Bipolar Disorder

In a world that is more connected than ever, a silent epidemic is taking its toll. Overall, one in three US adults report chronic loneliness — a condition so detrimental that it rivals smoking and obesity with respect to its negative effect on health and well-being. From anxiety and depression to life-threatening conditions like cardiovascular disease, stroke, and Alzheimer’s and Parkinson’s diseases, loneliness is more than an emotion — it’s a serious threat to both the brain and body.

In 2023, a US Surgeon General advisory raised the alarm about the national problem of loneliness and isolation, describing it as an epidemic.

“Given the significant health consequences of loneliness and isolation, we must prioritize building social connection in the same way we have prioritized other critical public health issues such as tobacco, obesity, and substance use disorders. Together, we can build a country that’s healthier, more resilient, less lonely, and more connected,” the report concluded.

But how, exactly, does chronic loneliness affect the physiology and function of the brain? What does the latest research reveal about the link between loneliness and neurologic and psychiatric illness, and what can clinicians do to address the issue?

This news organization spoke to multiple experts in the field to explore these issues.
 

A Major Risk Factor

Anna Finley, PhD, assistant professor of psychology at North Dakota State University, Fargo, explained that loneliness and social isolation are different entities. Social isolation is an objective measure of the number of people someone interacts with on a regular basis, whereas loneliness is a subjective feeling that occurs when close connections are lacking.

“These two things are not actually as related as you think they would be. People can feel lonely in a crowd or feel well connected with only a few friendships. It’s more about the quality of the connection and the quality of your perception of it. So someone could be in some very supportive relationships but still feel that there’s something missing,” she said in an interview.

So what do we know about how loneliness affects health? Evidence supporting the hypothesis that loneliness is an emerging risk factor for many diseases is steadily building.

Recently, the American Heart Association published a statement summarizing the evidence for a direct association between social isolation and loneliness and coronary heart disease and stroke mortality.

In addition, many studies have shown that individuals experiencing social isolation or loneliness have an increased risk for anxiety and depression, dementia, infectious disease, hospitalization, and all-cause death, even after adjusting for age and many other traditional risk factors.

One study revealed that eliminating loneliness has the potential to prevent nearly 20% of cases of depression in adults aged 50 years or older.

Indu Subramanian, MD, professor of neurology at the University of California, Los Angeles, and colleagues conducted a study involving patients with Parkinson’s disease, which showed that the negative impact of loneliness on disease severity was as significant as the positive effects of 30 minutes of daily exercise.

“The importance of loneliness is under-recognized and undervalued, and it poses a major risk for health outcomes and quality of life,” said Subramanian.

Subramanian noted that loneliness is stigmatizing, causing people to feel unlikable and blame themselves, which prevents them from opening up to doctors or loved ones about their struggle. At the same time, healthcare providers may not think to ask about loneliness or know about potential interventions. She emphasized that much more work is needed to address this issue.
 

Early Mortality Risk

Julianne Holt-Lunstad, PhD, professor of psychology and neuroscience at Brigham Young University in Provo, Utah, is the author of two large meta-analyses that suggest loneliness, social isolation, or living alone are independent risk factors for early mortality, increasing this risk by about a third — the equivalent to the risk of smoking 15 cigarettes per day.

“We have quite robust evidence across a number of health outcomes implicating the harmful effects of loneliness and social isolation. While these are observational studies and show mainly associations, we do have evidence from longitudinal studies that show lacking social connection, whether that be loneliness or social isolation, predicts subsequent worse outcomes, and most of these studies have adjusted for alternative kinds of explanations, like age, initial health status, lifestyle factors,” Holt-Lunstad said.

There is some evidence to suggest that isolation is more predictive of physical health outcomes, whereas loneliness is more predictive of mental health outcomes. That said, both isolation and loneliness have significant effects on mental and physical health outcomes, she noted.

There is also the question of whether loneliness is causing poor health or whether people who are in poor health feel lonely because poor health can lead to social isolation.

Finley said there’s probably a bit of both going on, but longitudinal studies, where loneliness is measured at a fixed timepoint then health outcomes are reported a few years later, suggest that loneliness is contributing to these adverse outcomes.

She added that there is also some evidence in animal models to suggest that loneliness is a causal risk factor for adverse health outcomes. “But you can’t ask a mouse or rat how lonely they’re feeling. All you can do is house them individually — removing them from social connection. This isn’t necessarily the same thing as loneliness in humans.”

Finley is studying mechanisms in the brain that may be involved in mediating the adverse health consequences of loneliness.

“What I’ve been seeing in the data so far is that it tends to be the self-report of how lonely folks are feeling that has the associations with differences in the brain, as opposed to the number of social connections people have. It does seem to be the more subjective, emotional perception of loneliness that is important.”

In a review of potential mechanisms involved, she concluded that it is dysregulated emotions and altered perceptions of social interactions that has profound impacts on the brain, suggesting that people who are lonely may have a tendency to interpret social cues in a negative way, preventing them from forming productive positive relationships.
 

Lack of Trust

One researcher who has studied this phenomenon is Dirk Scheele, PhD, professor of social neuroscience at Ruhr University Bochum in Germany.

“We were interested to find out why people remained lonely,” he said in an interview. “Loneliness is an unpleasant experience, and there are so many opportunities for social contacts nowadays, it’s not really clear at first sight why people are chronically lonely.”

To examine this question, Scheele and his team conducted a study in which functional MRI was used to examine the brain in otherwise healthy individuals with high or low loneliness scores while they played a trust game.

They also simulated a positive social interaction between participants and researchers, in which they talked about plans for a fictitious lottery win, and about their hobbies and interests, during which mood was measured with questionnaires, and saliva samples were collected to measure hormone levels.

Results showed that the high-lonely individuals had reduced activation in the insula cortex during the trust decisions. “This area of the brain is involved in the processing of bodily signals, such as ‘gut feelings.’ So reduced activity here could be interpreted as fewer gut feelings on who can be trusted,” Scheele explained.

The high-lonely individuals also had reduced responsiveness to the positive social interaction with a lower release of oxytocin and a smaller elevation in mood compared with the control individuals.

Scheele pointed out that there is some evidence that oxytocin might increase trust, and there is reduced release of endogenous oxytocin in high loneliness.

“Our results are consistent with the idea that loneliness is associated with negative biases about other people. So if we expect negative things from other people — for instance, that they cannot be trusted — then that would hamper further social interactions and could lead to loneliness,” he added.
 

A Role for Oxytocin?

In another study, the same researchers tested short-term (five weekly sessions) group psychotherapy to reduce loneliness using established techniques to target these negative biases. They also investigated whether the effects of this group psychotherapy could be augmented by administering intranasal oxytocin (vs placebo) before the group psychotherapy sessions.

Results showed that the group psychotherapy intervention reduced trait loneliness (loneliness experienced over a prolonged period). The oxytocin did not show a significant effect on trait loneliness, but there was a suggestion that it may enhance the reduction in state loneliness (how someone is feeling at a specific time) brought about by the psychotherapy sessions.

“We found that bonding within the groups was experienced as more positive in the oxytocin treated groups. It is possible that a longer intervention would be helpful for longer-term results,” Scheele concluded. “It’s not going to be a quick fix for loneliness, but there may be a role for oxytocin as an adjunct to psychotherapy.”
 

A Basic Human Need

Another loneliness researcher, Livia Tomova, PhD, assistant professor of psychology at Cardiff University in Wales, has used social isolation to induce loneliness in young people and found that this intervention was linked to brain patterns similar to those associated with hunger.

“We know that the drive to eat food is a very basic human need. We know quite well how it is represented in the brain,” she explained.

The researchers tested how the brains of the participants responded to seeing pictures of social interactions after they underwent a prolonged period of social isolation. In a subsequent session, the same people were asked to undergo food fasting and then underwent brain scans when looking at pictures of food. Results showed that the neural patterns were similar in the two situations with increased activity in the substantia nigra area within the midbrain.

“This area of the brain processes rewards and motivation. It consists primarily of dopamine neurons and increased activity corresponds to a feeling of craving something. So this area of the brain that controls essential homeostatic needs is activated when people feel lonely, suggesting that our need for social contact with others is potentially a very basic need similar to eating,” Tomova said.
 

Lower Gray Matter Volumes in Key Brain Areas

And another group from Germany has found that higher loneliness scores are negatively associated with specific brain regions responsible for memory, emotion regulation, and social processing.

Sandra Düzel, PhD, and colleagues from the Max Planck Institute for Human Development and the Charité – Universitätsmedizin Berlin, both in Berlin, Germany, reported a study in which individuals who reported higher loneliness had smaller gray matter volumes in brain regions such as the left amygdala, anterior hippocampus, and cerebellum, regions which are crucial for both emotional regulation and higher-order cognitive processes, such as self-reflection and executive function.

Düzel believes that possible mechanisms behind the link between loneliness and brain volume differences could include stress-related damage, with prolonged loneliness associated with elevated levels of stress hormones, which can damage the hippocampus over time, and reduced cognitive and social stimulation, which may contribute to brain volume reductions in regions critical for memory and emotional processing.

“Loneliness is often characterized by reduced social and environmental diversity, leading to less engagement with novel experiences and potentially lower hippocampal-striatal connectivity.

Since novelty-seeking and environmental diversity are associated with positive emotional states, individuals experiencing loneliness might benefit from increased exposure to new environments which could stimulate the brain’s reward circuits, fostering positive affect and potentially mitigating the emotional burden of loneliness,” she said.
 

Is Social Prescribing the Answer?

So are there enough data now to act and attempt to develop interventions to reduce loneliness? Most of these researchers believe so.

“I think we have enough information to act on this now. There are a number of national academies consensus reports, which suggest that, while certainly there are still gaps in our evidence and more to be learned, there is sufficient evidence that a concerning portion of the population seems to lack connection, and that the consequences are serious enough that we need to do something about it,” said Holt-Lunstad.

Some countries have introduced social prescribing where doctors can prescribe a group activity or a regular visit or telephone conversation with a supportive person.

Subramanian pointed out that it’s easier to implement in countries with national health services and may be more difficult to embrace in the US healthcare system.

“We are not so encouraged from a financial perspective to think about preventive care in the US. We don’t have an easy way to recognize in any tangible way the downstream of such activities in terms of preventing future problems. That is something we need to work on,” she said.

Finley cautioned that to work well, social prescribing will require an understanding of each person’s individual situation.

“Some people may only receive benefit of interacting with others if they are also getting some sort of support to address the social and emotional concerns that are tagging along with loneliness. I’m not sure that just telling people to go join their local gardening club or whatever will be the correct answer for everyone.”

She pointed out that many people will have issues in their life that are making it hard for them to be social. These could be mobility or financial challenges, care responsibilities, or concerns about illnesses or life events. “We need to figure out what would have the most bang for the person’s buck, so to speak, as an intervention. That could mean connecting them to a group relevant to their individual situation.”
 

Opportunity to Connect Not Enough?

Tomova believes that training people in social skills may be a better option. “It appears that some people who are chronically lonely seem to struggle to make relationships with others. So just encouraging them to interact with others more will not necessarily help. We need to better understand the pathways involved and who are the people who become ill. We can then develop and target better interventions and teach people coping strategies for that situation.”

Scheele agreed. “While just giving people the opportunity to connect may work for some, others who are experiencing really chronic loneliness may not benefit very much from this unless their negative belief systems are addressed.” He suggested some sort of psychotherapy may be helpful in this situation.

But at least all seem to agree that healthcare providers need to be more aware of loneliness as a health risk factor, try to identify people at risk, and to think about how best to support them.

Holt-Lunstad noted that one of the recommendations in the US Surgeon General’s advisory was to increase the education, training, and resources on loneliness for healthcare providers.

“If we want this to be addressed, we need to give healthcare providers the time, resources, and training in order to do that, otherwise, we are adding one more thing to an already overburdened system. They need to understand how important it is, and how it might help them take care of the patient.”

“Our hope is that we can start to reverse some of the trends that we are seeing, both in terms of the prevalence rates of loneliness, but also that we could start seeing improvements in health and other kinds of outcomes,” she concluded.

Progress is being made in increasing awareness about the dangers of chronic loneliness. It’s now recognized as a serious health risk, but there are actionable steps that can help. Loneliness doesn’t have to be a permanent condition for anyone, said Scheele.

Holt-Lunstad served as an adviser for Foundation for Social Connection, Global Initiative on Loneliness and Connection, and Nextdoor Neighborhood Vitality Board and received research grants/income from Templeton Foundation, Eventbrite, Foundation for Social Connection, and Triple-S Foundation. Subramanian served as a speaker bureau for Acorda Pharma. The other researchers reported no disclosures.

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

In a world that is more connected than ever, a silent epidemic is taking its toll. Overall, one in three US adults report chronic loneliness — a condition so detrimental that it rivals smoking and obesity with respect to its negative effect on health and well-being. From anxiety and depression to life-threatening conditions like cardiovascular disease, stroke, and Alzheimer’s and Parkinson’s diseases, loneliness is more than an emotion — it’s a serious threat to both the brain and body.

In 2023, a US Surgeon General advisory raised the alarm about the national problem of loneliness and isolation, describing it as an epidemic.

“Given the significant health consequences of loneliness and isolation, we must prioritize building social connection in the same way we have prioritized other critical public health issues such as tobacco, obesity, and substance use disorders. Together, we can build a country that’s healthier, more resilient, less lonely, and more connected,” the report concluded.

But how, exactly, does chronic loneliness affect the physiology and function of the brain? What does the latest research reveal about the link between loneliness and neurologic and psychiatric illness, and what can clinicians do to address the issue?

This news organization spoke to multiple experts in the field to explore these issues.
 

A Major Risk Factor

Anna Finley, PhD, assistant professor of psychology at North Dakota State University, Fargo, explained that loneliness and social isolation are different entities. Social isolation is an objective measure of the number of people someone interacts with on a regular basis, whereas loneliness is a subjective feeling that occurs when close connections are lacking.

“These two things are not actually as related as you think they would be. People can feel lonely in a crowd or feel well connected with only a few friendships. It’s more about the quality of the connection and the quality of your perception of it. So someone could be in some very supportive relationships but still feel that there’s something missing,” she said in an interview.

So what do we know about how loneliness affects health? Evidence supporting the hypothesis that loneliness is an emerging risk factor for many diseases is steadily building.

Recently, the American Heart Association published a statement summarizing the evidence for a direct association between social isolation and loneliness and coronary heart disease and stroke mortality.

In addition, many studies have shown that individuals experiencing social isolation or loneliness have an increased risk for anxiety and depression, dementia, infectious disease, hospitalization, and all-cause death, even after adjusting for age and many other traditional risk factors.

One study revealed that eliminating loneliness has the potential to prevent nearly 20% of cases of depression in adults aged 50 years or older.

Indu Subramanian, MD, professor of neurology at the University of California, Los Angeles, and colleagues conducted a study involving patients with Parkinson’s disease, which showed that the negative impact of loneliness on disease severity was as significant as the positive effects of 30 minutes of daily exercise.

“The importance of loneliness is under-recognized and undervalued, and it poses a major risk for health outcomes and quality of life,” said Subramanian.

Subramanian noted that loneliness is stigmatizing, causing people to feel unlikable and blame themselves, which prevents them from opening up to doctors or loved ones about their struggle. At the same time, healthcare providers may not think to ask about loneliness or know about potential interventions. She emphasized that much more work is needed to address this issue.
 

Early Mortality Risk

Julianne Holt-Lunstad, PhD, professor of psychology and neuroscience at Brigham Young University in Provo, Utah, is the author of two large meta-analyses that suggest loneliness, social isolation, or living alone are independent risk factors for early mortality, increasing this risk by about a third — the equivalent to the risk of smoking 15 cigarettes per day.

“We have quite robust evidence across a number of health outcomes implicating the harmful effects of loneliness and social isolation. While these are observational studies and show mainly associations, we do have evidence from longitudinal studies that show lacking social connection, whether that be loneliness or social isolation, predicts subsequent worse outcomes, and most of these studies have adjusted for alternative kinds of explanations, like age, initial health status, lifestyle factors,” Holt-Lunstad said.

There is some evidence to suggest that isolation is more predictive of physical health outcomes, whereas loneliness is more predictive of mental health outcomes. That said, both isolation and loneliness have significant effects on mental and physical health outcomes, she noted.

There is also the question of whether loneliness is causing poor health or whether people who are in poor health feel lonely because poor health can lead to social isolation.

Finley said there’s probably a bit of both going on, but longitudinal studies, where loneliness is measured at a fixed timepoint then health outcomes are reported a few years later, suggest that loneliness is contributing to these adverse outcomes.

She added that there is also some evidence in animal models to suggest that loneliness is a causal risk factor for adverse health outcomes. “But you can’t ask a mouse or rat how lonely they’re feeling. All you can do is house them individually — removing them from social connection. This isn’t necessarily the same thing as loneliness in humans.”

Finley is studying mechanisms in the brain that may be involved in mediating the adverse health consequences of loneliness.

“What I’ve been seeing in the data so far is that it tends to be the self-report of how lonely folks are feeling that has the associations with differences in the brain, as opposed to the number of social connections people have. It does seem to be the more subjective, emotional perception of loneliness that is important.”

In a review of potential mechanisms involved, she concluded that it is dysregulated emotions and altered perceptions of social interactions that has profound impacts on the brain, suggesting that people who are lonely may have a tendency to interpret social cues in a negative way, preventing them from forming productive positive relationships.
 

Lack of Trust

One researcher who has studied this phenomenon is Dirk Scheele, PhD, professor of social neuroscience at Ruhr University Bochum in Germany.

“We were interested to find out why people remained lonely,” he said in an interview. “Loneliness is an unpleasant experience, and there are so many opportunities for social contacts nowadays, it’s not really clear at first sight why people are chronically lonely.”

To examine this question, Scheele and his team conducted a study in which functional MRI was used to examine the brain in otherwise healthy individuals with high or low loneliness scores while they played a trust game.

They also simulated a positive social interaction between participants and researchers, in which they talked about plans for a fictitious lottery win, and about their hobbies and interests, during which mood was measured with questionnaires, and saliva samples were collected to measure hormone levels.

Results showed that the high-lonely individuals had reduced activation in the insula cortex during the trust decisions. “This area of the brain is involved in the processing of bodily signals, such as ‘gut feelings.’ So reduced activity here could be interpreted as fewer gut feelings on who can be trusted,” Scheele explained.

The high-lonely individuals also had reduced responsiveness to the positive social interaction with a lower release of oxytocin and a smaller elevation in mood compared with the control individuals.

Scheele pointed out that there is some evidence that oxytocin might increase trust, and there is reduced release of endogenous oxytocin in high loneliness.

“Our results are consistent with the idea that loneliness is associated with negative biases about other people. So if we expect negative things from other people — for instance, that they cannot be trusted — then that would hamper further social interactions and could lead to loneliness,” he added.
 

A Role for Oxytocin?

In another study, the same researchers tested short-term (five weekly sessions) group psychotherapy to reduce loneliness using established techniques to target these negative biases. They also investigated whether the effects of this group psychotherapy could be augmented by administering intranasal oxytocin (vs placebo) before the group psychotherapy sessions.

Results showed that the group psychotherapy intervention reduced trait loneliness (loneliness experienced over a prolonged period). The oxytocin did not show a significant effect on trait loneliness, but there was a suggestion that it may enhance the reduction in state loneliness (how someone is feeling at a specific time) brought about by the psychotherapy sessions.

“We found that bonding within the groups was experienced as more positive in the oxytocin treated groups. It is possible that a longer intervention would be helpful for longer-term results,” Scheele concluded. “It’s not going to be a quick fix for loneliness, but there may be a role for oxytocin as an adjunct to psychotherapy.”
 

A Basic Human Need

Another loneliness researcher, Livia Tomova, PhD, assistant professor of psychology at Cardiff University in Wales, has used social isolation to induce loneliness in young people and found that this intervention was linked to brain patterns similar to those associated with hunger.

“We know that the drive to eat food is a very basic human need. We know quite well how it is represented in the brain,” she explained.

The researchers tested how the brains of the participants responded to seeing pictures of social interactions after they underwent a prolonged period of social isolation. In a subsequent session, the same people were asked to undergo food fasting and then underwent brain scans when looking at pictures of food. Results showed that the neural patterns were similar in the two situations with increased activity in the substantia nigra area within the midbrain.

“This area of the brain processes rewards and motivation. It consists primarily of dopamine neurons and increased activity corresponds to a feeling of craving something. So this area of the brain that controls essential homeostatic needs is activated when people feel lonely, suggesting that our need for social contact with others is potentially a very basic need similar to eating,” Tomova said.
 

Lower Gray Matter Volumes in Key Brain Areas

And another group from Germany has found that higher loneliness scores are negatively associated with specific brain regions responsible for memory, emotion regulation, and social processing.

Sandra Düzel, PhD, and colleagues from the Max Planck Institute for Human Development and the Charité – Universitätsmedizin Berlin, both in Berlin, Germany, reported a study in which individuals who reported higher loneliness had smaller gray matter volumes in brain regions such as the left amygdala, anterior hippocampus, and cerebellum, regions which are crucial for both emotional regulation and higher-order cognitive processes, such as self-reflection and executive function.

Düzel believes that possible mechanisms behind the link between loneliness and brain volume differences could include stress-related damage, with prolonged loneliness associated with elevated levels of stress hormones, which can damage the hippocampus over time, and reduced cognitive and social stimulation, which may contribute to brain volume reductions in regions critical for memory and emotional processing.

“Loneliness is often characterized by reduced social and environmental diversity, leading to less engagement with novel experiences and potentially lower hippocampal-striatal connectivity.

Since novelty-seeking and environmental diversity are associated with positive emotional states, individuals experiencing loneliness might benefit from increased exposure to new environments which could stimulate the brain’s reward circuits, fostering positive affect and potentially mitigating the emotional burden of loneliness,” she said.
 

Is Social Prescribing the Answer?

So are there enough data now to act and attempt to develop interventions to reduce loneliness? Most of these researchers believe so.

“I think we have enough information to act on this now. There are a number of national academies consensus reports, which suggest that, while certainly there are still gaps in our evidence and more to be learned, there is sufficient evidence that a concerning portion of the population seems to lack connection, and that the consequences are serious enough that we need to do something about it,” said Holt-Lunstad.

Some countries have introduced social prescribing where doctors can prescribe a group activity or a regular visit or telephone conversation with a supportive person.

Subramanian pointed out that it’s easier to implement in countries with national health services and may be more difficult to embrace in the US healthcare system.

“We are not so encouraged from a financial perspective to think about preventive care in the US. We don’t have an easy way to recognize in any tangible way the downstream of such activities in terms of preventing future problems. That is something we need to work on,” she said.

Finley cautioned that to work well, social prescribing will require an understanding of each person’s individual situation.

“Some people may only receive benefit of interacting with others if they are also getting some sort of support to address the social and emotional concerns that are tagging along with loneliness. I’m not sure that just telling people to go join their local gardening club or whatever will be the correct answer for everyone.”

She pointed out that many people will have issues in their life that are making it hard for them to be social. These could be mobility or financial challenges, care responsibilities, or concerns about illnesses or life events. “We need to figure out what would have the most bang for the person’s buck, so to speak, as an intervention. That could mean connecting them to a group relevant to their individual situation.”
 

Opportunity to Connect Not Enough?

Tomova believes that training people in social skills may be a better option. “It appears that some people who are chronically lonely seem to struggle to make relationships with others. So just encouraging them to interact with others more will not necessarily help. We need to better understand the pathways involved and who are the people who become ill. We can then develop and target better interventions and teach people coping strategies for that situation.”

Scheele agreed. “While just giving people the opportunity to connect may work for some, others who are experiencing really chronic loneliness may not benefit very much from this unless their negative belief systems are addressed.” He suggested some sort of psychotherapy may be helpful in this situation.

But at least all seem to agree that healthcare providers need to be more aware of loneliness as a health risk factor, try to identify people at risk, and to think about how best to support them.

Holt-Lunstad noted that one of the recommendations in the US Surgeon General’s advisory was to increase the education, training, and resources on loneliness for healthcare providers.

“If we want this to be addressed, we need to give healthcare providers the time, resources, and training in order to do that, otherwise, we are adding one more thing to an already overburdened system. They need to understand how important it is, and how it might help them take care of the patient.”

“Our hope is that we can start to reverse some of the trends that we are seeing, both in terms of the prevalence rates of loneliness, but also that we could start seeing improvements in health and other kinds of outcomes,” she concluded.

Progress is being made in increasing awareness about the dangers of chronic loneliness. It’s now recognized as a serious health risk, but there are actionable steps that can help. Loneliness doesn’t have to be a permanent condition for anyone, said Scheele.

Holt-Lunstad served as an adviser for Foundation for Social Connection, Global Initiative on Loneliness and Connection, and Nextdoor Neighborhood Vitality Board and received research grants/income from Templeton Foundation, Eventbrite, Foundation for Social Connection, and Triple-S Foundation. Subramanian served as a speaker bureau for Acorda Pharma. The other researchers reported no disclosures.

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

In a world that is more connected than ever, a silent epidemic is taking its toll. Overall, one in three US adults report chronic loneliness — a condition so detrimental that it rivals smoking and obesity with respect to its negative effect on health and well-being. From anxiety and depression to life-threatening conditions like cardiovascular disease, stroke, and Alzheimer’s and Parkinson’s diseases, loneliness is more than an emotion — it’s a serious threat to both the brain and body.

In 2023, a US Surgeon General advisory raised the alarm about the national problem of loneliness and isolation, describing it as an epidemic.

“Given the significant health consequences of loneliness and isolation, we must prioritize building social connection in the same way we have prioritized other critical public health issues such as tobacco, obesity, and substance use disorders. Together, we can build a country that’s healthier, more resilient, less lonely, and more connected,” the report concluded.

But how, exactly, does chronic loneliness affect the physiology and function of the brain? What does the latest research reveal about the link between loneliness and neurologic and psychiatric illness, and what can clinicians do to address the issue?

This news organization spoke to multiple experts in the field to explore these issues.
 

A Major Risk Factor

Anna Finley, PhD, assistant professor of psychology at North Dakota State University, Fargo, explained that loneliness and social isolation are different entities. Social isolation is an objective measure of the number of people someone interacts with on a regular basis, whereas loneliness is a subjective feeling that occurs when close connections are lacking.

“These two things are not actually as related as you think they would be. People can feel lonely in a crowd or feel well connected with only a few friendships. It’s more about the quality of the connection and the quality of your perception of it. So someone could be in some very supportive relationships but still feel that there’s something missing,” she said in an interview.

So what do we know about how loneliness affects health? Evidence supporting the hypothesis that loneliness is an emerging risk factor for many diseases is steadily building.

Recently, the American Heart Association published a statement summarizing the evidence for a direct association between social isolation and loneliness and coronary heart disease and stroke mortality.

In addition, many studies have shown that individuals experiencing social isolation or loneliness have an increased risk for anxiety and depression, dementia, infectious disease, hospitalization, and all-cause death, even after adjusting for age and many other traditional risk factors.

One study revealed that eliminating loneliness has the potential to prevent nearly 20% of cases of depression in adults aged 50 years or older.

Indu Subramanian, MD, professor of neurology at the University of California, Los Angeles, and colleagues conducted a study involving patients with Parkinson’s disease, which showed that the negative impact of loneliness on disease severity was as significant as the positive effects of 30 minutes of daily exercise.

“The importance of loneliness is under-recognized and undervalued, and it poses a major risk for health outcomes and quality of life,” said Subramanian.

Subramanian noted that loneliness is stigmatizing, causing people to feel unlikable and blame themselves, which prevents them from opening up to doctors or loved ones about their struggle. At the same time, healthcare providers may not think to ask about loneliness or know about potential interventions. She emphasized that much more work is needed to address this issue.
 

Early Mortality Risk

Julianne Holt-Lunstad, PhD, professor of psychology and neuroscience at Brigham Young University in Provo, Utah, is the author of two large meta-analyses that suggest loneliness, social isolation, or living alone are independent risk factors for early mortality, increasing this risk by about a third — the equivalent to the risk of smoking 15 cigarettes per day.

“We have quite robust evidence across a number of health outcomes implicating the harmful effects of loneliness and social isolation. While these are observational studies and show mainly associations, we do have evidence from longitudinal studies that show lacking social connection, whether that be loneliness or social isolation, predicts subsequent worse outcomes, and most of these studies have adjusted for alternative kinds of explanations, like age, initial health status, lifestyle factors,” Holt-Lunstad said.

There is some evidence to suggest that isolation is more predictive of physical health outcomes, whereas loneliness is more predictive of mental health outcomes. That said, both isolation and loneliness have significant effects on mental and physical health outcomes, she noted.

There is also the question of whether loneliness is causing poor health or whether people who are in poor health feel lonely because poor health can lead to social isolation.

Finley said there’s probably a bit of both going on, but longitudinal studies, where loneliness is measured at a fixed timepoint then health outcomes are reported a few years later, suggest that loneliness is contributing to these adverse outcomes.

She added that there is also some evidence in animal models to suggest that loneliness is a causal risk factor for adverse health outcomes. “But you can’t ask a mouse or rat how lonely they’re feeling. All you can do is house them individually — removing them from social connection. This isn’t necessarily the same thing as loneliness in humans.”

Finley is studying mechanisms in the brain that may be involved in mediating the adverse health consequences of loneliness.

“What I’ve been seeing in the data so far is that it tends to be the self-report of how lonely folks are feeling that has the associations with differences in the brain, as opposed to the number of social connections people have. It does seem to be the more subjective, emotional perception of loneliness that is important.”

In a review of potential mechanisms involved, she concluded that it is dysregulated emotions and altered perceptions of social interactions that has profound impacts on the brain, suggesting that people who are lonely may have a tendency to interpret social cues in a negative way, preventing them from forming productive positive relationships.
 

Lack of Trust

One researcher who has studied this phenomenon is Dirk Scheele, PhD, professor of social neuroscience at Ruhr University Bochum in Germany.

“We were interested to find out why people remained lonely,” he said in an interview. “Loneliness is an unpleasant experience, and there are so many opportunities for social contacts nowadays, it’s not really clear at first sight why people are chronically lonely.”

To examine this question, Scheele and his team conducted a study in which functional MRI was used to examine the brain in otherwise healthy individuals with high or low loneliness scores while they played a trust game.

They also simulated a positive social interaction between participants and researchers, in which they talked about plans for a fictitious lottery win, and about their hobbies and interests, during which mood was measured with questionnaires, and saliva samples were collected to measure hormone levels.

Results showed that the high-lonely individuals had reduced activation in the insula cortex during the trust decisions. “This area of the brain is involved in the processing of bodily signals, such as ‘gut feelings.’ So reduced activity here could be interpreted as fewer gut feelings on who can be trusted,” Scheele explained.

The high-lonely individuals also had reduced responsiveness to the positive social interaction with a lower release of oxytocin and a smaller elevation in mood compared with the control individuals.

Scheele pointed out that there is some evidence that oxytocin might increase trust, and there is reduced release of endogenous oxytocin in high loneliness.

“Our results are consistent with the idea that loneliness is associated with negative biases about other people. So if we expect negative things from other people — for instance, that they cannot be trusted — then that would hamper further social interactions and could lead to loneliness,” he added.
 

A Role for Oxytocin?

In another study, the same researchers tested short-term (five weekly sessions) group psychotherapy to reduce loneliness using established techniques to target these negative biases. They also investigated whether the effects of this group psychotherapy could be augmented by administering intranasal oxytocin (vs placebo) before the group psychotherapy sessions.

Results showed that the group psychotherapy intervention reduced trait loneliness (loneliness experienced over a prolonged period). The oxytocin did not show a significant effect on trait loneliness, but there was a suggestion that it may enhance the reduction in state loneliness (how someone is feeling at a specific time) brought about by the psychotherapy sessions.

“We found that bonding within the groups was experienced as more positive in the oxytocin treated groups. It is possible that a longer intervention would be helpful for longer-term results,” Scheele concluded. “It’s not going to be a quick fix for loneliness, but there may be a role for oxytocin as an adjunct to psychotherapy.”
 

A Basic Human Need

Another loneliness researcher, Livia Tomova, PhD, assistant professor of psychology at Cardiff University in Wales, has used social isolation to induce loneliness in young people and found that this intervention was linked to brain patterns similar to those associated with hunger.

“We know that the drive to eat food is a very basic human need. We know quite well how it is represented in the brain,” she explained.

The researchers tested how the brains of the participants responded to seeing pictures of social interactions after they underwent a prolonged period of social isolation. In a subsequent session, the same people were asked to undergo food fasting and then underwent brain scans when looking at pictures of food. Results showed that the neural patterns were similar in the two situations with increased activity in the substantia nigra area within the midbrain.

“This area of the brain processes rewards and motivation. It consists primarily of dopamine neurons and increased activity corresponds to a feeling of craving something. So this area of the brain that controls essential homeostatic needs is activated when people feel lonely, suggesting that our need for social contact with others is potentially a very basic need similar to eating,” Tomova said.
 

Lower Gray Matter Volumes in Key Brain Areas

And another group from Germany has found that higher loneliness scores are negatively associated with specific brain regions responsible for memory, emotion regulation, and social processing.

Sandra Düzel, PhD, and colleagues from the Max Planck Institute for Human Development and the Charité – Universitätsmedizin Berlin, both in Berlin, Germany, reported a study in which individuals who reported higher loneliness had smaller gray matter volumes in brain regions such as the left amygdala, anterior hippocampus, and cerebellum, regions which are crucial for both emotional regulation and higher-order cognitive processes, such as self-reflection and executive function.

Düzel believes that possible mechanisms behind the link between loneliness and brain volume differences could include stress-related damage, with prolonged loneliness associated with elevated levels of stress hormones, which can damage the hippocampus over time, and reduced cognitive and social stimulation, which may contribute to brain volume reductions in regions critical for memory and emotional processing.

“Loneliness is often characterized by reduced social and environmental diversity, leading to less engagement with novel experiences and potentially lower hippocampal-striatal connectivity.

Since novelty-seeking and environmental diversity are associated with positive emotional states, individuals experiencing loneliness might benefit from increased exposure to new environments which could stimulate the brain’s reward circuits, fostering positive affect and potentially mitigating the emotional burden of loneliness,” she said.
 

Is Social Prescribing the Answer?

So are there enough data now to act and attempt to develop interventions to reduce loneliness? Most of these researchers believe so.

“I think we have enough information to act on this now. There are a number of national academies consensus reports, which suggest that, while certainly there are still gaps in our evidence and more to be learned, there is sufficient evidence that a concerning portion of the population seems to lack connection, and that the consequences are serious enough that we need to do something about it,” said Holt-Lunstad.

Some countries have introduced social prescribing where doctors can prescribe a group activity or a regular visit or telephone conversation with a supportive person.

Subramanian pointed out that it’s easier to implement in countries with national health services and may be more difficult to embrace in the US healthcare system.

“We are not so encouraged from a financial perspective to think about preventive care in the US. We don’t have an easy way to recognize in any tangible way the downstream of such activities in terms of preventing future problems. That is something we need to work on,” she said.

Finley cautioned that to work well, social prescribing will require an understanding of each person’s individual situation.

“Some people may only receive benefit of interacting with others if they are also getting some sort of support to address the social and emotional concerns that are tagging along with loneliness. I’m not sure that just telling people to go join their local gardening club or whatever will be the correct answer for everyone.”

She pointed out that many people will have issues in their life that are making it hard for them to be social. These could be mobility or financial challenges, care responsibilities, or concerns about illnesses or life events. “We need to figure out what would have the most bang for the person’s buck, so to speak, as an intervention. That could mean connecting them to a group relevant to their individual situation.”
 

Opportunity to Connect Not Enough?

Tomova believes that training people in social skills may be a better option. “It appears that some people who are chronically lonely seem to struggle to make relationships with others. So just encouraging them to interact with others more will not necessarily help. We need to better understand the pathways involved and who are the people who become ill. We can then develop and target better interventions and teach people coping strategies for that situation.”

Scheele agreed. “While just giving people the opportunity to connect may work for some, others who are experiencing really chronic loneliness may not benefit very much from this unless their negative belief systems are addressed.” He suggested some sort of psychotherapy may be helpful in this situation.

But at least all seem to agree that healthcare providers need to be more aware of loneliness as a health risk factor, try to identify people at risk, and to think about how best to support them.

Holt-Lunstad noted that one of the recommendations in the US Surgeon General’s advisory was to increase the education, training, and resources on loneliness for healthcare providers.

“If we want this to be addressed, we need to give healthcare providers the time, resources, and training in order to do that, otherwise, we are adding one more thing to an already overburdened system. They need to understand how important it is, and how it might help them take care of the patient.”

“Our hope is that we can start to reverse some of the trends that we are seeing, both in terms of the prevalence rates of loneliness, but also that we could start seeing improvements in health and other kinds of outcomes,” she concluded.

Progress is being made in increasing awareness about the dangers of chronic loneliness. It’s now recognized as a serious health risk, but there are actionable steps that can help. Loneliness doesn’t have to be a permanent condition for anyone, said Scheele.

Holt-Lunstad served as an adviser for Foundation for Social Connection, Global Initiative on Loneliness and Connection, and Nextdoor Neighborhood Vitality Board and received research grants/income from Templeton Foundation, Eventbrite, Foundation for Social Connection, and Triple-S Foundation. Subramanian served as a speaker bureau for Acorda Pharma. The other researchers reported no disclosures.

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

TOPLINE:

Children of mothers who had obesity or eating disorders before or during pregnancy may face higher risks for neurodevelopmental and psychiatric disorders.

METHODOLOGY:

• Researchers conducted a population-based cohort study to investigate the association of maternal eating disorders and high prepregnancy body mass index (BMI) with psychiatric disorder and neurodevelopmental diagnoses in offspring.
• They used Finnish national registers to assess all live births from 2004 through 2014, with follow-up until 2021.
• Data of 392,098 mothers (mean age, 30.15 years) and 649,956 offspring (48.86% girls) were included.
• Maternal eating disorders and prepregnancy BMI were the main exposures, with 1.60% of mothers having a history of eating disorders; 5.89% were underweight and 53.13% had obesity.
• Diagnoses of children were identified and grouped by ICD-10 codes of mental, behavioral, and neurodevelopmental disorders, mood disorders, anxiety disorders, sleep disorders, attention-deficit/hyperactivity disorder, and conduct disorders, among several others.

TAKEAWAY:

• From birth until 7-17 years of age, 16.43% of offspring were diagnosed with a neurodevelopmental or psychiatric disorder.
• Maternal eating disorders were associated with psychiatric disorders in the offspring, with the largest effect sizes observed for sleep disorders (hazard ratio [HR], 2.36) and social functioning and tic disorders (HR, 2.18; P < .001 for both).
• The offspring of mothers with severe prepregnancy obesity had a more than twofold increased risk for intellectual disabilities (HR, 2.04; 95% CI, 1.83-2.28); being underweight before pregnancy was also linked to many psychiatric disorders in offspring.
• The occurrence of adverse birth outcomes along with maternal eating disorders or high BMI further increased the risk for neurodevelopmental and psychiatric disorders in the offspring.

IN PRACTICE:

“The findings underline the risk of offspring mental illness associated with maternal eating disorders and prepregnancy BMI and suggest the need to consider these exposures clinically to help prevent offspring mental illness,” the authors wrote.

SOURCE:

This study was led by Ida A.K. Nilsson, PhD, of the Department of Molecular Medicine and Surgery at the Karolinska Institutet in Stockholm, Sweden, and was published online in JAMA Network Open.

LIMITATIONS:

A limitation of the study was the relatively short follow-up time, which restricted the inclusion of late-onset psychiatric disorder diagnoses, such as schizophrenia spectrum disorders. Paternal data and genetic information, which may have influenced the interpretation of the data, were not available. Another potential bias was that mothers with eating disorders may have been more perceptive to their child’s eating behavior, leading to greater access to care and diagnosis for these children.

DISCLOSURES:

This work was supported by the Swedish Research Council, the regional agreement on medical training and clinical research between Region Stockholm and the Karolinska Institutet, the Swedish Brain Foundation, and other sources. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Children of mothers who had obesity or eating disorders before or during pregnancy may face higher risks for neurodevelopmental and psychiatric disorders.

METHODOLOGY:

• Researchers conducted a population-based cohort study to investigate the association of maternal eating disorders and high prepregnancy body mass index (BMI) with psychiatric disorder and neurodevelopmental diagnoses in offspring.
• They used Finnish national registers to assess all live births from 2004 through 2014, with follow-up until 2021.
• Data of 392,098 mothers (mean age, 30.15 years) and 649,956 offspring (48.86% girls) were included.
• Maternal eating disorders and prepregnancy BMI were the main exposures, with 1.60% of mothers having a history of eating disorders; 5.89% were underweight and 53.13% had obesity.
• Diagnoses of children were identified and grouped by ICD-10 codes of mental, behavioral, and neurodevelopmental disorders, mood disorders, anxiety disorders, sleep disorders, attention-deficit/hyperactivity disorder, and conduct disorders, among several others.

TAKEAWAY:

• From birth until 7-17 years of age, 16.43% of offspring were diagnosed with a neurodevelopmental or psychiatric disorder.
• Maternal eating disorders were associated with psychiatric disorders in the offspring, with the largest effect sizes observed for sleep disorders (hazard ratio [HR], 2.36) and social functioning and tic disorders (HR, 2.18; P < .001 for both).
• The offspring of mothers with severe prepregnancy obesity had a more than twofold increased risk for intellectual disabilities (HR, 2.04; 95% CI, 1.83-2.28); being underweight before pregnancy was also linked to many psychiatric disorders in offspring.
• The occurrence of adverse birth outcomes along with maternal eating disorders or high BMI further increased the risk for neurodevelopmental and psychiatric disorders in the offspring.

IN PRACTICE:

“The findings underline the risk of offspring mental illness associated with maternal eating disorders and prepregnancy BMI and suggest the need to consider these exposures clinically to help prevent offspring mental illness,” the authors wrote.

SOURCE:

This study was led by Ida A.K. Nilsson, PhD, of the Department of Molecular Medicine and Surgery at the Karolinska Institutet in Stockholm, Sweden, and was published online in JAMA Network Open.

LIMITATIONS:

A limitation of the study was the relatively short follow-up time, which restricted the inclusion of late-onset psychiatric disorder diagnoses, such as schizophrenia spectrum disorders. Paternal data and genetic information, which may have influenced the interpretation of the data, were not available. Another potential bias was that mothers with eating disorders may have been more perceptive to their child’s eating behavior, leading to greater access to care and diagnosis for these children.

DISCLOSURES:

This work was supported by the Swedish Research Council, the regional agreement on medical training and clinical research between Region Stockholm and the Karolinska Institutet, the Swedish Brain Foundation, and other sources. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Children of mothers who had obesity or eating disorders before or during pregnancy may face higher risks for neurodevelopmental and psychiatric disorders.

METHODOLOGY:

• Researchers conducted a population-based cohort study to investigate the association of maternal eating disorders and high prepregnancy body mass index (BMI) with psychiatric disorder and neurodevelopmental diagnoses in offspring.
• They used Finnish national registers to assess all live births from 2004 through 2014, with follow-up until 2021.
• Data of 392,098 mothers (mean age, 30.15 years) and 649,956 offspring (48.86% girls) were included.
• Maternal eating disorders and prepregnancy BMI were the main exposures, with 1.60% of mothers having a history of eating disorders; 5.89% were underweight and 53.13% had obesity.
• Diagnoses of children were identified and grouped by ICD-10 codes of mental, behavioral, and neurodevelopmental disorders, mood disorders, anxiety disorders, sleep disorders, attention-deficit/hyperactivity disorder, and conduct disorders, among several others.

TAKEAWAY:

• From birth until 7-17 years of age, 16.43% of offspring were diagnosed with a neurodevelopmental or psychiatric disorder.
• Maternal eating disorders were associated with psychiatric disorders in the offspring, with the largest effect sizes observed for sleep disorders (hazard ratio [HR], 2.36) and social functioning and tic disorders (HR, 2.18; P < .001 for both).
• The offspring of mothers with severe prepregnancy obesity had a more than twofold increased risk for intellectual disabilities (HR, 2.04; 95% CI, 1.83-2.28); being underweight before pregnancy was also linked to many psychiatric disorders in offspring.
• The occurrence of adverse birth outcomes along with maternal eating disorders or high BMI further increased the risk for neurodevelopmental and psychiatric disorders in the offspring.

IN PRACTICE:

“The findings underline the risk of offspring mental illness associated with maternal eating disorders and prepregnancy BMI and suggest the need to consider these exposures clinically to help prevent offspring mental illness,” the authors wrote.

SOURCE:

This study was led by Ida A.K. Nilsson, PhD, of the Department of Molecular Medicine and Surgery at the Karolinska Institutet in Stockholm, Sweden, and was published online in JAMA Network Open.

LIMITATIONS:

A limitation of the study was the relatively short follow-up time, which restricted the inclusion of late-onset psychiatric disorder diagnoses, such as schizophrenia spectrum disorders. Paternal data and genetic information, which may have influenced the interpretation of the data, were not available. Another potential bias was that mothers with eating disorders may have been more perceptive to their child’s eating behavior, leading to greater access to care and diagnosis for these children.

DISCLOSURES:

This work was supported by the Swedish Research Council, the regional agreement on medical training and clinical research between Region Stockholm and the Karolinska Institutet, the Swedish Brain Foundation, and other sources. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with dry eye disease are more than three times as likely to have mental health conditions, such as depression and anxiety, as those without the condition.

METHODOLOGY:

• Researchers used a database from the National Institutes of Health to investigate the association between dry eye disease and mental health disorders in a large and diverse nationwide population of American adults.
• They identified 18,257 patients (mean age, 64.9 years; 67% women) with dry eye disease who were propensity score–matched with 54,765 participants without the condition.
• The cases of dry eye disease were identified using Systematized Nomenclature of Medicine codes for dry eyes, meibomian gland dysfunction, and tear film insufficiency.
• The outcome measures for mental health conditions were clinical diagnoses of depressive disorders, anxiety-related disorders, bipolar disorder, and schizophrenia spectrum disorders.

TAKEAWAY:

• Patients with dry eye disease had more than triple the risk for mental health conditions than participants without the condition (adjusted odds ratio [aOR], 3.21; P < .001).
• Patients with dry eye disease had a higher risk for a depressive disorder (aOR, 3.47), anxiety-related disorder (aOR, 2.74), bipolar disorder (aOR, 2.23), and schizophrenia spectrum disorder (aOR, 2.48; P < .001 for all) than participants without the condition.
• The associations between dry eye disease and mental health conditions were significantly stronger among Black individuals than among White individuals, except for bipolar disorder.
• Dry eye disease was associated with two- to threefold higher odds of depressive disorders, anxiety-related disorders, bipolar disorder, and schizophrenia spectrum disorders even in participants who never used medications for mental health (P < .001 for all).

IN PRACTICE:

“Greater efforts should be undertaken to screen patients with DED [dry eye disease] for mental health conditions, particularly in historically medically underserved populations,” the authors of the study wrote.

SOURCE:

This study was led by Aaron T. Zhao, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and was published online on October 15, 2024, in the American Journal of Ophthalmology.

LIMITATIONS:

This study relied on electronic health record data, which may have led to the inclusion of participants with undiagnosed dry eye disease as control participants. Moreover, the study did not evaluate the severity of dry eye disease or the severity and duration of mental health conditions, which may have affected the results. The database analyzed in this study may not have fully captured the complete demographic profile of the nationwide population, which may have affected the generalizability of the findings.

DISCLOSURES:

This study was supported by funding from the National Institutes of Health and Research to Prevent Blindness. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with dry eye disease are more than three times as likely to have mental health conditions, such as depression and anxiety, as those without the condition.

METHODOLOGY:

• Researchers used a database from the National Institutes of Health to investigate the association between dry eye disease and mental health disorders in a large and diverse nationwide population of American adults.
• They identified 18,257 patients (mean age, 64.9 years; 67% women) with dry eye disease who were propensity score–matched with 54,765 participants without the condition.
• The cases of dry eye disease were identified using Systematized Nomenclature of Medicine codes for dry eyes, meibomian gland dysfunction, and tear film insufficiency.
• The outcome measures for mental health conditions were clinical diagnoses of depressive disorders, anxiety-related disorders, bipolar disorder, and schizophrenia spectrum disorders.

TAKEAWAY:

• Patients with dry eye disease had more than triple the risk for mental health conditions than participants without the condition (adjusted odds ratio [aOR], 3.21; P < .001).
• Patients with dry eye disease had a higher risk for a depressive disorder (aOR, 3.47), anxiety-related disorder (aOR, 2.74), bipolar disorder (aOR, 2.23), and schizophrenia spectrum disorder (aOR, 2.48; P < .001 for all) than participants without the condition.
• The associations between dry eye disease and mental health conditions were significantly stronger among Black individuals than among White individuals, except for bipolar disorder.
• Dry eye disease was associated with two- to threefold higher odds of depressive disorders, anxiety-related disorders, bipolar disorder, and schizophrenia spectrum disorders even in participants who never used medications for mental health (P < .001 for all).

IN PRACTICE:

“Greater efforts should be undertaken to screen patients with DED [dry eye disease] for mental health conditions, particularly in historically medically underserved populations,” the authors of the study wrote.

SOURCE:

This study was led by Aaron T. Zhao, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and was published online on October 15, 2024, in the American Journal of Ophthalmology.

LIMITATIONS:

This study relied on electronic health record data, which may have led to the inclusion of participants with undiagnosed dry eye disease as control participants. Moreover, the study did not evaluate the severity of dry eye disease or the severity and duration of mental health conditions, which may have affected the results. The database analyzed in this study may not have fully captured the complete demographic profile of the nationwide population, which may have affected the generalizability of the findings.

DISCLOSURES:

This study was supported by funding from the National Institutes of Health and Research to Prevent Blindness. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with dry eye disease are more than three times as likely to have mental health conditions, such as depression and anxiety, as those without the condition.

METHODOLOGY:

• Researchers used a database from the National Institutes of Health to investigate the association between dry eye disease and mental health disorders in a large and diverse nationwide population of American adults.
• They identified 18,257 patients (mean age, 64.9 years; 67% women) with dry eye disease who were propensity score–matched with 54,765 participants without the condition.
• The cases of dry eye disease were identified using Systematized Nomenclature of Medicine codes for dry eyes, meibomian gland dysfunction, and tear film insufficiency.
• The outcome measures for mental health conditions were clinical diagnoses of depressive disorders, anxiety-related disorders, bipolar disorder, and schizophrenia spectrum disorders.

TAKEAWAY:

• Patients with dry eye disease had more than triple the risk for mental health conditions than participants without the condition (adjusted odds ratio [aOR], 3.21; P < .001).
• Patients with dry eye disease had a higher risk for a depressive disorder (aOR, 3.47), anxiety-related disorder (aOR, 2.74), bipolar disorder (aOR, 2.23), and schizophrenia spectrum disorder (aOR, 2.48; P < .001 for all) than participants without the condition.
• The associations between dry eye disease and mental health conditions were significantly stronger among Black individuals than among White individuals, except for bipolar disorder.
• Dry eye disease was associated with two- to threefold higher odds of depressive disorders, anxiety-related disorders, bipolar disorder, and schizophrenia spectrum disorders even in participants who never used medications for mental health (P < .001 for all).

IN PRACTICE:

“Greater efforts should be undertaken to screen patients with DED [dry eye disease] for mental health conditions, particularly in historically medically underserved populations,” the authors of the study wrote.

SOURCE:

This study was led by Aaron T. Zhao, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and was published online on October 15, 2024, in the American Journal of Ophthalmology.

LIMITATIONS:

This study relied on electronic health record data, which may have led to the inclusion of participants with undiagnosed dry eye disease as control participants. Moreover, the study did not evaluate the severity of dry eye disease or the severity and duration of mental health conditions, which may have affected the results. The database analyzed in this study may not have fully captured the complete demographic profile of the nationwide population, which may have affected the generalizability of the findings.

DISCLOSURES:

This study was supported by funding from the National Institutes of Health and Research to Prevent Blindness. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Palliative care has proven to be one of the most promising fields for research on interventions with psychedelic substances. One of the most prominent researchers in this area was the American psychopharmacologist Roland Griffiths, PhD.

In 2016, Dr. Griffiths and his team at Johns Hopkins University in Baltimore, Maryland, published one of the most relevant contributions to the field by demonstrating in a placebo-controlled study that psilocybin can reduce depressive and anxiety symptoms in patients with cancer. The study, conducted with 51 patients diagnosed with advanced-stage cancer, compared the effects of a low dose and a high dose of psilocybin, showing that the high dose resulted in improvements in mood, quality of life, and sense of life, reducing death-related anxiety.

In 2021, after a routine examination, Dr. Griffiths himself was diagnosed with advanced colon cancer. Unexpectedly, the researcher found himself in the position of his research subjects. In an interview with The New York Times in April 2023, he stated that, after some resistance, he agreed to undergo an LSD session.

In the conversation, he revealed that he had a 50% chance of being alive by Halloween. Despite the diagnosis, he showed no discouragement. “As a scientist, I feel like a kid in a candy store, considering all the research and questions that need to be answered about psychedelics and the theme of human flourishing,” he said.

In his last months of life, in the various appearances and interviews he gave, Dr. Griffiths demonstrated a perception of life uncommon in people facing death. “I’m excited to communicate, to shake off the dust and tell people: ‘Come on, wake up!’ ”

He passed away on October 16, 2023, at age 77 years, opening new horizons for clinical research with psychedelics and becoming an example of the therapeutic potential of these substances.
 

Innovative Treatments

“I believe this will be one of the next conditions, if not the next condition, to be considered for the designation of innovative treatment in future psilocybin regulation in the United States, where the field is more advanced,” said Lucas Maia, PhD, a psychopharmacologist and researcher affiliated with the Advanced Center for Psychedelic Medicine (CAMP) at the Federal University of Rio Grande do Norte (UFRN) and the Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO) at the State University of Campinas in São Paulo, Brazil.

Currently, MDMA (for the treatment of posttraumatic stress disorder), psilocybin (for depressive disorder), and MM120 (an LSD analogue used to treat generalized anxiety disorder) are the only psychedelic substances that have received the designation of innovative treatment by the Food and Drug Administration (FDA).

In 2022, Dr. Maia and a colleague from ICARO, Ana Cláudia Mesquita Garcia, PhD, a professor at the School of Nursing at the Federal University of Alfenas in Brazil and leader of the Interdisciplinary Center for Studies in Palliative Care, published a systematic review in the Journal of Pain and Symptom Management that evaluated the use of psychedelic-assisted treatments for symptom control in patients with serious or terminal illnesses.

Of the 20 articles reviewed, 9 (45%) used LSD, 5 (25%) psilocybin, 2 (10%) dipropyltryptamine (DPT), 1 (5%) used ketamine, and 1 (5%) used MDMA. In 10% of the studies, LSD and DPT were combined. Altogether, 347 participants (54%) received LSD, 116 (18%) psilocybin, 81 (13%) LSD and DPT, 64 (10%) DPT, 18 (3%) MDMA, and 14 (2%) ketamine.

The conclusion of the study is that psychedelics provide therapeutic effects on physical, psychological, social, and existential outcomes. They are associated with a reduction in pain and improvement in sleep. A decrease in depressive and anxiety symptoms is also observed; such symptoms are common in patients with serious diseases. In addition, interpersonal relationships become closer and more empathetic. Finally, there is a reduction in the fear of death and suffering, an increase in acceptance, and a redefinition of the disease.

In 55% of the studies, the adverse effects were mild to moderate and transient. They included nausea, vomiting, dry mouth, and fatigue, as well as anxiety, panic, and hallucinations. The researchers concluded that the scarcity and difficulty of access to professional training in psychedelic-assisted treatments represent a significant challenge for the advancement of these interventions, especially in countries in the Global South.

Another systematic review and meta-analysis published in July by researchers at the University of Michigan in Ann Arbor, Michigan, included seven studies with 132 participants and showed significant improvements in quality of life, pain control, and anxiety relief after psychedelic-assisted psychotherapy with psilocybin. The combined effects indicated statistically significant reductions in anxiety symptoms after 4.0-4.5 months and after 6.0-6.5 months post administration, compared with the initial evaluations.

One of the most advanced research studies currently being conducted is led by Stephen Ross, MD, a psychiatrist affiliated with New York University’s Langone Medical Center, New York City. The phase 2b clinical study is randomized, double blind, and placebo controlled, and involves 300 participants. The study aims to evaluate the effects of psilocybin-assisted psychotherapy on psychiatric and existential distress in patients with advanced cancer. Its expected completion date is in 2027.

“We still lack effective interventions in minimizing psychological, spiritual, and existential suffering,” said Dr. Garcia. “In this sense, respecting the contraindications of a physical nature (including pre-existing illnesses at study initiation, disease staging, patient functionality level, comorbidities, concurrent pharmacological treatments, etc) and of a psychiatric nature for the use of psychedelics, depending on the clinical picture, end-of-life patients facing existential crises and psychological suffering will likely benefit more from psychedelic-assisted psychotherapy, which highlights the need for more research and the integration of this treatment into clinical practice.”
 

Changing Perceptions

Since 2021, the Cancer Institute of the State of São Paulo (Icesp) has been providing palliative treatment with ketamine — an atypical psychedelic — following a rigorous and carefully monitored clinical protocol. The substance is already used off label to treat refractory depressive disorder. In addition, in 2020, Brazil’s National Health Surveillance Agency approved the use of Spravato, an intranasal antidepressant based on the ketamine derivative esketamine.

Icesp has hospice beds for clinical oncology patients, and a pain management team evaluates which patients meet the inclusion criteria for ketamine use. In addition to difficult-to-control pain, it is important that the patient present emotional, existential, or spiritual symptoms that amplify that pain.

After this evaluation, a psychoeducation process takes place, in which the patient receives clear information about the treatment, its potential benefits and risks, and understands how ketamine can be a viable option for managing their symptoms. Finally, it is essential that the patient accept the referral and demonstrate a willingness to participate in the treatment, agreeing to the proposed terms.

The treatment takes place in a hospital environment, with an ambiance that aims to provide comfort and safety. Clinicians consider not only the substance dose (such as 0.5 mg/kg) but also the emotional state (“set”) and the treatment environment (“setting”). The experience is facilitated through psychological support for the patient during and after treatment.

According to Alessandro Campolina, MD, PhD, a researcher at the Center for Translational Oncology Research at Icesp, it is important to highlight that quality of life is intrinsically linked to the patient’s self-perception, including how they see themselves in terms of health and in the context in which they live.

The doctor explains that psychedelic interventions can provide a “window of opportunity,” allowing a qualified clinician to help the patient explore new perspectives based on their experiences.

“Often, although the intensity of pain remains the same, the way the patient perceives it can change significantly. For example, a patient may report that, despite the pain, they now feel less concerned about it because they were able to contemplate more significant aspects of their life,” said Dr. Campolina.

“This observation shows that treatment is not limited to addressing the pain or primary symptoms, but also addresses the associated suffering. While some patients have profound insights, many others experience more subtle changes that, under the guidance of a competent therapist, can turn into valuable clinical insights, thus improving quality of life and how they deal with their pathologies.”

Dr. Griffiths exemplified this in the interview with the Times when he reflected on his own cancer. He came to believe, as if guided an external observer, that “there is a meaning and a purpose in this [disease] that go beyond your understanding, and the way you are dealing with it is exactly how you should.”

Toshio Chiba, MD, chief physician of the Palliative Care Service at Icesp, emphasized that ketamine is already in use. “It is not feasible to wait years for the approval of psilocybin or for the FDA’s decision on MDMA, especially if the patient needs immediate care,” he said.

Furthermore, recreational and therapeutic uses are distinct. “It is essential to note that responsibilities are shared between the professional and the patient,” said Dr. Chiba. “In the therapeutic setting, there is an ethical and civil responsibility of the medical professional, as well as the patient actively engaging in treatment.”

Early palliative care can also facilitate the establishment of care goals. “I prefer to avoid terms like ‘coping’ or ‘fighting the disease,’” said Dr. Chiba. “Nowadays, dealing with cancer is more about coexisting with the disease properly, as treatments can last for years. 

“Of course, there are still highly lethal tumors. However, for neoplasms like breast, colorectal, and prostate cancers, we often talk about 5, 10, or even 15 years of coexistence [with the condition]. The lack of this information [about the disease, treatments, and existential issues] can generate distress in some patients, who end up excessively worrying about the future,” he added.

But palliative treatment with psychedelics as a panacea, he said.

In addition, Marcelo Falchi, MD, medical director of CAMP at UFRN, also emphasized that psychedelics are not a risk-free intervention. Substances like LSD and psilocybin, for example, can cause increases in blood pressure and tachycardia, which, may limit their use for patients at high cardiovascular risk. Crises of anxiety or dissociative symptoms also may occur, and they require mitigation strategies such as psychological support and attention to set and setting.

“But research seems to agree that the risks can be managed effectively through a diligent process, allowing for the responsible exploration of the therapeutic potential of psychedelics,” said Dr. Falchi, who is responsible for CAMP’s postgraduate course in psychedelic therapies. The program provides training in substances used in Brazil, such as ketamine and ibogaine.

The use of psychedelics in palliative care requires a significant shift in how professionals relate to patients.

Unlike in traditional practice, where the prescription is followed by quick consultations, palliative care with psychedelics requires deep and continuous involvement, as Dr. Campolina pointed out. “We joke that it’s not a high-tech specialty, but ‘high touch,’ because it demands the constant presence of the doctor or therapist with the patient. This can involve sessions of several hours, with frequent monitoring and regular contact after sessions. This dynamic emphasizes the importance of human touch and connection during the process, reflecting a new way of practicing medicine.”

In his last months of life, Dr. Griffiths sought to emphasize this point, suggesting that, from a broader perspective, doctors and patients face the same fundamental questions. “We all know we are terminal,” he said. “Essentially, we shouldn’t need a stage 4 cancer diagnosis to awaken to this reality.”

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Palliative care has proven to be one of the most promising fields for research on interventions with psychedelic substances. One of the most prominent researchers in this area was the American psychopharmacologist Roland Griffiths, PhD.

In 2016, Dr. Griffiths and his team at Johns Hopkins University in Baltimore, Maryland, published one of the most relevant contributions to the field by demonstrating in a placebo-controlled study that psilocybin can reduce depressive and anxiety symptoms in patients with cancer. The study, conducted with 51 patients diagnosed with advanced-stage cancer, compared the effects of a low dose and a high dose of psilocybin, showing that the high dose resulted in improvements in mood, quality of life, and sense of life, reducing death-related anxiety.

In 2021, after a routine examination, Dr. Griffiths himself was diagnosed with advanced colon cancer. Unexpectedly, the researcher found himself in the position of his research subjects. In an interview with The New York Times in April 2023, he stated that, after some resistance, he agreed to undergo an LSD session.

In the conversation, he revealed that he had a 50% chance of being alive by Halloween. Despite the diagnosis, he showed no discouragement. “As a scientist, I feel like a kid in a candy store, considering all the research and questions that need to be answered about psychedelics and the theme of human flourishing,” he said.

In his last months of life, in the various appearances and interviews he gave, Dr. Griffiths demonstrated a perception of life uncommon in people facing death. “I’m excited to communicate, to shake off the dust and tell people: ‘Come on, wake up!’ ”

He passed away on October 16, 2023, at age 77 years, opening new horizons for clinical research with psychedelics and becoming an example of the therapeutic potential of these substances.
 

Innovative Treatments

“I believe this will be one of the next conditions, if not the next condition, to be considered for the designation of innovative treatment in future psilocybin regulation in the United States, where the field is more advanced,” said Lucas Maia, PhD, a psychopharmacologist and researcher affiliated with the Advanced Center for Psychedelic Medicine (CAMP) at the Federal University of Rio Grande do Norte (UFRN) and the Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO) at the State University of Campinas in São Paulo, Brazil.

Currently, MDMA (for the treatment of posttraumatic stress disorder), psilocybin (for depressive disorder), and MM120 (an LSD analogue used to treat generalized anxiety disorder) are the only psychedelic substances that have received the designation of innovative treatment by the Food and Drug Administration (FDA).

In 2022, Dr. Maia and a colleague from ICARO, Ana Cláudia Mesquita Garcia, PhD, a professor at the School of Nursing at the Federal University of Alfenas in Brazil and leader of the Interdisciplinary Center for Studies in Palliative Care, published a systematic review in the Journal of Pain and Symptom Management that evaluated the use of psychedelic-assisted treatments for symptom control in patients with serious or terminal illnesses.

Of the 20 articles reviewed, 9 (45%) used LSD, 5 (25%) psilocybin, 2 (10%) dipropyltryptamine (DPT), 1 (5%) used ketamine, and 1 (5%) used MDMA. In 10% of the studies, LSD and DPT were combined. Altogether, 347 participants (54%) received LSD, 116 (18%) psilocybin, 81 (13%) LSD and DPT, 64 (10%) DPT, 18 (3%) MDMA, and 14 (2%) ketamine.

The conclusion of the study is that psychedelics provide therapeutic effects on physical, psychological, social, and existential outcomes. They are associated with a reduction in pain and improvement in sleep. A decrease in depressive and anxiety symptoms is also observed; such symptoms are common in patients with serious diseases. In addition, interpersonal relationships become closer and more empathetic. Finally, there is a reduction in the fear of death and suffering, an increase in acceptance, and a redefinition of the disease.

In 55% of the studies, the adverse effects were mild to moderate and transient. They included nausea, vomiting, dry mouth, and fatigue, as well as anxiety, panic, and hallucinations. The researchers concluded that the scarcity and difficulty of access to professional training in psychedelic-assisted treatments represent a significant challenge for the advancement of these interventions, especially in countries in the Global South.

Another systematic review and meta-analysis published in July by researchers at the University of Michigan in Ann Arbor, Michigan, included seven studies with 132 participants and showed significant improvements in quality of life, pain control, and anxiety relief after psychedelic-assisted psychotherapy with psilocybin. The combined effects indicated statistically significant reductions in anxiety symptoms after 4.0-4.5 months and after 6.0-6.5 months post administration, compared with the initial evaluations.

One of the most advanced research studies currently being conducted is led by Stephen Ross, MD, a psychiatrist affiliated with New York University’s Langone Medical Center, New York City. The phase 2b clinical study is randomized, double blind, and placebo controlled, and involves 300 participants. The study aims to evaluate the effects of psilocybin-assisted psychotherapy on psychiatric and existential distress in patients with advanced cancer. Its expected completion date is in 2027.

“We still lack effective interventions in minimizing psychological, spiritual, and existential suffering,” said Dr. Garcia. “In this sense, respecting the contraindications of a physical nature (including pre-existing illnesses at study initiation, disease staging, patient functionality level, comorbidities, concurrent pharmacological treatments, etc) and of a psychiatric nature for the use of psychedelics, depending on the clinical picture, end-of-life patients facing existential crises and psychological suffering will likely benefit more from psychedelic-assisted psychotherapy, which highlights the need for more research and the integration of this treatment into clinical practice.”
 

Changing Perceptions

Since 2021, the Cancer Institute of the State of São Paulo (Icesp) has been providing palliative treatment with ketamine — an atypical psychedelic — following a rigorous and carefully monitored clinical protocol. The substance is already used off label to treat refractory depressive disorder. In addition, in 2020, Brazil’s National Health Surveillance Agency approved the use of Spravato, an intranasal antidepressant based on the ketamine derivative esketamine.

Icesp has hospice beds for clinical oncology patients, and a pain management team evaluates which patients meet the inclusion criteria for ketamine use. In addition to difficult-to-control pain, it is important that the patient present emotional, existential, or spiritual symptoms that amplify that pain.

After this evaluation, a psychoeducation process takes place, in which the patient receives clear information about the treatment, its potential benefits and risks, and understands how ketamine can be a viable option for managing their symptoms. Finally, it is essential that the patient accept the referral and demonstrate a willingness to participate in the treatment, agreeing to the proposed terms.

The treatment takes place in a hospital environment, with an ambiance that aims to provide comfort and safety. Clinicians consider not only the substance dose (such as 0.5 mg/kg) but also the emotional state (“set”) and the treatment environment (“setting”). The experience is facilitated through psychological support for the patient during and after treatment.

According to Alessandro Campolina, MD, PhD, a researcher at the Center for Translational Oncology Research at Icesp, it is important to highlight that quality of life is intrinsically linked to the patient’s self-perception, including how they see themselves in terms of health and in the context in which they live.

The doctor explains that psychedelic interventions can provide a “window of opportunity,” allowing a qualified clinician to help the patient explore new perspectives based on their experiences.

“Often, although the intensity of pain remains the same, the way the patient perceives it can change significantly. For example, a patient may report that, despite the pain, they now feel less concerned about it because they were able to contemplate more significant aspects of their life,” said Dr. Campolina.

“This observation shows that treatment is not limited to addressing the pain or primary symptoms, but also addresses the associated suffering. While some patients have profound insights, many others experience more subtle changes that, under the guidance of a competent therapist, can turn into valuable clinical insights, thus improving quality of life and how they deal with their pathologies.”

Dr. Griffiths exemplified this in the interview with the Times when he reflected on his own cancer. He came to believe, as if guided an external observer, that “there is a meaning and a purpose in this [disease] that go beyond your understanding, and the way you are dealing with it is exactly how you should.”

Toshio Chiba, MD, chief physician of the Palliative Care Service at Icesp, emphasized that ketamine is already in use. “It is not feasible to wait years for the approval of psilocybin or for the FDA’s decision on MDMA, especially if the patient needs immediate care,” he said.

Furthermore, recreational and therapeutic uses are distinct. “It is essential to note that responsibilities are shared between the professional and the patient,” said Dr. Chiba. “In the therapeutic setting, there is an ethical and civil responsibility of the medical professional, as well as the patient actively engaging in treatment.”

Early palliative care can also facilitate the establishment of care goals. “I prefer to avoid terms like ‘coping’ or ‘fighting the disease,’” said Dr. Chiba. “Nowadays, dealing with cancer is more about coexisting with the disease properly, as treatments can last for years. 

“Of course, there are still highly lethal tumors. However, for neoplasms like breast, colorectal, and prostate cancers, we often talk about 5, 10, or even 15 years of coexistence [with the condition]. The lack of this information [about the disease, treatments, and existential issues] can generate distress in some patients, who end up excessively worrying about the future,” he added.

But palliative treatment with psychedelics as a panacea, he said.

In addition, Marcelo Falchi, MD, medical director of CAMP at UFRN, also emphasized that psychedelics are not a risk-free intervention. Substances like LSD and psilocybin, for example, can cause increases in blood pressure and tachycardia, which, may limit their use for patients at high cardiovascular risk. Crises of anxiety or dissociative symptoms also may occur, and they require mitigation strategies such as psychological support and attention to set and setting.

“But research seems to agree that the risks can be managed effectively through a diligent process, allowing for the responsible exploration of the therapeutic potential of psychedelics,” said Dr. Falchi, who is responsible for CAMP’s postgraduate course in psychedelic therapies. The program provides training in substances used in Brazil, such as ketamine and ibogaine.

The use of psychedelics in palliative care requires a significant shift in how professionals relate to patients.

Unlike in traditional practice, where the prescription is followed by quick consultations, palliative care with psychedelics requires deep and continuous involvement, as Dr. Campolina pointed out. “We joke that it’s not a high-tech specialty, but ‘high touch,’ because it demands the constant presence of the doctor or therapist with the patient. This can involve sessions of several hours, with frequent monitoring and regular contact after sessions. This dynamic emphasizes the importance of human touch and connection during the process, reflecting a new way of practicing medicine.”

In his last months of life, Dr. Griffiths sought to emphasize this point, suggesting that, from a broader perspective, doctors and patients face the same fundamental questions. “We all know we are terminal,” he said. “Essentially, we shouldn’t need a stage 4 cancer diagnosis to awaken to this reality.”

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Palliative care has proven to be one of the most promising fields for research on interventions with psychedelic substances. One of the most prominent researchers in this area was the American psychopharmacologist Roland Griffiths, PhD.

In 2016, Dr. Griffiths and his team at Johns Hopkins University in Baltimore, Maryland, published one of the most relevant contributions to the field by demonstrating in a placebo-controlled study that psilocybin can reduce depressive and anxiety symptoms in patients with cancer. The study, conducted with 51 patients diagnosed with advanced-stage cancer, compared the effects of a low dose and a high dose of psilocybin, showing that the high dose resulted in improvements in mood, quality of life, and sense of life, reducing death-related anxiety.

In 2021, after a routine examination, Dr. Griffiths himself was diagnosed with advanced colon cancer. Unexpectedly, the researcher found himself in the position of his research subjects. In an interview with The New York Times in April 2023, he stated that, after some resistance, he agreed to undergo an LSD session.

In the conversation, he revealed that he had a 50% chance of being alive by Halloween. Despite the diagnosis, he showed no discouragement. “As a scientist, I feel like a kid in a candy store, considering all the research and questions that need to be answered about psychedelics and the theme of human flourishing,” he said.

In his last months of life, in the various appearances and interviews he gave, Dr. Griffiths demonstrated a perception of life uncommon in people facing death. “I’m excited to communicate, to shake off the dust and tell people: ‘Come on, wake up!’ ”

He passed away on October 16, 2023, at age 77 years, opening new horizons for clinical research with psychedelics and becoming an example of the therapeutic potential of these substances.
 

Innovative Treatments

“I believe this will be one of the next conditions, if not the next condition, to be considered for the designation of innovative treatment in future psilocybin regulation in the United States, where the field is more advanced,” said Lucas Maia, PhD, a psychopharmacologist and researcher affiliated with the Advanced Center for Psychedelic Medicine (CAMP) at the Federal University of Rio Grande do Norte (UFRN) and the Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO) at the State University of Campinas in São Paulo, Brazil.

Currently, MDMA (for the treatment of posttraumatic stress disorder), psilocybin (for depressive disorder), and MM120 (an LSD analogue used to treat generalized anxiety disorder) are the only psychedelic substances that have received the designation of innovative treatment by the Food and Drug Administration (FDA).

In 2022, Dr. Maia and a colleague from ICARO, Ana Cláudia Mesquita Garcia, PhD, a professor at the School of Nursing at the Federal University of Alfenas in Brazil and leader of the Interdisciplinary Center for Studies in Palliative Care, published a systematic review in the Journal of Pain and Symptom Management that evaluated the use of psychedelic-assisted treatments for symptom control in patients with serious or terminal illnesses.

Of the 20 articles reviewed, 9 (45%) used LSD, 5 (25%) psilocybin, 2 (10%) dipropyltryptamine (DPT), 1 (5%) used ketamine, and 1 (5%) used MDMA. In 10% of the studies, LSD and DPT were combined. Altogether, 347 participants (54%) received LSD, 116 (18%) psilocybin, 81 (13%) LSD and DPT, 64 (10%) DPT, 18 (3%) MDMA, and 14 (2%) ketamine.

The conclusion of the study is that psychedelics provide therapeutic effects on physical, psychological, social, and existential outcomes. They are associated with a reduction in pain and improvement in sleep. A decrease in depressive and anxiety symptoms is also observed; such symptoms are common in patients with serious diseases. In addition, interpersonal relationships become closer and more empathetic. Finally, there is a reduction in the fear of death and suffering, an increase in acceptance, and a redefinition of the disease.

In 55% of the studies, the adverse effects were mild to moderate and transient. They included nausea, vomiting, dry mouth, and fatigue, as well as anxiety, panic, and hallucinations. The researchers concluded that the scarcity and difficulty of access to professional training in psychedelic-assisted treatments represent a significant challenge for the advancement of these interventions, especially in countries in the Global South.

Another systematic review and meta-analysis published in July by researchers at the University of Michigan in Ann Arbor, Michigan, included seven studies with 132 participants and showed significant improvements in quality of life, pain control, and anxiety relief after psychedelic-assisted psychotherapy with psilocybin. The combined effects indicated statistically significant reductions in anxiety symptoms after 4.0-4.5 months and after 6.0-6.5 months post administration, compared with the initial evaluations.

One of the most advanced research studies currently being conducted is led by Stephen Ross, MD, a psychiatrist affiliated with New York University’s Langone Medical Center, New York City. The phase 2b clinical study is randomized, double blind, and placebo controlled, and involves 300 participants. The study aims to evaluate the effects of psilocybin-assisted psychotherapy on psychiatric and existential distress in patients with advanced cancer. Its expected completion date is in 2027.

“We still lack effective interventions in minimizing psychological, spiritual, and existential suffering,” said Dr. Garcia. “In this sense, respecting the contraindications of a physical nature (including pre-existing illnesses at study initiation, disease staging, patient functionality level, comorbidities, concurrent pharmacological treatments, etc) and of a psychiatric nature for the use of psychedelics, depending on the clinical picture, end-of-life patients facing existential crises and psychological suffering will likely benefit more from psychedelic-assisted psychotherapy, which highlights the need for more research and the integration of this treatment into clinical practice.”
 

Changing Perceptions

Since 2021, the Cancer Institute of the State of São Paulo (Icesp) has been providing palliative treatment with ketamine — an atypical psychedelic — following a rigorous and carefully monitored clinical protocol. The substance is already used off label to treat refractory depressive disorder. In addition, in 2020, Brazil’s National Health Surveillance Agency approved the use of Spravato, an intranasal antidepressant based on the ketamine derivative esketamine.

Icesp has hospice beds for clinical oncology patients, and a pain management team evaluates which patients meet the inclusion criteria for ketamine use. In addition to difficult-to-control pain, it is important that the patient present emotional, existential, or spiritual symptoms that amplify that pain.

After this evaluation, a psychoeducation process takes place, in which the patient receives clear information about the treatment, its potential benefits and risks, and understands how ketamine can be a viable option for managing their symptoms. Finally, it is essential that the patient accept the referral and demonstrate a willingness to participate in the treatment, agreeing to the proposed terms.

The treatment takes place in a hospital environment, with an ambiance that aims to provide comfort and safety. Clinicians consider not only the substance dose (such as 0.5 mg/kg) but also the emotional state (“set”) and the treatment environment (“setting”). The experience is facilitated through psychological support for the patient during and after treatment.

According to Alessandro Campolina, MD, PhD, a researcher at the Center for Translational Oncology Research at Icesp, it is important to highlight that quality of life is intrinsically linked to the patient’s self-perception, including how they see themselves in terms of health and in the context in which they live.

The doctor explains that psychedelic interventions can provide a “window of opportunity,” allowing a qualified clinician to help the patient explore new perspectives based on their experiences.

“Often, although the intensity of pain remains the same, the way the patient perceives it can change significantly. For example, a patient may report that, despite the pain, they now feel less concerned about it because they were able to contemplate more significant aspects of their life,” said Dr. Campolina.

“This observation shows that treatment is not limited to addressing the pain or primary symptoms, but also addresses the associated suffering. While some patients have profound insights, many others experience more subtle changes that, under the guidance of a competent therapist, can turn into valuable clinical insights, thus improving quality of life and how they deal with their pathologies.”

Dr. Griffiths exemplified this in the interview with the Times when he reflected on his own cancer. He came to believe, as if guided an external observer, that “there is a meaning and a purpose in this [disease] that go beyond your understanding, and the way you are dealing with it is exactly how you should.”

Toshio Chiba, MD, chief physician of the Palliative Care Service at Icesp, emphasized that ketamine is already in use. “It is not feasible to wait years for the approval of psilocybin or for the FDA’s decision on MDMA, especially if the patient needs immediate care,” he said.

Furthermore, recreational and therapeutic uses are distinct. “It is essential to note that responsibilities are shared between the professional and the patient,” said Dr. Chiba. “In the therapeutic setting, there is an ethical and civil responsibility of the medical professional, as well as the patient actively engaging in treatment.”

Early palliative care can also facilitate the establishment of care goals. “I prefer to avoid terms like ‘coping’ or ‘fighting the disease,’” said Dr. Chiba. “Nowadays, dealing with cancer is more about coexisting with the disease properly, as treatments can last for years. 

“Of course, there are still highly lethal tumors. However, for neoplasms like breast, colorectal, and prostate cancers, we often talk about 5, 10, or even 15 years of coexistence [with the condition]. The lack of this information [about the disease, treatments, and existential issues] can generate distress in some patients, who end up excessively worrying about the future,” he added.

But palliative treatment with psychedelics as a panacea, he said.

In addition, Marcelo Falchi, MD, medical director of CAMP at UFRN, also emphasized that psychedelics are not a risk-free intervention. Substances like LSD and psilocybin, for example, can cause increases in blood pressure and tachycardia, which, may limit their use for patients at high cardiovascular risk. Crises of anxiety or dissociative symptoms also may occur, and they require mitigation strategies such as psychological support and attention to set and setting.

“But research seems to agree that the risks can be managed effectively through a diligent process, allowing for the responsible exploration of the therapeutic potential of psychedelics,” said Dr. Falchi, who is responsible for CAMP’s postgraduate course in psychedelic therapies. The program provides training in substances used in Brazil, such as ketamine and ibogaine.

The use of psychedelics in palliative care requires a significant shift in how professionals relate to patients.

Unlike in traditional practice, where the prescription is followed by quick consultations, palliative care with psychedelics requires deep and continuous involvement, as Dr. Campolina pointed out. “We joke that it’s not a high-tech specialty, but ‘high touch,’ because it demands the constant presence of the doctor or therapist with the patient. This can involve sessions of several hours, with frequent monitoring and regular contact after sessions. This dynamic emphasizes the importance of human touch and connection during the process, reflecting a new way of practicing medicine.”

In his last months of life, Dr. Griffiths sought to emphasize this point, suggesting that, from a broader perspective, doctors and patients face the same fundamental questions. “We all know we are terminal,” he said. “Essentially, we shouldn’t need a stage 4 cancer diagnosis to awaken to this reality.”

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In 2022, nearly 22% of people who died of drug overdose had a non–substance-related mental health disorder (MHD), new data from the Centers for Disease Control and Prevention (CDC) show. Investigators say the findings point to the need for incorporating mental health care in overdose prevention efforts.

METHODOLOGY:

• The study analyzed data from the CDC’s State Unintentional Drug Overdose Reporting System for 2022, covering 43 states and the District of Columbia.
• A total of 63,424 unintentional and undetermined intent drug overdose deaths during 2022 were included; 92.3% had medical examiner or coroner reports.
• MHDs were identified using source documents such as medical records and categorized according to the DSM-5 criteria.
• Potential intervention opportunities within 1 month of death, such as release from institutional settings or emergency department visits, were also analyzed.

TAKEAWAY:

• In 2022, 21.9% of drug overdose deaths involved people with non–substance-related MHDs, most commonly depression (12.9%), anxiety (9.4%), and bipolar disorder (5.9%).
• Opioids were involved in 82.2% of overdose deaths, with fentanyl or its analogs present in 75.2% of cases.
• Decedents with MHDs had higher usage rates of antidepressants (9.7% vs 3.3%), benzodiazepines (15.3% vs 8.5%), and prescription opioids (16% vs 11.6%) compared with those without MHDs.
• About 24.5% of decedents with MHDs had at least one potential intervention opportunity within 1 month of death, compared with 14.6% of those without MHDs, most commonly release from an institutional setting, treatment for substance use disorder, emergency department or urgent care visit, and nonfatal overdose.

IN PRACTICE:

“This finding suggests the need to screen for SUDs [ substance use disorders] and other MHDs, which is consistent with US Preventive Services Task Force recommendations for adults in primary care settings, and the need to link and integrate treatments to prevent overdose and improve mental health,” the authors wrote.

SOURCE:

The study was led by Amanda T. Dinwiddie, MPH, Division of Overdose Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. It was published online on August 29, 2024, in Morbidity and Mortality Weekly Report.

LIMITATIONS:

The findings might not be applicable to the entire US population. MHDs could have been undiagnosed or underreported, possibly leading to underestimation. Additionally, variations in the completeness of source documents could have affected the accuracy of identifying MHDs. Data on current or recent mental health treatment were also unavailable. Lastly, substance use disorders may have been recorded as MHDs when not specified.

DISCLOSURES:

The study funding source was not reported. The authors did not disclose any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In 2022, nearly 22% of people who died of drug overdose had a non–substance-related mental health disorder (MHD), new data from the Centers for Disease Control and Prevention (CDC) show. Investigators say the findings point to the need for incorporating mental health care in overdose prevention efforts.

METHODOLOGY:

• The study analyzed data from the CDC’s State Unintentional Drug Overdose Reporting System for 2022, covering 43 states and the District of Columbia.
• A total of 63,424 unintentional and undetermined intent drug overdose deaths during 2022 were included; 92.3% had medical examiner or coroner reports.
• MHDs were identified using source documents such as medical records and categorized according to the DSM-5 criteria.
• Potential intervention opportunities within 1 month of death, such as release from institutional settings or emergency department visits, were also analyzed.

TAKEAWAY:

• In 2022, 21.9% of drug overdose deaths involved people with non–substance-related MHDs, most commonly depression (12.9%), anxiety (9.4%), and bipolar disorder (5.9%).
• Opioids were involved in 82.2% of overdose deaths, with fentanyl or its analogs present in 75.2% of cases.
• Decedents with MHDs had higher usage rates of antidepressants (9.7% vs 3.3%), benzodiazepines (15.3% vs 8.5%), and prescription opioids (16% vs 11.6%) compared with those without MHDs.
• About 24.5% of decedents with MHDs had at least one potential intervention opportunity within 1 month of death, compared with 14.6% of those without MHDs, most commonly release from an institutional setting, treatment for substance use disorder, emergency department or urgent care visit, and nonfatal overdose.

IN PRACTICE:

“This finding suggests the need to screen for SUDs [ substance use disorders] and other MHDs, which is consistent with US Preventive Services Task Force recommendations for adults in primary care settings, and the need to link and integrate treatments to prevent overdose and improve mental health,” the authors wrote.

SOURCE:

The study was led by Amanda T. Dinwiddie, MPH, Division of Overdose Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. It was published online on August 29, 2024, in Morbidity and Mortality Weekly Report.

LIMITATIONS:

The findings might not be applicable to the entire US population. MHDs could have been undiagnosed or underreported, possibly leading to underestimation. Additionally, variations in the completeness of source documents could have affected the accuracy of identifying MHDs. Data on current or recent mental health treatment were also unavailable. Lastly, substance use disorders may have been recorded as MHDs when not specified.

DISCLOSURES:

The study funding source was not reported. The authors did not disclose any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In 2022, nearly 22% of people who died of drug overdose had a non–substance-related mental health disorder (MHD), new data from the Centers for Disease Control and Prevention (CDC) show. Investigators say the findings point to the need for incorporating mental health care in overdose prevention efforts.

METHODOLOGY:

• The study analyzed data from the CDC’s State Unintentional Drug Overdose Reporting System for 2022, covering 43 states and the District of Columbia.
• A total of 63,424 unintentional and undetermined intent drug overdose deaths during 2022 were included; 92.3% had medical examiner or coroner reports.
• MHDs were identified using source documents such as medical records and categorized according to the DSM-5 criteria.
• Potential intervention opportunities within 1 month of death, such as release from institutional settings or emergency department visits, were also analyzed.

TAKEAWAY:

• In 2022, 21.9% of drug overdose deaths involved people with non–substance-related MHDs, most commonly depression (12.9%), anxiety (9.4%), and bipolar disorder (5.9%).
• Opioids were involved in 82.2% of overdose deaths, with fentanyl or its analogs present in 75.2% of cases.
• Decedents with MHDs had higher usage rates of antidepressants (9.7% vs 3.3%), benzodiazepines (15.3% vs 8.5%), and prescription opioids (16% vs 11.6%) compared with those without MHDs.
• About 24.5% of decedents with MHDs had at least one potential intervention opportunity within 1 month of death, compared with 14.6% of those without MHDs, most commonly release from an institutional setting, treatment for substance use disorder, emergency department or urgent care visit, and nonfatal overdose.

IN PRACTICE:

“This finding suggests the need to screen for SUDs [ substance use disorders] and other MHDs, which is consistent with US Preventive Services Task Force recommendations for adults in primary care settings, and the need to link and integrate treatments to prevent overdose and improve mental health,” the authors wrote.

SOURCE:

The study was led by Amanda T. Dinwiddie, MPH, Division of Overdose Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. It was published online on August 29, 2024, in Morbidity and Mortality Weekly Report.

LIMITATIONS:

The findings might not be applicable to the entire US population. MHDs could have been undiagnosed or underreported, possibly leading to underestimation. Additionally, variations in the completeness of source documents could have affected the accuracy of identifying MHDs. Data on current or recent mental health treatment were also unavailable. Lastly, substance use disorders may have been recorded as MHDs when not specified.

DISCLOSURES:

The study funding source was not reported. The authors did not disclose any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

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

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

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

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

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

An accelerated schedule of intermittent theta burst transcranial magnetic stimulation (aiTBS) completed in less than a week is effective for treatment-resistant bipolar depression, the results of a small randomized controlled trial showed.

Investigators found those who received active aiTBS had a substantial decrease in depressive symptoms compared with those who received sham stimulation.

“aiTBS offers a new potential therapy for depressed patients with bipolar disorder who may not respond well to drugs or cannot tolerate their side effects while also significantly shortening the treatment window,” lead researcher Yvette Sheline, MD, director of the Center for Neuromodulation in Depression and Stress at the University of Pennsylvania, Philadelphia, said in a news release.

The study was published online in JAMA Psychiatry.
 

Remission After 5 Days

The Food and Drug Administration (FDA) cleared aiTBS to treat major depressive disorder. However, the treatment is not yet approved for bipolar depression.

The investigators assessed the effectiveness of aiTBS in 12 men and 12 women (mean age, 43 years) with treatment-resistant bipolar disorder. All participants were on mood stabilizers for at least 4 weeks and had Montgomery-Åsberg Depression Rating Scale (MADRS) scores of 20 or greater.

Of the 24 participants, 22 had a diagnosis of bipolar II disorder. Over 5 days, participants were randomized to receive, on a 1:1 basis, 10 sessions per day of imaging-guided active aiTBS or sham aiTBS over the left dorsolateral prefrontal cortex. Each session lasted for 1 hour. All 24 participants completed the assigned treatment and 1-month follow-up.

Active aiTBS was significantly more effective than sham stimulation in relieving depressive symptoms.

In the active treatment group, MADRS scores dropped from a mean of 30.4 at baseline to 10.5 after treatment. In contrast, the sham group experienced a minor change in MADRS scores, which decreased from a mean of 28.0 at baseline to 25.3 posttreatment.

After 5 days of treatment, half of the participants in the active aiTBS group were in remission, compared with none in the sham group.

The results demonstrate the “clinical efficacy and a short time to achieve improvement in this difficult-to-treat condition. The effect was seen even though the participant sample had high depression severity and treatment resistance, both associated with poor response,” the investigators noted.

Dr. Sheline said there were no differences between active and sham stimulation in the “expected adverse events of headache and dizziness. There were no incidences of manic “flip,” and the Young Mania Rating Scale scores were stable in both active and sham groups with no difference between them.”

The researchers noted that the “large effect size” of active aiTBS could be caused by several factors, including optimized stimulation targeting, accelerated time course, and high pulse number (18,000 per day, 90,000 total).

Future studies are needed to examine the relative contributions of the different protocol components to optimize and personalize treatment and evaluate the durability of the antidepressant effects of aiTBS, they added.
 

A Revolutionary Approach

For comment on the study, we reached out to Nolan Williams, MD, associate professor of psychiatry and behavioral sciences at Stanford University and director of the Stanford Brain Stimulation Lab, Stanford, California.

His laboratory pioneered the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), which was cleared by the FDA in 2022 for treatment-resistant depression.

Dr. Williams noted that the stimulation and targeting approach used in the current study “mirrors most aspects of the SAINT protocol with very similar results.”

“It’s exciting that we see this kind of pseudo-replication essentially of our work and is supportive of the general view that this approach is revolutionary in its ability to treat people quickly and have such a dramatic clinical effect,” said Dr. Williams.

In March 2024, Dr. Williams and colleagues reported the results of a pilot study of SAINT for bipolar depression, which demonstrated antidepressant efficacy akin to what was observed in the unipolar depression population.

Dr. Williams said, in his experience, the accelerated treatment protocol is convenient and well-liked by patients and, in general, is where the field of psychiatric treatment is headed.

“A general theme that we see in depression and psychiatry is that patients no longer accept long time frames for treatment as being the norm. Whether it be ketamine or this or the upcoming psychedelics, rapid-acting treatments that match the level of acuity will be the norm,” Dr. Williams said.

The study was funded by the Milken Institute and the Baszucki Brain Research Fund. The authors have disclosed no conflicts of interest. Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting. He disclosed ties with Otsuka, NeuraWell, Magnus Medical, and Nooma.

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

An accelerated schedule of intermittent theta burst transcranial magnetic stimulation (aiTBS) completed in less than a week is effective for treatment-resistant bipolar depression, the results of a small randomized controlled trial showed.

Investigators found those who received active aiTBS had a substantial decrease in depressive symptoms compared with those who received sham stimulation.

“aiTBS offers a new potential therapy for depressed patients with bipolar disorder who may not respond well to drugs or cannot tolerate their side effects while also significantly shortening the treatment window,” lead researcher Yvette Sheline, MD, director of the Center for Neuromodulation in Depression and Stress at the University of Pennsylvania, Philadelphia, said in a news release.

The study was published online in JAMA Psychiatry.
 

Remission After 5 Days

The Food and Drug Administration (FDA) cleared aiTBS to treat major depressive disorder. However, the treatment is not yet approved for bipolar depression.

The investigators assessed the effectiveness of aiTBS in 12 men and 12 women (mean age, 43 years) with treatment-resistant bipolar disorder. All participants were on mood stabilizers for at least 4 weeks and had Montgomery-Åsberg Depression Rating Scale (MADRS) scores of 20 or greater.

Of the 24 participants, 22 had a diagnosis of bipolar II disorder. Over 5 days, participants were randomized to receive, on a 1:1 basis, 10 sessions per day of imaging-guided active aiTBS or sham aiTBS over the left dorsolateral prefrontal cortex. Each session lasted for 1 hour. All 24 participants completed the assigned treatment and 1-month follow-up.

Active aiTBS was significantly more effective than sham stimulation in relieving depressive symptoms.

In the active treatment group, MADRS scores dropped from a mean of 30.4 at baseline to 10.5 after treatment. In contrast, the sham group experienced a minor change in MADRS scores, which decreased from a mean of 28.0 at baseline to 25.3 posttreatment.

After 5 days of treatment, half of the participants in the active aiTBS group were in remission, compared with none in the sham group.

The results demonstrate the “clinical efficacy and a short time to achieve improvement in this difficult-to-treat condition. The effect was seen even though the participant sample had high depression severity and treatment resistance, both associated with poor response,” the investigators noted.

Dr. Sheline said there were no differences between active and sham stimulation in the “expected adverse events of headache and dizziness. There were no incidences of manic “flip,” and the Young Mania Rating Scale scores were stable in both active and sham groups with no difference between them.”

The researchers noted that the “large effect size” of active aiTBS could be caused by several factors, including optimized stimulation targeting, accelerated time course, and high pulse number (18,000 per day, 90,000 total).

Future studies are needed to examine the relative contributions of the different protocol components to optimize and personalize treatment and evaluate the durability of the antidepressant effects of aiTBS, they added.
 

A Revolutionary Approach

For comment on the study, we reached out to Nolan Williams, MD, associate professor of psychiatry and behavioral sciences at Stanford University and director of the Stanford Brain Stimulation Lab, Stanford, California.

His laboratory pioneered the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), which was cleared by the FDA in 2022 for treatment-resistant depression.

Dr. Williams noted that the stimulation and targeting approach used in the current study “mirrors most aspects of the SAINT protocol with very similar results.”

“It’s exciting that we see this kind of pseudo-replication essentially of our work and is supportive of the general view that this approach is revolutionary in its ability to treat people quickly and have such a dramatic clinical effect,” said Dr. Williams.

In March 2024, Dr. Williams and colleagues reported the results of a pilot study of SAINT for bipolar depression, which demonstrated antidepressant efficacy akin to what was observed in the unipolar depression population.

Dr. Williams said, in his experience, the accelerated treatment protocol is convenient and well-liked by patients and, in general, is where the field of psychiatric treatment is headed.

“A general theme that we see in depression and psychiatry is that patients no longer accept long time frames for treatment as being the norm. Whether it be ketamine or this or the upcoming psychedelics, rapid-acting treatments that match the level of acuity will be the norm,” Dr. Williams said.

The study was funded by the Milken Institute and the Baszucki Brain Research Fund. The authors have disclosed no conflicts of interest. Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting. He disclosed ties with Otsuka, NeuraWell, Magnus Medical, and Nooma.

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

An accelerated schedule of intermittent theta burst transcranial magnetic stimulation (aiTBS) completed in less than a week is effective for treatment-resistant bipolar depression, the results of a small randomized controlled trial showed.

Investigators found those who received active aiTBS had a substantial decrease in depressive symptoms compared with those who received sham stimulation.

“aiTBS offers a new potential therapy for depressed patients with bipolar disorder who may not respond well to drugs or cannot tolerate their side effects while also significantly shortening the treatment window,” lead researcher Yvette Sheline, MD, director of the Center for Neuromodulation in Depression and Stress at the University of Pennsylvania, Philadelphia, said in a news release.

The study was published online in JAMA Psychiatry.
 

Remission After 5 Days

The Food and Drug Administration (FDA) cleared aiTBS to treat major depressive disorder. However, the treatment is not yet approved for bipolar depression.

The investigators assessed the effectiveness of aiTBS in 12 men and 12 women (mean age, 43 years) with treatment-resistant bipolar disorder. All participants were on mood stabilizers for at least 4 weeks and had Montgomery-Åsberg Depression Rating Scale (MADRS) scores of 20 or greater.

Of the 24 participants, 22 had a diagnosis of bipolar II disorder. Over 5 days, participants were randomized to receive, on a 1:1 basis, 10 sessions per day of imaging-guided active aiTBS or sham aiTBS over the left dorsolateral prefrontal cortex. Each session lasted for 1 hour. All 24 participants completed the assigned treatment and 1-month follow-up.

Active aiTBS was significantly more effective than sham stimulation in relieving depressive symptoms.

In the active treatment group, MADRS scores dropped from a mean of 30.4 at baseline to 10.5 after treatment. In contrast, the sham group experienced a minor change in MADRS scores, which decreased from a mean of 28.0 at baseline to 25.3 posttreatment.

After 5 days of treatment, half of the participants in the active aiTBS group were in remission, compared with none in the sham group.

The results demonstrate the “clinical efficacy and a short time to achieve improvement in this difficult-to-treat condition. The effect was seen even though the participant sample had high depression severity and treatment resistance, both associated with poor response,” the investigators noted.

Dr. Sheline said there were no differences between active and sham stimulation in the “expected adverse events of headache and dizziness. There were no incidences of manic “flip,” and the Young Mania Rating Scale scores were stable in both active and sham groups with no difference between them.”

The researchers noted that the “large effect size” of active aiTBS could be caused by several factors, including optimized stimulation targeting, accelerated time course, and high pulse number (18,000 per day, 90,000 total).

Future studies are needed to examine the relative contributions of the different protocol components to optimize and personalize treatment and evaluate the durability of the antidepressant effects of aiTBS, they added.
 

A Revolutionary Approach

For comment on the study, we reached out to Nolan Williams, MD, associate professor of psychiatry and behavioral sciences at Stanford University and director of the Stanford Brain Stimulation Lab, Stanford, California.

His laboratory pioneered the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), which was cleared by the FDA in 2022 for treatment-resistant depression.

Dr. Williams noted that the stimulation and targeting approach used in the current study “mirrors most aspects of the SAINT protocol with very similar results.”

“It’s exciting that we see this kind of pseudo-replication essentially of our work and is supportive of the general view that this approach is revolutionary in its ability to treat people quickly and have such a dramatic clinical effect,” said Dr. Williams.

In March 2024, Dr. Williams and colleagues reported the results of a pilot study of SAINT for bipolar depression, which demonstrated antidepressant efficacy akin to what was observed in the unipolar depression population.

Dr. Williams said, in his experience, the accelerated treatment protocol is convenient and well-liked by patients and, in general, is where the field of psychiatric treatment is headed.

“A general theme that we see in depression and psychiatry is that patients no longer accept long time frames for treatment as being the norm. Whether it be ketamine or this or the upcoming psychedelics, rapid-acting treatments that match the level of acuity will be the norm,” Dr. Williams said.

The study was funded by the Milken Institute and the Baszucki Brain Research Fund. The authors have disclosed no conflicts of interest. Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting. He disclosed ties with Otsuka, NeuraWell, Magnus Medical, and Nooma.

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

Most people experiencing homelessness have mental health disorders, according to a systematic review and meta-analysis.

In an examination of studies that included nearly 50,000 participants, the current prevalence of mental health disorders among people experiencing homelessness was 67% and the lifetime prevalence was 77%.

“The relationship is likely bidirectional, where experiencing homelessness may exacerbate mental health symptoms or where having a mental health disorder may increase an individual’s risk for experiencing homelessness,” lead author Rebecca Barry, PhD, a postdoctoral fellow at the University of Calgary in Calgary, Alberta, Canada, told this news organization. 

“There are also likely stressors that increase both risk for homelessness and risk for developing mental health disorders. This study examines prevalence but does not examine causal relationships,” she said.

The findings were published in JAMA Psychiatry.
 

A Growing Problem 

To determine the current and lifetime prevalence of mental health disorders among the homeless population, the researchers analyzed 85 studies that examined this question in participants aged ≥ 18 years. The review included 48,414 participants, including 11,154 (23%) women and 37,260 (77%) men.

The lifetime prevalence of mental health disorders was significantly higher in men experiencing homelessness (86%) than in women (69%). The most common mental health disorder was substance use disorder (44%), followed by antisocial personality disorder (26%), major depression (19%), bipolar disorder (8%), and schizophrenia (7%).

The prevalence of current and lifetime mental health disorders among the homeless population was higher than that that observed in the general population (13%-15% and 12%-47%, respectively).

The results resembled those of a previous review that estimated that 76% of people experiencing homelessness living in high-income countries have mental health disorders.

“Even though our results are not surprising, they still are drawing attention to this issue because it is a big problem in Canada, the United States, Europe, and other places,” senior author Dallas Seitz, MD, PhD, professor of psychiatry at the University of Calgary’s Cumming School of Medicine, told this news organization. “The problem is concerning, and it’s not getting better. Addiction and mental health problems are becoming more common among people who are homeless.” 

The bottom line is that people need affordable housing and mental health support, said Dr. Seitz. “It’s a housing problem and a health problem, and we need adequate resources to find better ways for those two systems to collaborate. There are public safety concerns, and we have to try and bring services to people experiencing homelessness. You have to come and meet people where they’re at. You have to try and establish a trusting relationship so that we can get people on the path to recovery.”
 

‘It’s Really About Income’ 

Commenting on the findings for this news organization, Stephen Hwang, MD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said, “There have been previous studies of this type, but it is good to have an updated one.” Dr. Hwang, who is also chair in Homelessness, Housing, and Health at St. Michael’s Hospital, did not participate in the research. 

The findings must be understood in the proper context, he added. For one thing, grouping together all mental health disorders and giving a single prevalence figure can be misleading. “They are including in that category a diverse group of conditions. Substance use disorder, personality disorder, schizophrenia, and depression are all lumped together. The 67% prevalence seems very high, but it is a combination of many different conditions. I just don’t want people to look at that number and think that this means that everyone is a substance user or everyone has schizophrenia,” said Dr. Hwang. 

Also, some readers might interpret the findings to mean that mental problems are the reason people are homeless, he added. “That would be an incorrect interpretation because what this study is showing is that people with mental health disorders have a higher risk for becoming homeless. It doesn’t mean that it caused their homelessness. What really causes homelessness is a lack of affordable housing,” said Dr. Hwang.

“In a city or community where housing is very expensive, there’s not enough for everyone to be housed, there is a lot of competition for housing, and there’s not enough affordable housing for a number of reasons, we know that people with mental health conditions and substance use disorders will be among the first to lose their housing,” he said.

“It’s really about income. There are many reasons why a person cannot afford housing. So, not being able to earn enough money to afford it because you have a mental health disorder or substance use disorder is a common underlying reason for homelessness.”

Dr. Hwang also pointed out that people with mental illness who can access support, either through family members or through mental health care, and who also have the income to afford such services do not become homeless.

“Schizophrenia is seen in every population of the world at a rate of 1%. But you travel to certain cities and you see people who appear to have schizophrenia wandering the streets, and you go to other cities in the world and you don’t see anyone who looks like they’re homeless and have schizophrenia,” he said. 

“It’s not because there are fewer people with schizophrenia in those cities or countries; it’s because people with schizophrenia are treated differently. The rate of homelessness is determined not by how many people have that condition [eg, schizophrenia] but by how we treat those people and how we set up our society to either support or not support people who have disabilities.”

The study was funded by the Precision Care With Information, Science and Experience – Mental Health grant funded by the Calgary Health Foundation. Dr. Barry is supported by the Harley Hotchkiss Samuel Weiss Postdoctoral Fellowship awarded by the Hotchkiss Brain Institute at the University of Calgary. Dr. Barry reported having no relevant financial relationships. Dr. Seitz reported grants from Calgary Health Foundation during the conduct of the study as well as grants from University Health Foundation, the Canadian Institutes of Health Research, the Public Health Agency of Canada, the Alzheimer’s Association, and the Hotchkiss Brain Institute. He received honoraria for guideline development from the Canadian Coalition for Seniors Mental Health outside the submitted work. Dr. Hwang reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Most people experiencing homelessness have mental health disorders, according to a systematic review and meta-analysis.

In an examination of studies that included nearly 50,000 participants, the current prevalence of mental health disorders among people experiencing homelessness was 67% and the lifetime prevalence was 77%.

“The relationship is likely bidirectional, where experiencing homelessness may exacerbate mental health symptoms or where having a mental health disorder may increase an individual’s risk for experiencing homelessness,” lead author Rebecca Barry, PhD, a postdoctoral fellow at the University of Calgary in Calgary, Alberta, Canada, told this news organization. 

“There are also likely stressors that increase both risk for homelessness and risk for developing mental health disorders. This study examines prevalence but does not examine causal relationships,” she said.

The findings were published in JAMA Psychiatry.
 

A Growing Problem 

To determine the current and lifetime prevalence of mental health disorders among the homeless population, the researchers analyzed 85 studies that examined this question in participants aged ≥ 18 years. The review included 48,414 participants, including 11,154 (23%) women and 37,260 (77%) men.

The lifetime prevalence of mental health disorders was significantly higher in men experiencing homelessness (86%) than in women (69%). The most common mental health disorder was substance use disorder (44%), followed by antisocial personality disorder (26%), major depression (19%), bipolar disorder (8%), and schizophrenia (7%).

The prevalence of current and lifetime mental health disorders among the homeless population was higher than that that observed in the general population (13%-15% and 12%-47%, respectively).

The results resembled those of a previous review that estimated that 76% of people experiencing homelessness living in high-income countries have mental health disorders.

“Even though our results are not surprising, they still are drawing attention to this issue because it is a big problem in Canada, the United States, Europe, and other places,” senior author Dallas Seitz, MD, PhD, professor of psychiatry at the University of Calgary’s Cumming School of Medicine, told this news organization. “The problem is concerning, and it’s not getting better. Addiction and mental health problems are becoming more common among people who are homeless.” 

The bottom line is that people need affordable housing and mental health support, said Dr. Seitz. “It’s a housing problem and a health problem, and we need adequate resources to find better ways for those two systems to collaborate. There are public safety concerns, and we have to try and bring services to people experiencing homelessness. You have to come and meet people where they’re at. You have to try and establish a trusting relationship so that we can get people on the path to recovery.”
 

‘It’s Really About Income’ 

Commenting on the findings for this news organization, Stephen Hwang, MD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said, “There have been previous studies of this type, but it is good to have an updated one.” Dr. Hwang, who is also chair in Homelessness, Housing, and Health at St. Michael’s Hospital, did not participate in the research. 

The findings must be understood in the proper context, he added. For one thing, grouping together all mental health disorders and giving a single prevalence figure can be misleading. “They are including in that category a diverse group of conditions. Substance use disorder, personality disorder, schizophrenia, and depression are all lumped together. The 67% prevalence seems very high, but it is a combination of many different conditions. I just don’t want people to look at that number and think that this means that everyone is a substance user or everyone has schizophrenia,” said Dr. Hwang. 

Also, some readers might interpret the findings to mean that mental problems are the reason people are homeless, he added. “That would be an incorrect interpretation because what this study is showing is that people with mental health disorders have a higher risk for becoming homeless. It doesn’t mean that it caused their homelessness. What really causes homelessness is a lack of affordable housing,” said Dr. Hwang.

“In a city or community where housing is very expensive, there’s not enough for everyone to be housed, there is a lot of competition for housing, and there’s not enough affordable housing for a number of reasons, we know that people with mental health conditions and substance use disorders will be among the first to lose their housing,” he said.

“It’s really about income. There are many reasons why a person cannot afford housing. So, not being able to earn enough money to afford it because you have a mental health disorder or substance use disorder is a common underlying reason for homelessness.”

Dr. Hwang also pointed out that people with mental illness who can access support, either through family members or through mental health care, and who also have the income to afford such services do not become homeless.

“Schizophrenia is seen in every population of the world at a rate of 1%. But you travel to certain cities and you see people who appear to have schizophrenia wandering the streets, and you go to other cities in the world and you don’t see anyone who looks like they’re homeless and have schizophrenia,” he said. 

“It’s not because there are fewer people with schizophrenia in those cities or countries; it’s because people with schizophrenia are treated differently. The rate of homelessness is determined not by how many people have that condition [eg, schizophrenia] but by how we treat those people and how we set up our society to either support or not support people who have disabilities.”

The study was funded by the Precision Care With Information, Science and Experience – Mental Health grant funded by the Calgary Health Foundation. Dr. Barry is supported by the Harley Hotchkiss Samuel Weiss Postdoctoral Fellowship awarded by the Hotchkiss Brain Institute at the University of Calgary. Dr. Barry reported having no relevant financial relationships. Dr. Seitz reported grants from Calgary Health Foundation during the conduct of the study as well as grants from University Health Foundation, the Canadian Institutes of Health Research, the Public Health Agency of Canada, the Alzheimer’s Association, and the Hotchkiss Brain Institute. He received honoraria for guideline development from the Canadian Coalition for Seniors Mental Health outside the submitted work. Dr. Hwang reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Most people experiencing homelessness have mental health disorders, according to a systematic review and meta-analysis.

In an examination of studies that included nearly 50,000 participants, the current prevalence of mental health disorders among people experiencing homelessness was 67% and the lifetime prevalence was 77%.

“The relationship is likely bidirectional, where experiencing homelessness may exacerbate mental health symptoms or where having a mental health disorder may increase an individual’s risk for experiencing homelessness,” lead author Rebecca Barry, PhD, a postdoctoral fellow at the University of Calgary in Calgary, Alberta, Canada, told this news organization. 

“There are also likely stressors that increase both risk for homelessness and risk for developing mental health disorders. This study examines prevalence but does not examine causal relationships,” she said.

The findings were published in JAMA Psychiatry.
 

A Growing Problem 

To determine the current and lifetime prevalence of mental health disorders among the homeless population, the researchers analyzed 85 studies that examined this question in participants aged ≥ 18 years. The review included 48,414 participants, including 11,154 (23%) women and 37,260 (77%) men.

The lifetime prevalence of mental health disorders was significantly higher in men experiencing homelessness (86%) than in women (69%). The most common mental health disorder was substance use disorder (44%), followed by antisocial personality disorder (26%), major depression (19%), bipolar disorder (8%), and schizophrenia (7%).

The prevalence of current and lifetime mental health disorders among the homeless population was higher than that that observed in the general population (13%-15% and 12%-47%, respectively).

The results resembled those of a previous review that estimated that 76% of people experiencing homelessness living in high-income countries have mental health disorders.

“Even though our results are not surprising, they still are drawing attention to this issue because it is a big problem in Canada, the United States, Europe, and other places,” senior author Dallas Seitz, MD, PhD, professor of psychiatry at the University of Calgary’s Cumming School of Medicine, told this news organization. “The problem is concerning, and it’s not getting better. Addiction and mental health problems are becoming more common among people who are homeless.” 

The bottom line is that people need affordable housing and mental health support, said Dr. Seitz. “It’s a housing problem and a health problem, and we need adequate resources to find better ways for those two systems to collaborate. There are public safety concerns, and we have to try and bring services to people experiencing homelessness. You have to come and meet people where they’re at. You have to try and establish a trusting relationship so that we can get people on the path to recovery.”
 

‘It’s Really About Income’ 

Commenting on the findings for this news organization, Stephen Hwang, MD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said, “There have been previous studies of this type, but it is good to have an updated one.” Dr. Hwang, who is also chair in Homelessness, Housing, and Health at St. Michael’s Hospital, did not participate in the research. 

The findings must be understood in the proper context, he added. For one thing, grouping together all mental health disorders and giving a single prevalence figure can be misleading. “They are including in that category a diverse group of conditions. Substance use disorder, personality disorder, schizophrenia, and depression are all lumped together. The 67% prevalence seems very high, but it is a combination of many different conditions. I just don’t want people to look at that number and think that this means that everyone is a substance user or everyone has schizophrenia,” said Dr. Hwang. 

Also, some readers might interpret the findings to mean that mental problems are the reason people are homeless, he added. “That would be an incorrect interpretation because what this study is showing is that people with mental health disorders have a higher risk for becoming homeless. It doesn’t mean that it caused their homelessness. What really causes homelessness is a lack of affordable housing,” said Dr. Hwang.

“In a city or community where housing is very expensive, there’s not enough for everyone to be housed, there is a lot of competition for housing, and there’s not enough affordable housing for a number of reasons, we know that people with mental health conditions and substance use disorders will be among the first to lose their housing,” he said.

“It’s really about income. There are many reasons why a person cannot afford housing. So, not being able to earn enough money to afford it because you have a mental health disorder or substance use disorder is a common underlying reason for homelessness.”

Dr. Hwang also pointed out that people with mental illness who can access support, either through family members or through mental health care, and who also have the income to afford such services do not become homeless.

“Schizophrenia is seen in every population of the world at a rate of 1%. But you travel to certain cities and you see people who appear to have schizophrenia wandering the streets, and you go to other cities in the world and you don’t see anyone who looks like they’re homeless and have schizophrenia,” he said. 

“It’s not because there are fewer people with schizophrenia in those cities or countries; it’s because people with schizophrenia are treated differently. The rate of homelessness is determined not by how many people have that condition [eg, schizophrenia] but by how we treat those people and how we set up our society to either support or not support people who have disabilities.”

The study was funded by the Precision Care With Information, Science and Experience – Mental Health grant funded by the Calgary Health Foundation. Dr. Barry is supported by the Harley Hotchkiss Samuel Weiss Postdoctoral Fellowship awarded by the Hotchkiss Brain Institute at the University of Calgary. Dr. Barry reported having no relevant financial relationships. Dr. Seitz reported grants from Calgary Health Foundation during the conduct of the study as well as grants from University Health Foundation, the Canadian Institutes of Health Research, the Public Health Agency of Canada, the Alzheimer’s Association, and the Hotchkiss Brain Institute. He received honoraria for guideline development from the Canadian Coalition for Seniors Mental Health outside the submitted work. Dr. Hwang reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The ketogenic diet shows promise in reducing the symptoms of bipolar disorder and schizophrenia and reversing metabolic syndrome, results of a new pilot study show. 

Participants who adhered to the high-fat, low-carb diet experienced a 30% reduction in psychiatric symptoms and an average 10% reduction in weight. 

“We’re seeing huge changes,” first author Shebani Sethi, MD, of Stanford University in Stanford, California said in a press release. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, and the insulin resistance. I think that’s very encouraging for patients.”

The findings were published online in Psychiatric Research. 
 

Neuroprotective Effect? 

Recent research supports the hypothesis that psychiatric illness may stem, at least in part, from deficits in brain metabolism and that a keto diet may be neuroprotective by reducing inflammation and oxidative stress. 

The pilot study included 21 participants with schizophrenia (n = 5) or bipolar disorder (n = 16) who were aged 18-75 years. All were currently taking psychotropic medications. Participants were overweight (body mass index [BMI] ≥ 25) and had gained more than 5% of their body mass while taking psychotropic medication, or they had at least one metabolic abnormality, such as insulin resistance or dyslipidemia. 

At baseline, participants received a physical and psychiatric evaluation and 1 hour of instruction on how to implement the keto diet, which included 10% carbohydrate, 30% protein, and 60% fat. 

Investigators monitored blood ketone levels at least once a week and defined participants as keto-adherent if their levels were 0.5-5 mM for 80%-100% of the times they were measured.

Health coaches checked in with participants for about 5-10 minutes each week to answer diet-related questions.

Psychiatric assessments, which included mood rating and global functioning scales, were completed at baseline, 2 months, and at the end of the 4-month study. 

The research team tracked participants’ adherence to the diet by weekly measurement of blood ketone levels. 

By the end of the trial, 14 patients had been fully adherent with the diet, six had been semi-adherent, and only one had been nonadherent. Higher ketone levels, suggesting greater adherence, correlated with better metabolic health.

As measured by the Clinical Global Impression-Schizophrenia and Clinical Global Impression for Bipolar Disorder–Overall Severity, participants experienced a 31% reduction in symptom severity (P < .001). Overall, 43% (P < .02) of participants achieved recovery as defined by the Clinical Mood Monitoring Form criteria: 50% of the adherent group and 33% of those who were semi-adherent.
 

Metabolic Benefits

Initially, 29% of participants had metabolic syndrome and more than 85% had co-occurring medical conditions such as obesity, hyperlipidemia, or prediabetes. By the end of the study, none met criteria for metabolic syndrome.

On average, participants experienced a 10% reduction in weight and BMI. Waist circumference was reduced by 11%, fat mass index dropped by 17%, and systolic blood pressure decreased by 6%. In addition, metabolic markers including visceral fat, inflammation, A1c, and insulin resistance also improved. All outcomes were significant at P < .001 except for systolic blood pressure, at P < .005.

There was also a 20% reduction in triglycerides and a 21% increase in low-density lipoprotein cholesterol (both at P < .02). 

The study’s limitations include its small sample size, the lack of control arm, and short duration.

“Mental health and physical health are interconnected and addressing metabolic issues can complement psychiatric treatment to enhance overall well-being. Understanding the

mechanisms and potential synergies between psychiatric treatment and metabolic improvements can also inform the development of more effective interventions,” the researchers wrote. 

The study was funded by the Baszucki Group, Kuen Lau Fund, and the Obesity Treatment Foundation. The authors declare no competing interests.

A version of this article appeared on Medscape.com.

The ketogenic diet shows promise in reducing the symptoms of bipolar disorder and schizophrenia and reversing metabolic syndrome, results of a new pilot study show. 

Participants who adhered to the high-fat, low-carb diet experienced a 30% reduction in psychiatric symptoms and an average 10% reduction in weight. 

“We’re seeing huge changes,” first author Shebani Sethi, MD, of Stanford University in Stanford, California said in a press release. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, and the insulin resistance. I think that’s very encouraging for patients.”

The findings were published online in Psychiatric Research. 
 

Neuroprotective Effect? 

Recent research supports the hypothesis that psychiatric illness may stem, at least in part, from deficits in brain metabolism and that a keto diet may be neuroprotective by reducing inflammation and oxidative stress. 

The pilot study included 21 participants with schizophrenia (n = 5) or bipolar disorder (n = 16) who were aged 18-75 years. All were currently taking psychotropic medications. Participants were overweight (body mass index [BMI] ≥ 25) and had gained more than 5% of their body mass while taking psychotropic medication, or they had at least one metabolic abnormality, such as insulin resistance or dyslipidemia. 

At baseline, participants received a physical and psychiatric evaluation and 1 hour of instruction on how to implement the keto diet, which included 10% carbohydrate, 30% protein, and 60% fat. 

Investigators monitored blood ketone levels at least once a week and defined participants as keto-adherent if their levels were 0.5-5 mM for 80%-100% of the times they were measured.

Health coaches checked in with participants for about 5-10 minutes each week to answer diet-related questions.

Psychiatric assessments, which included mood rating and global functioning scales, were completed at baseline, 2 months, and at the end of the 4-month study. 

The research team tracked participants’ adherence to the diet by weekly measurement of blood ketone levels. 

By the end of the trial, 14 patients had been fully adherent with the diet, six had been semi-adherent, and only one had been nonadherent. Higher ketone levels, suggesting greater adherence, correlated with better metabolic health.

As measured by the Clinical Global Impression-Schizophrenia and Clinical Global Impression for Bipolar Disorder–Overall Severity, participants experienced a 31% reduction in symptom severity (P < .001). Overall, 43% (P < .02) of participants achieved recovery as defined by the Clinical Mood Monitoring Form criteria: 50% of the adherent group and 33% of those who were semi-adherent.
 

Metabolic Benefits

Initially, 29% of participants had metabolic syndrome and more than 85% had co-occurring medical conditions such as obesity, hyperlipidemia, or prediabetes. By the end of the study, none met criteria for metabolic syndrome.

On average, participants experienced a 10% reduction in weight and BMI. Waist circumference was reduced by 11%, fat mass index dropped by 17%, and systolic blood pressure decreased by 6%. In addition, metabolic markers including visceral fat, inflammation, A1c, and insulin resistance also improved. All outcomes were significant at P < .001 except for systolic blood pressure, at P < .005.

There was also a 20% reduction in triglycerides and a 21% increase in low-density lipoprotein cholesterol (both at P < .02). 

The study’s limitations include its small sample size, the lack of control arm, and short duration.

“Mental health and physical health are interconnected and addressing metabolic issues can complement psychiatric treatment to enhance overall well-being. Understanding the

mechanisms and potential synergies between psychiatric treatment and metabolic improvements can also inform the development of more effective interventions,” the researchers wrote. 

The study was funded by the Baszucki Group, Kuen Lau Fund, and the Obesity Treatment Foundation. The authors declare no competing interests.

A version of this article appeared on Medscape.com.

The ketogenic diet shows promise in reducing the symptoms of bipolar disorder and schizophrenia and reversing metabolic syndrome, results of a new pilot study show. 

Participants who adhered to the high-fat, low-carb diet experienced a 30% reduction in psychiatric symptoms and an average 10% reduction in weight. 

“We’re seeing huge changes,” first author Shebani Sethi, MD, of Stanford University in Stanford, California said in a press release. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, and the insulin resistance. I think that’s very encouraging for patients.”

The findings were published online in Psychiatric Research. 
 

Neuroprotective Effect? 

Recent research supports the hypothesis that psychiatric illness may stem, at least in part, from deficits in brain metabolism and that a keto diet may be neuroprotective by reducing inflammation and oxidative stress. 

The pilot study included 21 participants with schizophrenia (n = 5) or bipolar disorder (n = 16) who were aged 18-75 years. All were currently taking psychotropic medications. Participants were overweight (body mass index [BMI] ≥ 25) and had gained more than 5% of their body mass while taking psychotropic medication, or they had at least one metabolic abnormality, such as insulin resistance or dyslipidemia. 

At baseline, participants received a physical and psychiatric evaluation and 1 hour of instruction on how to implement the keto diet, which included 10% carbohydrate, 30% protein, and 60% fat. 

Investigators monitored blood ketone levels at least once a week and defined participants as keto-adherent if their levels were 0.5-5 mM for 80%-100% of the times they were measured.

Health coaches checked in with participants for about 5-10 minutes each week to answer diet-related questions.

Psychiatric assessments, which included mood rating and global functioning scales, were completed at baseline, 2 months, and at the end of the 4-month study. 

The research team tracked participants’ adherence to the diet by weekly measurement of blood ketone levels. 

By the end of the trial, 14 patients had been fully adherent with the diet, six had been semi-adherent, and only one had been nonadherent. Higher ketone levels, suggesting greater adherence, correlated with better metabolic health.

As measured by the Clinical Global Impression-Schizophrenia and Clinical Global Impression for Bipolar Disorder–Overall Severity, participants experienced a 31% reduction in symptom severity (P < .001). Overall, 43% (P < .02) of participants achieved recovery as defined by the Clinical Mood Monitoring Form criteria: 50% of the adherent group and 33% of those who were semi-adherent.
 

Metabolic Benefits

Initially, 29% of participants had metabolic syndrome and more than 85% had co-occurring medical conditions such as obesity, hyperlipidemia, or prediabetes. By the end of the study, none met criteria for metabolic syndrome.

On average, participants experienced a 10% reduction in weight and BMI. Waist circumference was reduced by 11%, fat mass index dropped by 17%, and systolic blood pressure decreased by 6%. In addition, metabolic markers including visceral fat, inflammation, A1c, and insulin resistance also improved. All outcomes were significant at P < .001 except for systolic blood pressure, at P < .005.

There was also a 20% reduction in triglycerides and a 21% increase in low-density lipoprotein cholesterol (both at P < .02). 

The study’s limitations include its small sample size, the lack of control arm, and short duration.

“Mental health and physical health are interconnected and addressing metabolic issues can complement psychiatric treatment to enhance overall well-being. Understanding the

mechanisms and potential synergies between psychiatric treatment and metabolic improvements can also inform the development of more effective interventions,” the researchers wrote. 

The study was funded by the Baszucki Group, Kuen Lau Fund, and the Obesity Treatment Foundation. The authors declare no competing interests.

A version of this article appeared on Medscape.com.