Mental Health

I am going to guess that if we asked 500,000 adults in this country if they felt that children and adolescents were spending too much time on their smartphones, we would elicit almost uniform agreement that, yes indeed, smartphone use is gobbling up too much time from our young people. And, the adults would volunteer a long laundry list of all the bad consequences this overuse was generating. If you ask this same sample of adults if they too were spending too much time on their smartphones they would answer yes and, again, give you a list of the problems they feel are the result of this overuse.

We might begin to find a scattering of responses if we ask the adults when a child is too young to have his/her own cell phone. But, they would all agree that “young children” weren’t ready to be trusted with a cell phone. The “when” they were ready would be up for discussion. However, I suspect we might see a clustering around age 10 years. The reality is that despite what the majority may believe, a 2022 survey found that 42% of children have a cell phone by age 10, 71% by age 12, and 91% by age 14.

So, it would appear that, while we believe there can be significant downsides to having a cell phone, we are having great difficulty in policing ourselves and creating limits for our children. Does cell phone use qualify as an addiction, or is it just another example of how adults have lost the ability to say “no” to themselves and to their children?

When it comes to cell phones in school, the situation gets increasingly murky. The teachers I speak with are very clear that cell phones are creating problems for both the academic and the social experiences of their students. One teacher referred me to an article from the Norwegian Institute of Public Health, which found that banning cell phones in school decreased the incidence of psychological symptoms and diseases in girls. Bullying decreased in both genders and the girls’ GPA scores improved. In schools with cell phone bans, girls were more likely to choose and attend academic track programs, an effect which was more pronounced in young women with lower socioeconomic backgrounds. But, the if, when, and how to institute smartphone bans in school is complicated.

On one front, the movement toward cell phone bans in school has been given a major boost with the publication and publicity of a new book titled The Anxious Generation by social psychologist Jonathan Haidt, PhD. The New York University professor sees the GenZ’ers as experiencing a tsunami of mental health challenges including anxiety, self-harm, and suicide. And, he lays much of the blame for this situation on cell phone use.

He is optimistic about turning the tide because he claims that everywhere he speaks about the problem he says “I feel that I’m pushing on open doors.” Comparing the phenomenon to the collapse of the Berlin Wall, Dr. Haidt says “When you have a system that everyone hates, and then you have a way to escape it, it can change in a year.”

I wish I could share in his optimism, although I did just encounter a news story in the Portland paper describing a national program called “Wait Until 8th,” which is being considered by a parents’ group here in Maine.

The usual suspects have their own predictable take on the issue. The House and Senate have proposed a study on the use of cell phones in elementary and secondary schools and a pilot program awarding grants to some schools to create mobile device–free environments. Sounds like a momentum killer to me.

Not surprisingly, the issue of cell phone bans in school has taken on a bit of a political odor. The National Parents Union reports in a very small and inadequately described sample that 56% of parents are against total school bans. In the accompanying press release, the organizations offers an extensive list of concerns parents have reported — many cite the need to remain in contact with their children throughout the day. One has to wonder how often these concerns are a reflection of unresolved separation anxiety.

The American Academy of Pediatrics has rolled out a “5 Cs” framework that pediatricians can use to discuss media use with families. As usual, the thought is that talking about a problem is going to somehow convince parents to do what they already know is the correct action. And, of course, pediatricians have plenty of time to initiate this discussion of the obvious.

A recent study from the Department of Pediatrics at University of California, San Francisco, has found that parental monitoring, limit setting, and modeling good screen use behavior (my bolding) are the most effective strategies for reducing adolescent screen time. Using screen time allowances as a reward or punishment does not seem to be effective.

So there you have it. It looks like cell phone overuse, particularly in school, is something most of us see as a problem deserving an immediate solution. However, despite Dr. Haidt’s optimism about a seismic turnaround, I suspect it will more likely be guerrilla warfare — one family, one school, or one school district at a time.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

I am going to guess that if we asked 500,000 adults in this country if they felt that children and adolescents were spending too much time on their smartphones, we would elicit almost uniform agreement that, yes indeed, smartphone use is gobbling up too much time from our young people. And, the adults would volunteer a long laundry list of all the bad consequences this overuse was generating. If you ask this same sample of adults if they too were spending too much time on their smartphones they would answer yes and, again, give you a list of the problems they feel are the result of this overuse.

We might begin to find a scattering of responses if we ask the adults when a child is too young to have his/her own cell phone. But, they would all agree that “young children” weren’t ready to be trusted with a cell phone. The “when” they were ready would be up for discussion. However, I suspect we might see a clustering around age 10 years. The reality is that despite what the majority may believe, a 2022 survey found that 42% of children have a cell phone by age 10, 71% by age 12, and 91% by age 14.

So, it would appear that, while we believe there can be significant downsides to having a cell phone, we are having great difficulty in policing ourselves and creating limits for our children. Does cell phone use qualify as an addiction, or is it just another example of how adults have lost the ability to say “no” to themselves and to their children?

When it comes to cell phones in school, the situation gets increasingly murky. The teachers I speak with are very clear that cell phones are creating problems for both the academic and the social experiences of their students. One teacher referred me to an article from the Norwegian Institute of Public Health, which found that banning cell phones in school decreased the incidence of psychological symptoms and diseases in girls. Bullying decreased in both genders and the girls’ GPA scores improved. In schools with cell phone bans, girls were more likely to choose and attend academic track programs, an effect which was more pronounced in young women with lower socioeconomic backgrounds. But, the if, when, and how to institute smartphone bans in school is complicated.

On one front, the movement toward cell phone bans in school has been given a major boost with the publication and publicity of a new book titled The Anxious Generation by social psychologist Jonathan Haidt, PhD. The New York University professor sees the GenZ’ers as experiencing a tsunami of mental health challenges including anxiety, self-harm, and suicide. And, he lays much of the blame for this situation on cell phone use.

He is optimistic about turning the tide because he claims that everywhere he speaks about the problem he says “I feel that I’m pushing on open doors.” Comparing the phenomenon to the collapse of the Berlin Wall, Dr. Haidt says “When you have a system that everyone hates, and then you have a way to escape it, it can change in a year.”

I wish I could share in his optimism, although I did just encounter a news story in the Portland paper describing a national program called “Wait Until 8th,” which is being considered by a parents’ group here in Maine.

The usual suspects have their own predictable take on the issue. The House and Senate have proposed a study on the use of cell phones in elementary and secondary schools and a pilot program awarding grants to some schools to create mobile device–free environments. Sounds like a momentum killer to me.

Not surprisingly, the issue of cell phone bans in school has taken on a bit of a political odor. The National Parents Union reports in a very small and inadequately described sample that 56% of parents are against total school bans. In the accompanying press release, the organizations offers an extensive list of concerns parents have reported — many cite the need to remain in contact with their children throughout the day. One has to wonder how often these concerns are a reflection of unresolved separation anxiety.

The American Academy of Pediatrics has rolled out a “5 Cs” framework that pediatricians can use to discuss media use with families. As usual, the thought is that talking about a problem is going to somehow convince parents to do what they already know is the correct action. And, of course, pediatricians have plenty of time to initiate this discussion of the obvious.

A recent study from the Department of Pediatrics at University of California, San Francisco, has found that parental monitoring, limit setting, and modeling good screen use behavior (my bolding) are the most effective strategies for reducing adolescent screen time. Using screen time allowances as a reward or punishment does not seem to be effective.

So there you have it. It looks like cell phone overuse, particularly in school, is something most of us see as a problem deserving an immediate solution. However, despite Dr. Haidt’s optimism about a seismic turnaround, I suspect it will more likely be guerrilla warfare — one family, one school, or one school district at a time.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

I am going to guess that if we asked 500,000 adults in this country if they felt that children and adolescents were spending too much time on their smartphones, we would elicit almost uniform agreement that, yes indeed, smartphone use is gobbling up too much time from our young people. And, the adults would volunteer a long laundry list of all the bad consequences this overuse was generating. If you ask this same sample of adults if they too were spending too much time on their smartphones they would answer yes and, again, give you a list of the problems they feel are the result of this overuse.

We might begin to find a scattering of responses if we ask the adults when a child is too young to have his/her own cell phone. But, they would all agree that “young children” weren’t ready to be trusted with a cell phone. The “when” they were ready would be up for discussion. However, I suspect we might see a clustering around age 10 years. The reality is that despite what the majority may believe, a 2022 survey found that 42% of children have a cell phone by age 10, 71% by age 12, and 91% by age 14.

So, it would appear that, while we believe there can be significant downsides to having a cell phone, we are having great difficulty in policing ourselves and creating limits for our children. Does cell phone use qualify as an addiction, or is it just another example of how adults have lost the ability to say “no” to themselves and to their children?

When it comes to cell phones in school, the situation gets increasingly murky. The teachers I speak with are very clear that cell phones are creating problems for both the academic and the social experiences of their students. One teacher referred me to an article from the Norwegian Institute of Public Health, which found that banning cell phones in school decreased the incidence of psychological symptoms and diseases in girls. Bullying decreased in both genders and the girls’ GPA scores improved. In schools with cell phone bans, girls were more likely to choose and attend academic track programs, an effect which was more pronounced in young women with lower socioeconomic backgrounds. But, the if, when, and how to institute smartphone bans in school is complicated.

On one front, the movement toward cell phone bans in school has been given a major boost with the publication and publicity of a new book titled The Anxious Generation by social psychologist Jonathan Haidt, PhD. The New York University professor sees the GenZ’ers as experiencing a tsunami of mental health challenges including anxiety, self-harm, and suicide. And, he lays much of the blame for this situation on cell phone use.

He is optimistic about turning the tide because he claims that everywhere he speaks about the problem he says “I feel that I’m pushing on open doors.” Comparing the phenomenon to the collapse of the Berlin Wall, Dr. Haidt says “When you have a system that everyone hates, and then you have a way to escape it, it can change in a year.”

I wish I could share in his optimism, although I did just encounter a news story in the Portland paper describing a national program called “Wait Until 8th,” which is being considered by a parents’ group here in Maine.

The usual suspects have their own predictable take on the issue. The House and Senate have proposed a study on the use of cell phones in elementary and secondary schools and a pilot program awarding grants to some schools to create mobile device–free environments. Sounds like a momentum killer to me.

Not surprisingly, the issue of cell phone bans in school has taken on a bit of a political odor. The National Parents Union reports in a very small and inadequately described sample that 56% of parents are against total school bans. In the accompanying press release, the organizations offers an extensive list of concerns parents have reported — many cite the need to remain in contact with their children throughout the day. One has to wonder how often these concerns are a reflection of unresolved separation anxiety.

The American Academy of Pediatrics has rolled out a “5 Cs” framework that pediatricians can use to discuss media use with families. As usual, the thought is that talking about a problem is going to somehow convince parents to do what they already know is the correct action. And, of course, pediatricians have plenty of time to initiate this discussion of the obvious.

A recent study from the Department of Pediatrics at University of California, San Francisco, has found that parental monitoring, limit setting, and modeling good screen use behavior (my bolding) are the most effective strategies for reducing adolescent screen time. Using screen time allowances as a reward or punishment does not seem to be effective.

So there you have it. It looks like cell phone overuse, particularly in school, is something most of us see as a problem deserving an immediate solution. However, despite Dr. Haidt’s optimism about a seismic turnaround, I suspect it will more likely be guerrilla warfare — one family, one school, or one school district at a time.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Posttraumatic stress disorder (PTSD) rates among college students more than doubled between 2017 and 2022, new data showed. Rates of acute stress disorder (ASD) also increased during that time.

METHODOLOGY:

• Researchers conducted five waves of cross-sectional study from 2017 to 2022, involving 392,377 participants across 332 colleges and universities.
• The study utilized the Healthy Minds Study data, ensuring representativeness by applying sample weights based on institutional demographics.
• Outcome variables were diagnoses of PTSD and ASD, confirmed by healthcare practitioners, with statistical analysis assessing change in odds of estimated prevalence during 2017-2022.

TAKEAWAY:

• The prevalence of PTSD among US college students increased from 3.4% in 2017-2018 to 7.5% in 2021-2022.
• ASD diagnoses also rose from 0.2% in 2017-2018 to 0.7% in 2021-2022, with both increases remaining statistically significant after adjusting for demographic differences.
• Investigators noted that these findings underscore the need for targeted, trauma-informed intervention strategies in college settings.

IN PRACTICE:

“These trends highlight the escalating mental health challenges among college students, which is consistent with recent research reporting a surge in psychiatric diagnoses,” the authors wrote. “Factors contributing to this rise may include pandemic-related stressors (eg, loss of loved ones) and the effect of traumatic events (eg, campus shootings and racial trauma),” they added.

SOURCE:

The study was led by Yusen Zhai, PhD, University of Alabama at Birmingham. It was published online on May 30, 2024, in JAMA Network Open.

LIMITATIONS:

The study’s reliance on self-reported data and single questions for diagnosed PTSD and ASD may have limited the accuracy of the findings. The retrospective design and the absence of longitudinal follow-up may have restricted the ability to infer causality from the observed trends.

DISCLOSURES:

No disclosures were reported. No funding information was available.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Posttraumatic stress disorder (PTSD) rates among college students more than doubled between 2017 and 2022, new data showed. Rates of acute stress disorder (ASD) also increased during that time.

METHODOLOGY:

• Researchers conducted five waves of cross-sectional study from 2017 to 2022, involving 392,377 participants across 332 colleges and universities.
• The study utilized the Healthy Minds Study data, ensuring representativeness by applying sample weights based on institutional demographics.
• Outcome variables were diagnoses of PTSD and ASD, confirmed by healthcare practitioners, with statistical analysis assessing change in odds of estimated prevalence during 2017-2022.

TAKEAWAY:

• The prevalence of PTSD among US college students increased from 3.4% in 2017-2018 to 7.5% in 2021-2022.
• ASD diagnoses also rose from 0.2% in 2017-2018 to 0.7% in 2021-2022, with both increases remaining statistically significant after adjusting for demographic differences.
• Investigators noted that these findings underscore the need for targeted, trauma-informed intervention strategies in college settings.

IN PRACTICE:

“These trends highlight the escalating mental health challenges among college students, which is consistent with recent research reporting a surge in psychiatric diagnoses,” the authors wrote. “Factors contributing to this rise may include pandemic-related stressors (eg, loss of loved ones) and the effect of traumatic events (eg, campus shootings and racial trauma),” they added.

SOURCE:

The study was led by Yusen Zhai, PhD, University of Alabama at Birmingham. It was published online on May 30, 2024, in JAMA Network Open.

LIMITATIONS:

The study’s reliance on self-reported data and single questions for diagnosed PTSD and ASD may have limited the accuracy of the findings. The retrospective design and the absence of longitudinal follow-up may have restricted the ability to infer causality from the observed trends.

DISCLOSURES:

No disclosures were reported. No funding information was available.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Posttraumatic stress disorder (PTSD) rates among college students more than doubled between 2017 and 2022, new data showed. Rates of acute stress disorder (ASD) also increased during that time.

METHODOLOGY:

• Researchers conducted five waves of cross-sectional study from 2017 to 2022, involving 392,377 participants across 332 colleges and universities.
• The study utilized the Healthy Minds Study data, ensuring representativeness by applying sample weights based on institutional demographics.
• Outcome variables were diagnoses of PTSD and ASD, confirmed by healthcare practitioners, with statistical analysis assessing change in odds of estimated prevalence during 2017-2022.

TAKEAWAY:

• The prevalence of PTSD among US college students increased from 3.4% in 2017-2018 to 7.5% in 2021-2022.
• ASD diagnoses also rose from 0.2% in 2017-2018 to 0.7% in 2021-2022, with both increases remaining statistically significant after adjusting for demographic differences.
• Investigators noted that these findings underscore the need for targeted, trauma-informed intervention strategies in college settings.

IN PRACTICE:

“These trends highlight the escalating mental health challenges among college students, which is consistent with recent research reporting a surge in psychiatric diagnoses,” the authors wrote. “Factors contributing to this rise may include pandemic-related stressors (eg, loss of loved ones) and the effect of traumatic events (eg, campus shootings and racial trauma),” they added.

SOURCE:

The study was led by Yusen Zhai, PhD, University of Alabama at Birmingham. It was published online on May 30, 2024, in JAMA Network Open.

LIMITATIONS:

The study’s reliance on self-reported data and single questions for diagnosed PTSD and ASD may have limited the accuracy of the findings. The retrospective design and the absence of longitudinal follow-up may have restricted the ability to infer causality from the observed trends.

DISCLOSURES:

No disclosures were reported. No funding information was available.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

Early-life exposure to air and noise pollution is associated with a higher risk for psychosis, depression, and anxiety in adolescence and early adulthood, results from a longitudinal birth cohort study showed.

While air pollution was associated primarily with psychotic experiences and depression, noise pollution was more likely to be associated with anxiety in adolescence and early adulthood.

“Early-life exposure could be detrimental to mental health given the extensive brain development and epigenetic processes that occur in utero and during infancy,” the researchers, led by Joanne Newbury, PhD, of Bristol Medical School, University of Bristol, England, wrote, adding that “the results of this cohort study provide novel evidence that early-life exposure to particulate matter is prospectively associated with the development of psychotic experiences and depression in youth.”

The findings were published online on May 28 in JAMA Network Open.
 

Large, Longitudinal Study

To learn more about how air and noise pollution may affect the brain from an early age, the investigators used data from the Avon Longitudinal Study of Parents and Children, an ongoing longitudinal birth cohort capturing data on new births in Southwest England from 1991 to 1992.

Investigators captured levels of air pollutants, which included nitrogen dioxide and fine particulate matter with a diameter smaller than 2.5 µm (PM2.5), in the areas where expectant mothers lived and where their children lived until age 12.

They also collected decibel levels of noise pollution in neighborhoods where expectant mothers and their children lived.

Participants were assessed for psychotic experiences, depression, and anxiety when they were 13, 18, and 24 years old.

Among the 9065 participants who had mental health data, 20% reported psychotic experiences, 11% reported depression, and 10% reported anxiety. About 60% of the participants had a family history of mental illness.

When they were age 13, 13.6% of participants reported psychotic experiences; 9.2% reported them at age 18, and 12.6% at age 24.

A lower number of participants reported feeling depressed and anxious at 13 years (5.6% for depression and 3.6% for anxiety) and 18 years (7.9% for depression and 5.7% for anxiety).

After adjusting for individual and family-level variables, including family psychiatric history, maternal social class, and neighborhood deprivation, elevated PM2.5 levels during pregnancy (P = .002) and childhood (P = .04) were associated with a significantly increased risk for psychotic experiences later in life. Pregnancy PM2.5 exposure was also associated with depression (P = .01).

Participants exposed to higher noise pollution in childhood and adolescence had an increased risk for anxiety (P = .03) as teenagers.
 

Vulnerability of the Developing Brain

The investigators noted that more information is needed to understand the underlying mechanisms behind these associations but noted that early-life exposure could be detrimental to mental health given “extensive brain development and epigenetic processes that occur in utero.”

They also noted that air pollution could lead to restricted fetal growth and premature birth, both of which are risk factors for psychopathology.

Martin Clift, PhD, of Swansea University in Swansea, Wales, who was not involved in the study, said that the paper highlights the need for more consideration of health consequences related to these exposures.

“As noted by the authors, this is an area that has received a lot of recent attention, yet there remains a large void of knowledge,” Dr. Clift said in a UK Science Media Centre release. “It highlights that some of the most dominant air pollutants can impact different mental health diagnoses, but that time-of-life is particularly important as to how each individual air pollutant may impact this diagnosis.”

Study limitations included limitations to generalizability of the data — the families in the study were more affluent and less diverse than the UK population overall.

The study was funded by the UK Medical Research Council, Wellcome Trust, and University of Bristol. Disclosures were noted in the original article.

A version of this article appeared on Medscape.com.

Early-life exposure to air and noise pollution is associated with a higher risk for psychosis, depression, and anxiety in adolescence and early adulthood, results from a longitudinal birth cohort study showed.

While air pollution was associated primarily with psychotic experiences and depression, noise pollution was more likely to be associated with anxiety in adolescence and early adulthood.

“Early-life exposure could be detrimental to mental health given the extensive brain development and epigenetic processes that occur in utero and during infancy,” the researchers, led by Joanne Newbury, PhD, of Bristol Medical School, University of Bristol, England, wrote, adding that “the results of this cohort study provide novel evidence that early-life exposure to particulate matter is prospectively associated with the development of psychotic experiences and depression in youth.”

The findings were published online on May 28 in JAMA Network Open.
 

Large, Longitudinal Study

To learn more about how air and noise pollution may affect the brain from an early age, the investigators used data from the Avon Longitudinal Study of Parents and Children, an ongoing longitudinal birth cohort capturing data on new births in Southwest England from 1991 to 1992.

Investigators captured levels of air pollutants, which included nitrogen dioxide and fine particulate matter with a diameter smaller than 2.5 µm (PM2.5), in the areas where expectant mothers lived and where their children lived until age 12.

They also collected decibel levels of noise pollution in neighborhoods where expectant mothers and their children lived.

Participants were assessed for psychotic experiences, depression, and anxiety when they were 13, 18, and 24 years old.

Among the 9065 participants who had mental health data, 20% reported psychotic experiences, 11% reported depression, and 10% reported anxiety. About 60% of the participants had a family history of mental illness.

When they were age 13, 13.6% of participants reported psychotic experiences; 9.2% reported them at age 18, and 12.6% at age 24.

A lower number of participants reported feeling depressed and anxious at 13 years (5.6% for depression and 3.6% for anxiety) and 18 years (7.9% for depression and 5.7% for anxiety).

After adjusting for individual and family-level variables, including family psychiatric history, maternal social class, and neighborhood deprivation, elevated PM2.5 levels during pregnancy (P = .002) and childhood (P = .04) were associated with a significantly increased risk for psychotic experiences later in life. Pregnancy PM2.5 exposure was also associated with depression (P = .01).

Participants exposed to higher noise pollution in childhood and adolescence had an increased risk for anxiety (P = .03) as teenagers.
 

Vulnerability of the Developing Brain

The investigators noted that more information is needed to understand the underlying mechanisms behind these associations but noted that early-life exposure could be detrimental to mental health given “extensive brain development and epigenetic processes that occur in utero.”

They also noted that air pollution could lead to restricted fetal growth and premature birth, both of which are risk factors for psychopathology.

Martin Clift, PhD, of Swansea University in Swansea, Wales, who was not involved in the study, said that the paper highlights the need for more consideration of health consequences related to these exposures.

“As noted by the authors, this is an area that has received a lot of recent attention, yet there remains a large void of knowledge,” Dr. Clift said in a UK Science Media Centre release. “It highlights that some of the most dominant air pollutants can impact different mental health diagnoses, but that time-of-life is particularly important as to how each individual air pollutant may impact this diagnosis.”

Study limitations included limitations to generalizability of the data — the families in the study were more affluent and less diverse than the UK population overall.

The study was funded by the UK Medical Research Council, Wellcome Trust, and University of Bristol. Disclosures were noted in the original article.

A version of this article appeared on Medscape.com.

Early-life exposure to air and noise pollution is associated with a higher risk for psychosis, depression, and anxiety in adolescence and early adulthood, results from a longitudinal birth cohort study showed.

While air pollution was associated primarily with psychotic experiences and depression, noise pollution was more likely to be associated with anxiety in adolescence and early adulthood.

“Early-life exposure could be detrimental to mental health given the extensive brain development and epigenetic processes that occur in utero and during infancy,” the researchers, led by Joanne Newbury, PhD, of Bristol Medical School, University of Bristol, England, wrote, adding that “the results of this cohort study provide novel evidence that early-life exposure to particulate matter is prospectively associated with the development of psychotic experiences and depression in youth.”

The findings were published online on May 28 in JAMA Network Open.
 

Large, Longitudinal Study

To learn more about how air and noise pollution may affect the brain from an early age, the investigators used data from the Avon Longitudinal Study of Parents and Children, an ongoing longitudinal birth cohort capturing data on new births in Southwest England from 1991 to 1992.

Investigators captured levels of air pollutants, which included nitrogen dioxide and fine particulate matter with a diameter smaller than 2.5 µm (PM2.5), in the areas where expectant mothers lived and where their children lived until age 12.

They also collected decibel levels of noise pollution in neighborhoods where expectant mothers and their children lived.

Participants were assessed for psychotic experiences, depression, and anxiety when they were 13, 18, and 24 years old.

Among the 9065 participants who had mental health data, 20% reported psychotic experiences, 11% reported depression, and 10% reported anxiety. About 60% of the participants had a family history of mental illness.

When they were age 13, 13.6% of participants reported psychotic experiences; 9.2% reported them at age 18, and 12.6% at age 24.

A lower number of participants reported feeling depressed and anxious at 13 years (5.6% for depression and 3.6% for anxiety) and 18 years (7.9% for depression and 5.7% for anxiety).

After adjusting for individual and family-level variables, including family psychiatric history, maternal social class, and neighborhood deprivation, elevated PM2.5 levels during pregnancy (P = .002) and childhood (P = .04) were associated with a significantly increased risk for psychotic experiences later in life. Pregnancy PM2.5 exposure was also associated with depression (P = .01).

Participants exposed to higher noise pollution in childhood and adolescence had an increased risk for anxiety (P = .03) as teenagers.
 

Vulnerability of the Developing Brain

The investigators noted that more information is needed to understand the underlying mechanisms behind these associations but noted that early-life exposure could be detrimental to mental health given “extensive brain development and epigenetic processes that occur in utero.”

They also noted that air pollution could lead to restricted fetal growth and premature birth, both of which are risk factors for psychopathology.

Martin Clift, PhD, of Swansea University in Swansea, Wales, who was not involved in the study, said that the paper highlights the need for more consideration of health consequences related to these exposures.

“As noted by the authors, this is an area that has received a lot of recent attention, yet there remains a large void of knowledge,” Dr. Clift said in a UK Science Media Centre release. “It highlights that some of the most dominant air pollutants can impact different mental health diagnoses, but that time-of-life is particularly important as to how each individual air pollutant may impact this diagnosis.”

Study limitations included limitations to generalizability of the data — the families in the study were more affluent and less diverse than the UK population overall.

The study was funded by the UK Medical Research Council, Wellcome Trust, and University of Bristol. Disclosures were noted in the original article.

A version of this article appeared on Medscape.com.

The incidence of antidepressant discontinuation symptoms appears to be much lower than was previously thought, results from a new meta-analysis of studies assessing this issue showed.

After accounting for placebo effects, results showed that about 15% of patients who discontinue antidepressant therapy had true discontinuation symptoms, with severe symptoms occurring in about 2% of patients. 

“Considering all available data, we conservatively estimate that one out of every six to seven patients has truly pharmacologically-caused antidepressant discontinuation symptoms. This might still be an over-estimate, as it is difficult to factor in residual or re-emerging symptoms of depression or anxiety,” the researchers concluded. 

The study was published online in The Lancet.
 

More Reliable Data

“We are not saying all antidepressant discontinuation symptoms are a placebo effect. It is a real phenomenon. And we are not saying that there is no problem discontinuing antidepressants. But these findings suggest that true antidepressant discontinuation symptoms are lower than previous studies have suggested,” study investigator, Christopher Baethge, MD, University of Cologne, Germany, said at a Science Media Centre press briefing.

“Our data should de-emotionalize the debate on this issue. Yes, antidepressant discontinuation symptoms are a problem, but they should not cause undue alarm to patients or doctors,” Dr. Baethge added. 

Lead investigator, Jonathan Henssler, MD, Charité – Universitätsmedizin Berlin, Germany, noted that “previous studies on this issue have included surveys which have selection bias in that people with symptoms antidepressant discontinuation are more likely to participate. This study includes a broader range of research and excluded surveys, so we believe these are more reliable results.” 
 

A Controversial Issue

The investigators note that antidepressant discontinuation symptoms can be highly variable and nonspecific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. These symptoms typically occur within a few days and are usually transient but can last up to several weeks or months.

Explaining the mechanism behind the phenomenon, Dr. Baethge noted that selective serotonin reuptake inhibitor antidepressants increase the available serotonin in the brain, but the body responds by reducing the number of serotonin receptors. If the amount of available serotonin is reduced after stopping the medication, then this can lead to discontinuation symptoms. 

However, the incidence and severity of these symptoms remains controversial, the researchers noted. They point out that some estimates suggest that antidepressant discontinuation symptoms occurred in the majority of patients (56%), with almost half of cases classed as severe. 

Previous attempts at assessment have been questioned on methodologic grounds especially because of inclusion of online surveys or other studies prone to selection and dissatisfaction bias.

“Medical professionals continue to hold polarized positions on the incidence and severity of antidepressant discontinuation symptoms, and the debate continues in public media,” they wrote.

This is the first publication of a larger project on antidepressant discontinuation symptoms.

For the study, the researchers conducted a meta-analysis of 44 controlled trials and 35 observational studies assessing the incidence of antidepressant discontinuation symptoms including a total of 21,002 patients. Of these, 16,532 patients discontinued antidepressant treatment, and 4470 patients discontinued placebo. 

Incidence of at least one antidepressant discontinuation symptom occurred in 31% of patients stopping antidepressant therapy and in 17% after discontinuation of placebo, giving a true rate of pharmacologic-driven antidepressant discontinuation symptoms of 14%-15%.

The study also showed that severe discontinuation symptoms occurred in 2.8% of those stopping antidepressants and in 0.6% of those stopping placebo, giving a true rate of severe antidepressant discontinuation symptoms of around 2%. 

There was no association with treatment duration or with pharmaceutical company funding, and different statistical analyses produced similar results, suggesting the findings are robust, Dr. Baethge reported.

 

Risks by Medication

Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequency of discontinuation symptoms and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms.

Fluoxetine, sertraline, and citalopram had lower rates of discontinuation symptoms. No data were available for bupropion, mirtazapine, and amitriptyline.

As for the clinical implications of the findings, Dr. Henssler said that he does consider discontinuation symptoms when selecting a medication. “I would choose a drug with lower rate of these symptoms unless there was a specific reason to choose one with a higher rate,” he said. 

Dr. Henssler added that these data raise awareness of the placebo effect.

“Considering the placebo results, approximately half of antidepressant discontinuation symptoms could be attributable to expectation or non-specific symptoms,” the researchers noted.

“This is not to say all antidepressant discontinuation symptoms are caused by patient expectations; in practice, all patients discontinuing antidepressants need to be counseled and monitored, and patients who report antidepressant discontinuation symptoms must be helped, in particular those who develop severe antidepressant discontinuation symptoms,” they concluded.

 

Experts Weigh In

Commenting on the study at a press briefing, Oliver Howes, MD, chair of the psychopharmacology committee at the Royal College of Psychiatrists, United Kingdom, said that he welcomed “the insight that this robust study provides.”

“If someone chooses to stop taking their antidepressants, their doctor should help them to do so slowly and in a controlled manner that limits the impact of any potential withdrawal symptoms,” Dr. Howes said.

He added that the Royal College of Psychiatrists has produced a resource for patients and carers on stopping antidepressants that offers information on tapering medication at a pace that suits individual patient needs.

Also commenting, Tony Kendrick, MD, professor of primary care, University of Southampton, United Kingdom, pointed out some limitations of the new meta-analysis — in particular, that the method of assessment of discontinuation symptoms in the included studies was very variable, with specific measurement scales of discontinuation symptoms used in only six of the studies. 

“In most cases the assessment seemed to depend at least partly on the judgment of the authors of the included studies rather than being based on a systematic collection of data,” Dr. Kendrick added.

In an accompanying editorial, Glyn Lewis, PhD, and Gemma Lewis, PhD, University College London, United Kingdom, wrote that though the meta-analysis has its limitations, including the fact that many of the studies were small, often use antidepressants that are not commonly used now, and studied people who had not taken the antidepressants for a very long time, “the results here are a substantial improvement on anything that has been published before.”

They emphasize the importance of discussing the issue of a placebo effect with patients when stopping antidepressants. 

The editorialists pointed out that as antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. However, for individual clinicians, severe withdrawal symptoms will seem uncommon, and most patients will probably not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.

They noted that cessation of antidepressants can lead to an increase in depressive and anxious symptoms, and distinguishing between relapsing symptoms and withdrawal is difficult. 

“Short-term symptoms that reduce quickly, without intervention, are best thought of as a form of withdrawal, even if those symptoms might be similar or identical to the symptoms of depression and anxiety. More serious and longer-term symptoms might best be managed by tapering more slowly, or even deciding to remain on the antidepressant,” the editorialists wrote.

There was no funding source for this study. The authors declare no competing interests. Dr. Kendrick led the NIHR REDUCE trial of internet and telephone support for antidepressant discontinuation and was a member of the guideline committee for the NICE 2022 Depression Guideline.

A version of this article appeared on Medscape.com.

The incidence of antidepressant discontinuation symptoms appears to be much lower than was previously thought, results from a new meta-analysis of studies assessing this issue showed.

After accounting for placebo effects, results showed that about 15% of patients who discontinue antidepressant therapy had true discontinuation symptoms, with severe symptoms occurring in about 2% of patients. 

“Considering all available data, we conservatively estimate that one out of every six to seven patients has truly pharmacologically-caused antidepressant discontinuation symptoms. This might still be an over-estimate, as it is difficult to factor in residual or re-emerging symptoms of depression or anxiety,” the researchers concluded. 

The study was published online in The Lancet.
 

More Reliable Data

“We are not saying all antidepressant discontinuation symptoms are a placebo effect. It is a real phenomenon. And we are not saying that there is no problem discontinuing antidepressants. But these findings suggest that true antidepressant discontinuation symptoms are lower than previous studies have suggested,” study investigator, Christopher Baethge, MD, University of Cologne, Germany, said at a Science Media Centre press briefing.

“Our data should de-emotionalize the debate on this issue. Yes, antidepressant discontinuation symptoms are a problem, but they should not cause undue alarm to patients or doctors,” Dr. Baethge added. 

Lead investigator, Jonathan Henssler, MD, Charité – Universitätsmedizin Berlin, Germany, noted that “previous studies on this issue have included surveys which have selection bias in that people with symptoms antidepressant discontinuation are more likely to participate. This study includes a broader range of research and excluded surveys, so we believe these are more reliable results.” 
 

A Controversial Issue

The investigators note that antidepressant discontinuation symptoms can be highly variable and nonspecific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. These symptoms typically occur within a few days and are usually transient but can last up to several weeks or months.

Explaining the mechanism behind the phenomenon, Dr. Baethge noted that selective serotonin reuptake inhibitor antidepressants increase the available serotonin in the brain, but the body responds by reducing the number of serotonin receptors. If the amount of available serotonin is reduced after stopping the medication, then this can lead to discontinuation symptoms. 

However, the incidence and severity of these symptoms remains controversial, the researchers noted. They point out that some estimates suggest that antidepressant discontinuation symptoms occurred in the majority of patients (56%), with almost half of cases classed as severe. 

Previous attempts at assessment have been questioned on methodologic grounds especially because of inclusion of online surveys or other studies prone to selection and dissatisfaction bias.

“Medical professionals continue to hold polarized positions on the incidence and severity of antidepressant discontinuation symptoms, and the debate continues in public media,” they wrote.

This is the first publication of a larger project on antidepressant discontinuation symptoms.

For the study, the researchers conducted a meta-analysis of 44 controlled trials and 35 observational studies assessing the incidence of antidepressant discontinuation symptoms including a total of 21,002 patients. Of these, 16,532 patients discontinued antidepressant treatment, and 4470 patients discontinued placebo. 

Incidence of at least one antidepressant discontinuation symptom occurred in 31% of patients stopping antidepressant therapy and in 17% after discontinuation of placebo, giving a true rate of pharmacologic-driven antidepressant discontinuation symptoms of 14%-15%.

The study also showed that severe discontinuation symptoms occurred in 2.8% of those stopping antidepressants and in 0.6% of those stopping placebo, giving a true rate of severe antidepressant discontinuation symptoms of around 2%. 

There was no association with treatment duration or with pharmaceutical company funding, and different statistical analyses produced similar results, suggesting the findings are robust, Dr. Baethge reported.

 

Risks by Medication

Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequency of discontinuation symptoms and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms.

Fluoxetine, sertraline, and citalopram had lower rates of discontinuation symptoms. No data were available for bupropion, mirtazapine, and amitriptyline.

As for the clinical implications of the findings, Dr. Henssler said that he does consider discontinuation symptoms when selecting a medication. “I would choose a drug with lower rate of these symptoms unless there was a specific reason to choose one with a higher rate,” he said. 

Dr. Henssler added that these data raise awareness of the placebo effect.

“Considering the placebo results, approximately half of antidepressant discontinuation symptoms could be attributable to expectation or non-specific symptoms,” the researchers noted.

“This is not to say all antidepressant discontinuation symptoms are caused by patient expectations; in practice, all patients discontinuing antidepressants need to be counseled and monitored, and patients who report antidepressant discontinuation symptoms must be helped, in particular those who develop severe antidepressant discontinuation symptoms,” they concluded.

 

Experts Weigh In

Commenting on the study at a press briefing, Oliver Howes, MD, chair of the psychopharmacology committee at the Royal College of Psychiatrists, United Kingdom, said that he welcomed “the insight that this robust study provides.”

“If someone chooses to stop taking their antidepressants, their doctor should help them to do so slowly and in a controlled manner that limits the impact of any potential withdrawal symptoms,” Dr. Howes said.

He added that the Royal College of Psychiatrists has produced a resource for patients and carers on stopping antidepressants that offers information on tapering medication at a pace that suits individual patient needs.

Also commenting, Tony Kendrick, MD, professor of primary care, University of Southampton, United Kingdom, pointed out some limitations of the new meta-analysis — in particular, that the method of assessment of discontinuation symptoms in the included studies was very variable, with specific measurement scales of discontinuation symptoms used in only six of the studies. 

“In most cases the assessment seemed to depend at least partly on the judgment of the authors of the included studies rather than being based on a systematic collection of data,” Dr. Kendrick added.

In an accompanying editorial, Glyn Lewis, PhD, and Gemma Lewis, PhD, University College London, United Kingdom, wrote that though the meta-analysis has its limitations, including the fact that many of the studies were small, often use antidepressants that are not commonly used now, and studied people who had not taken the antidepressants for a very long time, “the results here are a substantial improvement on anything that has been published before.”

They emphasize the importance of discussing the issue of a placebo effect with patients when stopping antidepressants. 

The editorialists pointed out that as antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. However, for individual clinicians, severe withdrawal symptoms will seem uncommon, and most patients will probably not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.

They noted that cessation of antidepressants can lead to an increase in depressive and anxious symptoms, and distinguishing between relapsing symptoms and withdrawal is difficult. 

“Short-term symptoms that reduce quickly, without intervention, are best thought of as a form of withdrawal, even if those symptoms might be similar or identical to the symptoms of depression and anxiety. More serious and longer-term symptoms might best be managed by tapering more slowly, or even deciding to remain on the antidepressant,” the editorialists wrote.

There was no funding source for this study. The authors declare no competing interests. Dr. Kendrick led the NIHR REDUCE trial of internet and telephone support for antidepressant discontinuation and was a member of the guideline committee for the NICE 2022 Depression Guideline.

A version of this article appeared on Medscape.com.

The incidence of antidepressant discontinuation symptoms appears to be much lower than was previously thought, results from a new meta-analysis of studies assessing this issue showed.

After accounting for placebo effects, results showed that about 15% of patients who discontinue antidepressant therapy had true discontinuation symptoms, with severe symptoms occurring in about 2% of patients. 

“Considering all available data, we conservatively estimate that one out of every six to seven patients has truly pharmacologically-caused antidepressant discontinuation symptoms. This might still be an over-estimate, as it is difficult to factor in residual or re-emerging symptoms of depression or anxiety,” the researchers concluded. 

The study was published online in The Lancet.
 

More Reliable Data

“We are not saying all antidepressant discontinuation symptoms are a placebo effect. It is a real phenomenon. And we are not saying that there is no problem discontinuing antidepressants. But these findings suggest that true antidepressant discontinuation symptoms are lower than previous studies have suggested,” study investigator, Christopher Baethge, MD, University of Cologne, Germany, said at a Science Media Centre press briefing.

“Our data should de-emotionalize the debate on this issue. Yes, antidepressant discontinuation symptoms are a problem, but they should not cause undue alarm to patients or doctors,” Dr. Baethge added. 

Lead investigator, Jonathan Henssler, MD, Charité – Universitätsmedizin Berlin, Germany, noted that “previous studies on this issue have included surveys which have selection bias in that people with symptoms antidepressant discontinuation are more likely to participate. This study includes a broader range of research and excluded surveys, so we believe these are more reliable results.” 
 

A Controversial Issue

The investigators note that antidepressant discontinuation symptoms can be highly variable and nonspecific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. These symptoms typically occur within a few days and are usually transient but can last up to several weeks or months.

Explaining the mechanism behind the phenomenon, Dr. Baethge noted that selective serotonin reuptake inhibitor antidepressants increase the available serotonin in the brain, but the body responds by reducing the number of serotonin receptors. If the amount of available serotonin is reduced after stopping the medication, then this can lead to discontinuation symptoms. 

However, the incidence and severity of these symptoms remains controversial, the researchers noted. They point out that some estimates suggest that antidepressant discontinuation symptoms occurred in the majority of patients (56%), with almost half of cases classed as severe. 

Previous attempts at assessment have been questioned on methodologic grounds especially because of inclusion of online surveys or other studies prone to selection and dissatisfaction bias.

“Medical professionals continue to hold polarized positions on the incidence and severity of antidepressant discontinuation symptoms, and the debate continues in public media,” they wrote.

This is the first publication of a larger project on antidepressant discontinuation symptoms.

For the study, the researchers conducted a meta-analysis of 44 controlled trials and 35 observational studies assessing the incidence of antidepressant discontinuation symptoms including a total of 21,002 patients. Of these, 16,532 patients discontinued antidepressant treatment, and 4470 patients discontinued placebo. 

Incidence of at least one antidepressant discontinuation symptom occurred in 31% of patients stopping antidepressant therapy and in 17% after discontinuation of placebo, giving a true rate of pharmacologic-driven antidepressant discontinuation symptoms of 14%-15%.

The study also showed that severe discontinuation symptoms occurred in 2.8% of those stopping antidepressants and in 0.6% of those stopping placebo, giving a true rate of severe antidepressant discontinuation symptoms of around 2%. 

There was no association with treatment duration or with pharmaceutical company funding, and different statistical analyses produced similar results, suggesting the findings are robust, Dr. Baethge reported.

 

Risks by Medication

Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequency of discontinuation symptoms and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms.

Fluoxetine, sertraline, and citalopram had lower rates of discontinuation symptoms. No data were available for bupropion, mirtazapine, and amitriptyline.

As for the clinical implications of the findings, Dr. Henssler said that he does consider discontinuation symptoms when selecting a medication. “I would choose a drug with lower rate of these symptoms unless there was a specific reason to choose one with a higher rate,” he said. 

Dr. Henssler added that these data raise awareness of the placebo effect.

“Considering the placebo results, approximately half of antidepressant discontinuation symptoms could be attributable to expectation or non-specific symptoms,” the researchers noted.

“This is not to say all antidepressant discontinuation symptoms are caused by patient expectations; in practice, all patients discontinuing antidepressants need to be counseled and monitored, and patients who report antidepressant discontinuation symptoms must be helped, in particular those who develop severe antidepressant discontinuation symptoms,” they concluded.

 

Experts Weigh In

Commenting on the study at a press briefing, Oliver Howes, MD, chair of the psychopharmacology committee at the Royal College of Psychiatrists, United Kingdom, said that he welcomed “the insight that this robust study provides.”

“If someone chooses to stop taking their antidepressants, their doctor should help them to do so slowly and in a controlled manner that limits the impact of any potential withdrawal symptoms,” Dr. Howes said.

He added that the Royal College of Psychiatrists has produced a resource for patients and carers on stopping antidepressants that offers information on tapering medication at a pace that suits individual patient needs.

Also commenting, Tony Kendrick, MD, professor of primary care, University of Southampton, United Kingdom, pointed out some limitations of the new meta-analysis — in particular, that the method of assessment of discontinuation symptoms in the included studies was very variable, with specific measurement scales of discontinuation symptoms used in only six of the studies. 

“In most cases the assessment seemed to depend at least partly on the judgment of the authors of the included studies rather than being based on a systematic collection of data,” Dr. Kendrick added.

In an accompanying editorial, Glyn Lewis, PhD, and Gemma Lewis, PhD, University College London, United Kingdom, wrote that though the meta-analysis has its limitations, including the fact that many of the studies were small, often use antidepressants that are not commonly used now, and studied people who had not taken the antidepressants for a very long time, “the results here are a substantial improvement on anything that has been published before.”

They emphasize the importance of discussing the issue of a placebo effect with patients when stopping antidepressants. 

The editorialists pointed out that as antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. However, for individual clinicians, severe withdrawal symptoms will seem uncommon, and most patients will probably not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.

They noted that cessation of antidepressants can lead to an increase in depressive and anxious symptoms, and distinguishing between relapsing symptoms and withdrawal is difficult. 

“Short-term symptoms that reduce quickly, without intervention, are best thought of as a form of withdrawal, even if those symptoms might be similar or identical to the symptoms of depression and anxiety. More serious and longer-term symptoms might best be managed by tapering more slowly, or even deciding to remain on the antidepressant,” the editorialists wrote.

There was no funding source for this study. The authors declare no competing interests. Dr. Kendrick led the NIHR REDUCE trial of internet and telephone support for antidepressant discontinuation and was a member of the guideline committee for the NICE 2022 Depression Guideline.

A version of this article appeared on Medscape.com.

Early education is right up there with motherhood and apple pie as unarguable positive concepts. How could exposing young children to a school-like atmosphere not be a benefit, particularly in communities dominated by socioeconomic challenges? While there are some questions about the value of playing Mozart to infants, early education in the traditional sense continues to be viewed as a key strategy for providing young children a preschool foundation on which a successful academic career can be built. Several oft-cited randomized controlled trials have fueled both private and public interest and funding.

However, a recent commentary published in Science suggests that all programs are “not unequivocally positive and much more research is needed.” “Worrisome results in Tennessee,” “Success in Boston,” and “Largely null results for Headstart” are just a few of the article’s section titles and convey a sense of the inconsistency the investigators found as they reviewed early education systems around the country.

While there may be some politicians who may attempt to use the results of this investigation as a reason to cancel public funding of underperforming early education programs, the authors avoid this baby-and-the-bathwater conclusion. Instead, they urge more rigorous research “to understand how effective programs can be designed and implemented.”

The kind of re-thinking and brainstorming these investigators suggest takes time. While we’re waiting for this process to gain traction, this might be a good time to consider some of the benefits of early education that we don’t usually consider when our focus is on academic metrics.

A recent paper in Children’s Health Care by investigators at the Boston University Medical Center and School of Medicine considered the diet of children attending preschool. Looking at the dietary records of more than 300 children attending 30 childcare centers, the researchers found that the children’s diets before arrival at daycare was less healthy than while they were in daycare. “The hour after pickup appeared to be the least healthful” of any of the time periods surveyed. Of course, we will all conjure up images of what this chaotic post-daycare pickup may look like and cut the harried parents and grandparents some slack when it comes to nutritional choices. However, the bottom line is that for the group of children surveyed being in preschool or daycare protected them from a less healthy diet they were being provided outside of school hours.

Our recent experience with pandemic-related school closures provides more evidence that being in school was superior to any remote experience academically. School-age children and adolescents gained weight when school closures were the norm. Play patterns for children shifted from outdoor play to indoor play — often dominated by more sedentary video games. Both fatal and non-fatal gun-related injuries surged during the pandemic and, by far, the majority of these occur in the home and not at school.

Stepping back to look at this broader picture that includes diet, physical activity, and safety — not to mention the benefits of socialization — leads one to arrive at the unfortunate conclusion that for many children in this country, being at home is considerably less healthy than being in school. Of course there will be those who point to the belief that schools are petri dishes putting children at greater risk for respiratory infections. On the other hand, we must accept that schools haven’t proved to be a major factor in the spread of COVID that many had feared.

The authors of the study in Science are certainly correct in recommending a more thorough investigation into the academic benefits of preschool education. However, we must keep in mind that preschool offers an environment that can be a positive influence on young children.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Early education is right up there with motherhood and apple pie as unarguable positive concepts. How could exposing young children to a school-like atmosphere not be a benefit, particularly in communities dominated by socioeconomic challenges? While there are some questions about the value of playing Mozart to infants, early education in the traditional sense continues to be viewed as a key strategy for providing young children a preschool foundation on which a successful academic career can be built. Several oft-cited randomized controlled trials have fueled both private and public interest and funding.

However, a recent commentary published in Science suggests that all programs are “not unequivocally positive and much more research is needed.” “Worrisome results in Tennessee,” “Success in Boston,” and “Largely null results for Headstart” are just a few of the article’s section titles and convey a sense of the inconsistency the investigators found as they reviewed early education systems around the country.

While there may be some politicians who may attempt to use the results of this investigation as a reason to cancel public funding of underperforming early education programs, the authors avoid this baby-and-the-bathwater conclusion. Instead, they urge more rigorous research “to understand how effective programs can be designed and implemented.”

The kind of re-thinking and brainstorming these investigators suggest takes time. While we’re waiting for this process to gain traction, this might be a good time to consider some of the benefits of early education that we don’t usually consider when our focus is on academic metrics.

A recent paper in Children’s Health Care by investigators at the Boston University Medical Center and School of Medicine considered the diet of children attending preschool. Looking at the dietary records of more than 300 children attending 30 childcare centers, the researchers found that the children’s diets before arrival at daycare was less healthy than while they were in daycare. “The hour after pickup appeared to be the least healthful” of any of the time periods surveyed. Of course, we will all conjure up images of what this chaotic post-daycare pickup may look like and cut the harried parents and grandparents some slack when it comes to nutritional choices. However, the bottom line is that for the group of children surveyed being in preschool or daycare protected them from a less healthy diet they were being provided outside of school hours.

Our recent experience with pandemic-related school closures provides more evidence that being in school was superior to any remote experience academically. School-age children and adolescents gained weight when school closures were the norm. Play patterns for children shifted from outdoor play to indoor play — often dominated by more sedentary video games. Both fatal and non-fatal gun-related injuries surged during the pandemic and, by far, the majority of these occur in the home and not at school.

Stepping back to look at this broader picture that includes diet, physical activity, and safety — not to mention the benefits of socialization — leads one to arrive at the unfortunate conclusion that for many children in this country, being at home is considerably less healthy than being in school. Of course there will be those who point to the belief that schools are petri dishes putting children at greater risk for respiratory infections. On the other hand, we must accept that schools haven’t proved to be a major factor in the spread of COVID that many had feared.

The authors of the study in Science are certainly correct in recommending a more thorough investigation into the academic benefits of preschool education. However, we must keep in mind that preschool offers an environment that can be a positive influence on young children.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Early education is right up there with motherhood and apple pie as unarguable positive concepts. How could exposing young children to a school-like atmosphere not be a benefit, particularly in communities dominated by socioeconomic challenges? While there are some questions about the value of playing Mozart to infants, early education in the traditional sense continues to be viewed as a key strategy for providing young children a preschool foundation on which a successful academic career can be built. Several oft-cited randomized controlled trials have fueled both private and public interest and funding.

However, a recent commentary published in Science suggests that all programs are “not unequivocally positive and much more research is needed.” “Worrisome results in Tennessee,” “Success in Boston,” and “Largely null results for Headstart” are just a few of the article’s section titles and convey a sense of the inconsistency the investigators found as they reviewed early education systems around the country.

While there may be some politicians who may attempt to use the results of this investigation as a reason to cancel public funding of underperforming early education programs, the authors avoid this baby-and-the-bathwater conclusion. Instead, they urge more rigorous research “to understand how effective programs can be designed and implemented.”

The kind of re-thinking and brainstorming these investigators suggest takes time. While we’re waiting for this process to gain traction, this might be a good time to consider some of the benefits of early education that we don’t usually consider when our focus is on academic metrics.

A recent paper in Children’s Health Care by investigators at the Boston University Medical Center and School of Medicine considered the diet of children attending preschool. Looking at the dietary records of more than 300 children attending 30 childcare centers, the researchers found that the children’s diets before arrival at daycare was less healthy than while they were in daycare. “The hour after pickup appeared to be the least healthful” of any of the time periods surveyed. Of course, we will all conjure up images of what this chaotic post-daycare pickup may look like and cut the harried parents and grandparents some slack when it comes to nutritional choices. However, the bottom line is that for the group of children surveyed being in preschool or daycare protected them from a less healthy diet they were being provided outside of school hours.

Our recent experience with pandemic-related school closures provides more evidence that being in school was superior to any remote experience academically. School-age children and adolescents gained weight when school closures were the norm. Play patterns for children shifted from outdoor play to indoor play — often dominated by more sedentary video games. Both fatal and non-fatal gun-related injuries surged during the pandemic and, by far, the majority of these occur in the home and not at school.

Stepping back to look at this broader picture that includes diet, physical activity, and safety — not to mention the benefits of socialization — leads one to arrive at the unfortunate conclusion that for many children in this country, being at home is considerably less healthy than being in school. Of course there will be those who point to the belief that schools are petri dishes putting children at greater risk for respiratory infections. On the other hand, we must accept that schools haven’t proved to be a major factor in the spread of COVID that many had feared.

The authors of the study in Science are certainly correct in recommending a more thorough investigation into the academic benefits of preschool education. However, we must keep in mind that preschool offers an environment that can be a positive influence on young children.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Teenagers who use cannabis have a dramatic increased risk for a psychotic disorder, compared with their counterparts who don’t use the drug, new research showed.

Investigators at the University of Toronto, The Centre for Addiction and Mental Health (CAMH), and the Institute for Clinical Evaluative Sciences (ICES), in Canada, linked recent population-based survey data from more than 11,000 youngsters to health service use records, including hospitalizations, emergency department (ED) visits, and outpatient visits.

“We found a very strong association between cannabis use and risk of psychotic disorder in adolescence [although] surprisingly, we didn’t find evidence of association in young adulthood,” lead author André J. McDonald, PhD, currently a postdoctoral fellow at the Peter Boris Centre for Addictions Research and the Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada, said in a news release.

“These findings are consistent with the neurodevelopmental theory that teens are especially vulnerable to the effects of cannabis,” said Dr. McDonald, who conducted the research.

The study was published online in Psychological Medicine.


 

Increased Potency

“Epidemiologic research suggests that cannabis use may be a significant risk factor for psychotic disorders,” the authors wrote. However, methodological limitations of previous studies make it difficult to estimate the strength of association, with the current evidence base relying largely on cannabis use during the twentieth century, when the drug was “significantly less potent.” It’s plausible that the strength of association has increased due to increased cannabis potency.

The researchers believe youth cannabis use and psychotic disorders is “a critical public health issue,” especially as more jurisdictions liberalize cannabis use and the perception of harm declines among youth.

To estimate the association between cannabis use during youth and the risk for a psychotic disorder diagnosis, using recent population-based data, they used data from the 2009-2012 cycles of the Canadian Community Health Survey (CCHS) linked to administrative health data at ICES to study noninstitutionalized Ontario residents, aged 12-24 years, who had completed the CCHS during that period.

They excluded respondents who used health services for psychotic disorders during the 6 years prior to their CCHS interview date.

Respondents (n = 11,363; 51% men; mean age [SD], 18.3 [15.2-21.3] years) were followed for 6-9 years, with days to first hospitalization, ED visit, or outpatient visit related to a psychotic disorder as the primary outcome.

The researchers estimated age-specific hazard ratios during adolescence (12-19 years) and young adulthood (20-33 years) and conducted sensitivity analyses to explore alternative model conditions, including restricting the outcome to hospitalizations and ED visits, to increase specificity.

Compared with no cannabis use, cannabis use was significantly associated with an 11-fold increased risk for psychotic disorders during adolescence, although not during young adulthood (adjusted hazard ratio [aHR], 11.2; 95% CI, 4.6-27.3 and aHR, 1.3; 95% CI, 0.6-2.6, respectively).
 

Perception of Harm Declining

When the researchers restricted the outcome to hospitalizations and ED visits only, the strength of association “increased markedly” during adolescence, with a 26-fold higher association in cannabis users than in nonusers (aHR, 26.7; 95% CI, 7.7-92.8). However, there was no meaningful change during young adulthood (aHR, 1.8; 95% CI, 0.6-5.4).

“Many have hypothesized that adolescence is a more sensitive risk period than adulthood for the effect of cannabis use on psychotic disorder development, yet prior to this study, little epidemiologic evidence existed to support this view,” the authors wrote.

The data also suggest that cannabis use is “more strongly associated with more severe psychotic outcomes, as the strength of association during adolescence increased markedly when we restricted the outcome to hospitalizations and ED visits (the most severe types of health service use),” the investigators noted.

The authors noted several limitations. For instance, it’s unclear to what extent unmeasured confounders including genetic predisposition, family history of psychotic disorders, and trauma might have biased the results. In addition, they could not assess the potential confounding impact of genetic predisposition to psychotic disorders. The possibility of reverse causality also cannot be ruled out. It’s possible, they noted, that individuals with “psychotic dispositions” may self-medicate or show greater disposition to cannabis use.

Moreover, the dataset neither captured important factors regarding the cannabis itself, including delta-9-tetrahydrocannabinol potency, mode of use, product type, or cannabis dependence, nor captured institutionalized and homeless youth.

Nevertheless, they pointed to the findings as supporting a “precautionary principle” — as more jurisdictions move to liberalize cannabis use and perception of harm declines among youth, the findings suggest that evidence-based cannabis prevention strategies for adolescents are warranted.

This study was supported by CAMH, the University of Toronto, and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The authors declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

Teenagers who use cannabis have a dramatic increased risk for a psychotic disorder, compared with their counterparts who don’t use the drug, new research showed.

Investigators at the University of Toronto, The Centre for Addiction and Mental Health (CAMH), and the Institute for Clinical Evaluative Sciences (ICES), in Canada, linked recent population-based survey data from more than 11,000 youngsters to health service use records, including hospitalizations, emergency department (ED) visits, and outpatient visits.

“We found a very strong association between cannabis use and risk of psychotic disorder in adolescence [although] surprisingly, we didn’t find evidence of association in young adulthood,” lead author André J. McDonald, PhD, currently a postdoctoral fellow at the Peter Boris Centre for Addictions Research and the Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada, said in a news release.

“These findings are consistent with the neurodevelopmental theory that teens are especially vulnerable to the effects of cannabis,” said Dr. McDonald, who conducted the research.

The study was published online in Psychological Medicine.


 

Increased Potency

“Epidemiologic research suggests that cannabis use may be a significant risk factor for psychotic disorders,” the authors wrote. However, methodological limitations of previous studies make it difficult to estimate the strength of association, with the current evidence base relying largely on cannabis use during the twentieth century, when the drug was “significantly less potent.” It’s plausible that the strength of association has increased due to increased cannabis potency.

The researchers believe youth cannabis use and psychotic disorders is “a critical public health issue,” especially as more jurisdictions liberalize cannabis use and the perception of harm declines among youth.

To estimate the association between cannabis use during youth and the risk for a psychotic disorder diagnosis, using recent population-based data, they used data from the 2009-2012 cycles of the Canadian Community Health Survey (CCHS) linked to administrative health data at ICES to study noninstitutionalized Ontario residents, aged 12-24 years, who had completed the CCHS during that period.

They excluded respondents who used health services for psychotic disorders during the 6 years prior to their CCHS interview date.

Respondents (n = 11,363; 51% men; mean age [SD], 18.3 [15.2-21.3] years) were followed for 6-9 years, with days to first hospitalization, ED visit, or outpatient visit related to a psychotic disorder as the primary outcome.

The researchers estimated age-specific hazard ratios during adolescence (12-19 years) and young adulthood (20-33 years) and conducted sensitivity analyses to explore alternative model conditions, including restricting the outcome to hospitalizations and ED visits, to increase specificity.

Compared with no cannabis use, cannabis use was significantly associated with an 11-fold increased risk for psychotic disorders during adolescence, although not during young adulthood (adjusted hazard ratio [aHR], 11.2; 95% CI, 4.6-27.3 and aHR, 1.3; 95% CI, 0.6-2.6, respectively).
 

Perception of Harm Declining

When the researchers restricted the outcome to hospitalizations and ED visits only, the strength of association “increased markedly” during adolescence, with a 26-fold higher association in cannabis users than in nonusers (aHR, 26.7; 95% CI, 7.7-92.8). However, there was no meaningful change during young adulthood (aHR, 1.8; 95% CI, 0.6-5.4).

“Many have hypothesized that adolescence is a more sensitive risk period than adulthood for the effect of cannabis use on psychotic disorder development, yet prior to this study, little epidemiologic evidence existed to support this view,” the authors wrote.

The data also suggest that cannabis use is “more strongly associated with more severe psychotic outcomes, as the strength of association during adolescence increased markedly when we restricted the outcome to hospitalizations and ED visits (the most severe types of health service use),” the investigators noted.

The authors noted several limitations. For instance, it’s unclear to what extent unmeasured confounders including genetic predisposition, family history of psychotic disorders, and trauma might have biased the results. In addition, they could not assess the potential confounding impact of genetic predisposition to psychotic disorders. The possibility of reverse causality also cannot be ruled out. It’s possible, they noted, that individuals with “psychotic dispositions” may self-medicate or show greater disposition to cannabis use.

Moreover, the dataset neither captured important factors regarding the cannabis itself, including delta-9-tetrahydrocannabinol potency, mode of use, product type, or cannabis dependence, nor captured institutionalized and homeless youth.

Nevertheless, they pointed to the findings as supporting a “precautionary principle” — as more jurisdictions move to liberalize cannabis use and perception of harm declines among youth, the findings suggest that evidence-based cannabis prevention strategies for adolescents are warranted.

This study was supported by CAMH, the University of Toronto, and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The authors declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

Teenagers who use cannabis have a dramatic increased risk for a psychotic disorder, compared with their counterparts who don’t use the drug, new research showed.

Investigators at the University of Toronto, The Centre for Addiction and Mental Health (CAMH), and the Institute for Clinical Evaluative Sciences (ICES), in Canada, linked recent population-based survey data from more than 11,000 youngsters to health service use records, including hospitalizations, emergency department (ED) visits, and outpatient visits.

“We found a very strong association between cannabis use and risk of psychotic disorder in adolescence [although] surprisingly, we didn’t find evidence of association in young adulthood,” lead author André J. McDonald, PhD, currently a postdoctoral fellow at the Peter Boris Centre for Addictions Research and the Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada, said in a news release.

“These findings are consistent with the neurodevelopmental theory that teens are especially vulnerable to the effects of cannabis,” said Dr. McDonald, who conducted the research.

The study was published online in Psychological Medicine.


 

Increased Potency

“Epidemiologic research suggests that cannabis use may be a significant risk factor for psychotic disorders,” the authors wrote. However, methodological limitations of previous studies make it difficult to estimate the strength of association, with the current evidence base relying largely on cannabis use during the twentieth century, when the drug was “significantly less potent.” It’s plausible that the strength of association has increased due to increased cannabis potency.

The researchers believe youth cannabis use and psychotic disorders is “a critical public health issue,” especially as more jurisdictions liberalize cannabis use and the perception of harm declines among youth.

To estimate the association between cannabis use during youth and the risk for a psychotic disorder diagnosis, using recent population-based data, they used data from the 2009-2012 cycles of the Canadian Community Health Survey (CCHS) linked to administrative health data at ICES to study noninstitutionalized Ontario residents, aged 12-24 years, who had completed the CCHS during that period.

They excluded respondents who used health services for psychotic disorders during the 6 years prior to their CCHS interview date.

Respondents (n = 11,363; 51% men; mean age [SD], 18.3 [15.2-21.3] years) were followed for 6-9 years, with days to first hospitalization, ED visit, or outpatient visit related to a psychotic disorder as the primary outcome.

The researchers estimated age-specific hazard ratios during adolescence (12-19 years) and young adulthood (20-33 years) and conducted sensitivity analyses to explore alternative model conditions, including restricting the outcome to hospitalizations and ED visits, to increase specificity.

Compared with no cannabis use, cannabis use was significantly associated with an 11-fold increased risk for psychotic disorders during adolescence, although not during young adulthood (adjusted hazard ratio [aHR], 11.2; 95% CI, 4.6-27.3 and aHR, 1.3; 95% CI, 0.6-2.6, respectively).
 

Perception of Harm Declining

When the researchers restricted the outcome to hospitalizations and ED visits only, the strength of association “increased markedly” during adolescence, with a 26-fold higher association in cannabis users than in nonusers (aHR, 26.7; 95% CI, 7.7-92.8). However, there was no meaningful change during young adulthood (aHR, 1.8; 95% CI, 0.6-5.4).

“Many have hypothesized that adolescence is a more sensitive risk period than adulthood for the effect of cannabis use on psychotic disorder development, yet prior to this study, little epidemiologic evidence existed to support this view,” the authors wrote.

The data also suggest that cannabis use is “more strongly associated with more severe psychotic outcomes, as the strength of association during adolescence increased markedly when we restricted the outcome to hospitalizations and ED visits (the most severe types of health service use),” the investigators noted.

The authors noted several limitations. For instance, it’s unclear to what extent unmeasured confounders including genetic predisposition, family history of psychotic disorders, and trauma might have biased the results. In addition, they could not assess the potential confounding impact of genetic predisposition to psychotic disorders. The possibility of reverse causality also cannot be ruled out. It’s possible, they noted, that individuals with “psychotic dispositions” may self-medicate or show greater disposition to cannabis use.

Moreover, the dataset neither captured important factors regarding the cannabis itself, including delta-9-tetrahydrocannabinol potency, mode of use, product type, or cannabis dependence, nor captured institutionalized and homeless youth.

Nevertheless, they pointed to the findings as supporting a “precautionary principle” — as more jurisdictions move to liberalize cannabis use and perception of harm declines among youth, the findings suggest that evidence-based cannabis prevention strategies for adolescents are warranted.

This study was supported by CAMH, the University of Toronto, and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The authors declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

Seltorexant, an investigational drug being developed by Johnson & Johnson, met all primary and secondary endpoints in a phase 3 trial of patients with major depressive disorder (MDD) with insomnia symptoms, the company has announced.

Seltorexant is an investigational potential first-in-class selective antagonist of the human orexin 2 receptor being studied for the adjunctive treatment of MDD with insomnia symptoms. Its selective mechanism of action means it has the potential to improve both mood and sleep symptoms associated with depression.

The phase 3 MDD3001 study was a multicenter, randomized, double-blind trial comparing the efficacy and safety of 20-mg oral seltorexant once daily with placebo, added to background selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) therapy, for improving depressive symptoms in adult and elderly patients with MDD with insomnia symptoms.

In the study, seltorexant led to “statistically significant and clinically meaningful” improvement in depressive symptoms based on the Montgomery-Asberg Depression Rating Scale total score, as well as improved sleep disturbance outcomes, in patients with moderate to severe depression and severe sleep disturbance who had a prior inadequate response to SSRI/SNRI antidepressants alone, the company announced in a statement.

Consistent with previous trials of seltorexant, the drug was safe and well-tolerated, with similar rates of common adverse events seen in both treatment groups.

“Depression is a leading cause of disability worldwide and shares a strong link with sleep disturbances. In MDD, insomnia symptoms exacerbate the risk of depressive relapse, increase healthcare costs, and impact quality of life, and it often goes undertreated despite being one of the most common residual symptoms,” Andrew Krystal, MD, professor of psychiatry, University of California, San Francisco Weill Institute for Neurosciences, said in the statement.

“Seltorexant has the potential to fill a significant unmet need for new therapies to treat patients experiencing depression and insomnia and, most importantly, to improve outcomes and quality of life for these patients,” Dr. Krystal added.

The topline results are being presented at the American Society of Clinical Psychopharmacology (ASCP) 2024 Annual Meeting in Miami, Florida.

The positive phase 3 data follow earlier promising data reported in 2022, as reported by this news organization.

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

Seltorexant, an investigational drug being developed by Johnson & Johnson, met all primary and secondary endpoints in a phase 3 trial of patients with major depressive disorder (MDD) with insomnia symptoms, the company has announced.

Seltorexant is an investigational potential first-in-class selective antagonist of the human orexin 2 receptor being studied for the adjunctive treatment of MDD with insomnia symptoms. Its selective mechanism of action means it has the potential to improve both mood and sleep symptoms associated with depression.

The phase 3 MDD3001 study was a multicenter, randomized, double-blind trial comparing the efficacy and safety of 20-mg oral seltorexant once daily with placebo, added to background selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) therapy, for improving depressive symptoms in adult and elderly patients with MDD with insomnia symptoms.

In the study, seltorexant led to “statistically significant and clinically meaningful” improvement in depressive symptoms based on the Montgomery-Asberg Depression Rating Scale total score, as well as improved sleep disturbance outcomes, in patients with moderate to severe depression and severe sleep disturbance who had a prior inadequate response to SSRI/SNRI antidepressants alone, the company announced in a statement.

Consistent with previous trials of seltorexant, the drug was safe and well-tolerated, with similar rates of common adverse events seen in both treatment groups.

“Depression is a leading cause of disability worldwide and shares a strong link with sleep disturbances. In MDD, insomnia symptoms exacerbate the risk of depressive relapse, increase healthcare costs, and impact quality of life, and it often goes undertreated despite being one of the most common residual symptoms,” Andrew Krystal, MD, professor of psychiatry, University of California, San Francisco Weill Institute for Neurosciences, said in the statement.

“Seltorexant has the potential to fill a significant unmet need for new therapies to treat patients experiencing depression and insomnia and, most importantly, to improve outcomes and quality of life for these patients,” Dr. Krystal added.

The topline results are being presented at the American Society of Clinical Psychopharmacology (ASCP) 2024 Annual Meeting in Miami, Florida.

The positive phase 3 data follow earlier promising data reported in 2022, as reported by this news organization.

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

Seltorexant, an investigational drug being developed by Johnson & Johnson, met all primary and secondary endpoints in a phase 3 trial of patients with major depressive disorder (MDD) with insomnia symptoms, the company has announced.

Seltorexant is an investigational potential first-in-class selective antagonist of the human orexin 2 receptor being studied for the adjunctive treatment of MDD with insomnia symptoms. Its selective mechanism of action means it has the potential to improve both mood and sleep symptoms associated with depression.

The phase 3 MDD3001 study was a multicenter, randomized, double-blind trial comparing the efficacy and safety of 20-mg oral seltorexant once daily with placebo, added to background selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) therapy, for improving depressive symptoms in adult and elderly patients with MDD with insomnia symptoms.

In the study, seltorexant led to “statistically significant and clinically meaningful” improvement in depressive symptoms based on the Montgomery-Asberg Depression Rating Scale total score, as well as improved sleep disturbance outcomes, in patients with moderate to severe depression and severe sleep disturbance who had a prior inadequate response to SSRI/SNRI antidepressants alone, the company announced in a statement.

Consistent with previous trials of seltorexant, the drug was safe and well-tolerated, with similar rates of common adverse events seen in both treatment groups.

“Depression is a leading cause of disability worldwide and shares a strong link with sleep disturbances. In MDD, insomnia symptoms exacerbate the risk of depressive relapse, increase healthcare costs, and impact quality of life, and it often goes undertreated despite being one of the most common residual symptoms,” Andrew Krystal, MD, professor of psychiatry, University of California, San Francisco Weill Institute for Neurosciences, said in the statement.

“Seltorexant has the potential to fill a significant unmet need for new therapies to treat patients experiencing depression and insomnia and, most importantly, to improve outcomes and quality of life for these patients,” Dr. Krystal added.

The topline results are being presented at the American Society of Clinical Psychopharmacology (ASCP) 2024 Annual Meeting in Miami, Florida.

The positive phase 3 data follow earlier promising data reported in 2022, as reported by this news organization.

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

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.

What if there were tests that could tell you whether the following drugs were a good match for your patients: Antidepressants, statins, painkillers, anticlotting medicines, chemotherapy agents, HIV treatments, organ transplant antirejection drugs, proton pump inhibitors for heartburn, and more?

That’s quite a list. And that’s pharmacogenetics, testing patients for genetic differences that affect how well a given drug will work for them and what kind of side effects to expect.

“About 9 out of 10 people will have a genetic difference in their DNA that can impact how they respond to common medications,” said Emily J. Cicali, PharmD, a clinical associate at the University of Florida College of Pharmacy, Gainesville.

Dr. Cicali is the clinical director of UF Health’s MyRx, a virtual program that gives Florida and New Jersey residents access to pharmacogenetic (PGx) tests plus expert interpretation by the health system’s pharmacists. Genetic factors are thought to contribute to about 25% or more of inappropriate drug responses or adverse events, said Kristin Wiisanen, PharmD, dean of the College of Pharmacy at Rosalind Franklin University of Medicine and Science in North Chicago.

“Pharmacogenetics helps consumers avoid drugs that may not work well for them or could cause serious adverse events. It’s personalized medicine,” Dr. Cicali said.

Through a cheek swab or blood sample, the MyRx program — and a growing number of health system programs, doctors’ offices, and home tests available across the United States — gives consumers a window on inherited gene variants that can affect how their body activates, metabolizes, and clears away medications from a long list of widely used drugs.

Why PGx Tests Can Have a Big Impact

These tests work by looking for genes that control drug metabolism.

“You have several different drug-metabolizing enzymes in your liver,” Dr. Cicali explained. “Pharmacogenetic tests look for gene variants that encode for these enzymes. If you’re an ultrarapid metabolizer, you have more of the enzymes that metabolize certain drugs, and there could be a risk the drug won’t work well because it doesn’t stay in the body long enough. On the other end of the spectrum, poor metabolizers have low levels of enzymes that affect certain drugs, so the drugs hang around longer and cause side effects.”

While pharmacogenetics is still considered an emerging science, it’s becoming more mainstream as test prices drop, insurance coverage expands, and an explosion of new research boosts understanding of gene-drug interactions, Dr. Wiisanen said.

Politicians are trying to extend its reach, too. The Right Drug Dose Now Act of 2024, introduced in Congress in late March, aims to accelerate the use of PGx by boosting public awareness and by inserting PGx test results into consumers’ electronic health records. (Though a similar bill died in a US House subcommittee in 2023.)

“The use of pharmacogenetic data to guide prescribing is growing rapidly,” Dr. Wiisanen said. “It’s becoming a routine part of drug therapy for many medications.”

What the Research Shows

When researchers sequenced the DNA of more than 10,000 Mayo Clinic patients, they made a discovery that might surprise many Americans: Gene variants that affect the effectiveness and safety of widely used drugs are not rare glitches. More than 99% of study participants had at least one. And 79% had three or more.

The Mayo-Baylor RIGHT 10K Study — one of the largest PGx studies ever conducted in the United States — looked at 77 gene variants, most involved with drug metabolism in the liver. Researchers focused closely on 13 with extensively studied, gene-based prescribing recommendations for 21 drugs including antidepressants, statins, pain killers, anticlotting medications for heart conditions, HIV treatments, chemotherapy agents, and antirejection drugs for organ transplants.

When researchers added participants’ genetic data to their electronic health records, they also sent semi-urgent alerts, which are alerts with the potential for severe harm, to the clinicians of 61 study volunteers. Over half changed patients’ drugs or doses.

The changes made a difference. One participant taking the pain drug tramadol turned out to be a poor metabolizer and was having dizzy spells because blood levels of the drug stayed high for long periods. Stopping tramadol stopped the dizziness. A participant taking escitalopram plus bupropion for major depression found out that the combo was likely ineffective because they metabolized escitalopram rapidly. A switch to a higher dose of bupropion alone put their depression into full remission.

“So many factors play into how you respond to medications,” said Mayo Clinic pharmacogenomics pharmacist Jessica Wright, PharmD, BCACP, one of the study authors. “Genetics is one of those pieces. Pharmacogenetic testing can reveal things that clinicians may not have been aware of or could help explain a patient’s exaggerated side effect.”

Pharmacogenetics is also called pharmacogenomics. The terms are often used interchangeably, even among PGx pharmacists, though the first refers to how individual genes influence drug response and the second to the effects of multiple genes, said Kelly E. Caudle, PharmD, PhD, an associate member of the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. Dr. Caudle is also co-principal investigator and director of the National Institutes of Health (NIH)-funded Clinical Pharmacogenetics Implementation Consortium (CPIC). The group creates, publishes, and posts evidence-based clinical practice guidelines for drugs with well-researched PGx influences.

By any name, PGx may help explain, predict, and sidestep unpredictable responses to a variety of drugs:

• In a 2023 multicenter study of 6944 people from seven European countries in The Lancet, those given customized drug treatments based on a 12-gene PGx panel had 30% fewer side effects than those who didn’t get this personalized prescribing. People in the study were being treated for cancer, heart disease, and mental health issues, among other conditions.
• In a 2023  from China’s Tongji University, Shanghai, of 650 survivors of strokes and transient ischemic attacks, those whose antiplatelet drugs (such as clopidogrel) were customized based on PGx testing had a lower risk for stroke and other vascular events in the next 90 days. The study was published in Frontiers in Pharmacology.
• In a University of Pennsylvania  of 1944 adults with major depression, published in the Journal of the American Medical Association, those whose antidepressants were guided by PGx test results were 28% more likely to go into remission during the first 24 weeks of treatment than those in a control group. But by 24 weeks, equal numbers were in remission. A 2023 Chinese  of 11 depression studies, published in BMC Psychiatry, came to a similar conclusion: PGx-guided antidepressant prescriptions may help people feel better quicker, perhaps by avoiding some of the usual trial-and-error of different depression drugs.

PGx checks are already strongly recommended or considered routine before some medications are prescribed. These include abacavir (Ziagen), an antiviral treatment for HIV that can have severe side effects in people with one gene variant.

The US Food and Drug Administration (FDA) recommends genetic testing for people with colon cancer before starting the drug irinotecan (Camptosar), which can cause severe diarrhea and raise infection risk in people with a gene variant that slows the drug’s elimination from the body.

Genetic testing is also recommended by the FDA for people with acute lymphoblastic leukemia before receiving the chemotherapy drug mercaptopurine (Purinethol) because a gene variant that affects drug processing can trigger serious side effects and raise the risk for infection at standard dosages.

“One of the key benefits of pharmacogenomic testing is in preventing adverse drug reactions,” Dr. Wiisanen said. “Testing of the thiopurine methyltransferase enzyme to guide dosing with 6-mercaptopurine or azathioprine can help prevent myelosuppression, a serious adverse drug reaction caused by lower production of blood cells in bone marrow.”

When, Why, and How to Test

“A family doctor should consider a PGx test if a patient is planning on taking a medication for which there is a CPIC guideline with a dosing recommendation,” said Teri Klein, PhD, professor of biomedical data science at Stanford University in California, and principal investigator at PharmGKB, an online resource funded by the NIH that provides information for healthcare practitioners, researchers, and consumers about PGx. Affiliated with CPIC, it’s based at Stanford University.

You might also consider it for patients already on a drug who are “not responding or experiencing side effects,” Dr. Caudle said.

Here’s how four PGx experts suggest consumers and physicians approach this option.

Find a Test

More than a dozen PGx tests are on the market — some only a provider can order, others a consumer can order after a review by their provider or by a provider from the testing company. Some of the tests (using saliva) may be administered at home, while blood tests are done in a doctor’s office or laboratory. Companies that offer the tests include ARUP Laboratories, Genomind, Labcorp, Mayo Clinic Laboratories, Myriad Neuroscience, Precision Sciences Inc., Tempus, and OneOme, but there are many others online. (Keep in mind that many laboratories offer “lab-developed tests” — created for use in a single laboratory — but these can be harder to verify. “The FDA regulates pharmacogenomic testing in laboratories,” Dr. Wiisanen said, “but many of the regulatory parameters are still being defined.”)

Because PGx is so new, there is no official list of recommended tests. So you’ll have to do a little homework. You can check that the laboratory is accredited by searching for it in the NIH Genetic Testing Laboratory Registry database. Beyond that, you’ll have to consult other evidence-based resources to confirm that the drug you’re interested in has research-backed data about specific gene variants (alleles) that affect metabolism as well as research-based clinical guidelines for using PGx results to make prescribing decisions.

The CPIC’s guidelines include dosing and alternate drug recommendations for more than 100 antidepressants, chemotherapy drugs, the antiplatelet and anticlotting drugs clopidogrel and warfarin, local anesthetics, antivirals and antibacterials, pain killers and anti-inflammatory drugs, and some cholesterol-lowering statins such as lovastatin and fluvastatin.

For help figuring out if a test looks for the right gene variants, Dr. Caudle and Dr. Wright recommended checking with the Association for Molecular Pathology’s website. The group published a brief list of best practices for pharmacogenomic testing in 2019. And it keeps a list of gene variants (alleles) that should be included in tests. Clinical guidelines from the CPIC and other groups, available on PharmGKB’s website, also list gene variants that affect the metabolism of the drug.

Consider Cost

The price tag for a test is typically several hundred dollars — but it can run as high as $1000-$2500. And health insurance doesn’t always pick up the tab.

In a 2023 University of Florida study of more than 1000 insurance claims for PGx testing, the number reimbursed varied from 72% for a pain diagnosis to 52% for cardiology to 46% for psychiatry.

Medicare covers some PGx testing when a consumer and their providers meet certain criteria, including whether a drug being considered has a significant gene-drug interaction. California’s Medi-Cal health insurance program covers PGx as do Medicaid programs in some states, including Arkansas and Rhode Island. You can find state-by-state coverage information on the Genetics Policy Hub’s website.

Understand the Results

As more insurers cover PGx, Dr. Klein and Dr. Wiisanen say the field will grow and more providers will use it to inform prescribing. But some health systems aren’t waiting.

In addition to UF Health’s MyRx, PGx is part of personalized medicine programs at the University of Pennsylvania in Philadelphia, Endeavor Health in Chicago, the Mayo Clinic, the University of California, San Francisco, Sanford Health in Sioux Falls, South Dakota, and St. Jude Children’s Research Hospital in Memphis, Tennessee.

Beyond testing, they offer a very useful service: A consult with a pharmacogenetics pharmacist to review the results and explain what they mean for a consumer’s current and future medications.

Physicians and curious consumers can also consult CPIC’s guidelines, which give recommendations about how to interpret the results of a PGx test, said Dr. Klein, a co-principal investigator at CPIC. CPIC has a grading system for both the evidence that supports the recommendation (high, moderate, or weak) and the recommendation itself (strong, moderate, or optional).

Currently, labeling for 456 prescription drugs sold in the United States includes some type of PGx information, according to the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and an annotated guide from PharmGKB.

Just 108 drug labels currently tell doctors and patients what to do with the information — such as requiring or suggesting testing or offering prescribing recommendations, according to PharmGKB. In contrast, PharmGKB’s online resources include evidence-based clinical guidelines for 201 drugs from CPIC and from professional PGx societies in the Netherlands, Canada, France, and elsewhere.

Consumers and physicians can also look for a pharmacist with pharmacogenetics training in their area or through a nearby medical center to learn more, Dr. Wright suggested. And while consumers can test without working with their own physician, the experts advise against it. Don’t stop or change the dose of medications you already take on your own, they say . And do work with your primary care practitioner or specialist to get tested and understand how the results fit into the bigger picture of how your body responds to your medications.

A version of this article appeared on Medscape.com.