Clinical Psychiatry News

Attention-deficit/hyperactivity disorder (ADHD) is often a very challenging condition for parents to manage, both because of the “gleeful mayhem” children with ADHD manifest and because of the nature of effective treatments. Multiple randomized controlled studies and meta-analyses have demonstrated that stimulant medication with behavioral interventions is the optimal first-line treatment for children with both subtypes of ADHD, and that medications alone are superior to behavioral interventions alone. By improving attention and impulse control, the medications effectively decrease the many negative interactions with teachers, peers, and parents, aiding development and healthy self-esteem.

But many parents feel anxious about treating their young children with stimulants. Importantly, how children with ADHD will fare as adults is not predicted by their symptom level, but instead by the quality of their relationships with their parents, their ability to perform at school, and their social skills. Bring this framework to parents as you listen to their questions and help them decide on the best approach for their family. To assist you in these conversations, we will review the evidence for (or against) several of the most common alternatives to medication that parents are likely to ask about.
 

Diets and supplements

Dietary modifications are among the most popular “natural” approaches to managing ADHD in children. Diets that eliminate processed sugars or food additives (particularly artificial food coloring) are among the most common approaches discussed in the lay press. These diets are usually very time-consuming and disruptive for families to follow, and there is no evidence to support their general use in ADHD management. Those studies that rigorously examined them suggest that, for children with severe impairment who have failed to respond to medications for ADHD, a workup for food intolerance or nutritional deficits may reveal a different problem underlying their behavioral difficulties.¹

Similarly, supplementation with high-dose omega-3 fatty acids is modestly helpful only in a subset of children with ADHD symptoms, and not nearly as effective as medications or behavioral interventions. Spending time on an exacting diet or buying expensive supplements is very unlikely to relieve the children’s symptoms and may only add to their stress at home. The “sugar high” parents note may be the rare joy of eating a candy bar and not sugar causing ADHD. Offer parents the guidance to focus on a healthy diet, high in fruits and vegetables, whole grains, and healthy protein, and on meals that emphasize family time instead of struggles around food.
 

Neurofeedback

Neurofeedback is an approach that grew out of the observation that many adults with ADHD had resting patterns of brain wave activity different from those of neurotypical adults. In neurofeedback, patients learn strategies that amplify the brain waves associated with focused mental activity, rather than listless or hyperactive states. Businesses market this service for all sorts of illnesses and challenges, ADHD chief among them. Despite the marketing, there are very few randomized controlled studies of this intervention for ADHD in youth, and those have shown only the possibility of a benefit.

While there is no evidence of serious side effects, these treatments are time-consuming and expensive and unlikely to be covered by any insurance. You might suggest to parents that they could achieve some of the same theoretical benefits by looking for hobbies that invite sustained focus in their children. That is, they should think about activities that interest the children, such as music lessons or karate, that they could practice in classes and at home. If the children find these activities even somewhat interesting (or just enjoy the reward of their parents’ or teachers’ attention), regular practice will be supporting their developing attention while building social skills and authentic self-confidence, rather than the activities feeling like a treatment for an illness or condition.

Sleep and exercise

There are not many businesses or books selling worried and exhausted parents a quick nonmedication solution for their children’s ADHD in the form of healthy sleep and exercise habits. But these are safe and healthy ways to reduce symptoms and support development. Children with ADHD often enjoy and benefit from participating in a sport, and daily exercise can help with sleep and regulating their energy. They also often have difficulty with sleep initiation, and commonly do not get adequate or restful sleep. Inadequate sleep exacerbates inattention, distractibility, and irritability. Children with untreated ADHD also often spend a lot of time on screens, as it is difficult for them to shift away from rewarding activities, and parents can find screen time to be a welcome break from hyperactivity and negative interactions. But excessive screen time, especially close to bedtime, can worsen irritability and make sleep more difficult. Talk with parents about the value of establishing a routine around screen time, modest daily physical activity, and sleep that everyone can follow. If their family life is currently marked by late bedtimes and long hours in front of video games, this change will take effort. But within a few weeks, it could lead to significant improvements in energy, attention, and interactions at home.

Behavioral treatments

Effective behavioral treatments for ADHD do not change ADHD symptoms, but they do help children learn how to manage them. In “parent management training,” younger children and parents learn together how to avoid negative cycles of behavior (i.e., temper outbursts) by focusing on consistent routines and consequences that support children calmly learning to manage their impulses. The only other evidence-based treatment focuses on helping school age and older children develop executive functions – their planning, organization, and time management skills – with a range of age-appropriate tools. Both of these therapies may be more effective if the children are also receiving medication, but medication is not necessary for them to be helpful. It is important to note that play therapy and other evidence-based psychotherapies are not effective for management of ADHD, although they may treat comorbid problems.

Parent treatment

You may have diagnosed children with ADHD only to hear their parents respond by saying that they suspect (or know) that they (or their spouses) also have ADHD. This would not be surprising, as ADHD has one of the highest rates of heritability of psychiatric disorders, at 80%. Somewhere between 25% and 50% of parents of children with ADHD have ADHD themselves.² Screening for adults with ADHD, such as the Adult ADHD Self-Report Scale, is widely available and free. Speak with parents about the fact that behavioral treatments for their children’s ADHD are demanding. Such treatments require patience, calm, organization, and consistency.

If parents have ADHD, it may be very helpful for them to prioritize their own effective treatments, so that their attention and impulse control will support their parenting. They may be interested in learning about how treatment might also improve their performance at work and even the quality of their relationships. While there is some evidence that their children’s treatment outcome will hinge on the parents’ treatment,³ they deserve good care independent of the expectations of parenting.

Families benefit from a comprehensive “ADHD plan” for their children. This would start with an assessment of the severity of their children’s symptoms, specifying their impairment at home, school, and in social relationships. It would include their nonacademic performance, exploration of interests, and developing self-confidence. All of these considerations lead to setting reasonable expectations so the children can feel successful. Parents should think about how best to structure their children’s schedules to promote healthy sleep, exercise, and nutrition, and to expand opportunities for building their frustration tolerance, social skills, and executive function.

Parents will need to consider what kind of supports they themselves need to offer this structure. There are good resources available online for information and support, including Children and Adults with ADHD (chadd.org) and the ADHD Resource Center from the American Academy of Child and Adolescent Psychiatry (aacap.org). This approach may help parents to evaluate the potential risks and benefits of medications as a component of treatment. Most of the quick fixes for childhood ADHD on the market will take a family’s time and money without providing meaningful improvement. Parents should focus instead on the tried-and-true routines and supports that will help them to create the setting at home that will enable their children to flourish.
 

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at pdnews@mdedge.com.

References

1. Millichap JG and Yee MM. Pediatrics. 2012 Feb;129(2):330-7.

2. Grimm O et al. Curr Psychiatry Rep. 2020 Feb 27;22(4):18.

3. Chronis-Tuscano A et al. J Abnorm Child Psychol. 2017 Apr;45(3):501-7.

Attention-deficit/hyperactivity disorder (ADHD) is often a very challenging condition for parents to manage, both because of the “gleeful mayhem” children with ADHD manifest and because of the nature of effective treatments. Multiple randomized controlled studies and meta-analyses have demonstrated that stimulant medication with behavioral interventions is the optimal first-line treatment for children with both subtypes of ADHD, and that medications alone are superior to behavioral interventions alone. By improving attention and impulse control, the medications effectively decrease the many negative interactions with teachers, peers, and parents, aiding development and healthy self-esteem.

But many parents feel anxious about treating their young children with stimulants. Importantly, how children with ADHD will fare as adults is not predicted by their symptom level, but instead by the quality of their relationships with their parents, their ability to perform at school, and their social skills. Bring this framework to parents as you listen to their questions and help them decide on the best approach for their family. To assist you in these conversations, we will review the evidence for (or against) several of the most common alternatives to medication that parents are likely to ask about.
 

Diets and supplements

Dietary modifications are among the most popular “natural” approaches to managing ADHD in children. Diets that eliminate processed sugars or food additives (particularly artificial food coloring) are among the most common approaches discussed in the lay press. These diets are usually very time-consuming and disruptive for families to follow, and there is no evidence to support their general use in ADHD management. Those studies that rigorously examined them suggest that, for children with severe impairment who have failed to respond to medications for ADHD, a workup for food intolerance or nutritional deficits may reveal a different problem underlying their behavioral difficulties.¹

Similarly, supplementation with high-dose omega-3 fatty acids is modestly helpful only in a subset of children with ADHD symptoms, and not nearly as effective as medications or behavioral interventions. Spending time on an exacting diet or buying expensive supplements is very unlikely to relieve the children’s symptoms and may only add to their stress at home. The “sugar high” parents note may be the rare joy of eating a candy bar and not sugar causing ADHD. Offer parents the guidance to focus on a healthy diet, high in fruits and vegetables, whole grains, and healthy protein, and on meals that emphasize family time instead of struggles around food.
 

Neurofeedback

Neurofeedback is an approach that grew out of the observation that many adults with ADHD had resting patterns of brain wave activity different from those of neurotypical adults. In neurofeedback, patients learn strategies that amplify the brain waves associated with focused mental activity, rather than listless or hyperactive states. Businesses market this service for all sorts of illnesses and challenges, ADHD chief among them. Despite the marketing, there are very few randomized controlled studies of this intervention for ADHD in youth, and those have shown only the possibility of a benefit.

While there is no evidence of serious side effects, these treatments are time-consuming and expensive and unlikely to be covered by any insurance. You might suggest to parents that they could achieve some of the same theoretical benefits by looking for hobbies that invite sustained focus in their children. That is, they should think about activities that interest the children, such as music lessons or karate, that they could practice in classes and at home. If the children find these activities even somewhat interesting (or just enjoy the reward of their parents’ or teachers’ attention), regular practice will be supporting their developing attention while building social skills and authentic self-confidence, rather than the activities feeling like a treatment for an illness or condition.

Sleep and exercise

There are not many businesses or books selling worried and exhausted parents a quick nonmedication solution for their children’s ADHD in the form of healthy sleep and exercise habits. But these are safe and healthy ways to reduce symptoms and support development. Children with ADHD often enjoy and benefit from participating in a sport, and daily exercise can help with sleep and regulating their energy. They also often have difficulty with sleep initiation, and commonly do not get adequate or restful sleep. Inadequate sleep exacerbates inattention, distractibility, and irritability. Children with untreated ADHD also often spend a lot of time on screens, as it is difficult for them to shift away from rewarding activities, and parents can find screen time to be a welcome break from hyperactivity and negative interactions. But excessive screen time, especially close to bedtime, can worsen irritability and make sleep more difficult. Talk with parents about the value of establishing a routine around screen time, modest daily physical activity, and sleep that everyone can follow. If their family life is currently marked by late bedtimes and long hours in front of video games, this change will take effort. But within a few weeks, it could lead to significant improvements in energy, attention, and interactions at home.

Behavioral treatments

Effective behavioral treatments for ADHD do not change ADHD symptoms, but they do help children learn how to manage them. In “parent management training,” younger children and parents learn together how to avoid negative cycles of behavior (i.e., temper outbursts) by focusing on consistent routines and consequences that support children calmly learning to manage their impulses. The only other evidence-based treatment focuses on helping school age and older children develop executive functions – their planning, organization, and time management skills – with a range of age-appropriate tools. Both of these therapies may be more effective if the children are also receiving medication, but medication is not necessary for them to be helpful. It is important to note that play therapy and other evidence-based psychotherapies are not effective for management of ADHD, although they may treat comorbid problems.

Parent treatment

You may have diagnosed children with ADHD only to hear their parents respond by saying that they suspect (or know) that they (or their spouses) also have ADHD. This would not be surprising, as ADHD has one of the highest rates of heritability of psychiatric disorders, at 80%. Somewhere between 25% and 50% of parents of children with ADHD have ADHD themselves.² Screening for adults with ADHD, such as the Adult ADHD Self-Report Scale, is widely available and free. Speak with parents about the fact that behavioral treatments for their children’s ADHD are demanding. Such treatments require patience, calm, organization, and consistency.

If parents have ADHD, it may be very helpful for them to prioritize their own effective treatments, so that their attention and impulse control will support their parenting. They may be interested in learning about how treatment might also improve their performance at work and even the quality of their relationships. While there is some evidence that their children’s treatment outcome will hinge on the parents’ treatment,³ they deserve good care independent of the expectations of parenting.

Families benefit from a comprehensive “ADHD plan” for their children. This would start with an assessment of the severity of their children’s symptoms, specifying their impairment at home, school, and in social relationships. It would include their nonacademic performance, exploration of interests, and developing self-confidence. All of these considerations lead to setting reasonable expectations so the children can feel successful. Parents should think about how best to structure their children’s schedules to promote healthy sleep, exercise, and nutrition, and to expand opportunities for building their frustration tolerance, social skills, and executive function.

Parents will need to consider what kind of supports they themselves need to offer this structure. There are good resources available online for information and support, including Children and Adults with ADHD (chadd.org) and the ADHD Resource Center from the American Academy of Child and Adolescent Psychiatry (aacap.org). This approach may help parents to evaluate the potential risks and benefits of medications as a component of treatment. Most of the quick fixes for childhood ADHD on the market will take a family’s time and money without providing meaningful improvement. Parents should focus instead on the tried-and-true routines and supports that will help them to create the setting at home that will enable their children to flourish.
 

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at pdnews@mdedge.com.

References

1. Millichap JG and Yee MM. Pediatrics. 2012 Feb;129(2):330-7.

2. Grimm O et al. Curr Psychiatry Rep. 2020 Feb 27;22(4):18.

3. Chronis-Tuscano A et al. J Abnorm Child Psychol. 2017 Apr;45(3):501-7.

Attention-deficit/hyperactivity disorder (ADHD) is often a very challenging condition for parents to manage, both because of the “gleeful mayhem” children with ADHD manifest and because of the nature of effective treatments. Multiple randomized controlled studies and meta-analyses have demonstrated that stimulant medication with behavioral interventions is the optimal first-line treatment for children with both subtypes of ADHD, and that medications alone are superior to behavioral interventions alone. By improving attention and impulse control, the medications effectively decrease the many negative interactions with teachers, peers, and parents, aiding development and healthy self-esteem.

But many parents feel anxious about treating their young children with stimulants. Importantly, how children with ADHD will fare as adults is not predicted by their symptom level, but instead by the quality of their relationships with their parents, their ability to perform at school, and their social skills. Bring this framework to parents as you listen to their questions and help them decide on the best approach for their family. To assist you in these conversations, we will review the evidence for (or against) several of the most common alternatives to medication that parents are likely to ask about.
 

Diets and supplements

Dietary modifications are among the most popular “natural” approaches to managing ADHD in children. Diets that eliminate processed sugars or food additives (particularly artificial food coloring) are among the most common approaches discussed in the lay press. These diets are usually very time-consuming and disruptive for families to follow, and there is no evidence to support their general use in ADHD management. Those studies that rigorously examined them suggest that, for children with severe impairment who have failed to respond to medications for ADHD, a workup for food intolerance or nutritional deficits may reveal a different problem underlying their behavioral difficulties.¹

Similarly, supplementation with high-dose omega-3 fatty acids is modestly helpful only in a subset of children with ADHD symptoms, and not nearly as effective as medications or behavioral interventions. Spending time on an exacting diet or buying expensive supplements is very unlikely to relieve the children’s symptoms and may only add to their stress at home. The “sugar high” parents note may be the rare joy of eating a candy bar and not sugar causing ADHD. Offer parents the guidance to focus on a healthy diet, high in fruits and vegetables, whole grains, and healthy protein, and on meals that emphasize family time instead of struggles around food.
 

Neurofeedback

Neurofeedback is an approach that grew out of the observation that many adults with ADHD had resting patterns of brain wave activity different from those of neurotypical adults. In neurofeedback, patients learn strategies that amplify the brain waves associated with focused mental activity, rather than listless or hyperactive states. Businesses market this service for all sorts of illnesses and challenges, ADHD chief among them. Despite the marketing, there are very few randomized controlled studies of this intervention for ADHD in youth, and those have shown only the possibility of a benefit.

While there is no evidence of serious side effects, these treatments are time-consuming and expensive and unlikely to be covered by any insurance. You might suggest to parents that they could achieve some of the same theoretical benefits by looking for hobbies that invite sustained focus in their children. That is, they should think about activities that interest the children, such as music lessons or karate, that they could practice in classes and at home. If the children find these activities even somewhat interesting (or just enjoy the reward of their parents’ or teachers’ attention), regular practice will be supporting their developing attention while building social skills and authentic self-confidence, rather than the activities feeling like a treatment for an illness or condition.

Sleep and exercise

There are not many businesses or books selling worried and exhausted parents a quick nonmedication solution for their children’s ADHD in the form of healthy sleep and exercise habits. But these are safe and healthy ways to reduce symptoms and support development. Children with ADHD often enjoy and benefit from participating in a sport, and daily exercise can help with sleep and regulating their energy. They also often have difficulty with sleep initiation, and commonly do not get adequate or restful sleep. Inadequate sleep exacerbates inattention, distractibility, and irritability. Children with untreated ADHD also often spend a lot of time on screens, as it is difficult for them to shift away from rewarding activities, and parents can find screen time to be a welcome break from hyperactivity and negative interactions. But excessive screen time, especially close to bedtime, can worsen irritability and make sleep more difficult. Talk with parents about the value of establishing a routine around screen time, modest daily physical activity, and sleep that everyone can follow. If their family life is currently marked by late bedtimes and long hours in front of video games, this change will take effort. But within a few weeks, it could lead to significant improvements in energy, attention, and interactions at home.

Behavioral treatments

Effective behavioral treatments for ADHD do not change ADHD symptoms, but they do help children learn how to manage them. In “parent management training,” younger children and parents learn together how to avoid negative cycles of behavior (i.e., temper outbursts) by focusing on consistent routines and consequences that support children calmly learning to manage their impulses. The only other evidence-based treatment focuses on helping school age and older children develop executive functions – their planning, organization, and time management skills – with a range of age-appropriate tools. Both of these therapies may be more effective if the children are also receiving medication, but medication is not necessary for them to be helpful. It is important to note that play therapy and other evidence-based psychotherapies are not effective for management of ADHD, although they may treat comorbid problems.

Parent treatment

You may have diagnosed children with ADHD only to hear their parents respond by saying that they suspect (or know) that they (or their spouses) also have ADHD. This would not be surprising, as ADHD has one of the highest rates of heritability of psychiatric disorders, at 80%. Somewhere between 25% and 50% of parents of children with ADHD have ADHD themselves.² Screening for adults with ADHD, such as the Adult ADHD Self-Report Scale, is widely available and free. Speak with parents about the fact that behavioral treatments for their children’s ADHD are demanding. Such treatments require patience, calm, organization, and consistency.

If parents have ADHD, it may be very helpful for them to prioritize their own effective treatments, so that their attention and impulse control will support their parenting. They may be interested in learning about how treatment might also improve their performance at work and even the quality of their relationships. While there is some evidence that their children’s treatment outcome will hinge on the parents’ treatment,³ they deserve good care independent of the expectations of parenting.

Families benefit from a comprehensive “ADHD plan” for their children. This would start with an assessment of the severity of their children’s symptoms, specifying their impairment at home, school, and in social relationships. It would include their nonacademic performance, exploration of interests, and developing self-confidence. All of these considerations lead to setting reasonable expectations so the children can feel successful. Parents should think about how best to structure their children’s schedules to promote healthy sleep, exercise, and nutrition, and to expand opportunities for building their frustration tolerance, social skills, and executive function.

Parents will need to consider what kind of supports they themselves need to offer this structure. There are good resources available online for information and support, including Children and Adults with ADHD (chadd.org) and the ADHD Resource Center from the American Academy of Child and Adolescent Psychiatry (aacap.org). This approach may help parents to evaluate the potential risks and benefits of medications as a component of treatment. Most of the quick fixes for childhood ADHD on the market will take a family’s time and money without providing meaningful improvement. Parents should focus instead on the tried-and-true routines and supports that will help them to create the setting at home that will enable their children to flourish.
 

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at pdnews@mdedge.com.

References

1. Millichap JG and Yee MM. Pediatrics. 2012 Feb;129(2):330-7.

2. Grimm O et al. Curr Psychiatry Rep. 2020 Feb 27;22(4):18.

3. Chronis-Tuscano A et al. J Abnorm Child Psychol. 2017 Apr;45(3):501-7.

The highly anticipated Alzheimer’s drug lecanemab was granted accelerated approval status on Jan. 6 by the FDA, offering hope where there has been little for patients and their families affected by the devastating disease.

More than 6 million people in the United States live with Alzheimer’s.

It’s not a cure, but the drug, given intravenously every 2 weeks, has shown moderate positive effects in clinical trials in slowing early-stage disease.

But many are wary. As explained in an editorial in the journal The Lancet, “The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy.”

Some worry about lecanemab’s safety as some people in clinical trials experienced serious side effects of bleeding and swelling in the brain. Scientists recently attributed a third death to lecanemab, brand name Leqembi, though the drugmaker disputed the medication was the cause.

So what should patients and their families make of this news? Here we answer some of the top questions surrounding the drug.
 

What does the FDA action mean?

The FDA granted accelerated approval to Leqembi after it showed positive trial results in slowing the progression of early-stage disease.

The FDA can grant accelerated approval for drugs that treat serious conditions and fill an unmet medical need while drugs continue to be studied in larger trials.

With the FDA approval in hand, doctors can now prescribe the medication.

Rebecca Edelmayer, PhD, the Alzheimer’s Association senior director of scientific engagement, says that with the FDA’s move, ramping up manufacturing – and eventually nationwide distribution and implementation – will take some time.

“Ask your doctor about availability,” she says. “The main issue is that, without insurance and Medicare coverage of this class of treatments, access for those who could benefit from the newly approved treatment will only be available to those who can pay out-of-pocket. Without coverage, people simply won’t be able to get the treatment.”

The Washington Post reports that with accelerated approval, drugmaker Eisai is expected to immediately apply for full FDA approval, which wouldn’t be likely to come before later this year. Full approval could help clear the path for Medicare coverage of the drug.
 

Potential benefit?

Those who got Leqembi in a clinical trial for 18 months experienced 27% less decline in memory and thinking relative to the group who got a placebo. It also reduced amyloid in the brain, the sticky protein that builds up in the brains of people with Alzheimer’s and is considered a hallmark of the disease.

Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, says, “It’s the first phase 3 study in our field of a disease-modifying drug where the clinical efficacy was very clear.”
 

Concerns about side effects

The drug has raised safety concerns as it has been linked with certain serious adverse events, including brain swelling and bleeding. In the trial, 14% of patients who received the drug experienced side effects that included brain swelling and bleeding, compared with about 11% in the placebo group.

Scientists have reportedly linked three deaths during the clinical trial to lecanemab, though it is unclear whether it caused the deaths.

Dr. Fillit notes that the first two people who died were on blood thinners when they received lecanemab.

“There are things about the use of the drug in the real world that we need to work out, especially in the context of people with comorbidities,” he says.

The third death is a little different, Dr. Fillit says. The patient, who had a stroke, showed signs of vasculitis, or inflammation of the blood vessels.

“We don’t know exactly what happened, but we do know it was very, very rare” among the people involved in the trials, he says.

Dr. Edelmayer says that the most common reported side effects during the trials were infusion-related reactions, headache, and amyloid-related imaging abnormalities (ARIA). According to the FDA, these abnormalities “are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur.”

The FDA has added these as warnings to the drug’s label, describing the possible infusion-related reactions as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
 

How much will it cost?

Eisai says that lecanemab will cost $26,500 a year.

In a draft report released in December, the Institute for Clinical and Economic Review said a price ranging from $8,500 to $20,600 a year would make the drug cost-effective. While the group has no authority to set prices, many large health insurers consider its reports when they negotiate prices and some drugmakers take into account ICER’s recommendations when setting prices.

An editorial in The Lancet last month warns that the cost will likely be “prohibitive” for low- and middle-income countries and many health systems don’t have the infrastructure for a widespread rollout.
 

Will Medicare cover it?

The Centers for Medicare & Medicaid Services, which runs Medicare, which covers most people with Alzheimer’s, has indicated it won’t broadly cover amyloid-lowering drugs until the drug gets full U.S. approval based on clinical benefits, as opposed to accelerated approval.

That means people would have to pay thousands out of pocket at first to get it.

The CMS decision effectively denies Medicare coverage of fast-tracked FDA-approved medications for Alzheimer’s disease unless the person is enrolled in an approved clinical trial.

On Dec. 19, the Alzheimer’s Association filed a formal request asking CMS to remove the trial-only requirement and provide full and unrestricted coverage for FDA-approved Alzheimer’s treatments.

CMS says in a statement issued after the announcement: “Because Eisai’s product, lecanemab, was granted accelerated approval by the FDA, it falls under CMS’s existing national coverage determination. CMS is examining available information and may reconsider its current coverage based on this review.”

“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage,” the statement says.
 

Who benefits most from this drug?

Lecanemab is a treatment for people with early-stage Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or those in the later stages of Alzheimer’s disease, are not likely to improve with this drug.

Who makes lecanemab?  

Japan-based Eisai is developing the drug, a monoclonal antibody, in collaboration with the U.S. company Biogen.

What’s the Alzheimer’s Association’s view?

The association urged accelerated FDA approval. In a statement, it says it “welcomes and is further encouraged” by the clinical trial results.

It says data published in the New England Journal of Medicine confirms lecanemab “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”

“We are energized at the progress we are seeing in the research pipeline. The science is telling us that although antiamyloid treatments are not a cure – they are not going to be the end of treating Alzheimer’s – they are certainly the beginning,” Dr. Edelmayer says.
 

Are there alternatives?

The FDA gave accelerated approval to Biogen to produce another drug for Alzheimer’s, Aduhelm (aducanemab), in 2021, but the move was controversial as the drug’s effectiveness was widely questioned. It has since largely been pulled from the market.

Aduhelm had been the first approved early-stage Alzheimer’s treatment since 2003.

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

The highly anticipated Alzheimer’s drug lecanemab was granted accelerated approval status on Jan. 6 by the FDA, offering hope where there has been little for patients and their families affected by the devastating disease.

More than 6 million people in the United States live with Alzheimer’s.

It’s not a cure, but the drug, given intravenously every 2 weeks, has shown moderate positive effects in clinical trials in slowing early-stage disease.

But many are wary. As explained in an editorial in the journal The Lancet, “The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy.”

Some worry about lecanemab’s safety as some people in clinical trials experienced serious side effects of bleeding and swelling in the brain. Scientists recently attributed a third death to lecanemab, brand name Leqembi, though the drugmaker disputed the medication was the cause.

So what should patients and their families make of this news? Here we answer some of the top questions surrounding the drug.
 

What does the FDA action mean?

The FDA granted accelerated approval to Leqembi after it showed positive trial results in slowing the progression of early-stage disease.

The FDA can grant accelerated approval for drugs that treat serious conditions and fill an unmet medical need while drugs continue to be studied in larger trials.

With the FDA approval in hand, doctors can now prescribe the medication.

Rebecca Edelmayer, PhD, the Alzheimer’s Association senior director of scientific engagement, says that with the FDA’s move, ramping up manufacturing – and eventually nationwide distribution and implementation – will take some time.

“Ask your doctor about availability,” she says. “The main issue is that, without insurance and Medicare coverage of this class of treatments, access for those who could benefit from the newly approved treatment will only be available to those who can pay out-of-pocket. Without coverage, people simply won’t be able to get the treatment.”

The Washington Post reports that with accelerated approval, drugmaker Eisai is expected to immediately apply for full FDA approval, which wouldn’t be likely to come before later this year. Full approval could help clear the path for Medicare coverage of the drug.
 

Potential benefit?

Those who got Leqembi in a clinical trial for 18 months experienced 27% less decline in memory and thinking relative to the group who got a placebo. It also reduced amyloid in the brain, the sticky protein that builds up in the brains of people with Alzheimer’s and is considered a hallmark of the disease.

Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, says, “It’s the first phase 3 study in our field of a disease-modifying drug where the clinical efficacy was very clear.”
 

Concerns about side effects

The drug has raised safety concerns as it has been linked with certain serious adverse events, including brain swelling and bleeding. In the trial, 14% of patients who received the drug experienced side effects that included brain swelling and bleeding, compared with about 11% in the placebo group.

Scientists have reportedly linked three deaths during the clinical trial to lecanemab, though it is unclear whether it caused the deaths.

Dr. Fillit notes that the first two people who died were on blood thinners when they received lecanemab.

“There are things about the use of the drug in the real world that we need to work out, especially in the context of people with comorbidities,” he says.

The third death is a little different, Dr. Fillit says. The patient, who had a stroke, showed signs of vasculitis, or inflammation of the blood vessels.

“We don’t know exactly what happened, but we do know it was very, very rare” among the people involved in the trials, he says.

Dr. Edelmayer says that the most common reported side effects during the trials were infusion-related reactions, headache, and amyloid-related imaging abnormalities (ARIA). According to the FDA, these abnormalities “are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur.”

The FDA has added these as warnings to the drug’s label, describing the possible infusion-related reactions as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
 

How much will it cost?

Eisai says that lecanemab will cost $26,500 a year.

In a draft report released in December, the Institute for Clinical and Economic Review said a price ranging from $8,500 to $20,600 a year would make the drug cost-effective. While the group has no authority to set prices, many large health insurers consider its reports when they negotiate prices and some drugmakers take into account ICER’s recommendations when setting prices.

An editorial in The Lancet last month warns that the cost will likely be “prohibitive” for low- and middle-income countries and many health systems don’t have the infrastructure for a widespread rollout.
 

Will Medicare cover it?

The Centers for Medicare & Medicaid Services, which runs Medicare, which covers most people with Alzheimer’s, has indicated it won’t broadly cover amyloid-lowering drugs until the drug gets full U.S. approval based on clinical benefits, as opposed to accelerated approval.

That means people would have to pay thousands out of pocket at first to get it.

The CMS decision effectively denies Medicare coverage of fast-tracked FDA-approved medications for Alzheimer’s disease unless the person is enrolled in an approved clinical trial.

On Dec. 19, the Alzheimer’s Association filed a formal request asking CMS to remove the trial-only requirement and provide full and unrestricted coverage for FDA-approved Alzheimer’s treatments.

CMS says in a statement issued after the announcement: “Because Eisai’s product, lecanemab, was granted accelerated approval by the FDA, it falls under CMS’s existing national coverage determination. CMS is examining available information and may reconsider its current coverage based on this review.”

“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage,” the statement says.
 

Who benefits most from this drug?

Lecanemab is a treatment for people with early-stage Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or those in the later stages of Alzheimer’s disease, are not likely to improve with this drug.

Who makes lecanemab?  

Japan-based Eisai is developing the drug, a monoclonal antibody, in collaboration with the U.S. company Biogen.

What’s the Alzheimer’s Association’s view?

The association urged accelerated FDA approval. In a statement, it says it “welcomes and is further encouraged” by the clinical trial results.

It says data published in the New England Journal of Medicine confirms lecanemab “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”

“We are energized at the progress we are seeing in the research pipeline. The science is telling us that although antiamyloid treatments are not a cure – they are not going to be the end of treating Alzheimer’s – they are certainly the beginning,” Dr. Edelmayer says.
 

Are there alternatives?

The FDA gave accelerated approval to Biogen to produce another drug for Alzheimer’s, Aduhelm (aducanemab), in 2021, but the move was controversial as the drug’s effectiveness was widely questioned. It has since largely been pulled from the market.

Aduhelm had been the first approved early-stage Alzheimer’s treatment since 2003.

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

The highly anticipated Alzheimer’s drug lecanemab was granted accelerated approval status on Jan. 6 by the FDA, offering hope where there has been little for patients and their families affected by the devastating disease.

More than 6 million people in the United States live with Alzheimer’s.

It’s not a cure, but the drug, given intravenously every 2 weeks, has shown moderate positive effects in clinical trials in slowing early-stage disease.

But many are wary. As explained in an editorial in the journal The Lancet, “The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy.”

Some worry about lecanemab’s safety as some people in clinical trials experienced serious side effects of bleeding and swelling in the brain. Scientists recently attributed a third death to lecanemab, brand name Leqembi, though the drugmaker disputed the medication was the cause.

So what should patients and their families make of this news? Here we answer some of the top questions surrounding the drug.
 

What does the FDA action mean?

The FDA granted accelerated approval to Leqembi after it showed positive trial results in slowing the progression of early-stage disease.

The FDA can grant accelerated approval for drugs that treat serious conditions and fill an unmet medical need while drugs continue to be studied in larger trials.

With the FDA approval in hand, doctors can now prescribe the medication.

Rebecca Edelmayer, PhD, the Alzheimer’s Association senior director of scientific engagement, says that with the FDA’s move, ramping up manufacturing – and eventually nationwide distribution and implementation – will take some time.

“Ask your doctor about availability,” she says. “The main issue is that, without insurance and Medicare coverage of this class of treatments, access for those who could benefit from the newly approved treatment will only be available to those who can pay out-of-pocket. Without coverage, people simply won’t be able to get the treatment.”

The Washington Post reports that with accelerated approval, drugmaker Eisai is expected to immediately apply for full FDA approval, which wouldn’t be likely to come before later this year. Full approval could help clear the path for Medicare coverage of the drug.
 

Potential benefit?

Those who got Leqembi in a clinical trial for 18 months experienced 27% less decline in memory and thinking relative to the group who got a placebo. It also reduced amyloid in the brain, the sticky protein that builds up in the brains of people with Alzheimer’s and is considered a hallmark of the disease.

Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, says, “It’s the first phase 3 study in our field of a disease-modifying drug where the clinical efficacy was very clear.”
 

Concerns about side effects

The drug has raised safety concerns as it has been linked with certain serious adverse events, including brain swelling and bleeding. In the trial, 14% of patients who received the drug experienced side effects that included brain swelling and bleeding, compared with about 11% in the placebo group.

Scientists have reportedly linked three deaths during the clinical trial to lecanemab, though it is unclear whether it caused the deaths.

Dr. Fillit notes that the first two people who died were on blood thinners when they received lecanemab.

“There are things about the use of the drug in the real world that we need to work out, especially in the context of people with comorbidities,” he says.

The third death is a little different, Dr. Fillit says. The patient, who had a stroke, showed signs of vasculitis, or inflammation of the blood vessels.

“We don’t know exactly what happened, but we do know it was very, very rare” among the people involved in the trials, he says.

Dr. Edelmayer says that the most common reported side effects during the trials were infusion-related reactions, headache, and amyloid-related imaging abnormalities (ARIA). According to the FDA, these abnormalities “are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur.”

The FDA has added these as warnings to the drug’s label, describing the possible infusion-related reactions as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
 

How much will it cost?

Eisai says that lecanemab will cost $26,500 a year.

In a draft report released in December, the Institute for Clinical and Economic Review said a price ranging from $8,500 to $20,600 a year would make the drug cost-effective. While the group has no authority to set prices, many large health insurers consider its reports when they negotiate prices and some drugmakers take into account ICER’s recommendations when setting prices.

An editorial in The Lancet last month warns that the cost will likely be “prohibitive” for low- and middle-income countries and many health systems don’t have the infrastructure for a widespread rollout.
 

Will Medicare cover it?

The Centers for Medicare & Medicaid Services, which runs Medicare, which covers most people with Alzheimer’s, has indicated it won’t broadly cover amyloid-lowering drugs until the drug gets full U.S. approval based on clinical benefits, as opposed to accelerated approval.

That means people would have to pay thousands out of pocket at first to get it.

The CMS decision effectively denies Medicare coverage of fast-tracked FDA-approved medications for Alzheimer’s disease unless the person is enrolled in an approved clinical trial.

On Dec. 19, the Alzheimer’s Association filed a formal request asking CMS to remove the trial-only requirement and provide full and unrestricted coverage for FDA-approved Alzheimer’s treatments.

CMS says in a statement issued after the announcement: “Because Eisai’s product, lecanemab, was granted accelerated approval by the FDA, it falls under CMS’s existing national coverage determination. CMS is examining available information and may reconsider its current coverage based on this review.”

“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage,” the statement says.
 

Who benefits most from this drug?

Lecanemab is a treatment for people with early-stage Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or those in the later stages of Alzheimer’s disease, are not likely to improve with this drug.

Who makes lecanemab?  

Japan-based Eisai is developing the drug, a monoclonal antibody, in collaboration with the U.S. company Biogen.

What’s the Alzheimer’s Association’s view?

The association urged accelerated FDA approval. In a statement, it says it “welcomes and is further encouraged” by the clinical trial results.

It says data published in the New England Journal of Medicine confirms lecanemab “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”

“We are energized at the progress we are seeing in the research pipeline. The science is telling us that although antiamyloid treatments are not a cure – they are not going to be the end of treating Alzheimer’s – they are certainly the beginning,” Dr. Edelmayer says.
 

Are there alternatives?

The FDA gave accelerated approval to Biogen to produce another drug for Alzheimer’s, Aduhelm (aducanemab), in 2021, but the move was controversial as the drug’s effectiveness was widely questioned. It has since largely been pulled from the market.

Aduhelm had been the first approved early-stage Alzheimer’s treatment since 2003.

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

During the initial stage of the COVID-19 pandemic U.S. medical students were suspended from in-person clinical interaction. This decision was based on specific guidance from the Association of American Medical Colleges and subsequently implemented in medical schools across the United States.¹ Our research project addressed students’ stress level before and after clinical in-person suspension and assessed medical students perceived COVID-19–related risk level. We were particularly curious to learn about students’ emotional struggles as they navigated the initial pedagogical uncertainty associated with the pandemic.

Our study showed that students had a significantly higher stress level after the clinical suspension of in-person clinical interaction as compared with the time before the suspension of clinical in-person interaction. It is likely that heightened stress was greater than before and the rationale was likely multifactorial in nature.²

One key stressor U.S. medical students faced was the negative impacts of COVID-19 on medical education. U.S. Medical Licensing Examination exam-taking was severely impacted, and some students needed to reschedule their test dates because of increased restrictions at testing centers. Third-year medical students in particular were worried about how COVID-19 would influence their residency application; for example, in-person residency interviews and away rotations as fourth-year medical students. Another concern was not being able to be involved in clinical work during the direst stage of this public health emergency because of personal protective equipment shortages and attempts to reduce community spread of COVID-19.

Our study also showed that students had a relatively lower perceived risk level when it comes to COVID-19 than health care workers in the 2003 SARS epidemic, which we suspect is mostly attributable to the suspension of clinical in-person interaction. We also found that female gender and self-reported mental illness diagnosis were two risk factors for perceived stress level, consistent with our current literature.

The reality of clinical in-person inaction caused by PPE shortage and limited telehealth options, together with social isolation and uncertainty regarding future education opportunities, appear to have had a detrimental effect on medical students’ psychological wellbeing. This did not have to be the case. Some medical students found innovative ways to stay involved.

For example, in 2020 some of Dr. Zhang’s classmates helped proctor virtual group therapy sessions held by the local National Alliance on Mental Illness chapter. Medical students at the Icahn School of Medicine at Mount Sinai, New York were not only able to engage in telehealth but also join other task forces, such as PPE supply, distribution, and coordination, morale promotion, and administrative services.³ Finally, many medical students in New York volunteered in providing child care for frontline doctors to help relieve their burden.⁴ These actions, if implemented more widely, may have had a protective effect on the stress and well-being of medical students at that time.

While our study focused on the academic side of things, the personal impacts from COVID-19 need to be acknowledged – sickness from COVID-19 and its sequelae, family loss fromCOVID-19, financial struggle, and racial targeting of Asians to name a few. COVID-19 has influenced many families’ livelihood and changed our understanding of ourselves, others, and the world in unprecedented ways.

Fast forward to today – medical students are used to learning and living in a world with an ongoing pandemic, and medical education and residency application process have adapted to this new normal. The once-crippling uncertainty surrounding COVID-19 and disastrous PPE shortages have passed. Yet, COVID-19 continues to be a stressor. In fact, burnout related to “COVID-19 fatigue” has been on the rise and one recent national survey shows one in five physicians intends to leave practice within 2 years.⁵

Meanwhile, uncertainty continued to persist, as in August 2022 monkeypox was declared a public health emergency in the United States.⁶ What Dr. Zhang learned as a medical student during the initial months of COVID-19 continues to be relevant: connect with loved ones, understand the changing reality, process the emotions, recognize what is under one’s control, have a solution-oriented mindset, and be forgiving and patient with oneself and others.

Dr. Zhang is a second-year psychiatry resident physician at Saint Elizabeth’s Hospital/DC DBH, Washington. Dr. Himelhoch serves as professor and chair of the department of psychiatry at the University of Kentucky, Lexington. His research focuses on developing and studying the efficacy of innovative strategies aimed at improving the health and welfare among people with co-occurring psychiatric and substance use disorders.

References

1. Association of American Medical Colleges. Important Guidance for Medical Students on Clinical Rotations During the Coronavirus (COVID-19) Outbreak. 2020 Mar 17.

2. Zhang Y et al. Psychiatry Res. 2022;313:114595. doi: 10.1016/j.psychres.2022.114595.

3. Bahethi RR et al. Acad Med. 2021 Jun 1;96(6):859-63. doi: 10.1097/ACM.0000000000003863.

4. Krieger P and Goodnough A. Medical Students, Sidelined for Now, Find New Ways to Fight Coronavirus. The New York Times. 2020 Mar 23.

5. Abbasi J. JAMA. 2022 Apr 19;327(15):1435-7. doi: 10.1001/jama.2022.5074.

6. Department of Health & Human Services. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. 2022 Aug 4.

During the initial stage of the COVID-19 pandemic U.S. medical students were suspended from in-person clinical interaction. This decision was based on specific guidance from the Association of American Medical Colleges and subsequently implemented in medical schools across the United States.¹ Our research project addressed students’ stress level before and after clinical in-person suspension and assessed medical students perceived COVID-19–related risk level. We were particularly curious to learn about students’ emotional struggles as they navigated the initial pedagogical uncertainty associated with the pandemic.

Our study showed that students had a significantly higher stress level after the clinical suspension of in-person clinical interaction as compared with the time before the suspension of clinical in-person interaction. It is likely that heightened stress was greater than before and the rationale was likely multifactorial in nature.²

One key stressor U.S. medical students faced was the negative impacts of COVID-19 on medical education. U.S. Medical Licensing Examination exam-taking was severely impacted, and some students needed to reschedule their test dates because of increased restrictions at testing centers. Third-year medical students in particular were worried about how COVID-19 would influence their residency application; for example, in-person residency interviews and away rotations as fourth-year medical students. Another concern was not being able to be involved in clinical work during the direst stage of this public health emergency because of personal protective equipment shortages and attempts to reduce community spread of COVID-19.

Our study also showed that students had a relatively lower perceived risk level when it comes to COVID-19 than health care workers in the 2003 SARS epidemic, which we suspect is mostly attributable to the suspension of clinical in-person interaction. We also found that female gender and self-reported mental illness diagnosis were two risk factors for perceived stress level, consistent with our current literature.

The reality of clinical in-person inaction caused by PPE shortage and limited telehealth options, together with social isolation and uncertainty regarding future education opportunities, appear to have had a detrimental effect on medical students’ psychological wellbeing. This did not have to be the case. Some medical students found innovative ways to stay involved.

For example, in 2020 some of Dr. Zhang’s classmates helped proctor virtual group therapy sessions held by the local National Alliance on Mental Illness chapter. Medical students at the Icahn School of Medicine at Mount Sinai, New York were not only able to engage in telehealth but also join other task forces, such as PPE supply, distribution, and coordination, morale promotion, and administrative services.³ Finally, many medical students in New York volunteered in providing child care for frontline doctors to help relieve their burden.⁴ These actions, if implemented more widely, may have had a protective effect on the stress and well-being of medical students at that time.

While our study focused on the academic side of things, the personal impacts from COVID-19 need to be acknowledged – sickness from COVID-19 and its sequelae, family loss fromCOVID-19, financial struggle, and racial targeting of Asians to name a few. COVID-19 has influenced many families’ livelihood and changed our understanding of ourselves, others, and the world in unprecedented ways.

Fast forward to today – medical students are used to learning and living in a world with an ongoing pandemic, and medical education and residency application process have adapted to this new normal. The once-crippling uncertainty surrounding COVID-19 and disastrous PPE shortages have passed. Yet, COVID-19 continues to be a stressor. In fact, burnout related to “COVID-19 fatigue” has been on the rise and one recent national survey shows one in five physicians intends to leave practice within 2 years.⁵

Meanwhile, uncertainty continued to persist, as in August 2022 monkeypox was declared a public health emergency in the United States.⁶ What Dr. Zhang learned as a medical student during the initial months of COVID-19 continues to be relevant: connect with loved ones, understand the changing reality, process the emotions, recognize what is under one’s control, have a solution-oriented mindset, and be forgiving and patient with oneself and others.

Dr. Zhang is a second-year psychiatry resident physician at Saint Elizabeth’s Hospital/DC DBH, Washington. Dr. Himelhoch serves as professor and chair of the department of psychiatry at the University of Kentucky, Lexington. His research focuses on developing and studying the efficacy of innovative strategies aimed at improving the health and welfare among people with co-occurring psychiatric and substance use disorders.

References

1. Association of American Medical Colleges. Important Guidance for Medical Students on Clinical Rotations During the Coronavirus (COVID-19) Outbreak. 2020 Mar 17.

2. Zhang Y et al. Psychiatry Res. 2022;313:114595. doi: 10.1016/j.psychres.2022.114595.

3. Bahethi RR et al. Acad Med. 2021 Jun 1;96(6):859-63. doi: 10.1097/ACM.0000000000003863.

4. Krieger P and Goodnough A. Medical Students, Sidelined for Now, Find New Ways to Fight Coronavirus. The New York Times. 2020 Mar 23.

5. Abbasi J. JAMA. 2022 Apr 19;327(15):1435-7. doi: 10.1001/jama.2022.5074.

6. Department of Health & Human Services. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. 2022 Aug 4.

During the initial stage of the COVID-19 pandemic U.S. medical students were suspended from in-person clinical interaction. This decision was based on specific guidance from the Association of American Medical Colleges and subsequently implemented in medical schools across the United States.¹ Our research project addressed students’ stress level before and after clinical in-person suspension and assessed medical students perceived COVID-19–related risk level. We were particularly curious to learn about students’ emotional struggles as they navigated the initial pedagogical uncertainty associated with the pandemic.

Our study showed that students had a significantly higher stress level after the clinical suspension of in-person clinical interaction as compared with the time before the suspension of clinical in-person interaction. It is likely that heightened stress was greater than before and the rationale was likely multifactorial in nature.²

One key stressor U.S. medical students faced was the negative impacts of COVID-19 on medical education. U.S. Medical Licensing Examination exam-taking was severely impacted, and some students needed to reschedule their test dates because of increased restrictions at testing centers. Third-year medical students in particular were worried about how COVID-19 would influence their residency application; for example, in-person residency interviews and away rotations as fourth-year medical students. Another concern was not being able to be involved in clinical work during the direst stage of this public health emergency because of personal protective equipment shortages and attempts to reduce community spread of COVID-19.

Our study also showed that students had a relatively lower perceived risk level when it comes to COVID-19 than health care workers in the 2003 SARS epidemic, which we suspect is mostly attributable to the suspension of clinical in-person interaction. We also found that female gender and self-reported mental illness diagnosis were two risk factors for perceived stress level, consistent with our current literature.

The reality of clinical in-person inaction caused by PPE shortage and limited telehealth options, together with social isolation and uncertainty regarding future education opportunities, appear to have had a detrimental effect on medical students’ psychological wellbeing. This did not have to be the case. Some medical students found innovative ways to stay involved.

For example, in 2020 some of Dr. Zhang’s classmates helped proctor virtual group therapy sessions held by the local National Alliance on Mental Illness chapter. Medical students at the Icahn School of Medicine at Mount Sinai, New York were not only able to engage in telehealth but also join other task forces, such as PPE supply, distribution, and coordination, morale promotion, and administrative services.³ Finally, many medical students in New York volunteered in providing child care for frontline doctors to help relieve their burden.⁴ These actions, if implemented more widely, may have had a protective effect on the stress and well-being of medical students at that time.

While our study focused on the academic side of things, the personal impacts from COVID-19 need to be acknowledged – sickness from COVID-19 and its sequelae, family loss fromCOVID-19, financial struggle, and racial targeting of Asians to name a few. COVID-19 has influenced many families’ livelihood and changed our understanding of ourselves, others, and the world in unprecedented ways.

Fast forward to today – medical students are used to learning and living in a world with an ongoing pandemic, and medical education and residency application process have adapted to this new normal. The once-crippling uncertainty surrounding COVID-19 and disastrous PPE shortages have passed. Yet, COVID-19 continues to be a stressor. In fact, burnout related to “COVID-19 fatigue” has been on the rise and one recent national survey shows one in five physicians intends to leave practice within 2 years.⁵

Meanwhile, uncertainty continued to persist, as in August 2022 monkeypox was declared a public health emergency in the United States.⁶ What Dr. Zhang learned as a medical student during the initial months of COVID-19 continues to be relevant: connect with loved ones, understand the changing reality, process the emotions, recognize what is under one’s control, have a solution-oriented mindset, and be forgiving and patient with oneself and others.

Dr. Zhang is a second-year psychiatry resident physician at Saint Elizabeth’s Hospital/DC DBH, Washington. Dr. Himelhoch serves as professor and chair of the department of psychiatry at the University of Kentucky, Lexington. His research focuses on developing and studying the efficacy of innovative strategies aimed at improving the health and welfare among people with co-occurring psychiatric and substance use disorders.

References

1. Association of American Medical Colleges. Important Guidance for Medical Students on Clinical Rotations During the Coronavirus (COVID-19) Outbreak. 2020 Mar 17.

2. Zhang Y et al. Psychiatry Res. 2022;313:114595. doi: 10.1016/j.psychres.2022.114595.

3. Bahethi RR et al. Acad Med. 2021 Jun 1;96(6):859-63. doi: 10.1097/ACM.0000000000003863.

4. Krieger P and Goodnough A. Medical Students, Sidelined for Now, Find New Ways to Fight Coronavirus. The New York Times. 2020 Mar 23.

5. Abbasi J. JAMA. 2022 Apr 19;327(15):1435-7. doi: 10.1001/jama.2022.5074.

6. Department of Health & Human Services. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. 2022 Aug 4.

If you smoke, vape, or ingest cannabis, your anesthesiologist should know before you undergo a surgical procedure, according to new medical guidelines.

All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.

One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.

The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
 

Possible interactions

Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.

“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.

“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.

Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
 

Risks for vomiting, heart attack

The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.

Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.

The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.

Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.

Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.

The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.

Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.

“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.

For one, it can interact with numerous other drugs, including warfarin.

Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.

Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.

“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.

Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.

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

If you smoke, vape, or ingest cannabis, your anesthesiologist should know before you undergo a surgical procedure, according to new medical guidelines.

All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.

One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.

The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
 

Possible interactions

Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.

“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.

“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.

Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
 

Risks for vomiting, heart attack

The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.

Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.

The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.

Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.

Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.

The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.

Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.

“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.

For one, it can interact with numerous other drugs, including warfarin.

Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.

Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.

“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.

Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.

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

If you smoke, vape, or ingest cannabis, your anesthesiologist should know before you undergo a surgical procedure, according to new medical guidelines.

All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.

One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.

The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
 

Possible interactions

Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.

“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.

“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.

Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
 

Risks for vomiting, heart attack

The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.

Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.

The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.

Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.

Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.

The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.

Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.

“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.

For one, it can interact with numerous other drugs, including warfarin.

Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.

Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.

“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.

Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The U.S. Food and Drug Administration has approved the anti–amyloid-beta protofibril antibody lecanemab (Leqembi, Eisai) for the treatment of early Alzheimer’s disease.

Like its controversial cousin aducanumab (Aduhelm, Biogen/Eisai), lecanemab was approved under the FDA’s accelerated approval pathway, which can be used to fast-track a drug that provides a meaningful therapeutic advantage over existing treatments for a serious or life-threatening illness.

Unlike aducanumab, however, there was no formal FDA advisory committee meeting on lecanemab prior to approval.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease,” Dr. Dunn added.

Eisai has reported that lecanemab will cost $26,500 a year.

Modest benefit, adverse events

The FDA noted, “The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials.”

The agency approved the treatment on the basis of findings from the CLARITY AD trial, which showed modest cognitive benefit for patients with early AD – but at a cost of increased risk for amyloid-related edema and effusions.

The trial enrolled 1,795 adults with mild cognitive impairment or early Alzheimer’s disease in whom amyloid pathology in the brain had been confirmed. Treatment consisted of lecanemab 10 mg/kg biweekly or matching placebo.

After 18 months of treatment, lecanemab slowed cognitive decline by 27%, compared with placebo, as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemab vs. 1.66 with placebo; P < .001).

While the results are “welcome news,” a 0.45-point difference on the CDR-SB might not be clinically meaningful, authors of a recent editorial in The Lancet cautioned.

Amyloid-related imaging abnormalities that manifest as edema or microhemorrhages also occurred in one in five patients taking lecanemab.

In addition, a newly published case report in The New England Journal of Medicine describes a patient with Alzheimer’s disease who was taking lecanemab and who died after experiencing numerous intracerebral hemorrhages during treatment with tissue plasminogen activator (tPA) for acute ischemic stroke.

“The findings raise the possibility of cerebral hemorrhages and necrotizing vasculopathy associated with tPA infusion in a patient with cerebrovascular amyloid who had received lecanemab,” the authors wrote.
 

Alzheimer’s Association reaction

Still, in anticipation of accelerated approval of lecanemab and the antiamyloid drug donanemab (Eli Lilly), which the FDA has also fast-tracked, the Alzheimer’s Association filed a formal request last month with the Centers for Medicare & Medicaid Services asking that it provide full and unrestricted coverage for FDA-approved Alzheimer’s disease treatments.

In a letter addressed to CMS administrator Chiquita Brooks-LaSure, the association asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved antiamyloid monoclonal antibodies.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and CEO for the Alzheimer’s Association, noted in a news release at the time.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Dr. Pike added.

After news of today’s approval was released, Dr. Pike noted in a new release, “The Alzheimer’s Association welcomes and celebrates this action by the FDA. We now have a second approved treatment that changes the course of Alzheimer’s disease in a meaningful way for people in the early stages of the disease.”

Maria C. Carrillo, PhD, chief science officer at the Alzheimer’s Association, called today’s approval “a milestone achievement.”

“The progress we’ve seen in not only this class of treatments but also in the diversification of treatment types and targets over the past few years is exciting and provides real hope to those impacted by this devastating disease,” Dr. Carrillo said.
 

Critical issues

Commenting on the approval, Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School, Boston, and chief medical officer at Linus Health, said FDA approval of lecanemab and its adoption in the clinic represent a “very exciting development and prospect; but arguably some critical issues need to be considered.”

He noted that the health care system “is not currently prepared to cope with the challenges and demands of lecanemab,” as well as future pharmacologic agents.

“First, we need better workflows to identify suitable patients who can most benefit from this treatment,” said Dr. Pascual-Leone. He added that beyond identification of cognitive difficulties, amyloid status will need to be determined.

“Presently, this requires expensive and invasive tests,” such as positron-emission tomography scans or lumbar punctures for cerebrospinal fluid analysis. However, these are not fully covered by insurance companies and would be challenging to fully scale, he noted.

“In addition to screening, health systems will need to resolve the logistics challenges around the administration of lecanemab with twice-monthly infusions and the need for careful longitudinal evaluations for potential side effects,” said Dr. Pascual-Leone.

“While lecanemab may represent the first disease-modifying therapy widely available for early Alzheimer’s disease, the likely more promising approach is the addition of other therapies to lecanemab as part of a multi-intervention strategy combining pharmacologic and nonpharmacologic interventions,” he added.

Dr. Pascual-Leone has served as a paid member on scientific advisory boards for Neuroelectrics, Magstim, TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant and is a cofounder of TI Solutions and Linus Health.

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

This article was updated 1/9/23.

The U.S. Food and Drug Administration has approved the anti–amyloid-beta protofibril antibody lecanemab (Leqembi, Eisai) for the treatment of early Alzheimer’s disease.

Like its controversial cousin aducanumab (Aduhelm, Biogen/Eisai), lecanemab was approved under the FDA’s accelerated approval pathway, which can be used to fast-track a drug that provides a meaningful therapeutic advantage over existing treatments for a serious or life-threatening illness.

Unlike aducanumab, however, there was no formal FDA advisory committee meeting on lecanemab prior to approval.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease,” Dr. Dunn added.

Eisai has reported that lecanemab will cost $26,500 a year.

Modest benefit, adverse events

The FDA noted, “The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials.”

The agency approved the treatment on the basis of findings from the CLARITY AD trial, which showed modest cognitive benefit for patients with early AD – but at a cost of increased risk for amyloid-related edema and effusions.

The trial enrolled 1,795 adults with mild cognitive impairment or early Alzheimer’s disease in whom amyloid pathology in the brain had been confirmed. Treatment consisted of lecanemab 10 mg/kg biweekly or matching placebo.

After 18 months of treatment, lecanemab slowed cognitive decline by 27%, compared with placebo, as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemab vs. 1.66 with placebo; P < .001).

While the results are “welcome news,” a 0.45-point difference on the CDR-SB might not be clinically meaningful, authors of a recent editorial in The Lancet cautioned.

Amyloid-related imaging abnormalities that manifest as edema or microhemorrhages also occurred in one in five patients taking lecanemab.

In addition, a newly published case report in The New England Journal of Medicine describes a patient with Alzheimer’s disease who was taking lecanemab and who died after experiencing numerous intracerebral hemorrhages during treatment with tissue plasminogen activator (tPA) for acute ischemic stroke.

“The findings raise the possibility of cerebral hemorrhages and necrotizing vasculopathy associated with tPA infusion in a patient with cerebrovascular amyloid who had received lecanemab,” the authors wrote.
 

Alzheimer’s Association reaction

Still, in anticipation of accelerated approval of lecanemab and the antiamyloid drug donanemab (Eli Lilly), which the FDA has also fast-tracked, the Alzheimer’s Association filed a formal request last month with the Centers for Medicare & Medicaid Services asking that it provide full and unrestricted coverage for FDA-approved Alzheimer’s disease treatments.

In a letter addressed to CMS administrator Chiquita Brooks-LaSure, the association asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved antiamyloid monoclonal antibodies.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and CEO for the Alzheimer’s Association, noted in a news release at the time.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Dr. Pike added.

After news of today’s approval was released, Dr. Pike noted in a new release, “The Alzheimer’s Association welcomes and celebrates this action by the FDA. We now have a second approved treatment that changes the course of Alzheimer’s disease in a meaningful way for people in the early stages of the disease.”

Maria C. Carrillo, PhD, chief science officer at the Alzheimer’s Association, called today’s approval “a milestone achievement.”

“The progress we’ve seen in not only this class of treatments but also in the diversification of treatment types and targets over the past few years is exciting and provides real hope to those impacted by this devastating disease,” Dr. Carrillo said.
 

Critical issues

Commenting on the approval, Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School, Boston, and chief medical officer at Linus Health, said FDA approval of lecanemab and its adoption in the clinic represent a “very exciting development and prospect; but arguably some critical issues need to be considered.”

He noted that the health care system “is not currently prepared to cope with the challenges and demands of lecanemab,” as well as future pharmacologic agents.

“First, we need better workflows to identify suitable patients who can most benefit from this treatment,” said Dr. Pascual-Leone. He added that beyond identification of cognitive difficulties, amyloid status will need to be determined.

“Presently, this requires expensive and invasive tests,” such as positron-emission tomography scans or lumbar punctures for cerebrospinal fluid analysis. However, these are not fully covered by insurance companies and would be challenging to fully scale, he noted.

“In addition to screening, health systems will need to resolve the logistics challenges around the administration of lecanemab with twice-monthly infusions and the need for careful longitudinal evaluations for potential side effects,” said Dr. Pascual-Leone.

“While lecanemab may represent the first disease-modifying therapy widely available for early Alzheimer’s disease, the likely more promising approach is the addition of other therapies to lecanemab as part of a multi-intervention strategy combining pharmacologic and nonpharmacologic interventions,” he added.

Dr. Pascual-Leone has served as a paid member on scientific advisory boards for Neuroelectrics, Magstim, TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant and is a cofounder of TI Solutions and Linus Health.

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

This article was updated 1/9/23.

The U.S. Food and Drug Administration has approved the anti–amyloid-beta protofibril antibody lecanemab (Leqembi, Eisai) for the treatment of early Alzheimer’s disease.

Like its controversial cousin aducanumab (Aduhelm, Biogen/Eisai), lecanemab was approved under the FDA’s accelerated approval pathway, which can be used to fast-track a drug that provides a meaningful therapeutic advantage over existing treatments for a serious or life-threatening illness.

Unlike aducanumab, however, there was no formal FDA advisory committee meeting on lecanemab prior to approval.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease,” Dr. Dunn added.

Eisai has reported that lecanemab will cost $26,500 a year.

Modest benefit, adverse events

The FDA noted, “The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials.”

The agency approved the treatment on the basis of findings from the CLARITY AD trial, which showed modest cognitive benefit for patients with early AD – but at a cost of increased risk for amyloid-related edema and effusions.

The trial enrolled 1,795 adults with mild cognitive impairment or early Alzheimer’s disease in whom amyloid pathology in the brain had been confirmed. Treatment consisted of lecanemab 10 mg/kg biweekly or matching placebo.

After 18 months of treatment, lecanemab slowed cognitive decline by 27%, compared with placebo, as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemab vs. 1.66 with placebo; P < .001).

While the results are “welcome news,” a 0.45-point difference on the CDR-SB might not be clinically meaningful, authors of a recent editorial in The Lancet cautioned.

Amyloid-related imaging abnormalities that manifest as edema or microhemorrhages also occurred in one in five patients taking lecanemab.

In addition, a newly published case report in The New England Journal of Medicine describes a patient with Alzheimer’s disease who was taking lecanemab and who died after experiencing numerous intracerebral hemorrhages during treatment with tissue plasminogen activator (tPA) for acute ischemic stroke.

“The findings raise the possibility of cerebral hemorrhages and necrotizing vasculopathy associated with tPA infusion in a patient with cerebrovascular amyloid who had received lecanemab,” the authors wrote.
 

Alzheimer’s Association reaction

Still, in anticipation of accelerated approval of lecanemab and the antiamyloid drug donanemab (Eli Lilly), which the FDA has also fast-tracked, the Alzheimer’s Association filed a formal request last month with the Centers for Medicare & Medicaid Services asking that it provide full and unrestricted coverage for FDA-approved Alzheimer’s disease treatments.

In a letter addressed to CMS administrator Chiquita Brooks-LaSure, the association asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved antiamyloid monoclonal antibodies.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and CEO for the Alzheimer’s Association, noted in a news release at the time.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Dr. Pike added.

After news of today’s approval was released, Dr. Pike noted in a new release, “The Alzheimer’s Association welcomes and celebrates this action by the FDA. We now have a second approved treatment that changes the course of Alzheimer’s disease in a meaningful way for people in the early stages of the disease.”

Maria C. Carrillo, PhD, chief science officer at the Alzheimer’s Association, called today’s approval “a milestone achievement.”

“The progress we’ve seen in not only this class of treatments but also in the diversification of treatment types and targets over the past few years is exciting and provides real hope to those impacted by this devastating disease,” Dr. Carrillo said.
 

Critical issues

Commenting on the approval, Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School, Boston, and chief medical officer at Linus Health, said FDA approval of lecanemab and its adoption in the clinic represent a “very exciting development and prospect; but arguably some critical issues need to be considered.”

He noted that the health care system “is not currently prepared to cope with the challenges and demands of lecanemab,” as well as future pharmacologic agents.

“First, we need better workflows to identify suitable patients who can most benefit from this treatment,” said Dr. Pascual-Leone. He added that beyond identification of cognitive difficulties, amyloid status will need to be determined.

“Presently, this requires expensive and invasive tests,” such as positron-emission tomography scans or lumbar punctures for cerebrospinal fluid analysis. However, these are not fully covered by insurance companies and would be challenging to fully scale, he noted.

“In addition to screening, health systems will need to resolve the logistics challenges around the administration of lecanemab with twice-monthly infusions and the need for careful longitudinal evaluations for potential side effects,” said Dr. Pascual-Leone.

“While lecanemab may represent the first disease-modifying therapy widely available for early Alzheimer’s disease, the likely more promising approach is the addition of other therapies to lecanemab as part of a multi-intervention strategy combining pharmacologic and nonpharmacologic interventions,” he added.

Dr. Pascual-Leone has served as a paid member on scientific advisory boards for Neuroelectrics, Magstim, TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant and is a cofounder of TI Solutions and Linus Health.

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

This article was updated 1/9/23.

Individuals with schizophrenia showed larger discrepancies between actual and ideal positive affect, compared with healthy controls, in contrast to the investigators’ hypothesis in a study of 61 individuals.

Anhedonia is common in schizophrenia patients, but treatments have not been especially successful, possibly because of a lack of understanding the mechanisms behind anhedonia in these patients, Sydney H. James, a PhD candidate at the University of Georgia, Athens, and colleagues wrote.

Although many schizophrenia (SZ) patients exhibit anhedonia on diagnosis in a clinical interview setting, other recent research shows comparable response to pleasant stimuli between schizophrenic patients and healthy controls. The researchers proposed that anhedonia “reflects abnormalities in the valuation of desired affective states in individuals with SZ,” with differences between actual and ideal affect.

In a study published in the Journal of Psychiatric Research, the researchers identified 32 outpatients with schizophrenia and 29 healthy controls. The SZ participants were recruited from community outpatient mental health services in Georgia. All participants completed Structured Clinical Interview for DSM-5 Disorders and the SCID-5 Personality Disorders. Participants then completed the Affect Valuation Index and measures of negative symptom severity. Negative symptom severity was measured using the Negative Symptom Inventory-Self-Report, an 11-item questionnaire assessing three specific experiential and behavioral components (anhedonia, avolition, and asociality) over the past week.

The average age of the SZ patients and controls was approximately 40 years, and 10 SZ patients and 5 controls were male.

Overall, the researchers found a significant main effect of group, a significant main effect of arousal, and a significant group X arousal interaction for positive affect discrepancy scores. For negative affect discrepancy scores, they found a significant main effect on group, nonsignificant main effect of arousal, and significant group X arousal interaction.

Individuals with SZ showed greater positive and negative emotion discrepancy scores, compared with controls, in contrast to the researchers’ hypothesis. “Those diagnosed with SZ were more likely to want to feel less negative than they actually did,” they wrote. The negative affect discrepancy scores were positively associated with negative symptoms. The discrepancies between actual and ideal affect may be impacted by social interactions and the perceived expectations of others for levels of negative affect.

The study findings were limited by the small sample size and inability to test the relationship between ideal and actual affect as related to low-pleasure beliefs, which merits further study, the researchers noted. Other limitations include the focus on an outpatient population with mild to moderate SZ, and the use of a trait format to measure affect rather than experiential emotion knowledge.

However, the results have practical implications for treatment and suggest that, “given the positive associations between negative symptom and affect discrepancy scores, psychosocial treatments could target expectations for future positive and negative emotional experience,” and ecological momentary assessment could be used to track affect through a period of treatment and prompt conversations between SZ patients and therapists about discrepancies, they concluded.

The study participants were compensated by the National Institute of Mental Health through a grant to a corresponding author. Ms. James had no financial conflicts to disclose.

Individuals with schizophrenia showed larger discrepancies between actual and ideal positive affect, compared with healthy controls, in contrast to the investigators’ hypothesis in a study of 61 individuals.

Anhedonia is common in schizophrenia patients, but treatments have not been especially successful, possibly because of a lack of understanding the mechanisms behind anhedonia in these patients, Sydney H. James, a PhD candidate at the University of Georgia, Athens, and colleagues wrote.

Although many schizophrenia (SZ) patients exhibit anhedonia on diagnosis in a clinical interview setting, other recent research shows comparable response to pleasant stimuli between schizophrenic patients and healthy controls. The researchers proposed that anhedonia “reflects abnormalities in the valuation of desired affective states in individuals with SZ,” with differences between actual and ideal affect.

In a study published in the Journal of Psychiatric Research, the researchers identified 32 outpatients with schizophrenia and 29 healthy controls. The SZ participants were recruited from community outpatient mental health services in Georgia. All participants completed Structured Clinical Interview for DSM-5 Disorders and the SCID-5 Personality Disorders. Participants then completed the Affect Valuation Index and measures of negative symptom severity. Negative symptom severity was measured using the Negative Symptom Inventory-Self-Report, an 11-item questionnaire assessing three specific experiential and behavioral components (anhedonia, avolition, and asociality) over the past week.

The average age of the SZ patients and controls was approximately 40 years, and 10 SZ patients and 5 controls were male.

Overall, the researchers found a significant main effect of group, a significant main effect of arousal, and a significant group X arousal interaction for positive affect discrepancy scores. For negative affect discrepancy scores, they found a significant main effect on group, nonsignificant main effect of arousal, and significant group X arousal interaction.

Individuals with SZ showed greater positive and negative emotion discrepancy scores, compared with controls, in contrast to the researchers’ hypothesis. “Those diagnosed with SZ were more likely to want to feel less negative than they actually did,” they wrote. The negative affect discrepancy scores were positively associated with negative symptoms. The discrepancies between actual and ideal affect may be impacted by social interactions and the perceived expectations of others for levels of negative affect.

The study findings were limited by the small sample size and inability to test the relationship between ideal and actual affect as related to low-pleasure beliefs, which merits further study, the researchers noted. Other limitations include the focus on an outpatient population with mild to moderate SZ, and the use of a trait format to measure affect rather than experiential emotion knowledge.

However, the results have practical implications for treatment and suggest that, “given the positive associations between negative symptom and affect discrepancy scores, psychosocial treatments could target expectations for future positive and negative emotional experience,” and ecological momentary assessment could be used to track affect through a period of treatment and prompt conversations between SZ patients and therapists about discrepancies, they concluded.

The study participants were compensated by the National Institute of Mental Health through a grant to a corresponding author. Ms. James had no financial conflicts to disclose.

Individuals with schizophrenia showed larger discrepancies between actual and ideal positive affect, compared with healthy controls, in contrast to the investigators’ hypothesis in a study of 61 individuals.

Anhedonia is common in schizophrenia patients, but treatments have not been especially successful, possibly because of a lack of understanding the mechanisms behind anhedonia in these patients, Sydney H. James, a PhD candidate at the University of Georgia, Athens, and colleagues wrote.

Although many schizophrenia (SZ) patients exhibit anhedonia on diagnosis in a clinical interview setting, other recent research shows comparable response to pleasant stimuli between schizophrenic patients and healthy controls. The researchers proposed that anhedonia “reflects abnormalities in the valuation of desired affective states in individuals with SZ,” with differences between actual and ideal affect.

In a study published in the Journal of Psychiatric Research, the researchers identified 32 outpatients with schizophrenia and 29 healthy controls. The SZ participants were recruited from community outpatient mental health services in Georgia. All participants completed Structured Clinical Interview for DSM-5 Disorders and the SCID-5 Personality Disorders. Participants then completed the Affect Valuation Index and measures of negative symptom severity. Negative symptom severity was measured using the Negative Symptom Inventory-Self-Report, an 11-item questionnaire assessing three specific experiential and behavioral components (anhedonia, avolition, and asociality) over the past week.

The average age of the SZ patients and controls was approximately 40 years, and 10 SZ patients and 5 controls were male.

Overall, the researchers found a significant main effect of group, a significant main effect of arousal, and a significant group X arousal interaction for positive affect discrepancy scores. For negative affect discrepancy scores, they found a significant main effect on group, nonsignificant main effect of arousal, and significant group X arousal interaction.

Individuals with SZ showed greater positive and negative emotion discrepancy scores, compared with controls, in contrast to the researchers’ hypothesis. “Those diagnosed with SZ were more likely to want to feel less negative than they actually did,” they wrote. The negative affect discrepancy scores were positively associated with negative symptoms. The discrepancies between actual and ideal affect may be impacted by social interactions and the perceived expectations of others for levels of negative affect.

The study findings were limited by the small sample size and inability to test the relationship between ideal and actual affect as related to low-pleasure beliefs, which merits further study, the researchers noted. Other limitations include the focus on an outpatient population with mild to moderate SZ, and the use of a trait format to measure affect rather than experiential emotion knowledge.

However, the results have practical implications for treatment and suggest that, “given the positive associations between negative symptom and affect discrepancy scores, psychosocial treatments could target expectations for future positive and negative emotional experience,” and ecological momentary assessment could be used to track affect through a period of treatment and prompt conversations between SZ patients and therapists about discrepancies, they concluded.

The study participants were compensated by the National Institute of Mental Health through a grant to a corresponding author. Ms. James had no financial conflicts to disclose.

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

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

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

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

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

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

Treatment-resistant depression (TRD) is significantly linked to comorbid psychiatric conditions and a higher risk for mortality and can take more than a year to be diagnosed, new research shows.

In a population study of more than 145,000 patients, participants with TRD used outpatient resources and missed work at twice the rate as patients with treatment-responsive depression. They also had a threefold higher number of days spent in hospital.

Patients with TRD also had a 23% higher risk of dying during the time they were observed, compared with their matched counterparts with non-TRD depression, and their self-harm rates were twice as high.

In addition, it took an average of 1.5 years for patients with TRD to undergo two unsuccessful treatment attempts and reach their third treatment trial, which is several months longer than is recommended for assessing the efficacy of a treatment for depression.

“It seemed like ineffective treatments were allowed to continue for longer than should be needed and what is recommended in current guidelines,” lead investigator Johan Lundberg, MD, PhD, adjunct professor of psychiatry in the department of clinical neuroscience and head of the mood disorder section at the Northern Stockholm Psychiatry Clinic, told this news organization.

“If this is true, patients would most likely benefit from a more frequent evaluation of treatment effect and, when needed, optimization of ineffective treatments,” Dr. Lundberg said.

The findings were published online in JAMA Psychiatry.
 

More anxiety, sleep disorders, substance use

Using data from the Region Stockholm’s administrative health care database and the Swedish social insurance agency, the investigators identified nearly 160,000 unipolar major depressive disorder (MDD) episodes in 145,577 patients who sought treatment between January 2012 and December 2017.

Of those episodes, 12,800 fulfilled criteria for TRD, which meant there were three or more treatment trials with antidepressants, add-on medication (aripiprazole, lithium, olanzapine, quetiapine, and/or risperidone), electroshock therapy, or repetitive transcranial magnetic stimulation.

Each new treatment had to be initiated within the MDD episode more than 28 days after previous treatment initiation.

Investigators matched each TRD episode with up to five non-TRD episodes and found that patients with TRD were more likely to have comorbid psychiatric conditions than were their non-TRD counterparts.

This included anxiety (60% vs. 44%, respectively), sleep disorders (28% vs. 19%), substance use (15% vs. 11%) or alcohol use (10% vs. 7%) disorders, and personality disorders (6% vs. 3%). Rates of intentional self-harm were also higher in the TRD group (5% vs. 2%).

Perhaps in part because of the comorbid problems, patients with TRD had a more than 50% higher mean number of outpatient physician visits 1 year before and after the index date, defined as the date of the initiation of the third treatment trial.

The most important predictor of TRD depression was the severity of depression at diagnosis on the self-rated Montgomery Åsberg Depression Rating Scale, the researchers report.
 

Not generalizable?

Patients with TRD also had three times the number of inpatient bed days as did those with depression that responded to treatment (mean, 3.9 days vs. 1.3 days, respectively) and significantly more lost workdays (132.3 days vs. 58.7 days).

Most notably, patients with TRD episodes had a 23% higher risk of dying during the time they were observed than did their non-TRD counterparts.

“This finding in itself could be a reason to focus on how to avoid putting a patient on the TRD path. This could be done through prospective studies comparing different treatment options and their risk of leading to TRD,” Dr. Lundberg said.

Interestingly, he noted that the study results may not be generalizable to other populations, such as the United States.

“The biggest difference between Stockholm and the U.S. may not be the demographics, but the access to health care,” Dr. Lundberg said.

“In Stockholm, there is a universal access health care system, meaning that these results are what you can expect if you are able to get care. In the U.S., this is not the case, meaning that people outside the health care system may fare worse than what our study suggests,” he added.
 

Quality over quantity

In a comment, Sidney Zisook, MD, distinguished professor of psychiatry at the University of California, San Diego, said that the findings “highlight the need for our field to develop better-tolerated, more effective, and sustainable treatments for major depressive disorder and for better education of clinicians so they can employ up-to-date, evidence-based treatments and integrate sound clinical guidelines into clinical practice.”

Dr. Zisook has independently researched TRD but was not involved with the current study.

He noted that it was “striking how long patients remained on the same antidepressant, apparently despite suboptimal outcomes, without taking next steps.”

However, Dr. Zisook expressed concern that the diagnosis of TRD in the study was solely on the basis of the number of treatment trials for an episode.

“Somebody might have had three different antidepressant trials because they had had three episodes with interepisode periods of recovery followed by recurrent episodes. That would not be considered treatment-resistant depression,” he said.

Dr. Zisook also noted that patients might be given a new antidepressant for reasons other than treatment resistance. “For example, they lost an initial good response – this used to be called Prozac poop out, were nonadherent, or had troublesome side effects,” he said.

“We usually define treatment-resistant depression not only on the basis of number of trials but also the quality of the trial, taking both dose and duration into account,” Dr. Zisook added.

The study was funded by Region Stockholm. Dr. Zisook reports receiving research funding from COMPASS Pathways.

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

Treatment-resistant depression (TRD) is significantly linked to comorbid psychiatric conditions and a higher risk for mortality and can take more than a year to be diagnosed, new research shows.

In a population study of more than 145,000 patients, participants with TRD used outpatient resources and missed work at twice the rate as patients with treatment-responsive depression. They also had a threefold higher number of days spent in hospital.

Patients with TRD also had a 23% higher risk of dying during the time they were observed, compared with their matched counterparts with non-TRD depression, and their self-harm rates were twice as high.

In addition, it took an average of 1.5 years for patients with TRD to undergo two unsuccessful treatment attempts and reach their third treatment trial, which is several months longer than is recommended for assessing the efficacy of a treatment for depression.

“It seemed like ineffective treatments were allowed to continue for longer than should be needed and what is recommended in current guidelines,” lead investigator Johan Lundberg, MD, PhD, adjunct professor of psychiatry in the department of clinical neuroscience and head of the mood disorder section at the Northern Stockholm Psychiatry Clinic, told this news organization.

“If this is true, patients would most likely benefit from a more frequent evaluation of treatment effect and, when needed, optimization of ineffective treatments,” Dr. Lundberg said.

The findings were published online in JAMA Psychiatry.
 

More anxiety, sleep disorders, substance use

Using data from the Region Stockholm’s administrative health care database and the Swedish social insurance agency, the investigators identified nearly 160,000 unipolar major depressive disorder (MDD) episodes in 145,577 patients who sought treatment between January 2012 and December 2017.

Of those episodes, 12,800 fulfilled criteria for TRD, which meant there were three or more treatment trials with antidepressants, add-on medication (aripiprazole, lithium, olanzapine, quetiapine, and/or risperidone), electroshock therapy, or repetitive transcranial magnetic stimulation.

Each new treatment had to be initiated within the MDD episode more than 28 days after previous treatment initiation.

Investigators matched each TRD episode with up to five non-TRD episodes and found that patients with TRD were more likely to have comorbid psychiatric conditions than were their non-TRD counterparts.

This included anxiety (60% vs. 44%, respectively), sleep disorders (28% vs. 19%), substance use (15% vs. 11%) or alcohol use (10% vs. 7%) disorders, and personality disorders (6% vs. 3%). Rates of intentional self-harm were also higher in the TRD group (5% vs. 2%).

Perhaps in part because of the comorbid problems, patients with TRD had a more than 50% higher mean number of outpatient physician visits 1 year before and after the index date, defined as the date of the initiation of the third treatment trial.

The most important predictor of TRD depression was the severity of depression at diagnosis on the self-rated Montgomery Åsberg Depression Rating Scale, the researchers report.
 

Not generalizable?

Patients with TRD also had three times the number of inpatient bed days as did those with depression that responded to treatment (mean, 3.9 days vs. 1.3 days, respectively) and significantly more lost workdays (132.3 days vs. 58.7 days).

Most notably, patients with TRD episodes had a 23% higher risk of dying during the time they were observed than did their non-TRD counterparts.

“This finding in itself could be a reason to focus on how to avoid putting a patient on the TRD path. This could be done through prospective studies comparing different treatment options and their risk of leading to TRD,” Dr. Lundberg said.

Interestingly, he noted that the study results may not be generalizable to other populations, such as the United States.

“The biggest difference between Stockholm and the U.S. may not be the demographics, but the access to health care,” Dr. Lundberg said.

“In Stockholm, there is a universal access health care system, meaning that these results are what you can expect if you are able to get care. In the U.S., this is not the case, meaning that people outside the health care system may fare worse than what our study suggests,” he added.
 

Quality over quantity

In a comment, Sidney Zisook, MD, distinguished professor of psychiatry at the University of California, San Diego, said that the findings “highlight the need for our field to develop better-tolerated, more effective, and sustainable treatments for major depressive disorder and for better education of clinicians so they can employ up-to-date, evidence-based treatments and integrate sound clinical guidelines into clinical practice.”

Dr. Zisook has independently researched TRD but was not involved with the current study.

He noted that it was “striking how long patients remained on the same antidepressant, apparently despite suboptimal outcomes, without taking next steps.”

However, Dr. Zisook expressed concern that the diagnosis of TRD in the study was solely on the basis of the number of treatment trials for an episode.

“Somebody might have had three different antidepressant trials because they had had three episodes with interepisode periods of recovery followed by recurrent episodes. That would not be considered treatment-resistant depression,” he said.

Dr. Zisook also noted that patients might be given a new antidepressant for reasons other than treatment resistance. “For example, they lost an initial good response – this used to be called Prozac poop out, were nonadherent, or had troublesome side effects,” he said.

“We usually define treatment-resistant depression not only on the basis of number of trials but also the quality of the trial, taking both dose and duration into account,” Dr. Zisook added.

The study was funded by Region Stockholm. Dr. Zisook reports receiving research funding from COMPASS Pathways.

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

Treatment-resistant depression (TRD) is significantly linked to comorbid psychiatric conditions and a higher risk for mortality and can take more than a year to be diagnosed, new research shows.

In a population study of more than 145,000 patients, participants with TRD used outpatient resources and missed work at twice the rate as patients with treatment-responsive depression. They also had a threefold higher number of days spent in hospital.

Patients with TRD also had a 23% higher risk of dying during the time they were observed, compared with their matched counterparts with non-TRD depression, and their self-harm rates were twice as high.

In addition, it took an average of 1.5 years for patients with TRD to undergo two unsuccessful treatment attempts and reach their third treatment trial, which is several months longer than is recommended for assessing the efficacy of a treatment for depression.

“It seemed like ineffective treatments were allowed to continue for longer than should be needed and what is recommended in current guidelines,” lead investigator Johan Lundberg, MD, PhD, adjunct professor of psychiatry in the department of clinical neuroscience and head of the mood disorder section at the Northern Stockholm Psychiatry Clinic, told this news organization.

“If this is true, patients would most likely benefit from a more frequent evaluation of treatment effect and, when needed, optimization of ineffective treatments,” Dr. Lundberg said.

The findings were published online in JAMA Psychiatry.
 

More anxiety, sleep disorders, substance use

Using data from the Region Stockholm’s administrative health care database and the Swedish social insurance agency, the investigators identified nearly 160,000 unipolar major depressive disorder (MDD) episodes in 145,577 patients who sought treatment between January 2012 and December 2017.

Of those episodes, 12,800 fulfilled criteria for TRD, which meant there were three or more treatment trials with antidepressants, add-on medication (aripiprazole, lithium, olanzapine, quetiapine, and/or risperidone), electroshock therapy, or repetitive transcranial magnetic stimulation.

Each new treatment had to be initiated within the MDD episode more than 28 days after previous treatment initiation.

Investigators matched each TRD episode with up to five non-TRD episodes and found that patients with TRD were more likely to have comorbid psychiatric conditions than were their non-TRD counterparts.

This included anxiety (60% vs. 44%, respectively), sleep disorders (28% vs. 19%), substance use (15% vs. 11%) or alcohol use (10% vs. 7%) disorders, and personality disorders (6% vs. 3%). Rates of intentional self-harm were also higher in the TRD group (5% vs. 2%).

Perhaps in part because of the comorbid problems, patients with TRD had a more than 50% higher mean number of outpatient physician visits 1 year before and after the index date, defined as the date of the initiation of the third treatment trial.

The most important predictor of TRD depression was the severity of depression at diagnosis on the self-rated Montgomery Åsberg Depression Rating Scale, the researchers report.
 

Not generalizable?

Patients with TRD also had three times the number of inpatient bed days as did those with depression that responded to treatment (mean, 3.9 days vs. 1.3 days, respectively) and significantly more lost workdays (132.3 days vs. 58.7 days).

Most notably, patients with TRD episodes had a 23% higher risk of dying during the time they were observed than did their non-TRD counterparts.

“This finding in itself could be a reason to focus on how to avoid putting a patient on the TRD path. This could be done through prospective studies comparing different treatment options and their risk of leading to TRD,” Dr. Lundberg said.

Interestingly, he noted that the study results may not be generalizable to other populations, such as the United States.

“The biggest difference between Stockholm and the U.S. may not be the demographics, but the access to health care,” Dr. Lundberg said.

“In Stockholm, there is a universal access health care system, meaning that these results are what you can expect if you are able to get care. In the U.S., this is not the case, meaning that people outside the health care system may fare worse than what our study suggests,” he added.
 

Quality over quantity

In a comment, Sidney Zisook, MD, distinguished professor of psychiatry at the University of California, San Diego, said that the findings “highlight the need for our field to develop better-tolerated, more effective, and sustainable treatments for major depressive disorder and for better education of clinicians so they can employ up-to-date, evidence-based treatments and integrate sound clinical guidelines into clinical practice.”

Dr. Zisook has independently researched TRD but was not involved with the current study.

He noted that it was “striking how long patients remained on the same antidepressant, apparently despite suboptimal outcomes, without taking next steps.”

However, Dr. Zisook expressed concern that the diagnosis of TRD in the study was solely on the basis of the number of treatment trials for an episode.

“Somebody might have had three different antidepressant trials because they had had three episodes with interepisode periods of recovery followed by recurrent episodes. That would not be considered treatment-resistant depression,” he said.

Dr. Zisook also noted that patients might be given a new antidepressant for reasons other than treatment resistance. “For example, they lost an initial good response – this used to be called Prozac poop out, were nonadherent, or had troublesome side effects,” he said.

“We usually define treatment-resistant depression not only on the basis of number of trials but also the quality of the trial, taking both dose and duration into account,” Dr. Zisook added.

The study was funded by Region Stockholm. Dr. Zisook reports receiving research funding from COMPASS Pathways.

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