset of severe hyperactivity, psychosis, catatonia, and intermittent confusion. While there have been growing reports of this phenomenon over the last 2 decades, it remains poorly recognized and understood.^1,2 There is no widely accepted nosology for delirious mania and the condition is absent from DSM-5, which magnifies the difficulties in making a timely diagnosis and initiating appropriate treatment. Delayed diagnosis and treatment may result in a detrimental outcome.^2,3 Delirious mania has also been labeled as lethal catatonia, specific febrile delirium, hyperactive or exhaustive mania, and Bell’s mania.^2,4,5 The characterization and diagnosis of this condition have a long and inconsistent history (Box^1,6-11).

Box

Delirious mania continues to be met with incertitude in clinical practice, and numerous inconsistencies have been reported in the literature. For example, some cases that have been reported as delirious mania had more evidence of primary delirium due to another medical condition or primary mania.^12,13 Other cases have demonstrated swift improvement of symptoms after monotherapy with antipsychotics without a trial of benzodiazepines or electroconvulsive therapy (ECT); the exclusion of a sudden onset questions the validity of the diagnosis and promotes the use of less efficacious treatments.^14,15 Other reports have confirmed that the diagnosis is missed when certain symptoms are more predominant, such as a thought disorder (acute schizophrenia), grandiosity and delusional ideation (bipolar disorder [BD]), and less commonly assessed catatonic signs (ambitendency, automatic obedience). These symptoms are mistakenly attributed to the respective disease.^1,16 This especially holds true when delirious mania is initially diagnosed as a primary psychosis, which leads to the administration of antipsychotics.¹⁷ Other cases have reported that delirious mania was resistant to treatment, but ECT was never pursued.¹⁸

In this review, we provide a more comprehensive perspective of the clinical presentation, pathogenesis, and management of delirious mania. We searched PubMed and Google Scholar using the keywords “delirious mania,” “delirious mania AND catatonia,” or “manic delirium.” Most articles we found were case reports, case series, or retrospective chart reviews. There were no systematic reviews, meta analyses, or randomized control trials (RCTs). The 12 articles included in this review consist of 7 individual case reports, 4 case series, and 1 retrospective chart review that describe a total of 36 cases (Table^{1,2,5,17,19-26}).

Clinical presentation: What to look for

Patients with delirious mania typically develop symptoms extremely rapidly. In virtually all published literature, symptoms were reported to emerge within hours to days and consisted of severe forms of mania, psychosis, and delirium; 100% of the cases in our review had these symptoms. Commonly reported symptoms were:

• intense excitement
• emotional lability
• grandiose delusions
• profound insomnia
• pressured and rapid speech
• auditory and visual hallucinations
• hypersexuality
• thought disorganization.

Exquisite paranoia can also result in violent aggression (and may require the use of physical restraints). Patients may confine themselves to very small spaces (such as a closet) in response to the intense paranoia. Impairments in various neurocognitive domains—including inability to focus; disorientation; language and visuospatial disturbances; difficulty with shifting and sustaining attention; and short-term memory impairments—have been reported. Patients often cannot recall the events during the episode.^1,2,5,27,28

Catatonia has been closely associated with delirious mania.²⁹ Features of excited catatonia—such as excessive motor activity, negativism, grimacing, posturing, echolalia, echopraxia, stereotypy, automatic obedience, verbigeration, combativeness, impulsivity, and rigidity—typically accompany delirious mania.^1,5,10,19,27

In addition to these symptoms, patients may engage in specific behaviors. They may exhibit inappropriate toileting such as smearing feces on walls or in bags, fecal or urinary incontinence, disrobing or running naked in public places, or pouring liquid on the floor or on one’s head.^1,2

Continue to: Of the 36 cases...

Of the 36 cases reported in the literature we reviewed, 20 (55%) were female. Most patients had an underlining psychiatric condition, including BD (72%), major depressive disorder (8%), and schizophrenia (2%). Three patients had no psychiatric history.

Physical examination

On initial presentation, a patient with delirious mania may be dehydrated, with dry mucous membranes, pale conjunctiva, tongue dryness, and poor skin turgor.^28,30 Due to excessive motor activity, diaphoresis with tachycardia, fluctuating blood pressure, and fever may be present.³¹

Certain basic cognitive tasks should be assessed to determine the patient’s orientation to place, date, and time. Assess if the patient can recall recent events, names of objects, or perform serial 7s; clock drawing capabilities also should be ascertained.^1,2,5 A Mini-Mental State Examination is useful.³²

The Bush-Francis Catatonia Rating Scale should be used to elicit features of catatonia, such as waxy flexibility, negativism, gegenhalten, mitgehen, catalepsy, ambitendency, automatic obedience, and grasp reflex.¹⁰

Laboratory findings are nonspecific

Although no specific laboratory findings are associated with delirious mania, bloodwork and imaging are routinely investigated, especially if delirium characteristics are most striking. A complete blood count, chemistries, hepatic panel, thyroid functioning, blood and/or urine cultures, creatinine phosphokinase (CPK), and urinalysis can be ordered. Head imaging such as MRI and CT to rule out intracranial pathology are typically performed.¹⁹ However, the diagnosis of delirious mania is based on the presence of the phenotypic features, by verification of catatonia, and by the responsiveness to the treatment delivered.²⁹

Continue to: Pathogenisis: Several hypotheses

The pathogenesis of delirious mania is not well understood. There are several postulations but no salient theory. Most patients with delirious mania have an underlying systemic medical or psychiatric condition.

Mood disorders. Patients with BD or schizoaffective disorder are especially susceptible to delirious mania. The percentage of manic patients who present with delirious mania varies by study. One study suggested approximately 19% have features of the phenomenon,³³ while others estimated 15% to 25%.³⁴ Elias et al³⁵ calculated that 15% of patients with mania succumb to manic exhaustion; from this it can be reasonably concluded that these were cases of misdiagnosed delirious mania.

Delirium hypothesis. Patients with delirious mania typically have features of delirium, including fluctuation of consciousness, disorientation, and/or poor sleep-wake cycle.³⁶ During rapid eye movement (REM) and non-REM sleep, memory circuits are fortified. When there is a substantial loss of REM and non-REM sleep, these circuits become faulty, even after 1 night. Pathological brain waves on EEG reflect the inability to reinforce the memory circuits. Patients with these waves may develop hallucinations, bizarre delusions, and altered sensorium. ECT reduces the pathological slow wave morphologies, thus restoring the synaptic maintenance and correcting the incompetent circuitry. This can explain the robust and rapid response of ECT in a patient with delirious mania.^37,38

Neurotransmitter hypothesis. It has been shown that in patients with delirious mania there is dysregulation of dopamine transport, which leads to dopamine overflow in the synapse. In contrast to a drug effect (ie, cocaine or methamphetamine) that acts by inhibiting dopamine reuptake, dopamine overflow in delirious mania is caused by the loss of dopamine transporter regulation. This results in a dysfunctional dopaminergic state that precipitates an acute state of delirium and agitation.^39,40

Serotonin plays a role in mood disorders, including mania and depression.^41,42 More specifically, serotonin has been implicated in impulsivity and aggression as shown by reduced levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and depletion of 5-hydroxytryptophan (5-HTP).⁴³

Continue to: Alterations in gamma-aminobutyric acid (GABA) transmission...

Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.⁴⁴ Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.⁴⁵ Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbito­frontal, prefrontal, parietal, and motor cortical regions.⁴⁶ A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.⁴⁷

Other neurotransmitters, such as glutamate, at the N-methyl-D-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.⁴⁸ However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.

Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study⁴⁹ that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al⁵⁰ found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.

COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.^51,52 There also have been cases of COVID-19–induced catatonia.^53-55 One case of delirious mania in a patient with COVID-19 has been reported.²¹ The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.⁵⁶ These cytokines have been linked to psychosis and other psychiatric disorders.⁵⁷ The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.²¹

Management: Benzodiazepines and ECT

A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports^27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.

Continue to: Knowing which medications...

Knowing which medications to avoid is as important as knowing which agents to administer. Be vigilant in avoiding high-potency antipsychotics, as these medications can worsen extrapyramidal symptoms and may precipitate seizures or neuroleptic malignant syndrome (NMS).²⁸ Anticholinergic agents should also be avoided because they worsen confusion. Although lithium is effective in BD, in delirious mania, high doses of lithium and haloperidol may cause severe encephalopathic syndromes, with symptoms that can include lethargy, tremors, cerebellar dysfunction, and worsened confusion; it may also cause widespread and irreversible brain damage.⁵⁹While positive outcomes have been documented when using a combination of antipsychotics and lithium,^8,60 this approach should be considered carefully and tailored to individual cases, taking into account the severity of manic and psychotic symptoms in addition to the level of catatonia.

Due to long periods of hyperactivity, withdrawal, and diaphoresis, patients with delirious mania may be severely dehydrated with metabolic derangements, including elevated CPK due to rhabdomyolysis from prolonged exertion, IM antipsychotics, or rigidity. To prevent acute renal failure, this must be immediately addressed with rapid fluid resuscitation and electrolyte repletion.⁶¹

Benzodiazepines. The rapid use of lorazepam should be initiated when delirious mania is suspected. Doses of 6 to 20 mg have been reported to be effective if tolerated.^5,20 Typically, high-dose lorazepam will not have the sedative effect that would normally occur in a patient who does not have delirious mania.² Lorazepam should be titrated until full resolution of symptoms. Doses up to 30 mg have been reported as effective and tolerable.⁶² In our literature review, 50% of patients (18/36) responded or partially responded to lorazepam. However, only 3 case reports documented a complete remission with lorazepam, and many patients needed ECT for remission of symptoms.

ECT is generally reserved for patients who are not helped by benzodiazepine therapy, which is estimated to be up to 20%.⁵ ECT is highly effective in delirious mania, with remission rates ranging from 80% to 100%.¹ ECT is also effective in acute non­delirious mania (comparable to depression); however, it is only used in a small minority of cases (0.2% to 12%).³⁵ In our review, 58% of cases (21/36) reported using ECT, and in all cases it resulted in complete remission.

A dramatic improvement can be seen even after a single ECT session, though most patients show improvement after 4 sessions or 3 to 7 days.^1,2,5 In our review, most patients received 4 to 12 sessions until achieving complete remission.

Continue to: No RCTs have evaluated...

No RCTs have evaluated ECT electrode placement in patients with delirious mania. However, several RCTs have investigated electrode placement in patients with acute nondelirious mania. Hiremani et al⁶³ found that bitemporal placement had a more rapid response rate than bifrontal placement, but there was no overall difference in response rate. Barekatain et al⁶⁴ found no difference between these 2 bilateral approaches. Many of the delirious mania cases report using a bilateral placement (including 42% of the ECT cases in our review) due to the emergent need for rapid relief of symptoms, which is especially necessary if the patient is experiencing hemodynamic instability, excessive violence, risk for self-harm, worsening delirium, or resistance to lorazepam.

Prognosis: Often fatal if left untreated

Patients with delirious mania are at high risk to progress to a more severe form of NMS or malignant catatonia. Therefore, high-potency antipsychotics should be avoided; mortality can be elevated from 60% without antipsychotics to 78% with antipsychotics.⁴ Some researchers estimate 75% to 78% of cases of delirious mania can be fatal if left untreated.^3,6

Bottom Line

Delirious mania is routinely mistaken for more conventional manic or psychotic disorders. Clinicians need to be able to rapidly recognize the symptoms of this syndrome, which include mania, psychosis, delirium, and possible catatonia, so they can avoid administering toxic agents and instead initiate effective treatments such as benzodiazepines and electroconvulsive therapy.

Related Resources

• Arsan C, Baker C, Wong J, et al. Delirious mania: an approach to diagnosis and treatment. Prim Care Companion CNS Disord. 2021;23(1):20f02744. doi:10.4088/PCC.20f02744
• Lamba G, Kennedy EA, Vu CP. Case report: ECT for delirious mania. Clinical Psychiatry News. December 14, 2021. https://www.mdedge.com/psychiatry/article/249909/bipolar-disorder/case-report-ect-delirious-mania

Drug Brand Names

Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan

After several months of difficulty living in her current apartment complex, Ms. M asks you as her psychiatrist to write a letter to the management company requesting she be moved to an apartment on the opposite side of the maintenance closet because the noise aggravates her posttraumatic stress disorder. What should you consider when asked to write such a letter?

Psychiatric practice often extends beyond the treatment of mental illness to include addressing patients’ social well-being. Psychiatrists commonly inquire about a patient’s social situation to understand the impact of these environmental factors. Similarly, psychiatric illness may affect a patient’s ability to work or fulfill responsibilities. As a result, patients may ask their psychiatrists for assistance by requesting letters that address various aspects of their social well-being.¹ These communications may address an array of topics, from a patient’s readiness to return to work to their ability to pay child support. This article focuses on the role psychiatrists have in writing patient-requested letters across a variety of topics, including the consideration of potential legal liability and ethical implications.

Types of letters

The categories of letters patients request can be divided into 2 groups. The first is comprised of letters relating to the patient’s medical needs (Table 1^2,3). These address the patient’s ability to work (eg, medical leave, return to work, or accommodations) or travel (eg, ability to drive or use public transportation), or need for specific medical treatment (ie, gender-affirming care or cannabis use in specific settings). The second group relates to legal requests such as excusal from jury duty, emotional support animals, or any other letter used specifically for legal purposes (in civil or criminal cases) (Table 2^1,4-6).

The decision to write a letter on behalf of a patient should be based on whether you have sufficient knowledge to answer the referral question, and whether the requested evaluation fits within your role as the treating psychiatrist. Many requests fall short of the first condition. For example, a request to opine about an individual’s ability to perform their job duties requires specific knowledge and careful consideration of the patient’s work responsibilities, knowledge of the impact of their psychiatric symptoms, and specialized knowledge about interventions that would ameliorate symptoms in the specialized work setting. Most psychiatrists are not sufficiently familiar with a specific workplace to provide opinions regarding reasonable accommodations.

The second condition refers to the role and responsibilities of the psychiatrist. Many letter requests are clearly within the scope of the clinical psychiatrist, such as a medical leave note due to a psychiatric decompensation or a jury duty excusal due to an unstable mental state. Other letters reach beyond the role of the general or treating psychiatrist, such as opinions about suitable housing or a patient’s competency to stand trial.

Components of letters

The decision to write or not to write a letter should be discussed with the patient. Identify the reasons for and against letter writing. If you decide to write a letter, the letter should have the following basic framework (Figure): the identity of the person who requested the letter, the referral question, and an answer to the referral question with a clear rationale. Describe the patient’s psychiatric diagnosis using DSM criteria. Any limitations to the answer should be identified. The letter should not go beyond the referral question and should not include information that was not requested. It also should be preserved in the medical record.

It is recommended to write or review the letter in the presence of the patient to discuss the contents of the letter and what the psychiatrist can or cannot write. As in forensic reports, conclusory statements are not helpful. Provide descriptive information instead of relying on psychiatric jargon, and a rationale for the opinion as opposed to stating an opinion as fact. In the letter, you must acknowledge that your opinion is based upon information provided by the patient (and the patient’s family, when accurate) and as a result, is not fully objective.

Continue to: Liability and dual agency

Psychiatrists are familiar with clinical situations in which a duty to the patient is mitigated or superseded by a duty to a third party. As the Tarasoff court famously stated, “the protective privilege ends where the public peril begins.”⁷

To be liable to either a patient or a third party means to be “bound or obliged in law or equity; responsible; chargeable; answerable; compellable to make satisfaction, compensation, or restitution.”⁸ Liabilities related to clinical treatment are well-established; medical students learn the fundamentals before ever treating a patient, and physicians carry malpractice insurance throughout their careers.

Less well-established is the liability a treating psychiatrist owes a third party when forming an opinion that impacts both their patient and the third party (eg, an employer when writing a return-to-work letter, or a disability insurer when qualifying a patient for disability benefits). The American Academy of Psychiatry and the Law discourages treating psychiatrists from performing these types of evaluations of their patients based on the inherent conflict of serving as a dual agent, or acting both as an advocate for the patient and as an independent evaluator striving for objectivity.⁹ However, such requests commonly arise, and some may be unavoidable.

Dual-agency situations subject the treating psychiatrist to avenues of legal action arising from the patient-doctor relationship as well as the forensic evaluator relationship. If a letter is written during a clinical treatment, all duties owed to the patient continue to apply, and the relevant benchmarks of local statutes and principle of a standard of care are relevant. It is conceivable that a patient could bring a negligence lawsuit based on a standard of care allegation (eg, that writing certain types of letters is so ordinary that failure to write them would fall below the standard of care). Confidentiality is also of the utmost importance,¹⁰ and you should obtain a written release of information from the patient before releasing any letter with privileged information about the patient.¹¹ Additional relevant legal causes of action the patient could include are torts such as defamation of character, invasion of privacy, breach of contract, and intentional infliction of emotional distress. There is limited case law supporting patients’ rights to sue psychiatrists for defamation.¹⁰

A psychiatrist writing a letter to a third party may also subject themselves to avenues of legal action occurring outside the physician-patient relationship. Importantly, damages resulting from these breaches would not be covered by your malpractice insurance. Extreme cases involve allegations of fraud or perjury, which could be pursued in criminal court. If a psychiatrist intentionally deceives a third party for the purpose of obtaining some benefit for the patient, this is clear grounds for civil or criminal action. Fraud is defined as “a false representation of a matter of fact, whether by words or by conduct, by false or misleading allegations, or by concealment of that which should have been disclosed, which deceives and is intended to deceive another so that he shall act upon it to his legal injury.”⁸ Negligence can also be grounds for liability if a third party suffers injury or loss. Although the liability is clearer if the third party retains an independent psychiatrist rather than soliciting an opinion from a patient’s treating psychiatrist, both parties are subject to the claim of negligence.¹⁰

Continue to: There are some important protections...

There are some important protections that limit psychiatrists’ good-faith opinions from litigation. The primary one is the “professional medical judgment rule,” which shields physicians from the consequences of erroneous opinions so long as the examination was competent, complete, and performed in an ordinary fashion.¹⁰ In some cases, psychiatrists writing a letter or report for a government agency may also qualify for quasi-judicial immunity or witness immunity, but case law shows significant variation in when and how these privileges apply and whether such privileges would be applied to a clinical psychiatrist in the context of a traditional physician-patient relationship.¹² In general, these privileges are not absolute and may not be sufficiently well-established to discourage a plaintiff from filing suit or prompt early judicial dismissal of a case.

Like all aspects of practicing medicine, letter writing is subject to scrutiny and accountability. Think carefully about your obligations and the potential consequences of writing or not writing a letter to a third party.

Ethical considerations

The decision to write a letter for a patient must be carefully considered from multiple angles.⁶ In addition to liability concerns, various ethical considerations also arise. Guided by the principles of beneficence, nonmaleficence, autonomy, and justice,¹³ we recommend the following approaches.

Maintain objectivity

During letter writing, a conflict of interest may arise between your allegiance to the patient and the imperative to provide accurate information.^14-16 If the conflict is overwhelming, the most appropriate approach is to recuse yourself from the case and refer the patient to a third party. When electing to write a letter, you accept the responsibility to provide an objective assessment of the relevant situation. This promotes a just outcome and may also serve to promote the patient’s or society’s well-being.

Encourage activity and overall function

Evidence suggests that participation in multiple aspects of life promotes positive health outcomes.^17,18 As a physician, it is your duty to promote health and support and facilitate accommodations that allow patients to participate and flourish in society. By the same logic, when approached by patients with a request for letters in support of reduced activity, you should consider not only the benefits but also the potential detriments of such disruptions. This may entail recommending temporary restrictions or modifications, as appropriate.

Continue to: Think beyond the patient

Letter writing, particularly when recommending accommodations, can have implications beyond the patient.¹⁶ Such letters may cause unintended societal harm. For example, others may have to assume additional responsibilities; competitive goods (eg, housing) may be rendered to the patient rather than to a person with greater needs; and workplace safety could be compromised due to absence. Consider not only the individual patient but also possible public health and societal effects of letter writing.

Deciding not to write

From an ethical perspective, a physician cannot be compelled to write a letter if such an undertaking violates a stronger moral obligation. An example of this is if writing a letter could cause significant harm to the patient or society, or if writing a letter might compromise a physician’s professionalism.¹⁹ When you elect to not write a letter, the ethical principles of autonomy and truth telling dictate that you must inform your patients of this choice.⁶ You should also provide an explanation to the patient as long as such information would not cause undue psychological or physical harm.^20,21

Schedule time to write letters

Some physicians implement policies that all letters are to be completed during scheduled appointments. Others designate administrative time to complete requested letters. Finally, some physicians flexibly complete such requests between appointments or during other undedicated time slots. Any of these approaches are justifiable, though some urgent requests may require more immediate attention outside of appointments. Some physicians may choose to bill for the letter writing if completed outside an appointment and the patient is treated in private practice. Whatever your policy, inform patients of it at the beginning of care and remind them when appropriate, such as before completing a letter that may be billed.

Manage uncertainty

Always strive for objectivity in letter writing. However, some requests inherently hinge on subjective reports and assessments. For example, a patient may request an excuse letter due to feeling unwell. In the absence of objective findings, what should you do? We advise the following.

Acquire collateral information. Adequate information is essential when making any medical recommendation. The same is true for writing letters. With the patient’s permission, you may need to contact relevant parties to better understand the circumstance or activity about which you are being asked to write a letter. For example, a patient may request leave from work due to injury. If the specific parameters of the work impeded by the injury are unclear to you, refrain from writing the letter and explain the rationale to the patient.

Continue to: Integrate prior knowledge of the patient

Integrate prior knowledge of the patient. No letter writing request exists in a vacuum. If you know the patient, the letter should be contextualized within the patient’s prior behaviors.

Stay within your scope

Given the various dilemmas and challenges, you may want to consider whether some letter writing is out of your professional scope.^14-16 One solution would be to leave such requests to other entities (eg, requiring employers to retain medical personnel with specialized skills in occupational evaluations) and make such recommendations to patients. Regardless, physicians should think carefully about their professional boundaries and scope regarding letter requests and adopt and implement a consistent standard for all patients.

Regarding the letter requested by Ms. M, you should consider whether the appeal is consistent with the patient’s psychiatric illness. You should also consider whether you have sufficient knowledge about the patient’s living environment to support their claim. Such a letter should be written only if you understand both considerations. Regardless of your decision, you should explain your rationale to the patient.

Bottom Line

Patients may ask their psychiatrists to write letters that address aspects of their social well-being. However, psychiatrists must be alert to requests that are outside their scope of practice or ethically or legally fraught. Carefully consider whether writing a letter is appropriate and if not, discuss with the patient the reasons you cannot write such a letter and any recommended alternative avenues to address their request.

Related Resources

• Riese A. Writing letters for transgender patients undergoing medical transition. Current Psychiatry. 2021;20(8):51-52. doi:10.12788/cp.0159
• Joshi KG. Service animals and emotional support animals: should you write that letter? Current Psychiatry. 2021;20(11):16-19,24. doi:10.12788/cp.0183

After several months of difficulty living in her current apartment complex, Ms. M asks you as her psychiatrist to write a letter to the management company requesting she be moved to an apartment on the opposite side of the maintenance closet because the noise aggravates her posttraumatic stress disorder. What should you consider when asked to write such a letter?

Psychiatric practice often extends beyond the treatment of mental illness to include addressing patients’ social well-being. Psychiatrists commonly inquire about a patient’s social situation to understand the impact of these environmental factors. Similarly, psychiatric illness may affect a patient’s ability to work or fulfill responsibilities. As a result, patients may ask their psychiatrists for assistance by requesting letters that address various aspects of their social well-being.¹ These communications may address an array of topics, from a patient’s readiness to return to work to their ability to pay child support. This article focuses on the role psychiatrists have in writing patient-requested letters across a variety of topics, including the consideration of potential legal liability and ethical implications.

Types of letters

The categories of letters patients request can be divided into 2 groups. The first is comprised of letters relating to the patient’s medical needs (Table 1^2,3). These address the patient’s ability to work (eg, medical leave, return to work, or accommodations) or travel (eg, ability to drive or use public transportation), or need for specific medical treatment (ie, gender-affirming care or cannabis use in specific settings). The second group relates to legal requests such as excusal from jury duty, emotional support animals, or any other letter used specifically for legal purposes (in civil or criminal cases) (Table 2^1,4-6).

The decision to write a letter on behalf of a patient should be based on whether you have sufficient knowledge to answer the referral question, and whether the requested evaluation fits within your role as the treating psychiatrist. Many requests fall short of the first condition. For example, a request to opine about an individual’s ability to perform their job duties requires specific knowledge and careful consideration of the patient’s work responsibilities, knowledge of the impact of their psychiatric symptoms, and specialized knowledge about interventions that would ameliorate symptoms in the specialized work setting. Most psychiatrists are not sufficiently familiar with a specific workplace to provide opinions regarding reasonable accommodations.

The second condition refers to the role and responsibilities of the psychiatrist. Many letter requests are clearly within the scope of the clinical psychiatrist, such as a medical leave note due to a psychiatric decompensation or a jury duty excusal due to an unstable mental state. Other letters reach beyond the role of the general or treating psychiatrist, such as opinions about suitable housing or a patient’s competency to stand trial.

Components of letters

The decision to write or not to write a letter should be discussed with the patient. Identify the reasons for and against letter writing. If you decide to write a letter, the letter should have the following basic framework (Figure): the identity of the person who requested the letter, the referral question, and an answer to the referral question with a clear rationale. Describe the patient’s psychiatric diagnosis using DSM criteria. Any limitations to the answer should be identified. The letter should not go beyond the referral question and should not include information that was not requested. It also should be preserved in the medical record.

It is recommended to write or review the letter in the presence of the patient to discuss the contents of the letter and what the psychiatrist can or cannot write. As in forensic reports, conclusory statements are not helpful. Provide descriptive information instead of relying on psychiatric jargon, and a rationale for the opinion as opposed to stating an opinion as fact. In the letter, you must acknowledge that your opinion is based upon information provided by the patient (and the patient’s family, when accurate) and as a result, is not fully objective.

Continue to: Liability and dual agency

Psychiatrists are familiar with clinical situations in which a duty to the patient is mitigated or superseded by a duty to a third party. As the Tarasoff court famously stated, “the protective privilege ends where the public peril begins.”⁷

To be liable to either a patient or a third party means to be “bound or obliged in law or equity; responsible; chargeable; answerable; compellable to make satisfaction, compensation, or restitution.”⁸ Liabilities related to clinical treatment are well-established; medical students learn the fundamentals before ever treating a patient, and physicians carry malpractice insurance throughout their careers.

Less well-established is the liability a treating psychiatrist owes a third party when forming an opinion that impacts both their patient and the third party (eg, an employer when writing a return-to-work letter, or a disability insurer when qualifying a patient for disability benefits). The American Academy of Psychiatry and the Law discourages treating psychiatrists from performing these types of evaluations of their patients based on the inherent conflict of serving as a dual agent, or acting both as an advocate for the patient and as an independent evaluator striving for objectivity.⁹ However, such requests commonly arise, and some may be unavoidable.

Dual-agency situations subject the treating psychiatrist to avenues of legal action arising from the patient-doctor relationship as well as the forensic evaluator relationship. If a letter is written during a clinical treatment, all duties owed to the patient continue to apply, and the relevant benchmarks of local statutes and principle of a standard of care are relevant. It is conceivable that a patient could bring a negligence lawsuit based on a standard of care allegation (eg, that writing certain types of letters is so ordinary that failure to write them would fall below the standard of care). Confidentiality is also of the utmost importance,¹⁰ and you should obtain a written release of information from the patient before releasing any letter with privileged information about the patient.¹¹ Additional relevant legal causes of action the patient could include are torts such as defamation of character, invasion of privacy, breach of contract, and intentional infliction of emotional distress. There is limited case law supporting patients’ rights to sue psychiatrists for defamation.¹⁰

A psychiatrist writing a letter to a third party may also subject themselves to avenues of legal action occurring outside the physician-patient relationship. Importantly, damages resulting from these breaches would not be covered by your malpractice insurance. Extreme cases involve allegations of fraud or perjury, which could be pursued in criminal court. If a psychiatrist intentionally deceives a third party for the purpose of obtaining some benefit for the patient, this is clear grounds for civil or criminal action. Fraud is defined as “a false representation of a matter of fact, whether by words or by conduct, by false or misleading allegations, or by concealment of that which should have been disclosed, which deceives and is intended to deceive another so that he shall act upon it to his legal injury.”⁸ Negligence can also be grounds for liability if a third party suffers injury or loss. Although the liability is clearer if the third party retains an independent psychiatrist rather than soliciting an opinion from a patient’s treating psychiatrist, both parties are subject to the claim of negligence.¹⁰

Continue to: There are some important protections...

There are some important protections that limit psychiatrists’ good-faith opinions from litigation. The primary one is the “professional medical judgment rule,” which shields physicians from the consequences of erroneous opinions so long as the examination was competent, complete, and performed in an ordinary fashion.¹⁰ In some cases, psychiatrists writing a letter or report for a government agency may also qualify for quasi-judicial immunity or witness immunity, but case law shows significant variation in when and how these privileges apply and whether such privileges would be applied to a clinical psychiatrist in the context of a traditional physician-patient relationship.¹² In general, these privileges are not absolute and may not be sufficiently well-established to discourage a plaintiff from filing suit or prompt early judicial dismissal of a case.

Like all aspects of practicing medicine, letter writing is subject to scrutiny and accountability. Think carefully about your obligations and the potential consequences of writing or not writing a letter to a third party.

Ethical considerations

The decision to write a letter for a patient must be carefully considered from multiple angles.⁶ In addition to liability concerns, various ethical considerations also arise. Guided by the principles of beneficence, nonmaleficence, autonomy, and justice,¹³ we recommend the following approaches.

Maintain objectivity

During letter writing, a conflict of interest may arise between your allegiance to the patient and the imperative to provide accurate information.^14-16 If the conflict is overwhelming, the most appropriate approach is to recuse yourself from the case and refer the patient to a third party. When electing to write a letter, you accept the responsibility to provide an objective assessment of the relevant situation. This promotes a just outcome and may also serve to promote the patient’s or society’s well-being.

Encourage activity and overall function

Evidence suggests that participation in multiple aspects of life promotes positive health outcomes.^17,18 As a physician, it is your duty to promote health and support and facilitate accommodations that allow patients to participate and flourish in society. By the same logic, when approached by patients with a request for letters in support of reduced activity, you should consider not only the benefits but also the potential detriments of such disruptions. This may entail recommending temporary restrictions or modifications, as appropriate.

Continue to: Think beyond the patient

Letter writing, particularly when recommending accommodations, can have implications beyond the patient.¹⁶ Such letters may cause unintended societal harm. For example, others may have to assume additional responsibilities; competitive goods (eg, housing) may be rendered to the patient rather than to a person with greater needs; and workplace safety could be compromised due to absence. Consider not only the individual patient but also possible public health and societal effects of letter writing.

Deciding not to write

From an ethical perspective, a physician cannot be compelled to write a letter if such an undertaking violates a stronger moral obligation. An example of this is if writing a letter could cause significant harm to the patient or society, or if writing a letter might compromise a physician’s professionalism.¹⁹ When you elect to not write a letter, the ethical principles of autonomy and truth telling dictate that you must inform your patients of this choice.⁶ You should also provide an explanation to the patient as long as such information would not cause undue psychological or physical harm.^20,21

Schedule time to write letters

Some physicians implement policies that all letters are to be completed during scheduled appointments. Others designate administrative time to complete requested letters. Finally, some physicians flexibly complete such requests between appointments or during other undedicated time slots. Any of these approaches are justifiable, though some urgent requests may require more immediate attention outside of appointments. Some physicians may choose to bill for the letter writing if completed outside an appointment and the patient is treated in private practice. Whatever your policy, inform patients of it at the beginning of care and remind them when appropriate, such as before completing a letter that may be billed.

Manage uncertainty

Always strive for objectivity in letter writing. However, some requests inherently hinge on subjective reports and assessments. For example, a patient may request an excuse letter due to feeling unwell. In the absence of objective findings, what should you do? We advise the following.

Acquire collateral information. Adequate information is essential when making any medical recommendation. The same is true for writing letters. With the patient’s permission, you may need to contact relevant parties to better understand the circumstance or activity about which you are being asked to write a letter. For example, a patient may request leave from work due to injury. If the specific parameters of the work impeded by the injury are unclear to you, refrain from writing the letter and explain the rationale to the patient.

Continue to: Integrate prior knowledge of the patient

Integrate prior knowledge of the patient. No letter writing request exists in a vacuum. If you know the patient, the letter should be contextualized within the patient’s prior behaviors.

Stay within your scope

Given the various dilemmas and challenges, you may want to consider whether some letter writing is out of your professional scope.^14-16 One solution would be to leave such requests to other entities (eg, requiring employers to retain medical personnel with specialized skills in occupational evaluations) and make such recommendations to patients. Regardless, physicians should think carefully about their professional boundaries and scope regarding letter requests and adopt and implement a consistent standard for all patients.

Regarding the letter requested by Ms. M, you should consider whether the appeal is consistent with the patient’s psychiatric illness. You should also consider whether you have sufficient knowledge about the patient’s living environment to support their claim. Such a letter should be written only if you understand both considerations. Regardless of your decision, you should explain your rationale to the patient.

Bottom Line

Patients may ask their psychiatrists to write letters that address aspects of their social well-being. However, psychiatrists must be alert to requests that are outside their scope of practice or ethically or legally fraught. Carefully consider whether writing a letter is appropriate and if not, discuss with the patient the reasons you cannot write such a letter and any recommended alternative avenues to address their request.

Related Resources

• Riese A. Writing letters for transgender patients undergoing medical transition. Current Psychiatry. 2021;20(8):51-52. doi:10.12788/cp.0159
• Joshi KG. Service animals and emotional support animals: should you write that letter? Current Psychiatry. 2021;20(11):16-19,24. doi:10.12788/cp.0183

After several months of difficulty living in her current apartment complex, Ms. M asks you as her psychiatrist to write a letter to the management company requesting she be moved to an apartment on the opposite side of the maintenance closet because the noise aggravates her posttraumatic stress disorder. What should you consider when asked to write such a letter?

Psychiatric practice often extends beyond the treatment of mental illness to include addressing patients’ social well-being. Psychiatrists commonly inquire about a patient’s social situation to understand the impact of these environmental factors. Similarly, psychiatric illness may affect a patient’s ability to work or fulfill responsibilities. As a result, patients may ask their psychiatrists for assistance by requesting letters that address various aspects of their social well-being.¹ These communications may address an array of topics, from a patient’s readiness to return to work to their ability to pay child support. This article focuses on the role psychiatrists have in writing patient-requested letters across a variety of topics, including the consideration of potential legal liability and ethical implications.

Types of letters

The categories of letters patients request can be divided into 2 groups. The first is comprised of letters relating to the patient’s medical needs (Table 1^2,3). These address the patient’s ability to work (eg, medical leave, return to work, or accommodations) or travel (eg, ability to drive or use public transportation), or need for specific medical treatment (ie, gender-affirming care or cannabis use in specific settings). The second group relates to legal requests such as excusal from jury duty, emotional support animals, or any other letter used specifically for legal purposes (in civil or criminal cases) (Table 2^1,4-6).

The decision to write a letter on behalf of a patient should be based on whether you have sufficient knowledge to answer the referral question, and whether the requested evaluation fits within your role as the treating psychiatrist. Many requests fall short of the first condition. For example, a request to opine about an individual’s ability to perform their job duties requires specific knowledge and careful consideration of the patient’s work responsibilities, knowledge of the impact of their psychiatric symptoms, and specialized knowledge about interventions that would ameliorate symptoms in the specialized work setting. Most psychiatrists are not sufficiently familiar with a specific workplace to provide opinions regarding reasonable accommodations.

The second condition refers to the role and responsibilities of the psychiatrist. Many letter requests are clearly within the scope of the clinical psychiatrist, such as a medical leave note due to a psychiatric decompensation or a jury duty excusal due to an unstable mental state. Other letters reach beyond the role of the general or treating psychiatrist, such as opinions about suitable housing or a patient’s competency to stand trial.

Components of letters

The decision to write or not to write a letter should be discussed with the patient. Identify the reasons for and against letter writing. If you decide to write a letter, the letter should have the following basic framework (Figure): the identity of the person who requested the letter, the referral question, and an answer to the referral question with a clear rationale. Describe the patient’s psychiatric diagnosis using DSM criteria. Any limitations to the answer should be identified. The letter should not go beyond the referral question and should not include information that was not requested. It also should be preserved in the medical record.

It is recommended to write or review the letter in the presence of the patient to discuss the contents of the letter and what the psychiatrist can or cannot write. As in forensic reports, conclusory statements are not helpful. Provide descriptive information instead of relying on psychiatric jargon, and a rationale for the opinion as opposed to stating an opinion as fact. In the letter, you must acknowledge that your opinion is based upon information provided by the patient (and the patient’s family, when accurate) and as a result, is not fully objective.

Continue to: Liability and dual agency

Psychiatrists are familiar with clinical situations in which a duty to the patient is mitigated or superseded by a duty to a third party. As the Tarasoff court famously stated, “the protective privilege ends where the public peril begins.”⁷

To be liable to either a patient or a third party means to be “bound or obliged in law or equity; responsible; chargeable; answerable; compellable to make satisfaction, compensation, or restitution.”⁸ Liabilities related to clinical treatment are well-established; medical students learn the fundamentals before ever treating a patient, and physicians carry malpractice insurance throughout their careers.

Less well-established is the liability a treating psychiatrist owes a third party when forming an opinion that impacts both their patient and the third party (eg, an employer when writing a return-to-work letter, or a disability insurer when qualifying a patient for disability benefits). The American Academy of Psychiatry and the Law discourages treating psychiatrists from performing these types of evaluations of their patients based on the inherent conflict of serving as a dual agent, or acting both as an advocate for the patient and as an independent evaluator striving for objectivity.⁹ However, such requests commonly arise, and some may be unavoidable.

Dual-agency situations subject the treating psychiatrist to avenues of legal action arising from the patient-doctor relationship as well as the forensic evaluator relationship. If a letter is written during a clinical treatment, all duties owed to the patient continue to apply, and the relevant benchmarks of local statutes and principle of a standard of care are relevant. It is conceivable that a patient could bring a negligence lawsuit based on a standard of care allegation (eg, that writing certain types of letters is so ordinary that failure to write them would fall below the standard of care). Confidentiality is also of the utmost importance,¹⁰ and you should obtain a written release of information from the patient before releasing any letter with privileged information about the patient.¹¹ Additional relevant legal causes of action the patient could include are torts such as defamation of character, invasion of privacy, breach of contract, and intentional infliction of emotional distress. There is limited case law supporting patients’ rights to sue psychiatrists for defamation.¹⁰

A psychiatrist writing a letter to a third party may also subject themselves to avenues of legal action occurring outside the physician-patient relationship. Importantly, damages resulting from these breaches would not be covered by your malpractice insurance. Extreme cases involve allegations of fraud or perjury, which could be pursued in criminal court. If a psychiatrist intentionally deceives a third party for the purpose of obtaining some benefit for the patient, this is clear grounds for civil or criminal action. Fraud is defined as “a false representation of a matter of fact, whether by words or by conduct, by false or misleading allegations, or by concealment of that which should have been disclosed, which deceives and is intended to deceive another so that he shall act upon it to his legal injury.”⁸ Negligence can also be grounds for liability if a third party suffers injury or loss. Although the liability is clearer if the third party retains an independent psychiatrist rather than soliciting an opinion from a patient’s treating psychiatrist, both parties are subject to the claim of negligence.¹⁰

Continue to: There are some important protections...

There are some important protections that limit psychiatrists’ good-faith opinions from litigation. The primary one is the “professional medical judgment rule,” which shields physicians from the consequences of erroneous opinions so long as the examination was competent, complete, and performed in an ordinary fashion.¹⁰ In some cases, psychiatrists writing a letter or report for a government agency may also qualify for quasi-judicial immunity or witness immunity, but case law shows significant variation in when and how these privileges apply and whether such privileges would be applied to a clinical psychiatrist in the context of a traditional physician-patient relationship.¹² In general, these privileges are not absolute and may not be sufficiently well-established to discourage a plaintiff from filing suit or prompt early judicial dismissal of a case.

Like all aspects of practicing medicine, letter writing is subject to scrutiny and accountability. Think carefully about your obligations and the potential consequences of writing or not writing a letter to a third party.

Ethical considerations

The decision to write a letter for a patient must be carefully considered from multiple angles.⁶ In addition to liability concerns, various ethical considerations also arise. Guided by the principles of beneficence, nonmaleficence, autonomy, and justice,¹³ we recommend the following approaches.

Maintain objectivity

During letter writing, a conflict of interest may arise between your allegiance to the patient and the imperative to provide accurate information.^14-16 If the conflict is overwhelming, the most appropriate approach is to recuse yourself from the case and refer the patient to a third party. When electing to write a letter, you accept the responsibility to provide an objective assessment of the relevant situation. This promotes a just outcome and may also serve to promote the patient’s or society’s well-being.

Encourage activity and overall function

Evidence suggests that participation in multiple aspects of life promotes positive health outcomes.^17,18 As a physician, it is your duty to promote health and support and facilitate accommodations that allow patients to participate and flourish in society. By the same logic, when approached by patients with a request for letters in support of reduced activity, you should consider not only the benefits but also the potential detriments of such disruptions. This may entail recommending temporary restrictions or modifications, as appropriate.

Continue to: Think beyond the patient

Letter writing, particularly when recommending accommodations, can have implications beyond the patient.¹⁶ Such letters may cause unintended societal harm. For example, others may have to assume additional responsibilities; competitive goods (eg, housing) may be rendered to the patient rather than to a person with greater needs; and workplace safety could be compromised due to absence. Consider not only the individual patient but also possible public health and societal effects of letter writing.

Deciding not to write

From an ethical perspective, a physician cannot be compelled to write a letter if such an undertaking violates a stronger moral obligation. An example of this is if writing a letter could cause significant harm to the patient or society, or if writing a letter might compromise a physician’s professionalism.¹⁹ When you elect to not write a letter, the ethical principles of autonomy and truth telling dictate that you must inform your patients of this choice.⁶ You should also provide an explanation to the patient as long as such information would not cause undue psychological or physical harm.^20,21

Schedule time to write letters

Some physicians implement policies that all letters are to be completed during scheduled appointments. Others designate administrative time to complete requested letters. Finally, some physicians flexibly complete such requests between appointments or during other undedicated time slots. Any of these approaches are justifiable, though some urgent requests may require more immediate attention outside of appointments. Some physicians may choose to bill for the letter writing if completed outside an appointment and the patient is treated in private practice. Whatever your policy, inform patients of it at the beginning of care and remind them when appropriate, such as before completing a letter that may be billed.

Manage uncertainty

Always strive for objectivity in letter writing. However, some requests inherently hinge on subjective reports and assessments. For example, a patient may request an excuse letter due to feeling unwell. In the absence of objective findings, what should you do? We advise the following.

Acquire collateral information. Adequate information is essential when making any medical recommendation. The same is true for writing letters. With the patient’s permission, you may need to contact relevant parties to better understand the circumstance or activity about which you are being asked to write a letter. For example, a patient may request leave from work due to injury. If the specific parameters of the work impeded by the injury are unclear to you, refrain from writing the letter and explain the rationale to the patient.

Continue to: Integrate prior knowledge of the patient

Integrate prior knowledge of the patient. No letter writing request exists in a vacuum. If you know the patient, the letter should be contextualized within the patient’s prior behaviors.

Stay within your scope

Given the various dilemmas and challenges, you may want to consider whether some letter writing is out of your professional scope.^14-16 One solution would be to leave such requests to other entities (eg, requiring employers to retain medical personnel with specialized skills in occupational evaluations) and make such recommendations to patients. Regardless, physicians should think carefully about their professional boundaries and scope regarding letter requests and adopt and implement a consistent standard for all patients.

Regarding the letter requested by Ms. M, you should consider whether the appeal is consistent with the patient’s psychiatric illness. You should also consider whether you have sufficient knowledge about the patient’s living environment to support their claim. Such a letter should be written only if you understand both considerations. Regardless of your decision, you should explain your rationale to the patient.

Bottom Line

Patients may ask their psychiatrists to write letters that address aspects of their social well-being. However, psychiatrists must be alert to requests that are outside their scope of practice or ethically or legally fraught. Carefully consider whether writing a letter is appropriate and if not, discuss with the patient the reasons you cannot write such a letter and any recommended alternative avenues to address their request.

Related Resources

• Riese A. Writing letters for transgender patients undergoing medical transition. Current Psychiatry. 2021;20(8):51-52. doi:10.12788/cp.0159
• Joshi KG. Service animals and emotional support animals: should you write that letter? Current Psychiatry. 2021;20(11):16-19,24. doi:10.12788/cp.0183

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

The medical knowledge that William Shakespeare possessed has awed scholars for centuries. Theories about the provenance of his knowledge abound (such as his son-in-law being a physician), and the inclusion of medical terms and ailments throughout his plays suggests a broad knowledge of disease and sickness. Scholars have noted how he sprinkles references to dermatologic, neurologic, orthopedic, and metabolic ailments throughout his plays, mentioning carbuncles, fistulas, corpulence, rhinophyma, scurvy, ague, enuresis, kyphosis, epilepsy, and parkinsonism.¹ What seems to strike post-Enlightenment audiences—and what sets Shakespeare apart from many of his contemporaries—is his portrayal of “complex” characters, those with what we envision as rich interior worlds and with whom a modern audience can resonate. There is a reason psychiatrists such as Sigmund Freud have rushed back to Shakespeare and (sometimes anachronistically) found in his characters various psychiatric diagnoses such as depression, anxiety, paranoia, jealous delusions, and obsessive-compulsive disorder. Suicide and suicidal ideation are prevalent themes in some of Shakespeare’s most well-known characters.

A surprisingly common theme

The gravest outcome of a psychiatric illness is death by suicide, which occurs in 13 of Shakespeare’s characters.² There are additional characters who exhibit suicidal ideation without a completed act. Shakespearean characters whose lives end in suicide are variably portrayed, dying by various means and circumstances. Hamlet (who dies at the hand of his foe, Laertes), famously soliloquizes the theme of suicide and the afterlife. He ponders “tak[ing] arms against a sea of troubles.” Ophelia dies ambiguously. Immediately after, her mother and brother recount her death in a brook—having had “too much of water” when her garments “heavy with their drink, | pull’d the poor wretch from her melodious lay | To muddy death.” The 2 clowns/gravediggers then debate whether Ophelia deserves a Christian burial and if her death should be considered a suicide: did the water drown her, or did she drown herself?³

Lady Macbeth’s suicide is offstage, punctuated by a “night-shriek.” Romeo drinks poison and dies “with a kiss.” Juliet quickly follows, making her body the sword’s sheath which “there rust, and let [her] die.” Othello stabs himself after requesting that his peers will “speak of me as I am.” One of King Lear’s daughters poisons her sister “and after [slays] herself.” Timon dies by his cave, “entomb’d upon the very hem o’ the sea.” In Antony and Cleopatra, after being told that Cleopatra has killed herself with Antony’s name on her lips, Antony begs to be stabbed and then stabs himself; he is not defeated by Caesar, but rather conquered by himself: “none but Antony | Should conquer Antony.” Cleopatra and her lady-in-waiting, Charmian, kill themselves with an asp. In Julius Caesar, Brutus runs upon his sword. Cassius begs for his own death, asking that “this good sword, | That ran through Caesar’s bowels, search this bosom.” Portia, it is reported, “swallowed fire.”

Shakespeare uses specific stylized language to portray characters in psychological anguish and suicidal states. Scholars have discussed how he uses certain stylistic language to highlight the anguish that happens during solitary, solipsistic moments of contemplation.⁴ Moments of anguish and suicidal ideation are marked by verbal repetition. An example of this repetition comes in Hamlet’s speech after he returns to the kingdom where his uncle has usurped his father, when he laments that he cannot end his own life. He says:

O, that this too too sullied flesh would melt,
Thaw, and resolve itself into a dew!
Or that the Everlasting had not fix’d
His canon ’gainst self-slaughter! O God, God,
How weary, stale, flat, and unprofitable
Seem to me all the uses of this world.

In these 6 lines, there are 2 instances of verbal repetition: “too too” and “God, God.” In this moment of solitude and despair, Hamlet’s speech fractures; his fractured speech reflects his fractured psyche. While Hamlet speaks of staleness and stagnation in the world, his words represent a sterile excess. No meaning is elicited by their repetition; there is no forward momentum to his speech. The words reflect the extent to which Hamlet is stuck and divided in this moment. Something similar happens in Macbeth’s “Tomorrow and tomorrow and tomorrow” speech. The words march on, and with each repetition they become increasingly hollow and brittle.

Why does this discussion of suicide in Shakespeare hold value for a contemporary psychiatrist? First, there is no single prototypical suicidal character in Shakespeare. His characters who are suicidal vary in their demographics and incentives for ending their lives. In this way, he provides a rich framework, one with which many people can engage. Second, this discussion fits into an existing paradigm for using art therapy (specifically Shakespeare) as a treatment modality for trauma.⁵ Programs such as DE-CRUIT have used the recitation of Shakespearean verse as a means of processing trauma in veterans.⁵ While Shakespeare does not mention a remedy for suicide in his plays, perhaps the text can serve as medicine. Third, the repetitive speech that Shakespeare uses in times of anguish could be a fairly accurate reflection of speech patterns in patients who are suicidal. Research that completed a spoken language analysis of patients who were suicidal has found “mechanical and repetitive phrasing” as a quality of these patients’ speech.^6,7

For hundreds of years, critics have searched beyond the text for Shakespeare’s voice and opinion; what did he himself think of melancholy, despair, or suicide? We cannot know. We, as readers, are invited to explore a nuanced and multifaceted view of suicide, one that neither chides nor valorizes the act, and provides ambiguity rather than condemnation.

The medical knowledge that William Shakespeare possessed has awed scholars for centuries. Theories about the provenance of his knowledge abound (such as his son-in-law being a physician), and the inclusion of medical terms and ailments throughout his plays suggests a broad knowledge of disease and sickness. Scholars have noted how he sprinkles references to dermatologic, neurologic, orthopedic, and metabolic ailments throughout his plays, mentioning carbuncles, fistulas, corpulence, rhinophyma, scurvy, ague, enuresis, kyphosis, epilepsy, and parkinsonism.¹ What seems to strike post-Enlightenment audiences—and what sets Shakespeare apart from many of his contemporaries—is his portrayal of “complex” characters, those with what we envision as rich interior worlds and with whom a modern audience can resonate. There is a reason psychiatrists such as Sigmund Freud have rushed back to Shakespeare and (sometimes anachronistically) found in his characters various psychiatric diagnoses such as depression, anxiety, paranoia, jealous delusions, and obsessive-compulsive disorder. Suicide and suicidal ideation are prevalent themes in some of Shakespeare’s most well-known characters.

A surprisingly common theme

The gravest outcome of a psychiatric illness is death by suicide, which occurs in 13 of Shakespeare’s characters.² There are additional characters who exhibit suicidal ideation without a completed act. Shakespearean characters whose lives end in suicide are variably portrayed, dying by various means and circumstances. Hamlet (who dies at the hand of his foe, Laertes), famously soliloquizes the theme of suicide and the afterlife. He ponders “tak[ing] arms against a sea of troubles.” Ophelia dies ambiguously. Immediately after, her mother and brother recount her death in a brook—having had “too much of water” when her garments “heavy with their drink, | pull’d the poor wretch from her melodious lay | To muddy death.” The 2 clowns/gravediggers then debate whether Ophelia deserves a Christian burial and if her death should be considered a suicide: did the water drown her, or did she drown herself?³

Lady Macbeth’s suicide is offstage, punctuated by a “night-shriek.” Romeo drinks poison and dies “with a kiss.” Juliet quickly follows, making her body the sword’s sheath which “there rust, and let [her] die.” Othello stabs himself after requesting that his peers will “speak of me as I am.” One of King Lear’s daughters poisons her sister “and after [slays] herself.” Timon dies by his cave, “entomb’d upon the very hem o’ the sea.” In Antony and Cleopatra, after being told that Cleopatra has killed herself with Antony’s name on her lips, Antony begs to be stabbed and then stabs himself; he is not defeated by Caesar, but rather conquered by himself: “none but Antony | Should conquer Antony.” Cleopatra and her lady-in-waiting, Charmian, kill themselves with an asp. In Julius Caesar, Brutus runs upon his sword. Cassius begs for his own death, asking that “this good sword, | That ran through Caesar’s bowels, search this bosom.” Portia, it is reported, “swallowed fire.”

Shakespeare uses specific stylized language to portray characters in psychological anguish and suicidal states. Scholars have discussed how he uses certain stylistic language to highlight the anguish that happens during solitary, solipsistic moments of contemplation.⁴ Moments of anguish and suicidal ideation are marked by verbal repetition. An example of this repetition comes in Hamlet’s speech after he returns to the kingdom where his uncle has usurped his father, when he laments that he cannot end his own life. He says:

O, that this too too sullied flesh would melt,
Thaw, and resolve itself into a dew!
Or that the Everlasting had not fix’d
His canon ’gainst self-slaughter! O God, God,
How weary, stale, flat, and unprofitable
Seem to me all the uses of this world.

In these 6 lines, there are 2 instances of verbal repetition: “too too” and “God, God.” In this moment of solitude and despair, Hamlet’s speech fractures; his fractured speech reflects his fractured psyche. While Hamlet speaks of staleness and stagnation in the world, his words represent a sterile excess. No meaning is elicited by their repetition; there is no forward momentum to his speech. The words reflect the extent to which Hamlet is stuck and divided in this moment. Something similar happens in Macbeth’s “Tomorrow and tomorrow and tomorrow” speech. The words march on, and with each repetition they become increasingly hollow and brittle.

Why does this discussion of suicide in Shakespeare hold value for a contemporary psychiatrist? First, there is no single prototypical suicidal character in Shakespeare. His characters who are suicidal vary in their demographics and incentives for ending their lives. In this way, he provides a rich framework, one with which many people can engage. Second, this discussion fits into an existing paradigm for using art therapy (specifically Shakespeare) as a treatment modality for trauma.⁵ Programs such as DE-CRUIT have used the recitation of Shakespearean verse as a means of processing trauma in veterans.⁵ While Shakespeare does not mention a remedy for suicide in his plays, perhaps the text can serve as medicine. Third, the repetitive speech that Shakespeare uses in times of anguish could be a fairly accurate reflection of speech patterns in patients who are suicidal. Research that completed a spoken language analysis of patients who were suicidal has found “mechanical and repetitive phrasing” as a quality of these patients’ speech.^6,7

For hundreds of years, critics have searched beyond the text for Shakespeare’s voice and opinion; what did he himself think of melancholy, despair, or suicide? We cannot know. We, as readers, are invited to explore a nuanced and multifaceted view of suicide, one that neither chides nor valorizes the act, and provides ambiguity rather than condemnation.

The medical knowledge that William Shakespeare possessed has awed scholars for centuries. Theories about the provenance of his knowledge abound (such as his son-in-law being a physician), and the inclusion of medical terms and ailments throughout his plays suggests a broad knowledge of disease and sickness. Scholars have noted how he sprinkles references to dermatologic, neurologic, orthopedic, and metabolic ailments throughout his plays, mentioning carbuncles, fistulas, corpulence, rhinophyma, scurvy, ague, enuresis, kyphosis, epilepsy, and parkinsonism.¹ What seems to strike post-Enlightenment audiences—and what sets Shakespeare apart from many of his contemporaries—is his portrayal of “complex” characters, those with what we envision as rich interior worlds and with whom a modern audience can resonate. There is a reason psychiatrists such as Sigmund Freud have rushed back to Shakespeare and (sometimes anachronistically) found in his characters various psychiatric diagnoses such as depression, anxiety, paranoia, jealous delusions, and obsessive-compulsive disorder. Suicide and suicidal ideation are prevalent themes in some of Shakespeare’s most well-known characters.

A surprisingly common theme

The gravest outcome of a psychiatric illness is death by suicide, which occurs in 13 of Shakespeare’s characters.² There are additional characters who exhibit suicidal ideation without a completed act. Shakespearean characters whose lives end in suicide are variably portrayed, dying by various means and circumstances. Hamlet (who dies at the hand of his foe, Laertes), famously soliloquizes the theme of suicide and the afterlife. He ponders “tak[ing] arms against a sea of troubles.” Ophelia dies ambiguously. Immediately after, her mother and brother recount her death in a brook—having had “too much of water” when her garments “heavy with their drink, | pull’d the poor wretch from her melodious lay | To muddy death.” The 2 clowns/gravediggers then debate whether Ophelia deserves a Christian burial and if her death should be considered a suicide: did the water drown her, or did she drown herself?³

Lady Macbeth’s suicide is offstage, punctuated by a “night-shriek.” Romeo drinks poison and dies “with a kiss.” Juliet quickly follows, making her body the sword’s sheath which “there rust, and let [her] die.” Othello stabs himself after requesting that his peers will “speak of me as I am.” One of King Lear’s daughters poisons her sister “and after [slays] herself.” Timon dies by his cave, “entomb’d upon the very hem o’ the sea.” In Antony and Cleopatra, after being told that Cleopatra has killed herself with Antony’s name on her lips, Antony begs to be stabbed and then stabs himself; he is not defeated by Caesar, but rather conquered by himself: “none but Antony | Should conquer Antony.” Cleopatra and her lady-in-waiting, Charmian, kill themselves with an asp. In Julius Caesar, Brutus runs upon his sword. Cassius begs for his own death, asking that “this good sword, | That ran through Caesar’s bowels, search this bosom.” Portia, it is reported, “swallowed fire.”

Shakespeare uses specific stylized language to portray characters in psychological anguish and suicidal states. Scholars have discussed how he uses certain stylistic language to highlight the anguish that happens during solitary, solipsistic moments of contemplation.⁴ Moments of anguish and suicidal ideation are marked by verbal repetition. An example of this repetition comes in Hamlet’s speech after he returns to the kingdom where his uncle has usurped his father, when he laments that he cannot end his own life. He says:

O, that this too too sullied flesh would melt,
Thaw, and resolve itself into a dew!
Or that the Everlasting had not fix’d
His canon ’gainst self-slaughter! O God, God,
How weary, stale, flat, and unprofitable
Seem to me all the uses of this world.

In these 6 lines, there are 2 instances of verbal repetition: “too too” and “God, God.” In this moment of solitude and despair, Hamlet’s speech fractures; his fractured speech reflects his fractured psyche. While Hamlet speaks of staleness and stagnation in the world, his words represent a sterile excess. No meaning is elicited by their repetition; there is no forward momentum to his speech. The words reflect the extent to which Hamlet is stuck and divided in this moment. Something similar happens in Macbeth’s “Tomorrow and tomorrow and tomorrow” speech. The words march on, and with each repetition they become increasingly hollow and brittle.

Why does this discussion of suicide in Shakespeare hold value for a contemporary psychiatrist? First, there is no single prototypical suicidal character in Shakespeare. His characters who are suicidal vary in their demographics and incentives for ending their lives. In this way, he provides a rich framework, one with which many people can engage. Second, this discussion fits into an existing paradigm for using art therapy (specifically Shakespeare) as a treatment modality for trauma.⁵ Programs such as DE-CRUIT have used the recitation of Shakespearean verse as a means of processing trauma in veterans.⁵ While Shakespeare does not mention a remedy for suicide in his plays, perhaps the text can serve as medicine. Third, the repetitive speech that Shakespeare uses in times of anguish could be a fairly accurate reflection of speech patterns in patients who are suicidal. Research that completed a spoken language analysis of patients who were suicidal has found “mechanical and repetitive phrasing” as a quality of these patients’ speech.^6,7

For hundreds of years, critics have searched beyond the text for Shakespeare’s voice and opinion; what did he himself think of melancholy, despair, or suicide? We cannot know. We, as readers, are invited to explore a nuanced and multifaceted view of suicide, one that neither chides nor valorizes the act, and provides ambiguity rather than condemnation.

All that’s bright must fade,
The brightest still the fleetest;
All that’s sweet was made
But to be lost when sweetest.
Thomas Moore

I sometimes hold it half a sin
To put in words the grief I feel;
For words, like Nature, half reveal
And half conceal the Soul within.
Alfred, Lord Tennyson, In Memoriam

Dear Readers,

I have sad news to share with you. This is the last issue of Current Psychiatry.

During my travels around the country over the past 2 decades, countless psychiatrists have told me that Current Psychiatry is their favorite journal and they greatly appreciate it due to the practical, useful, and pithy clinical updates it provides them as busy clinicians.

Current Psychiatry was born on January 1, 2002, and will be 21 years old at its premature demise on December 31, 2023 (This reminds me of the Billy Joel song “Only the Good Die Young”). The first Editor-in-Chief was Randolph Hillard, MD, who at the time was the psychiatry chair at the University of Cincinnati. I succeeded him as Editor-in-Chief in 2006 and will have served in that role for 17 years when Current Psychiatry is sunset. I have established 2 other research journals, Schizophrenia Research and Biomarkers in Neuropsychiatry, both of which are thriving. However, editing Current Psychiatry has been one of the most gratifying roles I have had in my career because Current Psychiatry promotes sound, evidence-based clinical practice to its 45,000 psychiatric clinician readers, who provide care for millions of psychiatric patients of all ages and DSM-5-TR diagnostic categories every day.

As the saying goes: All good things eventually come to an end. I am so grateful to have had the opportunity to collaborate with a wonderful, highly competent editorial staff, as well as with outstanding colleagues who served on the editorial board all those years. A special shout-out to Jeff Bauer, the publishing staff editor, with whom I worked so closely. I very much appreciated all the authors and peer reviewers who contributed timely clinical articles month after month and made Current Psychiatry such a valuable, evidence-based educational medium.

This has been a unique journey for all of us who strived to transform Current Psychiatry into a prominent, must-read clinical journal. This valedictory is both a fond farewell and a warm appreciation to you, our loyal readers. I hope that in the future we will reconnect and interact again in another meaningful way, advocating for the health and welfare of our psychiatric patients.

All that’s bright must fade,
The brightest still the fleetest;
All that’s sweet was made
But to be lost when sweetest.
Thomas Moore

I sometimes hold it half a sin
To put in words the grief I feel;
For words, like Nature, half reveal
And half conceal the Soul within.
Alfred, Lord Tennyson, In Memoriam

Dear Readers,

I have sad news to share with you. This is the last issue of Current Psychiatry.

During my travels around the country over the past 2 decades, countless psychiatrists have told me that Current Psychiatry is their favorite journal and they greatly appreciate it due to the practical, useful, and pithy clinical updates it provides them as busy clinicians.

Current Psychiatry was born on January 1, 2002, and will be 21 years old at its premature demise on December 31, 2023 (This reminds me of the Billy Joel song “Only the Good Die Young”). The first Editor-in-Chief was Randolph Hillard, MD, who at the time was the psychiatry chair at the University of Cincinnati. I succeeded him as Editor-in-Chief in 2006 and will have served in that role for 17 years when Current Psychiatry is sunset. I have established 2 other research journals, Schizophrenia Research and Biomarkers in Neuropsychiatry, both of which are thriving. However, editing Current Psychiatry has been one of the most gratifying roles I have had in my career because Current Psychiatry promotes sound, evidence-based clinical practice to its 45,000 psychiatric clinician readers, who provide care for millions of psychiatric patients of all ages and DSM-5-TR diagnostic categories every day.

As the saying goes: All good things eventually come to an end. I am so grateful to have had the opportunity to collaborate with a wonderful, highly competent editorial staff, as well as with outstanding colleagues who served on the editorial board all those years. A special shout-out to Jeff Bauer, the publishing staff editor, with whom I worked so closely. I very much appreciated all the authors and peer reviewers who contributed timely clinical articles month after month and made Current Psychiatry such a valuable, evidence-based educational medium.

This has been a unique journey for all of us who strived to transform Current Psychiatry into a prominent, must-read clinical journal. This valedictory is both a fond farewell and a warm appreciation to you, our loyal readers. I hope that in the future we will reconnect and interact again in another meaningful way, advocating for the health and welfare of our psychiatric patients.

All that’s bright must fade,
The brightest still the fleetest;
All that’s sweet was made
But to be lost when sweetest.
Thomas Moore

I sometimes hold it half a sin
To put in words the grief I feel;
For words, like Nature, half reveal
And half conceal the Soul within.
Alfred, Lord Tennyson, In Memoriam

Dear Readers,

I have sad news to share with you. This is the last issue of Current Psychiatry.

During my travels around the country over the past 2 decades, countless psychiatrists have told me that Current Psychiatry is their favorite journal and they greatly appreciate it due to the practical, useful, and pithy clinical updates it provides them as busy clinicians.

Current Psychiatry was born on January 1, 2002, and will be 21 years old at its premature demise on December 31, 2023 (This reminds me of the Billy Joel song “Only the Good Die Young”). The first Editor-in-Chief was Randolph Hillard, MD, who at the time was the psychiatry chair at the University of Cincinnati. I succeeded him as Editor-in-Chief in 2006 and will have served in that role for 17 years when Current Psychiatry is sunset. I have established 2 other research journals, Schizophrenia Research and Biomarkers in Neuropsychiatry, both of which are thriving. However, editing Current Psychiatry has been one of the most gratifying roles I have had in my career because Current Psychiatry promotes sound, evidence-based clinical practice to its 45,000 psychiatric clinician readers, who provide care for millions of psychiatric patients of all ages and DSM-5-TR diagnostic categories every day.

As the saying goes: All good things eventually come to an end. I am so grateful to have had the opportunity to collaborate with a wonderful, highly competent editorial staff, as well as with outstanding colleagues who served on the editorial board all those years. A special shout-out to Jeff Bauer, the publishing staff editor, with whom I worked so closely. I very much appreciated all the authors and peer reviewers who contributed timely clinical articles month after month and made Current Psychiatry such a valuable, evidence-based educational medium.

This has been a unique journey for all of us who strived to transform Current Psychiatry into a prominent, must-read clinical journal. This valedictory is both a fond farewell and a warm appreciation to you, our loyal readers. I hope that in the future we will reconnect and interact again in another meaningful way, advocating for the health and welfare of our psychiatric patients.

In “Treating chronic insomnia: An alternating medication strategy” (Current Psychiatry, October 2023, p. 25-31, doi:10.12788/cp.0397), Dr. Kaplan correctly identified tolerance and tachyphylaxis as significant problems when prescribing traditional hypnotics, and proposed a solution of using 2 sleep medications, each having a different mechanism of action, on an alternating schedule. However, with the availability of the dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, this approach is unnecessary. Moreover, the mechanism of action of orexin receptor antagonism directly addresses extant hyperarousal by decreasing wake signaling, without any deleterious effect on sleep architecture.¹ Additionally, the DORAs are not associated with physiological dependence, withdrawal, or rebound. Their efficacy profile is as good as or better than other FDA-approved agents for insomnia disorder.¹ An obstacle to their use is that they are not yet available as generic products, but access is facilitated by the manufacturers’ patient assistance programs. Additional resources elaborate on indirect comparisons among agents using number needed to treat and number needed to harm, metrics that are helpful when clinically appraising new agents.^2-5

Leslie Citrome, MD, MPH
Valhalla, New York

In “Treating chronic insomnia: An alternating medication strategy” (Current Psychiatry, October 2023, p. 25-31, doi:10.12788/cp.0397), Dr. Kaplan correctly identified tolerance and tachyphylaxis as significant problems when prescribing traditional hypnotics, and proposed a solution of using 2 sleep medications, each having a different mechanism of action, on an alternating schedule. However, with the availability of the dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, this approach is unnecessary. Moreover, the mechanism of action of orexin receptor antagonism directly addresses extant hyperarousal by decreasing wake signaling, without any deleterious effect on sleep architecture.¹ Additionally, the DORAs are not associated with physiological dependence, withdrawal, or rebound. Their efficacy profile is as good as or better than other FDA-approved agents for insomnia disorder.¹ An obstacle to their use is that they are not yet available as generic products, but access is facilitated by the manufacturers’ patient assistance programs. Additional resources elaborate on indirect comparisons among agents using number needed to treat and number needed to harm, metrics that are helpful when clinically appraising new agents.^2-5

Leslie Citrome, MD, MPH
Valhalla, New York

In “Treating chronic insomnia: An alternating medication strategy” (Current Psychiatry, October 2023, p. 25-31, doi:10.12788/cp.0397), Dr. Kaplan correctly identified tolerance and tachyphylaxis as significant problems when prescribing traditional hypnotics, and proposed a solution of using 2 sleep medications, each having a different mechanism of action, on an alternating schedule. However, with the availability of the dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, this approach is unnecessary. Moreover, the mechanism of action of orexin receptor antagonism directly addresses extant hyperarousal by decreasing wake signaling, without any deleterious effect on sleep architecture.¹ Additionally, the DORAs are not associated with physiological dependence, withdrawal, or rebound. Their efficacy profile is as good as or better than other FDA-approved agents for insomnia disorder.¹ An obstacle to their use is that they are not yet available as generic products, but access is facilitated by the manufacturers’ patient assistance programs. Additional resources elaborate on indirect comparisons among agents using number needed to treat and number needed to harm, metrics that are helpful when clinically appraising new agents.^2-5

Leslie Citrome, MD, MPH
Valhalla, New York

Ms. B, age 45, has a history of major depressive disorder (MDD) and migraines. She is admitted after presenting with anhedonia, hopelessness, and hypersomnia. These symptoms have become more severe over the last few weeks. Ms. B describes a past suicide attempt via overdose on doxylamine for which she required treatment in the intensive care unit. The only activity she enjoys is her weekly girls’ night, during which she drinks a few glasses of wine. Ms. B’s current medications are dextromethorphan/bupropion 45/105 mg twice daily and aripiprazole 5 mg/d, which she has taken for 3 months. She states she has “been on every antidepressant there is.”

When clinicians review Ms. B’s medication history, it is clear she has had adequate trials of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), intranasal esketamine, multiple augmentation strategies, and electroconvulsive therapy (ECT). Ms. B seeks an alternative medication to improve her depressive symptoms.

Treatment-resistant depression (TRD) is commonly defined as depression that has not responded to ≥2 adequate trials of an antidepressant.¹ Some guidelines recommend monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) as second- or even third-line options for MDD,² while others recommend reserving them for patients with insufficient responses to alternative treatment modalities.^3,4 Although MAOIs and TCAs have been available since the 1950s, prescribing these medications has become less prevalent due to safety concerns, the availability of other pharmacologic options, and a lack of clinical training and comfort.^5,6 Most research notes that MAOIs are superior for treating atypical depression while TCAs are more effective for melancholic depression.^2-4 In a review of 20 studies, Thase et al⁷ found that 50% of TCA nonresponders benefited from an MAOI. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, monotherapy with the MAOI tranylcypromine was associated with a lower remission rate than the TCA nortriptyline; many argue the dose of tranylcypromine was suboptimal, and few participants completed an adequate trial in the last level.^8,9 A more recent study by Kim et al¹⁰ found MAOIs to be “generally more effective” than TCAs for TRD, particularly in patients with fewer antidepressant trials; however, this was a small retrospective exploratory trial. A network meta-analysis found both classes to be “competitive” with SSRIs based on efficacy and tolerability, which leads to the question of whether these medications should be considered earlier in therapy.¹¹ Considering patient-specific factors and particular medication properties is an effective strategy when prescribing an MAOI or TCA.

Monoamine oxidase inhibitors

Four MAOIs are FDA-approved for treating MDD (Table 1^5,12-17): phenelzine, isocarboxazid, tranylcypromine, and selegiline. These medications irreversibly inhibit MAO, which exists as isomers A and B. MAO-A primarily metabolizes serotonin and norepinephrine, which is largely responsible for these medications’ antidepressant effects. Both isomers equally metabolize dopamine.^5,12,18 It is best to avoid using MAOIs in patients with cerebrovascular disease, hepatic disease, or pheochromocytoma. Patients with active substance use disorders (particularly sympathomimetics and hallucinogens) are at an increased risk for hypertensive crises and serotonin syndrome, respectively. The most common adverse effects are orthostatic hypotension (despite more well-known concerns regarding hypertension), alterations in sleep patterns (insomnia or hypersomnia, depending on the agent), gastrointestinal issues, and anticholinergic adverse effects such as dry mouth and constipation.^13,19-21

In one review and meta-analysis, phenelzine displayed the highest efficacy across all MAOIs.¹¹ It likely requires high doses to achieve adequate MAO inhibition.¹¹ A metabolite of phenelzine inhibits gamma-aminobutyric acid transaminase and may be helpful for patients with comorbid anxiety disorders or MDD with anxious distress.^18,21 Additional considerations include phenelzine’s propensity for orthostasis (with rapid titrations and higher doses), sedation, weight gain, sexual dysfunction, and a rare adverse effect of vitamin B6 deficiency.^{5,13,14,20-22}

Use of isocarboxazid in clinical practice is rare. Its adverse effects are similar to those of phenelzine but isocarboxazid is less studied. Tranylcypromine has a similar chemical structure to amphetamine. It can be stimulating at higher doses, potentially benefitting patients with comorbid attention-deficit/hyperactivity disorder (ADHD) or significant apathy.^13,23 Selegiline’s distinct quality is its availability as a transdermal patch, which may be useful for patients who struggle to take oral medications. At low doses (6 mg/24 h), the selegiline transdermal patch allows patients to disregard a dietary tyramine restriction because it avoids first-pass metabolism. It inhibits both MAO isomers in the brain but is only selective for MAO-B once concentrations are distributed to the liver. Higher doses require a tyramine-restricted diet because there is still some MAO-A inhibition in the gut. Selegiline is also stimulating because it is converted to amphetamine and methamphetamine.^{5,12,13,17,19,24}

Despite promising results from the use of MAOIs, physicians and patients may be reluctant to use these medications due to perceived limitations. One prominent barrier is the infamous “cheese reaction.” Tyramine, an amino acid found in certain food and beverages (Table 2^{5,13-18,25-28}), is broken down by MAO-A in the gut. When this enzyme is inhibited, higher concentrations of tyramine reach systemic circulation. Tyramine’s release of norepinephrine (which now cannot be broken down) can lead to a hypertensive crisis. Consequently, a tyramine-restricted diet is recommended for patients taking an MAOI. However, the common notion that cheese, wine, and beer must be avoided is false, because most of the dietary restrictions developed following the discovery of MAOIs are antiquated.^5,12,25-28 Patients who take an MAOI only need to slightly adjust their diet, as outlined in Table 2.^{5,13-18,25-28} A reasonable serving size of most foods and beverages containing tyramine is unlikely to elicit this “pressor” response. Of the 4 MAOIs FDA-approved for MDD, tranylcypromine appears to be the most sensitive to tyramine.²¹ Transient postdose hypertension (regardless of tyramine) may occur after taking an MAOI.²⁹ Encourage patients to monitor their blood pressure.

Continue to: Additional hurdles include...

Additional hurdles include the required washout period from serotonergic medications and interactions with sympathomimetics. MAOIs pose the highest risk of serotonin syndrome; however, this usually occurs if given concomitantly with other serotonergic agents. The standard recommendation is a 14-day washout period from SSRIs (5 weeks for fluoxetine and 3 weeks for vortioxetine), SNRIs, mirtazapine, and other antidepressants. It can be distressing for patients to be without medication during that period. Because some antidepressants have much shorter half-lives, waiting 5 half-lives (typically 5 to 7 days) for the discontinued medication to be excreted is feasible if patients are closely monitored.^{5,12,13,25,27,30} There are rare instances where a TCA may be combined with an MAOI (typically initiated within 1 to 2 days of each other), but never clomipramine or imipramine due to their potent serotonin reuptake inhibition.³¹ If switching to an alternative MAOI, waiting 7 to 14 days is recommended to allow adequate time for the inhibited enzyme to regenerate.^14-17,32 Taking medications that increase dopamine and norepinephrine (eg, stimulants or oral over-the-counter decongestants) with an MAOI is typically not recommended due to the risk of hypertensive crisis.^25,27 In severe TRD or comorbid ADHD, successful simultaneous use of methylphenidate or amphetamine—typically at low doses—with close blood pressure monitoring has been reported.³³ There have also been positive cases of the use of modafinil in combination with an MAOI; however, this should be done with caution.^34,35 Clinicians must use clinical judgment when considering a combination of medications that pose a higher risk.

Tricyclic antidepressants

TCAs work differently than MAOIs to increase monoamines. They inhibit presynaptic serotonin and norepinephrine transporters in the CNS to increase levels of these chemicals in the synaptic cleft. While all TCAs inhibit these transporters, they do so at varying levels (Table 3^36-51). Based on their chemical structure, TCAs can be categorized into secondary and tertiary amines. Tertiary amines are metabolized via demethylation into their derivatives (Table 3^36-51). Patients who have recently suffered a myocardial infarction (MI) should avoid tertiary amines. TCAs can reduce heart rate variability, which is already decreased after an MI, thus presenting the potential for cardiac arrhythmias. TCAs should also be avoided in patients with cardiac conduction abnormalities.^38-46,52 Patients with a prior baseline cardiac conduction defect, such as a bundle branch block, are at higher risk for further cardiac abnormalities. In those with a preexisting first-degree heart block, TCAs can still be used, but electrocardiogram monitoring is recommended.^52,53 TCAs have also been reported to decrease the seizure threshold.^38-46 They can be used with caution in patients who have a history of epilepsy or head trauma, or with concomitant medications that lower the seizure threshold.^38-46

Overdose risk is a concern with TCAs because ingestion of 10 to 20 mg/kg can lead to significant toxicity.⁵⁴ This is due to their blockage of voltage-gated sodium channels found in the CNS and heart, which contributes to overdose symptoms such as a widened QRS complex and seizures. Symptoms usually develop within 2 hours but may be delayed up to 6 hours.⁵⁵ Patients with a history of overdose must be carefully assessed before initiating a TCA. Prescribing a limited supply of these medications may be valuable. The use of TCAs has often been limited due to their adverse effects, most of which are associated with their respective affinities for alpha 1, muscarinic 1, and histamine 1 receptors. Inhibition of the alpha 1 receptor is associated with hypotension, muscarinic 1 with anticholinergic adverse effects, and histamine 1 with sedation and weight gain. Tertiary amines have a higher affinity for these receptors compared to secondary amines, leading to a more significant adverse effect profile.^36,50 Among TCAs, amitriptyline is the most likely to cause hypotension, whereas desipramine and nortriptyline are least likely. Amitriptyline and clomipramine are most likely to cause anticholinergic adverse effects, whereas desipramine and nortriptyline are the least likely. Amitriptyline, doxepin, and imipramine have the highest propensity for QTc prolongation.³⁶

Beyond treating MDD, TCAs have shown benefits for treating other disease states (Table 4^{38-46,49,56-61}).These differing indications may help psychiatrists determine the best TCA to prescribe for a given patient. Amitriptyline is the most studied TCA for MDD; however, nortriptyline is typically preferred due to its favorable tolerability profile.^4,62 Nortriptyline also has data supporting its use in ECT to prevent relapse.⁶³ Amitriptyline and nortriptyline have shown benefits in patients with neuro­pathic pain and for migraine prophylaxis.^56-60 Although frequently used for MDD, clomipramine is not FDA-approved for this indication, but is for obsessive-compulsive disorder.³⁹ Doxepin is FDA-approved for insomnia at lower doses and for MDD at higher doses.⁴⁰ Therefore, it may benefit patients with sleep difficulties secondary to depression. Desipramine has been used off-label to treat ADHD in children and has shown some benefits in adults.^64-66 Protriptyline, trimipramine, and amoxapine are infrequently used in clinical practice.

A unique feature of TCAs is the ability to monitor serum concentrations (Table 3^36-51).Guidelines recommend therapeutic drug monitoring (TDM) with amitriptyline, clomi­pramine, imipramine, and nortriptyline for routine use. TDM is still recommended for doxepin, desipramine, and trimipramine, but its utility is largely for treatment failure or resistance.³⁷ These plasma levels can be altered based on coadministered medications (Table 5^38-46) and should be closely monitored. Physicians should obtain a trough level after at least 5 half-lives and before the next dose is due, and use TDM as indicated to optimize dosing.

Continue to: CASE CONTINUED

CASE CONTINUED

Ms. B’s outpatient psychiatrist provides collateral information about her medical history and confirms her long-standing MDD with multiple medication trials, though she has never received an MAOI or TCA. Ms. B is adamant she does not want a medication-free period between treatments and refuses to adjust her diet, despite being educated on the few changes necessary. She has no contraindications for TCAs and may benefit from a TCA for her comorbid migraines. The care team expresses concern for TCA overdose to Ms. B and her family. Ms. B’s sister reassures the team they will have someone monitor and dispense her medications at home. They decide to discontinue her current psychiatric regimen, and Ms. B is started on nortriptyline 50 mg/d at night, with plans to titrate based on tolerability.

Related Resources

• Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
• Espejo GD. Treating major depressive disorder after limited response to an initial agent. Current Psychiatry. 2021;20(10):51-53. doi:10.12788/cp.0178
• American Association of Psychiatric Pharmacists (AAPP) MAOI Pharmacist Toolkit. https://aapp.org/guideline/maoi

Drug Brand Names

Amitriptyline • Elavil
Amphetamine • Adzenys, Dyanavel
Aripiprazole • Abilify
Clomipramine • Anafranil
Desipramine • Norpramin
Dextromethorphan/bupropion • Auvelity
Doxepin • Sinequan, Adapin
Esketamine • Spravato
Fluoxetine • Prozac
Imipramine • Tofranil
Isocarboxazid • Marplan
Methamphetamine • Desoxyn
Mirtazapine • Remeron
Modafinil • Provigil
Nortriptyline • Pamelor
Phenelzine • Nardil
Protriptyline • Vivactil
Selegiline • Emsam
Tranylcypromine • Parnate
Trimipramine • Surmontil
Vortioxetine • Trintellix

Ms. B, age 45, has a history of major depressive disorder (MDD) and migraines. She is admitted after presenting with anhedonia, hopelessness, and hypersomnia. These symptoms have become more severe over the last few weeks. Ms. B describes a past suicide attempt via overdose on doxylamine for which she required treatment in the intensive care unit. The only activity she enjoys is her weekly girls’ night, during which she drinks a few glasses of wine. Ms. B’s current medications are dextromethorphan/bupropion 45/105 mg twice daily and aripiprazole 5 mg/d, which she has taken for 3 months. She states she has “been on every antidepressant there is.”

When clinicians review Ms. B’s medication history, it is clear she has had adequate trials of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), intranasal esketamine, multiple augmentation strategies, and electroconvulsive therapy (ECT). Ms. B seeks an alternative medication to improve her depressive symptoms.

Treatment-resistant depression (TRD) is commonly defined as depression that has not responded to ≥2 adequate trials of an antidepressant.¹ Some guidelines recommend monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) as second- or even third-line options for MDD,² while others recommend reserving them for patients with insufficient responses to alternative treatment modalities.^3,4 Although MAOIs and TCAs have been available since the 1950s, prescribing these medications has become less prevalent due to safety concerns, the availability of other pharmacologic options, and a lack of clinical training and comfort.^5,6 Most research notes that MAOIs are superior for treating atypical depression while TCAs are more effective for melancholic depression.^2-4 In a review of 20 studies, Thase et al⁷ found that 50% of TCA nonresponders benefited from an MAOI. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, monotherapy with the MAOI tranylcypromine was associated with a lower remission rate than the TCA nortriptyline; many argue the dose of tranylcypromine was suboptimal, and few participants completed an adequate trial in the last level.^8,9 A more recent study by Kim et al¹⁰ found MAOIs to be “generally more effective” than TCAs for TRD, particularly in patients with fewer antidepressant trials; however, this was a small retrospective exploratory trial. A network meta-analysis found both classes to be “competitive” with SSRIs based on efficacy and tolerability, which leads to the question of whether these medications should be considered earlier in therapy.¹¹ Considering patient-specific factors and particular medication properties is an effective strategy when prescribing an MAOI or TCA.

Monoamine oxidase inhibitors

Four MAOIs are FDA-approved for treating MDD (Table 1^5,12-17): phenelzine, isocarboxazid, tranylcypromine, and selegiline. These medications irreversibly inhibit MAO, which exists as isomers A and B. MAO-A primarily metabolizes serotonin and norepinephrine, which is largely responsible for these medications’ antidepressant effects. Both isomers equally metabolize dopamine.^5,12,18 It is best to avoid using MAOIs in patients with cerebrovascular disease, hepatic disease, or pheochromocytoma. Patients with active substance use disorders (particularly sympathomimetics and hallucinogens) are at an increased risk for hypertensive crises and serotonin syndrome, respectively. The most common adverse effects are orthostatic hypotension (despite more well-known concerns regarding hypertension), alterations in sleep patterns (insomnia or hypersomnia, depending on the agent), gastrointestinal issues, and anticholinergic adverse effects such as dry mouth and constipation.^13,19-21

In one review and meta-analysis, phenelzine displayed the highest efficacy across all MAOIs.¹¹ It likely requires high doses to achieve adequate MAO inhibition.¹¹ A metabolite of phenelzine inhibits gamma-aminobutyric acid transaminase and may be helpful for patients with comorbid anxiety disorders or MDD with anxious distress.^18,21 Additional considerations include phenelzine’s propensity for orthostasis (with rapid titrations and higher doses), sedation, weight gain, sexual dysfunction, and a rare adverse effect of vitamin B6 deficiency.^{5,13,14,20-22}

Use of isocarboxazid in clinical practice is rare. Its adverse effects are similar to those of phenelzine but isocarboxazid is less studied. Tranylcypromine has a similar chemical structure to amphetamine. It can be stimulating at higher doses, potentially benefitting patients with comorbid attention-deficit/hyperactivity disorder (ADHD) or significant apathy.^13,23 Selegiline’s distinct quality is its availability as a transdermal patch, which may be useful for patients who struggle to take oral medications. At low doses (6 mg/24 h), the selegiline transdermal patch allows patients to disregard a dietary tyramine restriction because it avoids first-pass metabolism. It inhibits both MAO isomers in the brain but is only selective for MAO-B once concentrations are distributed to the liver. Higher doses require a tyramine-restricted diet because there is still some MAO-A inhibition in the gut. Selegiline is also stimulating because it is converted to amphetamine and methamphetamine.^{5,12,13,17,19,24}

Despite promising results from the use of MAOIs, physicians and patients may be reluctant to use these medications due to perceived limitations. One prominent barrier is the infamous “cheese reaction.” Tyramine, an amino acid found in certain food and beverages (Table 2^{5,13-18,25-28}), is broken down by MAO-A in the gut. When this enzyme is inhibited, higher concentrations of tyramine reach systemic circulation. Tyramine’s release of norepinephrine (which now cannot be broken down) can lead to a hypertensive crisis. Consequently, a tyramine-restricted diet is recommended for patients taking an MAOI. However, the common notion that cheese, wine, and beer must be avoided is false, because most of the dietary restrictions developed following the discovery of MAOIs are antiquated.^5,12,25-28 Patients who take an MAOI only need to slightly adjust their diet, as outlined in Table 2.^{5,13-18,25-28} A reasonable serving size of most foods and beverages containing tyramine is unlikely to elicit this “pressor” response. Of the 4 MAOIs FDA-approved for MDD, tranylcypromine appears to be the most sensitive to tyramine.²¹ Transient postdose hypertension (regardless of tyramine) may occur after taking an MAOI.²⁹ Encourage patients to monitor their blood pressure.

Continue to: Additional hurdles include...

Additional hurdles include the required washout period from serotonergic medications and interactions with sympathomimetics. MAOIs pose the highest risk of serotonin syndrome; however, this usually occurs if given concomitantly with other serotonergic agents. The standard recommendation is a 14-day washout period from SSRIs (5 weeks for fluoxetine and 3 weeks for vortioxetine), SNRIs, mirtazapine, and other antidepressants. It can be distressing for patients to be without medication during that period. Because some antidepressants have much shorter half-lives, waiting 5 half-lives (typically 5 to 7 days) for the discontinued medication to be excreted is feasible if patients are closely monitored.^{5,12,13,25,27,30} There are rare instances where a TCA may be combined with an MAOI (typically initiated within 1 to 2 days of each other), but never clomipramine or imipramine due to their potent serotonin reuptake inhibition.³¹ If switching to an alternative MAOI, waiting 7 to 14 days is recommended to allow adequate time for the inhibited enzyme to regenerate.^14-17,32 Taking medications that increase dopamine and norepinephrine (eg, stimulants or oral over-the-counter decongestants) with an MAOI is typically not recommended due to the risk of hypertensive crisis.^25,27 In severe TRD or comorbid ADHD, successful simultaneous use of methylphenidate or amphetamine—typically at low doses—with close blood pressure monitoring has been reported.³³ There have also been positive cases of the use of modafinil in combination with an MAOI; however, this should be done with caution.^34,35 Clinicians must use clinical judgment when considering a combination of medications that pose a higher risk.

Tricyclic antidepressants

TCAs work differently than MAOIs to increase monoamines. They inhibit presynaptic serotonin and norepinephrine transporters in the CNS to increase levels of these chemicals in the synaptic cleft. While all TCAs inhibit these transporters, they do so at varying levels (Table 3^36-51). Based on their chemical structure, TCAs can be categorized into secondary and tertiary amines. Tertiary amines are metabolized via demethylation into their derivatives (Table 3^36-51). Patients who have recently suffered a myocardial infarction (MI) should avoid tertiary amines. TCAs can reduce heart rate variability, which is already decreased after an MI, thus presenting the potential for cardiac arrhythmias. TCAs should also be avoided in patients with cardiac conduction abnormalities.^38-46,52 Patients with a prior baseline cardiac conduction defect, such as a bundle branch block, are at higher risk for further cardiac abnormalities. In those with a preexisting first-degree heart block, TCAs can still be used, but electrocardiogram monitoring is recommended.^52,53 TCAs have also been reported to decrease the seizure threshold.^38-46 They can be used with caution in patients who have a history of epilepsy or head trauma, or with concomitant medications that lower the seizure threshold.^38-46

Overdose risk is a concern with TCAs because ingestion of 10 to 20 mg/kg can lead to significant toxicity.⁵⁴ This is due to their blockage of voltage-gated sodium channels found in the CNS and heart, which contributes to overdose symptoms such as a widened QRS complex and seizures. Symptoms usually develop within 2 hours but may be delayed up to 6 hours.⁵⁵ Patients with a history of overdose must be carefully assessed before initiating a TCA. Prescribing a limited supply of these medications may be valuable. The use of TCAs has often been limited due to their adverse effects, most of which are associated with their respective affinities for alpha 1, muscarinic 1, and histamine 1 receptors. Inhibition of the alpha 1 receptor is associated with hypotension, muscarinic 1 with anticholinergic adverse effects, and histamine 1 with sedation and weight gain. Tertiary amines have a higher affinity for these receptors compared to secondary amines, leading to a more significant adverse effect profile.^36,50 Among TCAs, amitriptyline is the most likely to cause hypotension, whereas desipramine and nortriptyline are least likely. Amitriptyline and clomipramine are most likely to cause anticholinergic adverse effects, whereas desipramine and nortriptyline are the least likely. Amitriptyline, doxepin, and imipramine have the highest propensity for QTc prolongation.³⁶

Beyond treating MDD, TCAs have shown benefits for treating other disease states (Table 4^{38-46,49,56-61}).These differing indications may help psychiatrists determine the best TCA to prescribe for a given patient. Amitriptyline is the most studied TCA for MDD; however, nortriptyline is typically preferred due to its favorable tolerability profile.^4,62 Nortriptyline also has data supporting its use in ECT to prevent relapse.⁶³ Amitriptyline and nortriptyline have shown benefits in patients with neuro­pathic pain and for migraine prophylaxis.^56-60 Although frequently used for MDD, clomipramine is not FDA-approved for this indication, but is for obsessive-compulsive disorder.³⁹ Doxepin is FDA-approved for insomnia at lower doses and for MDD at higher doses.⁴⁰ Therefore, it may benefit patients with sleep difficulties secondary to depression. Desipramine has been used off-label to treat ADHD in children and has shown some benefits in adults.^64-66 Protriptyline, trimipramine, and amoxapine are infrequently used in clinical practice.

A unique feature of TCAs is the ability to monitor serum concentrations (Table 3^36-51).Guidelines recommend therapeutic drug monitoring (TDM) with amitriptyline, clomi­pramine, imipramine, and nortriptyline for routine use. TDM is still recommended for doxepin, desipramine, and trimipramine, but its utility is largely for treatment failure or resistance.³⁷ These plasma levels can be altered based on coadministered medications (Table 5^38-46) and should be closely monitored. Physicians should obtain a trough level after at least 5 half-lives and before the next dose is due, and use TDM as indicated to optimize dosing.

Continue to: CASE CONTINUED

CASE CONTINUED

Ms. B’s outpatient psychiatrist provides collateral information about her medical history and confirms her long-standing MDD with multiple medication trials, though she has never received an MAOI or TCA. Ms. B is adamant she does not want a medication-free period between treatments and refuses to adjust her diet, despite being educated on the few changes necessary. She has no contraindications for TCAs and may benefit from a TCA for her comorbid migraines. The care team expresses concern for TCA overdose to Ms. B and her family. Ms. B’s sister reassures the team they will have someone monitor and dispense her medications at home. They decide to discontinue her current psychiatric regimen, and Ms. B is started on nortriptyline 50 mg/d at night, with plans to titrate based on tolerability.

Related Resources

• Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
• Espejo GD. Treating major depressive disorder after limited response to an initial agent. Current Psychiatry. 2021;20(10):51-53. doi:10.12788/cp.0178
• American Association of Psychiatric Pharmacists (AAPP) MAOI Pharmacist Toolkit. https://aapp.org/guideline/maoi

Drug Brand Names

Amitriptyline • Elavil
Amphetamine • Adzenys, Dyanavel
Aripiprazole • Abilify
Clomipramine • Anafranil
Desipramine • Norpramin
Dextromethorphan/bupropion • Auvelity
Doxepin • Sinequan, Adapin
Esketamine • Spravato
Fluoxetine • Prozac
Imipramine • Tofranil
Isocarboxazid • Marplan
Methamphetamine • Desoxyn
Mirtazapine • Remeron
Modafinil • Provigil
Nortriptyline • Pamelor
Phenelzine • Nardil
Protriptyline • Vivactil
Selegiline • Emsam
Tranylcypromine • Parnate
Trimipramine • Surmontil
Vortioxetine • Trintellix

Ms. B, age 45, has a history of major depressive disorder (MDD) and migraines. She is admitted after presenting with anhedonia, hopelessness, and hypersomnia. These symptoms have become more severe over the last few weeks. Ms. B describes a past suicide attempt via overdose on doxylamine for which she required treatment in the intensive care unit. The only activity she enjoys is her weekly girls’ night, during which she drinks a few glasses of wine. Ms. B’s current medications are dextromethorphan/bupropion 45/105 mg twice daily and aripiprazole 5 mg/d, which she has taken for 3 months. She states she has “been on every antidepressant there is.”

When clinicians review Ms. B’s medication history, it is clear she has had adequate trials of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), intranasal esketamine, multiple augmentation strategies, and electroconvulsive therapy (ECT). Ms. B seeks an alternative medication to improve her depressive symptoms.

Treatment-resistant depression (TRD) is commonly defined as depression that has not responded to ≥2 adequate trials of an antidepressant.¹ Some guidelines recommend monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) as second- or even third-line options for MDD,² while others recommend reserving them for patients with insufficient responses to alternative treatment modalities.^3,4 Although MAOIs and TCAs have been available since the 1950s, prescribing these medications has become less prevalent due to safety concerns, the availability of other pharmacologic options, and a lack of clinical training and comfort.^5,6 Most research notes that MAOIs are superior for treating atypical depression while TCAs are more effective for melancholic depression.^2-4 In a review of 20 studies, Thase et al⁷ found that 50% of TCA nonresponders benefited from an MAOI. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, monotherapy with the MAOI tranylcypromine was associated with a lower remission rate than the TCA nortriptyline; many argue the dose of tranylcypromine was suboptimal, and few participants completed an adequate trial in the last level.^8,9 A more recent study by Kim et al¹⁰ found MAOIs to be “generally more effective” than TCAs for TRD, particularly in patients with fewer antidepressant trials; however, this was a small retrospective exploratory trial. A network meta-analysis found both classes to be “competitive” with SSRIs based on efficacy and tolerability, which leads to the question of whether these medications should be considered earlier in therapy.¹¹ Considering patient-specific factors and particular medication properties is an effective strategy when prescribing an MAOI or TCA.

Monoamine oxidase inhibitors

Four MAOIs are FDA-approved for treating MDD (Table 1^5,12-17): phenelzine, isocarboxazid, tranylcypromine, and selegiline. These medications irreversibly inhibit MAO, which exists as isomers A and B. MAO-A primarily metabolizes serotonin and norepinephrine, which is largely responsible for these medications’ antidepressant effects. Both isomers equally metabolize dopamine.^5,12,18 It is best to avoid using MAOIs in patients with cerebrovascular disease, hepatic disease, or pheochromocytoma. Patients with active substance use disorders (particularly sympathomimetics and hallucinogens) are at an increased risk for hypertensive crises and serotonin syndrome, respectively. The most common adverse effects are orthostatic hypotension (despite more well-known concerns regarding hypertension), alterations in sleep patterns (insomnia or hypersomnia, depending on the agent), gastrointestinal issues, and anticholinergic adverse effects such as dry mouth and constipation.^13,19-21

In one review and meta-analysis, phenelzine displayed the highest efficacy across all MAOIs.¹¹ It likely requires high doses to achieve adequate MAO inhibition.¹¹ A metabolite of phenelzine inhibits gamma-aminobutyric acid transaminase and may be helpful for patients with comorbid anxiety disorders or MDD with anxious distress.^18,21 Additional considerations include phenelzine’s propensity for orthostasis (with rapid titrations and higher doses), sedation, weight gain, sexual dysfunction, and a rare adverse effect of vitamin B6 deficiency.^{5,13,14,20-22}

Use of isocarboxazid in clinical practice is rare. Its adverse effects are similar to those of phenelzine but isocarboxazid is less studied. Tranylcypromine has a similar chemical structure to amphetamine. It can be stimulating at higher doses, potentially benefitting patients with comorbid attention-deficit/hyperactivity disorder (ADHD) or significant apathy.^13,23 Selegiline’s distinct quality is its availability as a transdermal patch, which may be useful for patients who struggle to take oral medications. At low doses (6 mg/24 h), the selegiline transdermal patch allows patients to disregard a dietary tyramine restriction because it avoids first-pass metabolism. It inhibits both MAO isomers in the brain but is only selective for MAO-B once concentrations are distributed to the liver. Higher doses require a tyramine-restricted diet because there is still some MAO-A inhibition in the gut. Selegiline is also stimulating because it is converted to amphetamine and methamphetamine.^{5,12,13,17,19,24}

Despite promising results from the use of MAOIs, physicians and patients may be reluctant to use these medications due to perceived limitations. One prominent barrier is the infamous “cheese reaction.” Tyramine, an amino acid found in certain food and beverages (Table 2^{5,13-18,25-28}), is broken down by MAO-A in the gut. When this enzyme is inhibited, higher concentrations of tyramine reach systemic circulation. Tyramine’s release of norepinephrine (which now cannot be broken down) can lead to a hypertensive crisis. Consequently, a tyramine-restricted diet is recommended for patients taking an MAOI. However, the common notion that cheese, wine, and beer must be avoided is false, because most of the dietary restrictions developed following the discovery of MAOIs are antiquated.^5,12,25-28 Patients who take an MAOI only need to slightly adjust their diet, as outlined in Table 2.^{5,13-18,25-28} A reasonable serving size of most foods and beverages containing tyramine is unlikely to elicit this “pressor” response. Of the 4 MAOIs FDA-approved for MDD, tranylcypromine appears to be the most sensitive to tyramine.²¹ Transient postdose hypertension (regardless of tyramine) may occur after taking an MAOI.²⁹ Encourage patients to monitor their blood pressure.

Continue to: Additional hurdles include...

Additional hurdles include the required washout period from serotonergic medications and interactions with sympathomimetics. MAOIs pose the highest risk of serotonin syndrome; however, this usually occurs if given concomitantly with other serotonergic agents. The standard recommendation is a 14-day washout period from SSRIs (5 weeks for fluoxetine and 3 weeks for vortioxetine), SNRIs, mirtazapine, and other antidepressants. It can be distressing for patients to be without medication during that period. Because some antidepressants have much shorter half-lives, waiting 5 half-lives (typically 5 to 7 days) for the discontinued medication to be excreted is feasible if patients are closely monitored.^{5,12,13,25,27,30} There are rare instances where a TCA may be combined with an MAOI (typically initiated within 1 to 2 days of each other), but never clomipramine or imipramine due to their potent serotonin reuptake inhibition.³¹ If switching to an alternative MAOI, waiting 7 to 14 days is recommended to allow adequate time for the inhibited enzyme to regenerate.^14-17,32 Taking medications that increase dopamine and norepinephrine (eg, stimulants or oral over-the-counter decongestants) with an MAOI is typically not recommended due to the risk of hypertensive crisis.^25,27 In severe TRD or comorbid ADHD, successful simultaneous use of methylphenidate or amphetamine—typically at low doses—with close blood pressure monitoring has been reported.³³ There have also been positive cases of the use of modafinil in combination with an MAOI; however, this should be done with caution.^34,35 Clinicians must use clinical judgment when considering a combination of medications that pose a higher risk.

Tricyclic antidepressants

TCAs work differently than MAOIs to increase monoamines. They inhibit presynaptic serotonin and norepinephrine transporters in the CNS to increase levels of these chemicals in the synaptic cleft. While all TCAs inhibit these transporters, they do so at varying levels (Table 3^36-51). Based on their chemical structure, TCAs can be categorized into secondary and tertiary amines. Tertiary amines are metabolized via demethylation into their derivatives (Table 3^36-51). Patients who have recently suffered a myocardial infarction (MI) should avoid tertiary amines. TCAs can reduce heart rate variability, which is already decreased after an MI, thus presenting the potential for cardiac arrhythmias. TCAs should also be avoided in patients with cardiac conduction abnormalities.^38-46,52 Patients with a prior baseline cardiac conduction defect, such as a bundle branch block, are at higher risk for further cardiac abnormalities. In those with a preexisting first-degree heart block, TCAs can still be used, but electrocardiogram monitoring is recommended.^52,53 TCAs have also been reported to decrease the seizure threshold.^38-46 They can be used with caution in patients who have a history of epilepsy or head trauma, or with concomitant medications that lower the seizure threshold.^38-46

Overdose risk is a concern with TCAs because ingestion of 10 to 20 mg/kg can lead to significant toxicity.⁵⁴ This is due to their blockage of voltage-gated sodium channels found in the CNS and heart, which contributes to overdose symptoms such as a widened QRS complex and seizures. Symptoms usually develop within 2 hours but may be delayed up to 6 hours.⁵⁵ Patients with a history of overdose must be carefully assessed before initiating a TCA. Prescribing a limited supply of these medications may be valuable. The use of TCAs has often been limited due to their adverse effects, most of which are associated with their respective affinities for alpha 1, muscarinic 1, and histamine 1 receptors. Inhibition of the alpha 1 receptor is associated with hypotension, muscarinic 1 with anticholinergic adverse effects, and histamine 1 with sedation and weight gain. Tertiary amines have a higher affinity for these receptors compared to secondary amines, leading to a more significant adverse effect profile.^36,50 Among TCAs, amitriptyline is the most likely to cause hypotension, whereas desipramine and nortriptyline are least likely. Amitriptyline and clomipramine are most likely to cause anticholinergic adverse effects, whereas desipramine and nortriptyline are the least likely. Amitriptyline, doxepin, and imipramine have the highest propensity for QTc prolongation.³⁶

Beyond treating MDD, TCAs have shown benefits for treating other disease states (Table 4^{38-46,49,56-61}).These differing indications may help psychiatrists determine the best TCA to prescribe for a given patient. Amitriptyline is the most studied TCA for MDD; however, nortriptyline is typically preferred due to its favorable tolerability profile.^4,62 Nortriptyline also has data supporting its use in ECT to prevent relapse.⁶³ Amitriptyline and nortriptyline have shown benefits in patients with neuro­pathic pain and for migraine prophylaxis.^56-60 Although frequently used for MDD, clomipramine is not FDA-approved for this indication, but is for obsessive-compulsive disorder.³⁹ Doxepin is FDA-approved for insomnia at lower doses and for MDD at higher doses.⁴⁰ Therefore, it may benefit patients with sleep difficulties secondary to depression. Desipramine has been used off-label to treat ADHD in children and has shown some benefits in adults.^64-66 Protriptyline, trimipramine, and amoxapine are infrequently used in clinical practice.

A unique feature of TCAs is the ability to monitor serum concentrations (Table 3^36-51).Guidelines recommend therapeutic drug monitoring (TDM) with amitriptyline, clomi­pramine, imipramine, and nortriptyline for routine use. TDM is still recommended for doxepin, desipramine, and trimipramine, but its utility is largely for treatment failure or resistance.³⁷ These plasma levels can be altered based on coadministered medications (Table 5^38-46) and should be closely monitored. Physicians should obtain a trough level after at least 5 half-lives and before the next dose is due, and use TDM as indicated to optimize dosing.

Continue to: CASE CONTINUED

CASE CONTINUED

Ms. B’s outpatient psychiatrist provides collateral information about her medical history and confirms her long-standing MDD with multiple medication trials, though she has never received an MAOI or TCA. Ms. B is adamant she does not want a medication-free period between treatments and refuses to adjust her diet, despite being educated on the few changes necessary. She has no contraindications for TCAs and may benefit from a TCA for her comorbid migraines. The care team expresses concern for TCA overdose to Ms. B and her family. Ms. B’s sister reassures the team they will have someone monitor and dispense her medications at home. They decide to discontinue her current psychiatric regimen, and Ms. B is started on nortriptyline 50 mg/d at night, with plans to titrate based on tolerability.

Related Resources

• Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
• Espejo GD. Treating major depressive disorder after limited response to an initial agent. Current Psychiatry. 2021;20(10):51-53. doi:10.12788/cp.0178
• American Association of Psychiatric Pharmacists (AAPP) MAOI Pharmacist Toolkit. https://aapp.org/guideline/maoi

Drug Brand Names

Amitriptyline • Elavil
Amphetamine • Adzenys, Dyanavel
Aripiprazole • Abilify
Clomipramine • Anafranil
Desipramine • Norpramin
Dextromethorphan/bupropion • Auvelity
Doxepin • Sinequan, Adapin
Esketamine • Spravato
Fluoxetine • Prozac
Imipramine • Tofranil
Isocarboxazid • Marplan
Methamphetamine • Desoxyn
Mirtazapine • Remeron
Modafinil • Provigil
Nortriptyline • Pamelor
Phenelzine • Nardil
Protriptyline • Vivactil
Selegiline • Emsam
Tranylcypromine • Parnate
Trimipramine • Surmontil
Vortioxetine • Trintellix

CASE Thoughts of harming baby

Ms. A, age 37, is G4P2, 4 months postpartum, and breastfeeding. She has major depressive disorder (MDD) with peripartum onset, posttraumatic stress disorder, and mild intellectual disability. For years she has been stable on fluoxetine 40 mg/d and prazosin 2 mg/d. Despite recent titration of her medications, at her most recent outpatient appointment Ms. A reports having a depressed mood with frequent crying, insomnia, a lack of desire to bond with her baby, and feelings of shame. She also says she has had auditory hallucinations and thoughts of harming her baby. Ms. A’s outpatient physician makes an urgent request for her to be evaluated at the psychiatric emergency department (ED).

HISTORY Depression and possible auditory hallucinations

Ms. A developed MDD following the birth of her first child, for which her care team initiated fluoxetine at 20 mg/d and titrated it to 40 mg/d,which was effective. At that time, her outpatient physician documented potential psychotic features, including vague descriptions of derogatory auditory hallucinations. However, it was unclear if these auditory hallucinations were more representative of a distressing inner monologue without the quality of an external voice. The team determined that Ms. A was not at acute risk for harm to herself or her baby and was appropriate for outpatient care. Because the nature of these possible auditory hallucinations was mild, nondistressing, and nonthreatening, the treatment team did not initiate an antipsychotic and Ms. A was not hospitalized. She has no history of hypomanic/manic episodes and has never met criteria for a psychotic disorder.

EVALUATION Distressing thoughts and discontinued medications

During the evaluation by psychiatric emergency services, Ms. A reports that 2 weeks after giving birth she experienced a worsening of her depressive symptoms. She says she began hearing voices telling her to harm herself and her baby and describes frequent distressing thoughts, such as stabbing her baby with a knife and running over her baby with a car. Ms. A says she repeatedly wakes up at night to check on her baby’s breathing, overfeeds her baby due to a fear of inadequate nutrition, and notes intermittent feelings of confusion. Afraid of being alone with her infant, Ms. A asks her partner and mother to move in with her. Additionally, she says 2 weeks ago she discontinued all her medications at the suggestion of her partner, who recommended herbal supplements. Ms. A’s initial routine laboratory results are unremarkable and her urine drug screen is negative for all substances.

[polldaddy:13041928]

The authors’ observations

Approximately 85% of birthing parents experience some form of postpartum mood disturbance; 10% to 15% develop more significant symptoms of anxiety or depression.³ The etiology of postpartum illness is multifactorial, and includes psychiatric personal/family history, insomnia, acute and chronic psychosocial stressors, and rapid hormone fluctuations.¹ As a result, the postpartum period represents a vulnerable time for birthing parents, particularly those with previously established psychiatric illness.

Ms. A’s initial presentation was concerning for a possible diagnosis of postpartum psychosis vs obsessive-compulsive disorder (OCD) with postpartum onset; other differential diagnoses included MDD with peripartum onset and psychotic features (Table^1-6). Ms. A’s subjective clinical history was significant for critical pertinent findings of both OCD with postpartum onset (ie, egodystonic intrusive thoughts, checking behaviors, feelings of shame, and seeking reassurance) and postpartum psychosis (ie, command auditory hallucinations and waxing/waning confusion), which added to diagnostic complexity.

Although postpartum psychosis is rare (1 to 2 cases per 1,000 women),⁵ it is considered a psychiatric emergency because it has significant potential for infanticide, morbidity, and mortality. Most symptoms develop within the first 2 weeks of the postpartum period.² There are many risk factors for the development of postpartum psychosis; however, in first-time pregnancies, a previous diagnosis of BD I is the single most important risk factor.¹ Approximately 20% to 30% of women with BD experience postpartum psychosis.⁴

For many patients (approximately 56.7%, according to 1 meta-analysis⁷), postpartum psychosis denotes an episode of BD, representing a more severe form of illness with increased risk of recurrence. Most manic or mixed mood episodes reoccur within the first year removed from the perinatal period. In contrast, for some patients (approximately 43.5% according to the same meta-analysis), the episode denotes “isolated postpartum psychosis.”⁷ Isolated postpartum psychosis is a psychotic episode that occurs only in the postpartum period with no recurrence of psychosis or recurrence of psychosis exclusive to postpartum periods. If treated, this type of postpartum psychosis has a more favorable prognosis than postpartum psychosis in a patient with BD.⁷ As such, a BD diagnosis should not be established at the onset of a patient’s first postpartum psychosis presentation. Regardless of type, all presentations of postpartum psychosis are considered a psychiatry emergency.

Continue to: The prevalence of OCD...

The prevalence of OCD with postpartum onset varies. One study estimated it occurs in 2.43% of cases.⁴ However, the true prevalence is likely underreported due to feelings of guilt or shame associated with intrusive thoughts, and fear of stigmatization and separation from the baby. Approximately 70.6% of women experiencing OCD with postpartum onset have a comorbid depressive disorder.⁴

Ms. A’s presentation to the psychiatric ED carried with it diagnostic complexity and uncertainty. Her initial presentation was concerning for elements of both postpartum psychosis and OCD with postpartum onset. After her evaluation in the psychiatric ED, there remained a lack of clear and convincing evidence for a diagnosis of OCD with postpartum onset, which eliminated the possibility of discharging Ms. A with robust safety planning and reinitiation of a selective serotonin reuptake inhibitor.

Additionally, because auditory hallucinations are atypical in OCD, the treatment team remained concerned for a diagnosis of postpartum psychosis, which would warrant hospitalization. With assistance from the institution’s reproductive psychiatrists, the treatment team discussed the importance of inpatient hospitalization for risk mitigation, close observation, and thorough evaluation for greater diagnostic clarity and certainty.

TREATMENT Involuntary hospitalization

The treatment team counsels Ms. A and her partner on her differential diagnoses, including the elevated acute risk of harm to herself and her baby if she has postpartum psychosis, as well as the need for continued observation and evaluation. When alone with a clinician, Ms. A says she understands and agrees to voluntary hospitalization. However, following a subsequent risk-benefit discussion with her partner, they both grew increasingly concerned about her separation from the baby and reinitiating her medications. Amid these concerns, the treatment team notices that Ms. A attempts to minimize her symptoms. Ms. A changes her mind and no longer consents to hospitalization. She is placed on a psychiatric hold for involuntary hospitalization on the psychiatric inpatient unit.

On the inpatient unit, the inpatient clinicians and a reproductive psychiatrist continue to evaluate Ms. A. Though her diagnosis remains unclear, Ms. A agrees to start a trial of quetiapine 100 mg/d titrated to 150 mg/d to manage her potential postpartum psychosis, depressed mood, insomnia (off-label), anxiety (off-label), and OCD (off-label). Lithium is deferred because Ms. A is breastfeeding.

[polldaddy:13041932]

Continue to: The authors' observations

Due to an elevated acute risk of suicide and infanticide, postpartum psychosis represents a psychiatric emergency and often requires hospitalization. The Figure outlines steps in evaluating a patient with concerns for postpartum psychosis in a psychiatric emergency service setting. Due to the waxing and waning nature of symptoms, patients may appear psychiatrically stable at any time but remain at an overall elevated acute risk of harm to self and/or their baby.

If a patient is being considered for discharge based on yes answers to all questions in Step 2 of the Figure, the emergency psychiatric clinician must initiate appropriate psychotropic medications and complete robust safety planning with the patient and a trusted adult who will provide direct supervision. Safety planning may include (but is not limited to) strict return precautions, education on concerning symptoms and behaviors, psychotropic education and agreement of compliance, and detailed instructions on outpatient follow-up within 1 week. Ideally—and as was the case for Ms. A—a reproductive psychiatrist should be consulted in the emergency setting for shared decision-making on admission vs discharge, medication management, and outpatient follow-up considerations.

Because postpartum psychosis carries significant risks and hospitalization generally results in separating the patient from their baby, initiating psychotropics should not be delayed. Clinicians must consider the patient’s psychiatric history, allergies, and breastfeeding status.

Based on current evidence, first-line treatment for postpartum psychosis includes a mood stabilizer, an antipsychotic, and possibly a benzodiazepine.⁶ Thus, an appropriate initial treatment regimen would be a benzodiazepine (particularly lorazepam due to its relatively shorter half-life) and an antipsychotic (eg, haloperidol, olanzapine, or quetiapine) for acute psychosis, plus lithium for mood stabilization.^1,5

If the postpartum psychosis represents an episode of BD, use of a long-term mood stabilizer may be required. In contrast, for isolated postpartum psychosis, clinicians may consider initiating psychotropics only in the immediate postpartum period, with an eventual slow taper. In future pregnancies, psychotropics may be reintroduced postpartum, which will avoid peripartum fetal exposure.⁸ If the patient is breastfeeding, lithium may be deferred in an acute care setting. For patients with evidence of catatonia, severe suicidality, refusal of oral intake with compromised nutrition, severe agitation, or treatment resistance, electro­convulsive therapy remains a safe and effective treatment option.⁶ Additionally, the safety of continued breastfeeding in acute psychosis must be considered, with the potential for recommending discontinuation, which would decrease sleep disruptions at night and increase the ability of others to feed the baby. Comprehensive care requires nonpharmacologic interventions, including psychoeducation for the patient and their family, individual psychotherapy, and expansion of psychosocial supports.

Continue to: Patients who have experienced...

Patients who have experienced an episode of postpartum psychosis are predisposed to another episode in future pregnancies.¹ Current research recommends prophylaxis of recurrence with lithium monotherapy.^1,2,5,6 Similar to other psychotropics in reproductive psychiatry, maintenance therapy on lithium requires a thorough “risk vs risk” discussion with the patient. The risk of lithium use while pregnant and/or breastfeeding must be weighed against the risks associated with postpartum psychosis (ie, infanticide, suicide, poor peripartum care, or poor infant bonding).

OUTCOME Improved mood

After 7 days of inpatient treatment with quetiapine, Ms. A demonstrates improvement in the targeted depressive symptoms (including improved motivation/energy and insomnia, decreased feelings of guilt, and denial of ongoing suicidal ideation). Additionally, the thoughts of harming her baby are less frequent, and command auditory hallucinations resolve. Upon discharge, Ms. A and her partner meet with inpatient clinicians for continued counseling, safety planning, and plans for outpatient follow-up with the institution’s reproductive psychiatrist.

The authors’ observations

Many aspects of Ms. A’s initial presentation in the psychiatric ED were challenging. Given the presence of symptoms of both psychosis and OCD, a diagnosis was difficult to ascertain in the emergency setting. Since command auditory hallucinations are atypical in patients with postpartum OCD, the treatment team maintained high suspicion for postpartum psychosis, which represented an emergency requiring inpatient care.

Hospitalization separated Ms. A from her baby, for whom she was the primary caregiver. Additional considerations for inpatient admission and psychotropic initiation were necessary, because Ms. A was breastfeeding. Although Ms. A’s partner was able to provide full-time childcare, the patient ultimately did not agree to hospitalization and required an emergency hold for involuntary admission, which was an additional barrier to care. Furthermore, her partner held unfavorable beliefs regarding psychotropic medications and Ms. A’s need for hospital admission, which required ongoing patient and partner education in the emergency, inpatient, and outpatient settings. Moreover, if Ms. A’s symptoms were ultimately attributable to postpartum OCD, the patient’s involuntary hospitalization might have increased the risk of stigmatization of mental illness and treatment with psychotropics.

Bottom Line

The peripartum period is a vulnerable time for patients, particularly those with previously diagnosed psychiatric illnesses. Postpartum psychosis is the most severe form of postpartum psychiatric illness and often represents an episode of bipolar disorder. Due to an elevated acute risk of suicide and infanticide, postpartum psychosis is a psychiatric emergency and warrants inpatient hospitalization for immediate intervention.

Related Resources

• Sharma V. Does your patient have postpartum OCD? Current Psychiatry. 2019;18(5):9-10.
• Hatters Friedman S, Prakash C, Nagel-Yang S. Postpartum psychosis: protecting mother and infant. Current Psychiatry. 2019;18(4):12-21.

Drug Brand Names

Fluoxetine • Prozac
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Olanzapine • Zyprexa
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft
Valproic acid • Depakene

CASE Thoughts of harming baby

Ms. A, age 37, is G4P2, 4 months postpartum, and breastfeeding. She has major depressive disorder (MDD) with peripartum onset, posttraumatic stress disorder, and mild intellectual disability. For years she has been stable on fluoxetine 40 mg/d and prazosin 2 mg/d. Despite recent titration of her medications, at her most recent outpatient appointment Ms. A reports having a depressed mood with frequent crying, insomnia, a lack of desire to bond with her baby, and feelings of shame. She also says she has had auditory hallucinations and thoughts of harming her baby. Ms. A’s outpatient physician makes an urgent request for her to be evaluated at the psychiatric emergency department (ED).

HISTORY Depression and possible auditory hallucinations

Ms. A developed MDD following the birth of her first child, for which her care team initiated fluoxetine at 20 mg/d and titrated it to 40 mg/d,which was effective. At that time, her outpatient physician documented potential psychotic features, including vague descriptions of derogatory auditory hallucinations. However, it was unclear if these auditory hallucinations were more representative of a distressing inner monologue without the quality of an external voice. The team determined that Ms. A was not at acute risk for harm to herself or her baby and was appropriate for outpatient care. Because the nature of these possible auditory hallucinations was mild, nondistressing, and nonthreatening, the treatment team did not initiate an antipsychotic and Ms. A was not hospitalized. She has no history of hypomanic/manic episodes and has never met criteria for a psychotic disorder.

EVALUATION Distressing thoughts and discontinued medications

During the evaluation by psychiatric emergency services, Ms. A reports that 2 weeks after giving birth she experienced a worsening of her depressive symptoms. She says she began hearing voices telling her to harm herself and her baby and describes frequent distressing thoughts, such as stabbing her baby with a knife and running over her baby with a car. Ms. A says she repeatedly wakes up at night to check on her baby’s breathing, overfeeds her baby due to a fear of inadequate nutrition, and notes intermittent feelings of confusion. Afraid of being alone with her infant, Ms. A asks her partner and mother to move in with her. Additionally, she says 2 weeks ago she discontinued all her medications at the suggestion of her partner, who recommended herbal supplements. Ms. A’s initial routine laboratory results are unremarkable and her urine drug screen is negative for all substances.

[polldaddy:13041928]

The authors’ observations

Approximately 85% of birthing parents experience some form of postpartum mood disturbance; 10% to 15% develop more significant symptoms of anxiety or depression.³ The etiology of postpartum illness is multifactorial, and includes psychiatric personal/family history, insomnia, acute and chronic psychosocial stressors, and rapid hormone fluctuations.¹ As a result, the postpartum period represents a vulnerable time for birthing parents, particularly those with previously established psychiatric illness.

Ms. A’s initial presentation was concerning for a possible diagnosis of postpartum psychosis vs obsessive-compulsive disorder (OCD) with postpartum onset; other differential diagnoses included MDD with peripartum onset and psychotic features (Table^1-6). Ms. A’s subjective clinical history was significant for critical pertinent findings of both OCD with postpartum onset (ie, egodystonic intrusive thoughts, checking behaviors, feelings of shame, and seeking reassurance) and postpartum psychosis (ie, command auditory hallucinations and waxing/waning confusion), which added to diagnostic complexity.

Although postpartum psychosis is rare (1 to 2 cases per 1,000 women),⁵ it is considered a psychiatric emergency because it has significant potential for infanticide, morbidity, and mortality. Most symptoms develop within the first 2 weeks of the postpartum period.² There are many risk factors for the development of postpartum psychosis; however, in first-time pregnancies, a previous diagnosis of BD I is the single most important risk factor.¹ Approximately 20% to 30% of women with BD experience postpartum psychosis.⁴

For many patients (approximately 56.7%, according to 1 meta-analysis⁷), postpartum psychosis denotes an episode of BD, representing a more severe form of illness with increased risk of recurrence. Most manic or mixed mood episodes reoccur within the first year removed from the perinatal period. In contrast, for some patients (approximately 43.5% according to the same meta-analysis), the episode denotes “isolated postpartum psychosis.”⁷ Isolated postpartum psychosis is a psychotic episode that occurs only in the postpartum period with no recurrence of psychosis or recurrence of psychosis exclusive to postpartum periods. If treated, this type of postpartum psychosis has a more favorable prognosis than postpartum psychosis in a patient with BD.⁷ As such, a BD diagnosis should not be established at the onset of a patient’s first postpartum psychosis presentation. Regardless of type, all presentations of postpartum psychosis are considered a psychiatry emergency.

Continue to: The prevalence of OCD...

The prevalence of OCD with postpartum onset varies. One study estimated it occurs in 2.43% of cases.⁴ However, the true prevalence is likely underreported due to feelings of guilt or shame associated with intrusive thoughts, and fear of stigmatization and separation from the baby. Approximately 70.6% of women experiencing OCD with postpartum onset have a comorbid depressive disorder.⁴

Ms. A’s presentation to the psychiatric ED carried with it diagnostic complexity and uncertainty. Her initial presentation was concerning for elements of both postpartum psychosis and OCD with postpartum onset. After her evaluation in the psychiatric ED, there remained a lack of clear and convincing evidence for a diagnosis of OCD with postpartum onset, which eliminated the possibility of discharging Ms. A with robust safety planning and reinitiation of a selective serotonin reuptake inhibitor.

Additionally, because auditory hallucinations are atypical in OCD, the treatment team remained concerned for a diagnosis of postpartum psychosis, which would warrant hospitalization. With assistance from the institution’s reproductive psychiatrists, the treatment team discussed the importance of inpatient hospitalization for risk mitigation, close observation, and thorough evaluation for greater diagnostic clarity and certainty.

TREATMENT Involuntary hospitalization

The treatment team counsels Ms. A and her partner on her differential diagnoses, including the elevated acute risk of harm to herself and her baby if she has postpartum psychosis, as well as the need for continued observation and evaluation. When alone with a clinician, Ms. A says she understands and agrees to voluntary hospitalization. However, following a subsequent risk-benefit discussion with her partner, they both grew increasingly concerned about her separation from the baby and reinitiating her medications. Amid these concerns, the treatment team notices that Ms. A attempts to minimize her symptoms. Ms. A changes her mind and no longer consents to hospitalization. She is placed on a psychiatric hold for involuntary hospitalization on the psychiatric inpatient unit.

On the inpatient unit, the inpatient clinicians and a reproductive psychiatrist continue to evaluate Ms. A. Though her diagnosis remains unclear, Ms. A agrees to start a trial of quetiapine 100 mg/d titrated to 150 mg/d to manage her potential postpartum psychosis, depressed mood, insomnia (off-label), anxiety (off-label), and OCD (off-label). Lithium is deferred because Ms. A is breastfeeding.

[polldaddy:13041932]

Continue to: The authors' observations

Due to an elevated acute risk of suicide and infanticide, postpartum psychosis represents a psychiatric emergency and often requires hospitalization. The Figure outlines steps in evaluating a patient with concerns for postpartum psychosis in a psychiatric emergency service setting. Due to the waxing and waning nature of symptoms, patients may appear psychiatrically stable at any time but remain at an overall elevated acute risk of harm to self and/or their baby.

If a patient is being considered for discharge based on yes answers to all questions in Step 2 of the Figure, the emergency psychiatric clinician must initiate appropriate psychotropic medications and complete robust safety planning with the patient and a trusted adult who will provide direct supervision. Safety planning may include (but is not limited to) strict return precautions, education on concerning symptoms and behaviors, psychotropic education and agreement of compliance, and detailed instructions on outpatient follow-up within 1 week. Ideally—and as was the case for Ms. A—a reproductive psychiatrist should be consulted in the emergency setting for shared decision-making on admission vs discharge, medication management, and outpatient follow-up considerations.

Because postpartum psychosis carries significant risks and hospitalization generally results in separating the patient from their baby, initiating psychotropics should not be delayed. Clinicians must consider the patient’s psychiatric history, allergies, and breastfeeding status.

Based on current evidence, first-line treatment for postpartum psychosis includes a mood stabilizer, an antipsychotic, and possibly a benzodiazepine.⁶ Thus, an appropriate initial treatment regimen would be a benzodiazepine (particularly lorazepam due to its relatively shorter half-life) and an antipsychotic (eg, haloperidol, olanzapine, or quetiapine) for acute psychosis, plus lithium for mood stabilization.^1,5

If the postpartum psychosis represents an episode of BD, use of a long-term mood stabilizer may be required. In contrast, for isolated postpartum psychosis, clinicians may consider initiating psychotropics only in the immediate postpartum period, with an eventual slow taper. In future pregnancies, psychotropics may be reintroduced postpartum, which will avoid peripartum fetal exposure.⁸ If the patient is breastfeeding, lithium may be deferred in an acute care setting. For patients with evidence of catatonia, severe suicidality, refusal of oral intake with compromised nutrition, severe agitation, or treatment resistance, electro­convulsive therapy remains a safe and effective treatment option.⁶ Additionally, the safety of continued breastfeeding in acute psychosis must be considered, with the potential for recommending discontinuation, which would decrease sleep disruptions at night and increase the ability of others to feed the baby. Comprehensive care requires nonpharmacologic interventions, including psychoeducation for the patient and their family, individual psychotherapy, and expansion of psychosocial supports.

Continue to: Patients who have experienced...

Patients who have experienced an episode of postpartum psychosis are predisposed to another episode in future pregnancies.¹ Current research recommends prophylaxis of recurrence with lithium monotherapy.^1,2,5,6 Similar to other psychotropics in reproductive psychiatry, maintenance therapy on lithium requires a thorough “risk vs risk” discussion with the patient. The risk of lithium use while pregnant and/or breastfeeding must be weighed against the risks associated with postpartum psychosis (ie, infanticide, suicide, poor peripartum care, or poor infant bonding).

OUTCOME Improved mood

After 7 days of inpatient treatment with quetiapine, Ms. A demonstrates improvement in the targeted depressive symptoms (including improved motivation/energy and insomnia, decreased feelings of guilt, and denial of ongoing suicidal ideation). Additionally, the thoughts of harming her baby are less frequent, and command auditory hallucinations resolve. Upon discharge, Ms. A and her partner meet with inpatient clinicians for continued counseling, safety planning, and plans for outpatient follow-up with the institution’s reproductive psychiatrist.

The authors’ observations

Many aspects of Ms. A’s initial presentation in the psychiatric ED were challenging. Given the presence of symptoms of both psychosis and OCD, a diagnosis was difficult to ascertain in the emergency setting. Since command auditory hallucinations are atypical in patients with postpartum OCD, the treatment team maintained high suspicion for postpartum psychosis, which represented an emergency requiring inpatient care.

Hospitalization separated Ms. A from her baby, for whom she was the primary caregiver. Additional considerations for inpatient admission and psychotropic initiation were necessary, because Ms. A was breastfeeding. Although Ms. A’s partner was able to provide full-time childcare, the patient ultimately did not agree to hospitalization and required an emergency hold for involuntary admission, which was an additional barrier to care. Furthermore, her partner held unfavorable beliefs regarding psychotropic medications and Ms. A’s need for hospital admission, which required ongoing patient and partner education in the emergency, inpatient, and outpatient settings. Moreover, if Ms. A’s symptoms were ultimately attributable to postpartum OCD, the patient’s involuntary hospitalization might have increased the risk of stigmatization of mental illness and treatment with psychotropics.

Bottom Line

The peripartum period is a vulnerable time for patients, particularly those with previously diagnosed psychiatric illnesses. Postpartum psychosis is the most severe form of postpartum psychiatric illness and often represents an episode of bipolar disorder. Due to an elevated acute risk of suicide and infanticide, postpartum psychosis is a psychiatric emergency and warrants inpatient hospitalization for immediate intervention.

Related Resources

• Sharma V. Does your patient have postpartum OCD? Current Psychiatry. 2019;18(5):9-10.
• Hatters Friedman S, Prakash C, Nagel-Yang S. Postpartum psychosis: protecting mother and infant. Current Psychiatry. 2019;18(4):12-21.

Drug Brand Names

Fluoxetine • Prozac
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Olanzapine • Zyprexa
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft
Valproic acid • Depakene

CASE Thoughts of harming baby

Ms. A, age 37, is G4P2, 4 months postpartum, and breastfeeding. She has major depressive disorder (MDD) with peripartum onset, posttraumatic stress disorder, and mild intellectual disability. For years she has been stable on fluoxetine 40 mg/d and prazosin 2 mg/d. Despite recent titration of her medications, at her most recent outpatient appointment Ms. A reports having a depressed mood with frequent crying, insomnia, a lack of desire to bond with her baby, and feelings of shame. She also says she has had auditory hallucinations and thoughts of harming her baby. Ms. A’s outpatient physician makes an urgent request for her to be evaluated at the psychiatric emergency department (ED).

HISTORY Depression and possible auditory hallucinations

Ms. A developed MDD following the birth of her first child, for which her care team initiated fluoxetine at 20 mg/d and titrated it to 40 mg/d,which was effective. At that time, her outpatient physician documented potential psychotic features, including vague descriptions of derogatory auditory hallucinations. However, it was unclear if these auditory hallucinations were more representative of a distressing inner monologue without the quality of an external voice. The team determined that Ms. A was not at acute risk for harm to herself or her baby and was appropriate for outpatient care. Because the nature of these possible auditory hallucinations was mild, nondistressing, and nonthreatening, the treatment team did not initiate an antipsychotic and Ms. A was not hospitalized. She has no history of hypomanic/manic episodes and has never met criteria for a psychotic disorder.

EVALUATION Distressing thoughts and discontinued medications

During the evaluation by psychiatric emergency services, Ms. A reports that 2 weeks after giving birth she experienced a worsening of her depressive symptoms. She says she began hearing voices telling her to harm herself and her baby and describes frequent distressing thoughts, such as stabbing her baby with a knife and running over her baby with a car. Ms. A says she repeatedly wakes up at night to check on her baby’s breathing, overfeeds her baby due to a fear of inadequate nutrition, and notes intermittent feelings of confusion. Afraid of being alone with her infant, Ms. A asks her partner and mother to move in with her. Additionally, she says 2 weeks ago she discontinued all her medications at the suggestion of her partner, who recommended herbal supplements. Ms. A’s initial routine laboratory results are unremarkable and her urine drug screen is negative for all substances.

[polldaddy:13041928]

The authors’ observations

Approximately 85% of birthing parents experience some form of postpartum mood disturbance; 10% to 15% develop more significant symptoms of anxiety or depression.³ The etiology of postpartum illness is multifactorial, and includes psychiatric personal/family history, insomnia, acute and chronic psychosocial stressors, and rapid hormone fluctuations.¹ As a result, the postpartum period represents a vulnerable time for birthing parents, particularly those with previously established psychiatric illness.

Ms. A’s initial presentation was concerning for a possible diagnosis of postpartum psychosis vs obsessive-compulsive disorder (OCD) with postpartum onset; other differential diagnoses included MDD with peripartum onset and psychotic features (Table^1-6). Ms. A’s subjective clinical history was significant for critical pertinent findings of both OCD with postpartum onset (ie, egodystonic intrusive thoughts, checking behaviors, feelings of shame, and seeking reassurance) and postpartum psychosis (ie, command auditory hallucinations and waxing/waning confusion), which added to diagnostic complexity.

Although postpartum psychosis is rare (1 to 2 cases per 1,000 women),⁵ it is considered a psychiatric emergency because it has significant potential for infanticide, morbidity, and mortality. Most symptoms develop within the first 2 weeks of the postpartum period.² There are many risk factors for the development of postpartum psychosis; however, in first-time pregnancies, a previous diagnosis of BD I is the single most important risk factor.¹ Approximately 20% to 30% of women with BD experience postpartum psychosis.⁴

For many patients (approximately 56.7%, according to 1 meta-analysis⁷), postpartum psychosis denotes an episode of BD, representing a more severe form of illness with increased risk of recurrence. Most manic or mixed mood episodes reoccur within the first year removed from the perinatal period. In contrast, for some patients (approximately 43.5% according to the same meta-analysis), the episode denotes “isolated postpartum psychosis.”⁷ Isolated postpartum psychosis is a psychotic episode that occurs only in the postpartum period with no recurrence of psychosis or recurrence of psychosis exclusive to postpartum periods. If treated, this type of postpartum psychosis has a more favorable prognosis than postpartum psychosis in a patient with BD.⁷ As such, a BD diagnosis should not be established at the onset of a patient’s first postpartum psychosis presentation. Regardless of type, all presentations of postpartum psychosis are considered a psychiatry emergency.

Continue to: The prevalence of OCD...

The prevalence of OCD with postpartum onset varies. One study estimated it occurs in 2.43% of cases.⁴ However, the true prevalence is likely underreported due to feelings of guilt or shame associated with intrusive thoughts, and fear of stigmatization and separation from the baby. Approximately 70.6% of women experiencing OCD with postpartum onset have a comorbid depressive disorder.⁴

Ms. A’s presentation to the psychiatric ED carried with it diagnostic complexity and uncertainty. Her initial presentation was concerning for elements of both postpartum psychosis and OCD with postpartum onset. After her evaluation in the psychiatric ED, there remained a lack of clear and convincing evidence for a diagnosis of OCD with postpartum onset, which eliminated the possibility of discharging Ms. A with robust safety planning and reinitiation of a selective serotonin reuptake inhibitor.

Additionally, because auditory hallucinations are atypical in OCD, the treatment team remained concerned for a diagnosis of postpartum psychosis, which would warrant hospitalization. With assistance from the institution’s reproductive psychiatrists, the treatment team discussed the importance of inpatient hospitalization for risk mitigation, close observation, and thorough evaluation for greater diagnostic clarity and certainty.

TREATMENT Involuntary hospitalization

The treatment team counsels Ms. A and her partner on her differential diagnoses, including the elevated acute risk of harm to herself and her baby if she has postpartum psychosis, as well as the need for continued observation and evaluation. When alone with a clinician, Ms. A says she understands and agrees to voluntary hospitalization. However, following a subsequent risk-benefit discussion with her partner, they both grew increasingly concerned about her separation from the baby and reinitiating her medications. Amid these concerns, the treatment team notices that Ms. A attempts to minimize her symptoms. Ms. A changes her mind and no longer consents to hospitalization. She is placed on a psychiatric hold for involuntary hospitalization on the psychiatric inpatient unit.

On the inpatient unit, the inpatient clinicians and a reproductive psychiatrist continue to evaluate Ms. A. Though her diagnosis remains unclear, Ms. A agrees to start a trial of quetiapine 100 mg/d titrated to 150 mg/d to manage her potential postpartum psychosis, depressed mood, insomnia (off-label), anxiety (off-label), and OCD (off-label). Lithium is deferred because Ms. A is breastfeeding.

[polldaddy:13041932]

Continue to: The authors' observations

Due to an elevated acute risk of suicide and infanticide, postpartum psychosis represents a psychiatric emergency and often requires hospitalization. The Figure outlines steps in evaluating a patient with concerns for postpartum psychosis in a psychiatric emergency service setting. Due to the waxing and waning nature of symptoms, patients may appear psychiatrically stable at any time but remain at an overall elevated acute risk of harm to self and/or their baby.

If a patient is being considered for discharge based on yes answers to all questions in Step 2 of the Figure, the emergency psychiatric clinician must initiate appropriate psychotropic medications and complete robust safety planning with the patient and a trusted adult who will provide direct supervision. Safety planning may include (but is not limited to) strict return precautions, education on concerning symptoms and behaviors, psychotropic education and agreement of compliance, and detailed instructions on outpatient follow-up within 1 week. Ideally—and as was the case for Ms. A—a reproductive psychiatrist should be consulted in the emergency setting for shared decision-making on admission vs discharge, medication management, and outpatient follow-up considerations.

Because postpartum psychosis carries significant risks and hospitalization generally results in separating the patient from their baby, initiating psychotropics should not be delayed. Clinicians must consider the patient’s psychiatric history, allergies, and breastfeeding status.

Based on current evidence, first-line treatment for postpartum psychosis includes a mood stabilizer, an antipsychotic, and possibly a benzodiazepine.⁶ Thus, an appropriate initial treatment regimen would be a benzodiazepine (particularly lorazepam due to its relatively shorter half-life) and an antipsychotic (eg, haloperidol, olanzapine, or quetiapine) for acute psychosis, plus lithium for mood stabilization.^1,5

If the postpartum psychosis represents an episode of BD, use of a long-term mood stabilizer may be required. In contrast, for isolated postpartum psychosis, clinicians may consider initiating psychotropics only in the immediate postpartum period, with an eventual slow taper. In future pregnancies, psychotropics may be reintroduced postpartum, which will avoid peripartum fetal exposure.⁸ If the patient is breastfeeding, lithium may be deferred in an acute care setting. For patients with evidence of catatonia, severe suicidality, refusal of oral intake with compromised nutrition, severe agitation, or treatment resistance, electro­convulsive therapy remains a safe and effective treatment option.⁶ Additionally, the safety of continued breastfeeding in acute psychosis must be considered, with the potential for recommending discontinuation, which would decrease sleep disruptions at night and increase the ability of others to feed the baby. Comprehensive care requires nonpharmacologic interventions, including psychoeducation for the patient and their family, individual psychotherapy, and expansion of psychosocial supports.

Continue to: Patients who have experienced...

Patients who have experienced an episode of postpartum psychosis are predisposed to another episode in future pregnancies.¹ Current research recommends prophylaxis of recurrence with lithium monotherapy.^1,2,5,6 Similar to other psychotropics in reproductive psychiatry, maintenance therapy on lithium requires a thorough “risk vs risk” discussion with the patient. The risk of lithium use while pregnant and/or breastfeeding must be weighed against the risks associated with postpartum psychosis (ie, infanticide, suicide, poor peripartum care, or poor infant bonding).

OUTCOME Improved mood

After 7 days of inpatient treatment with quetiapine, Ms. A demonstrates improvement in the targeted depressive symptoms (including improved motivation/energy and insomnia, decreased feelings of guilt, and denial of ongoing suicidal ideation). Additionally, the thoughts of harming her baby are less frequent, and command auditory hallucinations resolve. Upon discharge, Ms. A and her partner meet with inpatient clinicians for continued counseling, safety planning, and plans for outpatient follow-up with the institution’s reproductive psychiatrist.

The authors’ observations

Many aspects of Ms. A’s initial presentation in the psychiatric ED were challenging. Given the presence of symptoms of both psychosis and OCD, a diagnosis was difficult to ascertain in the emergency setting. Since command auditory hallucinations are atypical in patients with postpartum OCD, the treatment team maintained high suspicion for postpartum psychosis, which represented an emergency requiring inpatient care.

Hospitalization separated Ms. A from her baby, for whom she was the primary caregiver. Additional considerations for inpatient admission and psychotropic initiation were necessary, because Ms. A was breastfeeding. Although Ms. A’s partner was able to provide full-time childcare, the patient ultimately did not agree to hospitalization and required an emergency hold for involuntary admission, which was an additional barrier to care. Furthermore, her partner held unfavorable beliefs regarding psychotropic medications and Ms. A’s need for hospital admission, which required ongoing patient and partner education in the emergency, inpatient, and outpatient settings. Moreover, if Ms. A’s symptoms were ultimately attributable to postpartum OCD, the patient’s involuntary hospitalization might have increased the risk of stigmatization of mental illness and treatment with psychotropics.

Bottom Line

The peripartum period is a vulnerable time for patients, particularly those with previously diagnosed psychiatric illnesses. Postpartum psychosis is the most severe form of postpartum psychiatric illness and often represents an episode of bipolar disorder. Due to an elevated acute risk of suicide and infanticide, postpartum psychosis is a psychiatric emergency and warrants inpatient hospitalization for immediate intervention.

Related Resources

• Sharma V. Does your patient have postpartum OCD? Current Psychiatry. 2019;18(5):9-10.
• Hatters Friedman S, Prakash C, Nagel-Yang S. Postpartum psychosis: protecting mother and infant. Current Psychiatry. 2019;18(4):12-21.

Drug Brand Names

Fluoxetine • Prozac
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Olanzapine • Zyprexa
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft
Valproic acid • Depakene