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Depression rates up threefold since start of COVID-19
A year into the COVID-19 pandemic, the share of the U.S. adult population reporting symptoms of elevated depression had more than tripled from prepandemic levels and worsened significantly since restrictions went into effect, a study of more than 1,000 adults surveyed at the start of the pandemic and 1 year into it has reported.
The study also found that younger adults, people with lower incomes and savings, unmarried people, and those exposed to multiple stress factors were most vulnerable to elevated levels of depression through the first year of the pandemic.
“The pandemic has been an ongoing exposure,” lead author Catherine K. Ettman, a PhD candidate at Brown University, Providence, R.I., said in an interview. “Mental health is sensitive to economic and social conditions. While living conditions have improved for some people over the last 12 months, the pandemic has been disruptive to life and economic well-being for many,” said Ms. Ettman, who is also chief of staff and director of strategic initiatives in the office of the dean at Boston University. Her study was published in Lancet Regional Health – Americas.
Ms. Ettman and coauthors reported that 32.8% (95% confidence interval, 29.1%-36.8%) of surveyed adults had elevated depressive symptoms in 2021, compared with 27.8% (95% CI, 24.9%-30.9%) in the early months of the pandemic in 2020 (P = .0016). That compares with a rate of 8.5% before the pandemic, a figure based on a prepandemic sample of 5,065 patients from the National Health and Nutrition Examination Survey reported previously by Ms. Ettman and associates.
“The COVID-19 pandemic and its economic consequences have displaced social networks, created ongoing stressors, and reduced access to the resources that protect mental health,” Ms. Ettman said.
Four groups most affected
In this latest research, a longitudinal panel study of a nationally representative group of U.S. adults, the researchers surveyed participants in March and April 2020 (n = 1,414) and the same group again in March and April 2021 (n = 1,161). The participants completed the Patient Health Questionnaire–9 (PHQ-9) and were enrolled in the COVID-19 and Life Stressors Impact on Mental Health and Well-Being study.
The study found that elevated depressive symptoms were most prevalent in four groups:
- Younger patients, with 43.9% of patients aged 18-39 years self-reporting elevated depressive symptoms, compared with 32.4% of those aged 40-59, and 19.1% of patients aged 60 and older.
- People with lower incomes, with 58.1% of people making $19,999 or less reporting elevated symptoms, compared with 41.3% of those making $20,000-$44,999, 31.4% of people making $45,000-$74,999, and 14.1% of those making $75,000 or more.
- People with less than $5,000 in family savings, with a rate of 51.1%, compared with 24.2% of those with more than that.
- People never married, with a rate of 39.8% versus 37.7% of those living with a partner; 31.5% widowed, divorced, or separated; and 18.3% married.
The study also found correlations between the number of self-reported stressors and elevated depression symptoms: a rate of 51.1% in people with four or more stressors; 25.8% in those with two or three stressors; and 17% in people with one or no stressors.
Among the groups reporting the lowest rates of depressive symptoms in 2021 were people making more than $75,000 a year; those with one or no COVID-19 stressors; and non-Hispanic Asian persons.
“Stressors such as difficulties finding childcare, difficulties paying for housing, and job loss were associated with greater depression 12 months into the COVID-19 pandemic,” Ms. Ettman said. “Efforts to address stressors and improve access to childcare, housing, employment, and fair wages can improve mental health.”
The duration of the pandemic is another explanation for the significant rise in depressive symptoms, senior author Sandro Galea, MD, MPH, DrPH, said in an interview. Dr. Galea added. “Unlike acute traumatic events, the COVID-19 pandemic has been ongoing.”
He said clinicians, public health officials, and policy makers need to be aware of the impact COVID-19 has had on mental health. “We can take steps as a society to treat and prevent depression and create conditions that allow all populations to be healthy,” said Dr. Galea, who is dean and a professor of family medicine at Boston University.
Age of sample cited as limitation
The study builds on existing evidence linking depression trends and the COVID-19 pandemic, David Puder, MD, a medical director at Loma Linda (Calif.) University, said in an interview. However, he noted it had some limitations. “The age range is only 18 and older, so we don’t get to see what is happening with a highly impacted group of students who have not been able to go to school and be with their friends during COVID,” said Dr. Puder, who also hosts the podcast “Psychiatry & Psychotherapy.” “Further, the PHQ-9 is often a screening tool for depression and is not best used for changes in mental health over time.”
At the same time, Dr. Puder said, one of the study’s strengths was that it showed how depressive symptoms increased during the COVID lockdown. “It shows certain groups are at higher risk, including those with less financial resources and those with higher amounts of stress,” Dr. Puder said.
Ms. Ettman, Dr. Galea, and Dr. Puder reported no relevant disclosures.
A year into the COVID-19 pandemic, the share of the U.S. adult population reporting symptoms of elevated depression had more than tripled from prepandemic levels and worsened significantly since restrictions went into effect, a study of more than 1,000 adults surveyed at the start of the pandemic and 1 year into it has reported.
The study also found that younger adults, people with lower incomes and savings, unmarried people, and those exposed to multiple stress factors were most vulnerable to elevated levels of depression through the first year of the pandemic.
“The pandemic has been an ongoing exposure,” lead author Catherine K. Ettman, a PhD candidate at Brown University, Providence, R.I., said in an interview. “Mental health is sensitive to economic and social conditions. While living conditions have improved for some people over the last 12 months, the pandemic has been disruptive to life and economic well-being for many,” said Ms. Ettman, who is also chief of staff and director of strategic initiatives in the office of the dean at Boston University. Her study was published in Lancet Regional Health – Americas.
Ms. Ettman and coauthors reported that 32.8% (95% confidence interval, 29.1%-36.8%) of surveyed adults had elevated depressive symptoms in 2021, compared with 27.8% (95% CI, 24.9%-30.9%) in the early months of the pandemic in 2020 (P = .0016). That compares with a rate of 8.5% before the pandemic, a figure based on a prepandemic sample of 5,065 patients from the National Health and Nutrition Examination Survey reported previously by Ms. Ettman and associates.
“The COVID-19 pandemic and its economic consequences have displaced social networks, created ongoing stressors, and reduced access to the resources that protect mental health,” Ms. Ettman said.
Four groups most affected
In this latest research, a longitudinal panel study of a nationally representative group of U.S. adults, the researchers surveyed participants in March and April 2020 (n = 1,414) and the same group again in March and April 2021 (n = 1,161). The participants completed the Patient Health Questionnaire–9 (PHQ-9) and were enrolled in the COVID-19 and Life Stressors Impact on Mental Health and Well-Being study.
The study found that elevated depressive symptoms were most prevalent in four groups:
- Younger patients, with 43.9% of patients aged 18-39 years self-reporting elevated depressive symptoms, compared with 32.4% of those aged 40-59, and 19.1% of patients aged 60 and older.
- People with lower incomes, with 58.1% of people making $19,999 or less reporting elevated symptoms, compared with 41.3% of those making $20,000-$44,999, 31.4% of people making $45,000-$74,999, and 14.1% of those making $75,000 or more.
- People with less than $5,000 in family savings, with a rate of 51.1%, compared with 24.2% of those with more than that.
- People never married, with a rate of 39.8% versus 37.7% of those living with a partner; 31.5% widowed, divorced, or separated; and 18.3% married.
The study also found correlations between the number of self-reported stressors and elevated depression symptoms: a rate of 51.1% in people with four or more stressors; 25.8% in those with two or three stressors; and 17% in people with one or no stressors.
Among the groups reporting the lowest rates of depressive symptoms in 2021 were people making more than $75,000 a year; those with one or no COVID-19 stressors; and non-Hispanic Asian persons.
“Stressors such as difficulties finding childcare, difficulties paying for housing, and job loss were associated with greater depression 12 months into the COVID-19 pandemic,” Ms. Ettman said. “Efforts to address stressors and improve access to childcare, housing, employment, and fair wages can improve mental health.”
The duration of the pandemic is another explanation for the significant rise in depressive symptoms, senior author Sandro Galea, MD, MPH, DrPH, said in an interview. Dr. Galea added. “Unlike acute traumatic events, the COVID-19 pandemic has been ongoing.”
He said clinicians, public health officials, and policy makers need to be aware of the impact COVID-19 has had on mental health. “We can take steps as a society to treat and prevent depression and create conditions that allow all populations to be healthy,” said Dr. Galea, who is dean and a professor of family medicine at Boston University.
Age of sample cited as limitation
The study builds on existing evidence linking depression trends and the COVID-19 pandemic, David Puder, MD, a medical director at Loma Linda (Calif.) University, said in an interview. However, he noted it had some limitations. “The age range is only 18 and older, so we don’t get to see what is happening with a highly impacted group of students who have not been able to go to school and be with their friends during COVID,” said Dr. Puder, who also hosts the podcast “Psychiatry & Psychotherapy.” “Further, the PHQ-9 is often a screening tool for depression and is not best used for changes in mental health over time.”
At the same time, Dr. Puder said, one of the study’s strengths was that it showed how depressive symptoms increased during the COVID lockdown. “It shows certain groups are at higher risk, including those with less financial resources and those with higher amounts of stress,” Dr. Puder said.
Ms. Ettman, Dr. Galea, and Dr. Puder reported no relevant disclosures.
A year into the COVID-19 pandemic, the share of the U.S. adult population reporting symptoms of elevated depression had more than tripled from prepandemic levels and worsened significantly since restrictions went into effect, a study of more than 1,000 adults surveyed at the start of the pandemic and 1 year into it has reported.
The study also found that younger adults, people with lower incomes and savings, unmarried people, and those exposed to multiple stress factors were most vulnerable to elevated levels of depression through the first year of the pandemic.
“The pandemic has been an ongoing exposure,” lead author Catherine K. Ettman, a PhD candidate at Brown University, Providence, R.I., said in an interview. “Mental health is sensitive to economic and social conditions. While living conditions have improved for some people over the last 12 months, the pandemic has been disruptive to life and economic well-being for many,” said Ms. Ettman, who is also chief of staff and director of strategic initiatives in the office of the dean at Boston University. Her study was published in Lancet Regional Health – Americas.
Ms. Ettman and coauthors reported that 32.8% (95% confidence interval, 29.1%-36.8%) of surveyed adults had elevated depressive symptoms in 2021, compared with 27.8% (95% CI, 24.9%-30.9%) in the early months of the pandemic in 2020 (P = .0016). That compares with a rate of 8.5% before the pandemic, a figure based on a prepandemic sample of 5,065 patients from the National Health and Nutrition Examination Survey reported previously by Ms. Ettman and associates.
“The COVID-19 pandemic and its economic consequences have displaced social networks, created ongoing stressors, and reduced access to the resources that protect mental health,” Ms. Ettman said.
Four groups most affected
In this latest research, a longitudinal panel study of a nationally representative group of U.S. adults, the researchers surveyed participants in March and April 2020 (n = 1,414) and the same group again in March and April 2021 (n = 1,161). The participants completed the Patient Health Questionnaire–9 (PHQ-9) and were enrolled in the COVID-19 and Life Stressors Impact on Mental Health and Well-Being study.
The study found that elevated depressive symptoms were most prevalent in four groups:
- Younger patients, with 43.9% of patients aged 18-39 years self-reporting elevated depressive symptoms, compared with 32.4% of those aged 40-59, and 19.1% of patients aged 60 and older.
- People with lower incomes, with 58.1% of people making $19,999 or less reporting elevated symptoms, compared with 41.3% of those making $20,000-$44,999, 31.4% of people making $45,000-$74,999, and 14.1% of those making $75,000 or more.
- People with less than $5,000 in family savings, with a rate of 51.1%, compared with 24.2% of those with more than that.
- People never married, with a rate of 39.8% versus 37.7% of those living with a partner; 31.5% widowed, divorced, or separated; and 18.3% married.
The study also found correlations between the number of self-reported stressors and elevated depression symptoms: a rate of 51.1% in people with four or more stressors; 25.8% in those with two or three stressors; and 17% in people with one or no stressors.
Among the groups reporting the lowest rates of depressive symptoms in 2021 were people making more than $75,000 a year; those with one or no COVID-19 stressors; and non-Hispanic Asian persons.
“Stressors such as difficulties finding childcare, difficulties paying for housing, and job loss were associated with greater depression 12 months into the COVID-19 pandemic,” Ms. Ettman said. “Efforts to address stressors and improve access to childcare, housing, employment, and fair wages can improve mental health.”
The duration of the pandemic is another explanation for the significant rise in depressive symptoms, senior author Sandro Galea, MD, MPH, DrPH, said in an interview. Dr. Galea added. “Unlike acute traumatic events, the COVID-19 pandemic has been ongoing.”
He said clinicians, public health officials, and policy makers need to be aware of the impact COVID-19 has had on mental health. “We can take steps as a society to treat and prevent depression and create conditions that allow all populations to be healthy,” said Dr. Galea, who is dean and a professor of family medicine at Boston University.
Age of sample cited as limitation
The study builds on existing evidence linking depression trends and the COVID-19 pandemic, David Puder, MD, a medical director at Loma Linda (Calif.) University, said in an interview. However, he noted it had some limitations. “The age range is only 18 and older, so we don’t get to see what is happening with a highly impacted group of students who have not been able to go to school and be with their friends during COVID,” said Dr. Puder, who also hosts the podcast “Psychiatry & Psychotherapy.” “Further, the PHQ-9 is often a screening tool for depression and is not best used for changes in mental health over time.”
At the same time, Dr. Puder said, one of the study’s strengths was that it showed how depressive symptoms increased during the COVID lockdown. “It shows certain groups are at higher risk, including those with less financial resources and those with higher amounts of stress,” Dr. Puder said.
Ms. Ettman, Dr. Galea, and Dr. Puder reported no relevant disclosures.
FROM LANCET REGIONAL HEALTH – AMERICAS
Web of antimicrobials doesn’t hold water
Music plus mushrooms equals therapy
Magic mushrooms have been used recreationally and medicinally for thousands of years, but researchers have found adding music could be a game changer in antidepressant treatment.
The ingredient that makes these mushrooms so magical is psilocybin. It works well for the clinical treatment of mental health conditions and some forms of depression because the “trip” can be contained to one work day, making it easy to administer under supervision. With the accompaniment of music, scientists have found that psilocybin evokes emotion.
This recent study, presented at the European College of Neuropsychopharmacology Congress in Lisbon, tested participants’ emotional response to music before and after the psilocybin. Ketanserin, an antihypertensive drug, was used to test against the effects of psilocybin. The scientist played Mozart and Elgar and found that participants on psilocybin had an emotional response increase of 60%. That response was even greater, compared with ketanserin, which actually lessened the emotional response to music.
“This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use,” said lead researcher Dea Siggaard Stenbæk of the University of Copenhagen.
Professor David J. Nutt of Imperial College in London, who was not involved in the study, said that it supports the use of music for treatment efficacy with psychedelics and suggested that the next step is to “optimise this approach probably through individualising and personalising music tracks in therapy.”
Cue the 1960s LSD music montage.
Chicken ‘white striping is not a disease’
Have you ever sliced open a new pack of chicken breasts to start dinner and noticed white fatty lines running through the chicken? Maybe you thought it was just some extra fat to trim off, but the Humane League calls it “white striping disease.”
Chicken is the No. 1 meat consumed by Americans, so it’s not surprising that chickens are factory farmed and raised to be ready for slaughter quickly, according to CBSNews.com, which reported that the Humane League claims white striping is found in 70% of the chicken in popular grocery stores. The league expressed concern for the chickens’ welfare as they are bred to grow bigger quickly, which is causing the white striping and increasing the fat content of the meat by as much as 224%.
The National Chicken Council told CBS that the league’s findings were unscientific. A spokesperson said, “White striping is not a disease. It is a quality factor in chicken breast meat caused by deposits of fat in the muscle during the bird’s growth and development.” He went on to say that severe white striping happens in 3%-6% of birds, which are mostly used in further processed products, not in chicken breast packages.
Somehow, that’s not making us feel any better.
The itsy bitsy spider lets us all down
Most people do not like spiders. That’s too bad, because spiders are generally nothing but helpful little creatures that prey upon annoying flies and other pests. Then there’s the silk they produce. The ancient Romans used it to treat conditions such as warts and skin lesions. Spiders wrap their eggs in silk to protect them from harmful bacteria.
Of course, we can hardly trust the medical opinions of people from 2,000 years ago, but modern-day studies have not definitively proved whether or not spider silk has any antimicrobial properties.
To settle the matter once and for all, researchers from Denmark built a silk-harvesting machine using the most famous of Danish inventions: Legos. The contraption, sort of a paddle wheel, pulled the silk from several different species of spider pinned down by the researchers. The silk was then tested against three different bacteria species, including good old Escherichia coli.
Unfortunately for our spider friends, their silk has no antimicrobial activity. The researchers suspected that any such activity seen in previous studies was actually caused by improper control for the solvents used to extract the silk; those solvents can have antimicrobial properties on their own. As for protecting their eggs, rather than killing bacteria, the silk likely provides a physical barrier alone.
It is bad news for spiders on the benefit-to-humanity front, but look at the bright side: If their silk had antimicrobial activity, we’d have to start farming them to acquire more silk. And that’s no good. Spiders deserve to roam free, hunt as they please, and drop down on your head from the ceiling.
Anxiety and allergies: Cause, effect, confusion
We’re big fans of science, but as longtime, totally impartial (Science rules!) observers of science’s medical realm, we can see that the day-to-day process of practicing the scientific method occasionally gets a bit messy. And no, we’re not talking about COVID-19.
We’re talking allergies. We’re talking mental health. We’re talking allergic disease and mental health.
We’re talking about a pair of press releases we came across during our never-ending search for material to educate, entertain, and astound our fabulously wonderful and loyal readers. (We say that, of course, in the most impartial way possible.)
The first release was titled, “Allergies including asthma and hay fever not linked to mental health traits” and covered research from the University of Bristol (England). The investigators were trying to determine if “allergic diseases actually causes mental health traits including anxiety, depression, bipolar disorder, and schizophrenia, or vice versa,” according to the release.
What they found, however, was “little evidence of a causal relationship between the onset of allergic disease and mental health.” Again, this is the press release talking.
The second release seemed to suggest the exact opposite: “Study uncovers link between allergies and mental health conditions.” That got our attention. A little more reading revealed that “people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism.”
One of the investigators was quoted as saying, “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”
Did you notice the “vice versa”? Did you notice that it appeared in quotes from both releases? We did, so we took a closer look at the source. The second release covered a group of investigators from the University of Bristol – the same group, and the same study, in fact, as the first one.
So there you have it. One study, two press releases, and one confused journalist. Thank you, science.
Music plus mushrooms equals therapy
Magic mushrooms have been used recreationally and medicinally for thousands of years, but researchers have found adding music could be a game changer in antidepressant treatment.
The ingredient that makes these mushrooms so magical is psilocybin. It works well for the clinical treatment of mental health conditions and some forms of depression because the “trip” can be contained to one work day, making it easy to administer under supervision. With the accompaniment of music, scientists have found that psilocybin evokes emotion.
This recent study, presented at the European College of Neuropsychopharmacology Congress in Lisbon, tested participants’ emotional response to music before and after the psilocybin. Ketanserin, an antihypertensive drug, was used to test against the effects of psilocybin. The scientist played Mozart and Elgar and found that participants on psilocybin had an emotional response increase of 60%. That response was even greater, compared with ketanserin, which actually lessened the emotional response to music.
“This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use,” said lead researcher Dea Siggaard Stenbæk of the University of Copenhagen.
Professor David J. Nutt of Imperial College in London, who was not involved in the study, said that it supports the use of music for treatment efficacy with psychedelics and suggested that the next step is to “optimise this approach probably through individualising and personalising music tracks in therapy.”
Cue the 1960s LSD music montage.
Chicken ‘white striping is not a disease’
Have you ever sliced open a new pack of chicken breasts to start dinner and noticed white fatty lines running through the chicken? Maybe you thought it was just some extra fat to trim off, but the Humane League calls it “white striping disease.”
Chicken is the No. 1 meat consumed by Americans, so it’s not surprising that chickens are factory farmed and raised to be ready for slaughter quickly, according to CBSNews.com, which reported that the Humane League claims white striping is found in 70% of the chicken in popular grocery stores. The league expressed concern for the chickens’ welfare as they are bred to grow bigger quickly, which is causing the white striping and increasing the fat content of the meat by as much as 224%.
The National Chicken Council told CBS that the league’s findings were unscientific. A spokesperson said, “White striping is not a disease. It is a quality factor in chicken breast meat caused by deposits of fat in the muscle during the bird’s growth and development.” He went on to say that severe white striping happens in 3%-6% of birds, which are mostly used in further processed products, not in chicken breast packages.
Somehow, that’s not making us feel any better.
The itsy bitsy spider lets us all down
Most people do not like spiders. That’s too bad, because spiders are generally nothing but helpful little creatures that prey upon annoying flies and other pests. Then there’s the silk they produce. The ancient Romans used it to treat conditions such as warts and skin lesions. Spiders wrap their eggs in silk to protect them from harmful bacteria.
Of course, we can hardly trust the medical opinions of people from 2,000 years ago, but modern-day studies have not definitively proved whether or not spider silk has any antimicrobial properties.
To settle the matter once and for all, researchers from Denmark built a silk-harvesting machine using the most famous of Danish inventions: Legos. The contraption, sort of a paddle wheel, pulled the silk from several different species of spider pinned down by the researchers. The silk was then tested against three different bacteria species, including good old Escherichia coli.
Unfortunately for our spider friends, their silk has no antimicrobial activity. The researchers suspected that any such activity seen in previous studies was actually caused by improper control for the solvents used to extract the silk; those solvents can have antimicrobial properties on their own. As for protecting their eggs, rather than killing bacteria, the silk likely provides a physical barrier alone.
It is bad news for spiders on the benefit-to-humanity front, but look at the bright side: If their silk had antimicrobial activity, we’d have to start farming them to acquire more silk. And that’s no good. Spiders deserve to roam free, hunt as they please, and drop down on your head from the ceiling.
Anxiety and allergies: Cause, effect, confusion
We’re big fans of science, but as longtime, totally impartial (Science rules!) observers of science’s medical realm, we can see that the day-to-day process of practicing the scientific method occasionally gets a bit messy. And no, we’re not talking about COVID-19.
We’re talking allergies. We’re talking mental health. We’re talking allergic disease and mental health.
We’re talking about a pair of press releases we came across during our never-ending search for material to educate, entertain, and astound our fabulously wonderful and loyal readers. (We say that, of course, in the most impartial way possible.)
The first release was titled, “Allergies including asthma and hay fever not linked to mental health traits” and covered research from the University of Bristol (England). The investigators were trying to determine if “allergic diseases actually causes mental health traits including anxiety, depression, bipolar disorder, and schizophrenia, or vice versa,” according to the release.
What they found, however, was “little evidence of a causal relationship between the onset of allergic disease and mental health.” Again, this is the press release talking.
The second release seemed to suggest the exact opposite: “Study uncovers link between allergies and mental health conditions.” That got our attention. A little more reading revealed that “people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism.”
One of the investigators was quoted as saying, “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”
Did you notice the “vice versa”? Did you notice that it appeared in quotes from both releases? We did, so we took a closer look at the source. The second release covered a group of investigators from the University of Bristol – the same group, and the same study, in fact, as the first one.
So there you have it. One study, two press releases, and one confused journalist. Thank you, science.
Music plus mushrooms equals therapy
Magic mushrooms have been used recreationally and medicinally for thousands of years, but researchers have found adding music could be a game changer in antidepressant treatment.
The ingredient that makes these mushrooms so magical is psilocybin. It works well for the clinical treatment of mental health conditions and some forms of depression because the “trip” can be contained to one work day, making it easy to administer under supervision. With the accompaniment of music, scientists have found that psilocybin evokes emotion.
This recent study, presented at the European College of Neuropsychopharmacology Congress in Lisbon, tested participants’ emotional response to music before and after the psilocybin. Ketanserin, an antihypertensive drug, was used to test against the effects of psilocybin. The scientist played Mozart and Elgar and found that participants on psilocybin had an emotional response increase of 60%. That response was even greater, compared with ketanserin, which actually lessened the emotional response to music.
“This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use,” said lead researcher Dea Siggaard Stenbæk of the University of Copenhagen.
Professor David J. Nutt of Imperial College in London, who was not involved in the study, said that it supports the use of music for treatment efficacy with psychedelics and suggested that the next step is to “optimise this approach probably through individualising and personalising music tracks in therapy.”
Cue the 1960s LSD music montage.
Chicken ‘white striping is not a disease’
Have you ever sliced open a new pack of chicken breasts to start dinner and noticed white fatty lines running through the chicken? Maybe you thought it was just some extra fat to trim off, but the Humane League calls it “white striping disease.”
Chicken is the No. 1 meat consumed by Americans, so it’s not surprising that chickens are factory farmed and raised to be ready for slaughter quickly, according to CBSNews.com, which reported that the Humane League claims white striping is found in 70% of the chicken in popular grocery stores. The league expressed concern for the chickens’ welfare as they are bred to grow bigger quickly, which is causing the white striping and increasing the fat content of the meat by as much as 224%.
The National Chicken Council told CBS that the league’s findings were unscientific. A spokesperson said, “White striping is not a disease. It is a quality factor in chicken breast meat caused by deposits of fat in the muscle during the bird’s growth and development.” He went on to say that severe white striping happens in 3%-6% of birds, which are mostly used in further processed products, not in chicken breast packages.
Somehow, that’s not making us feel any better.
The itsy bitsy spider lets us all down
Most people do not like spiders. That’s too bad, because spiders are generally nothing but helpful little creatures that prey upon annoying flies and other pests. Then there’s the silk they produce. The ancient Romans used it to treat conditions such as warts and skin lesions. Spiders wrap their eggs in silk to protect them from harmful bacteria.
Of course, we can hardly trust the medical opinions of people from 2,000 years ago, but modern-day studies have not definitively proved whether or not spider silk has any antimicrobial properties.
To settle the matter once and for all, researchers from Denmark built a silk-harvesting machine using the most famous of Danish inventions: Legos. The contraption, sort of a paddle wheel, pulled the silk from several different species of spider pinned down by the researchers. The silk was then tested against three different bacteria species, including good old Escherichia coli.
Unfortunately for our spider friends, their silk has no antimicrobial activity. The researchers suspected that any such activity seen in previous studies was actually caused by improper control for the solvents used to extract the silk; those solvents can have antimicrobial properties on their own. As for protecting their eggs, rather than killing bacteria, the silk likely provides a physical barrier alone.
It is bad news for spiders on the benefit-to-humanity front, but look at the bright side: If their silk had antimicrobial activity, we’d have to start farming them to acquire more silk. And that’s no good. Spiders deserve to roam free, hunt as they please, and drop down on your head from the ceiling.
Anxiety and allergies: Cause, effect, confusion
We’re big fans of science, but as longtime, totally impartial (Science rules!) observers of science’s medical realm, we can see that the day-to-day process of practicing the scientific method occasionally gets a bit messy. And no, we’re not talking about COVID-19.
We’re talking allergies. We’re talking mental health. We’re talking allergic disease and mental health.
We’re talking about a pair of press releases we came across during our never-ending search for material to educate, entertain, and astound our fabulously wonderful and loyal readers. (We say that, of course, in the most impartial way possible.)
The first release was titled, “Allergies including asthma and hay fever not linked to mental health traits” and covered research from the University of Bristol (England). The investigators were trying to determine if “allergic diseases actually causes mental health traits including anxiety, depression, bipolar disorder, and schizophrenia, or vice versa,” according to the release.
What they found, however, was “little evidence of a causal relationship between the onset of allergic disease and mental health.” Again, this is the press release talking.
The second release seemed to suggest the exact opposite: “Study uncovers link between allergies and mental health conditions.” That got our attention. A little more reading revealed that “people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism.”
One of the investigators was quoted as saying, “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”
Did you notice the “vice versa”? Did you notice that it appeared in quotes from both releases? We did, so we took a closer look at the source. The second release covered a group of investigators from the University of Bristol – the same group, and the same study, in fact, as the first one.
So there you have it. One study, two press releases, and one confused journalist. Thank you, science.
Customized brain stimulation: New hope for severe depression
Personalized deep brain stimulation (DBS) appears to rapidly and effectively improve symptoms of treatment-resistant depression, new research suggests.
In a proof-of-concept study, investigators identified specific brain activity patterns responsible for a single patient’s severe depression and customized a DBS protocol to modulate the patterns. Results showed rapid and sustained improvement in depression scores.
“This study points the way to a new paradigm that is desperately needed in psychiatry,” Andrew Krystal, PhD, Weill Institute for Neurosciences, University of California, San Francisco, said in a news release.
“ by identifying and modulating the circuit in her brain that’s uniquely associated with her symptoms,” Dr. Krystal added.
The findings were published online Oct. 4 in Nature Medicine.
Closed-loop, on-demand stimulation
The patient was a 36-year-old woman with longstanding, severe, and treatment-resistant major depressive disorder. She was unresponsive to multiple antidepressant combinations and electroconvulsive therapy.
The researchers used intracranial electrophysiology and focal electrical stimulation to identify the specific pattern of electrical brain activity that correlated with her depressed mood.
They identified the right ventral striatum – which is involved in emotion, motivation, and reward – as the stimulation site that led to consistent, sustained, and dose-dependent improvement of symptoms and served as the neural biomarker.
In addition, the investigators identified a neural activity pattern in the amygdala that predicted both the mood symptoms, symptom severity, and stimulation efficacy.
The patient was implanted with the Food and Drug Administration–approved NeuroPace RNS System. The device was placed in the right hemisphere. A single sensing lead was positioned in the amygdala and the second stimulation lead was placed in the ventral striatum.
When the sensing lead detected the activity pattern associated with depression, the other lead delivered a tiny dose (1 milliampere/1 mA) of electricity for 6 seconds, which altered the neural activity and relieved mood symptoms.
Remission achieved
Once this personalized, closed-loop therapy was fully operational, the patient’s depression score on the Montgomery-Åsberg Depression Rating Scale (MADRS) dropped from 33 before turning treatment ON to 14 at the first ON-treatment assessment carried out after 12 days of stimulation. The score dropped below 10, representing remission, several months later.
The treatment also rapidly improved symptom severity, as measured daily with Hamilton Depression Rating Scale (HAMD-6) and visual analog scales.
“Success was predicated on a clinical mapping stage before chronic device placement, a strategy that has been utilized in epilepsy to map seizure foci in a personalized manner but has not previously been performed in other neuropsychiatric conditions,” the investigators wrote.
This patient represents “one of the first examples of precision psychiatry – a treatment tailored to an individual,” the study’s lead author, Katherine Scangos, MD, also with UCSF Weill Institute, said in an interview.
She added that the treatment “was personally tailored both spatially,” meaning at the brain location, and temporally – the time it was delivered.
“This is the first time a neural biomarker has been used to automatically trigger therapeutic stimulation in depression as a successful long-term treatment,” said Dr. Scangos. However, “we have a lot of work left to do,” she added.
“This study provides proof-of-principle that we can utilize a multimodal brain mapping approach to identify a personalized depression circuit and target that circuit with successful treatment. We will need to test the approach in more patients before we can determine its efficacy,” Dr. Scangos said.
First reliable biomarker in psychiatry
In a statement from the UK nonprofit Science Media Centre, Vladimir Litvak, PhD, with the Wellcome Centre for Human Neuroimaging, University College London, said that the study is interesting, noting that it is from “one of the leading groups in the field.”
The fact that depression symptoms can be treated in some patients by electrical stimulation of the ventral striatum is not new, Dr. Litvak said. However, what is “exciting” is that the authors identified a particular neural activity pattern in the amygdala as a reliable predictor of both symptom severity and stimulation effectiveness, he noted.
“Patterns of brain activity correlated with disease symptoms when testing over a large group of patients are commonly discovered. But there are just a handful of examples of patterns that are reliable enough to be predictive on a short time scale in a single patient,” said Dr. Litvak, who was not associated with the research.
“Furthermore, to my knowledge, this is the first example of such a reliable biomarker for psychiatric symptoms. The other examples were all for neurological disorders such as Parkinson’s disease, dystonia, and epilepsy,” he added.
He cautioned that this is a single case, but “if reproduced in additional patients, it will bring at least some psychiatric conditions into the domain of brain diseases that can be characterized and diagnosed objectively rather than based on symptoms alone.”
Dr. Litvak pointed out two other critical aspects of the study: the use of exploratory recordings and stimulation to determine the most effective treatment strategy, and the use of a closed-loop device that stimulates only when detecting the amygdala biomarker.
“It is hard to say based on this single case how important these will be in the future. There is no comparison to constant stimulation that might have worked as well because the implanted device used in the study is not suitable for that,” Dr. Litvak said.
It should also be noted that implanting multiple depth electrodes at different brain sites is a “traumatic invasive procedure only reserved to date for severe cases of drug-resistant epilepsy,” he said. “Furthermore, it only allows [researchers] to test a small number of candidate sites, so it relies heavily on prior knowledge.
“Once clinicians know better what to look for, it might be possible to avoid this procedure altogether by using noninvasive methods,” such as functional MRI or EEG, to match the right treatment option to a patient, Dr. Litvak concluded.
The research was funded by the National Institutes of Health, the Brain & Behavior Research Foundation, and the Ray and Dagmar Dolby Family Fund through the department of psychiatry at UCSF. Dr. Scangos has reported no relevant financial relationships. A complete list of author disclosures is available in the original article. Dr. Litvak is participating in a research funding application to search for electrophysiological biomarkers of depression symptoms using invasive recordings.
A version of this article first appeared on Medscape.com.
Personalized deep brain stimulation (DBS) appears to rapidly and effectively improve symptoms of treatment-resistant depression, new research suggests.
In a proof-of-concept study, investigators identified specific brain activity patterns responsible for a single patient’s severe depression and customized a DBS protocol to modulate the patterns. Results showed rapid and sustained improvement in depression scores.
“This study points the way to a new paradigm that is desperately needed in psychiatry,” Andrew Krystal, PhD, Weill Institute for Neurosciences, University of California, San Francisco, said in a news release.
“ by identifying and modulating the circuit in her brain that’s uniquely associated with her symptoms,” Dr. Krystal added.
The findings were published online Oct. 4 in Nature Medicine.
Closed-loop, on-demand stimulation
The patient was a 36-year-old woman with longstanding, severe, and treatment-resistant major depressive disorder. She was unresponsive to multiple antidepressant combinations and electroconvulsive therapy.
The researchers used intracranial electrophysiology and focal electrical stimulation to identify the specific pattern of electrical brain activity that correlated with her depressed mood.
They identified the right ventral striatum – which is involved in emotion, motivation, and reward – as the stimulation site that led to consistent, sustained, and dose-dependent improvement of symptoms and served as the neural biomarker.
In addition, the investigators identified a neural activity pattern in the amygdala that predicted both the mood symptoms, symptom severity, and stimulation efficacy.
The patient was implanted with the Food and Drug Administration–approved NeuroPace RNS System. The device was placed in the right hemisphere. A single sensing lead was positioned in the amygdala and the second stimulation lead was placed in the ventral striatum.
When the sensing lead detected the activity pattern associated with depression, the other lead delivered a tiny dose (1 milliampere/1 mA) of electricity for 6 seconds, which altered the neural activity and relieved mood symptoms.
Remission achieved
Once this personalized, closed-loop therapy was fully operational, the patient’s depression score on the Montgomery-Åsberg Depression Rating Scale (MADRS) dropped from 33 before turning treatment ON to 14 at the first ON-treatment assessment carried out after 12 days of stimulation. The score dropped below 10, representing remission, several months later.
The treatment also rapidly improved symptom severity, as measured daily with Hamilton Depression Rating Scale (HAMD-6) and visual analog scales.
“Success was predicated on a clinical mapping stage before chronic device placement, a strategy that has been utilized in epilepsy to map seizure foci in a personalized manner but has not previously been performed in other neuropsychiatric conditions,” the investigators wrote.
This patient represents “one of the first examples of precision psychiatry – a treatment tailored to an individual,” the study’s lead author, Katherine Scangos, MD, also with UCSF Weill Institute, said in an interview.
She added that the treatment “was personally tailored both spatially,” meaning at the brain location, and temporally – the time it was delivered.
“This is the first time a neural biomarker has been used to automatically trigger therapeutic stimulation in depression as a successful long-term treatment,” said Dr. Scangos. However, “we have a lot of work left to do,” she added.
“This study provides proof-of-principle that we can utilize a multimodal brain mapping approach to identify a personalized depression circuit and target that circuit with successful treatment. We will need to test the approach in more patients before we can determine its efficacy,” Dr. Scangos said.
First reliable biomarker in psychiatry
In a statement from the UK nonprofit Science Media Centre, Vladimir Litvak, PhD, with the Wellcome Centre for Human Neuroimaging, University College London, said that the study is interesting, noting that it is from “one of the leading groups in the field.”
The fact that depression symptoms can be treated in some patients by electrical stimulation of the ventral striatum is not new, Dr. Litvak said. However, what is “exciting” is that the authors identified a particular neural activity pattern in the amygdala as a reliable predictor of both symptom severity and stimulation effectiveness, he noted.
“Patterns of brain activity correlated with disease symptoms when testing over a large group of patients are commonly discovered. But there are just a handful of examples of patterns that are reliable enough to be predictive on a short time scale in a single patient,” said Dr. Litvak, who was not associated with the research.
“Furthermore, to my knowledge, this is the first example of such a reliable biomarker for psychiatric symptoms. The other examples were all for neurological disorders such as Parkinson’s disease, dystonia, and epilepsy,” he added.
He cautioned that this is a single case, but “if reproduced in additional patients, it will bring at least some psychiatric conditions into the domain of brain diseases that can be characterized and diagnosed objectively rather than based on symptoms alone.”
Dr. Litvak pointed out two other critical aspects of the study: the use of exploratory recordings and stimulation to determine the most effective treatment strategy, and the use of a closed-loop device that stimulates only when detecting the amygdala biomarker.
“It is hard to say based on this single case how important these will be in the future. There is no comparison to constant stimulation that might have worked as well because the implanted device used in the study is not suitable for that,” Dr. Litvak said.
It should also be noted that implanting multiple depth electrodes at different brain sites is a “traumatic invasive procedure only reserved to date for severe cases of drug-resistant epilepsy,” he said. “Furthermore, it only allows [researchers] to test a small number of candidate sites, so it relies heavily on prior knowledge.
“Once clinicians know better what to look for, it might be possible to avoid this procedure altogether by using noninvasive methods,” such as functional MRI or EEG, to match the right treatment option to a patient, Dr. Litvak concluded.
The research was funded by the National Institutes of Health, the Brain & Behavior Research Foundation, and the Ray and Dagmar Dolby Family Fund through the department of psychiatry at UCSF. Dr. Scangos has reported no relevant financial relationships. A complete list of author disclosures is available in the original article. Dr. Litvak is participating in a research funding application to search for electrophysiological biomarkers of depression symptoms using invasive recordings.
A version of this article first appeared on Medscape.com.
Personalized deep brain stimulation (DBS) appears to rapidly and effectively improve symptoms of treatment-resistant depression, new research suggests.
In a proof-of-concept study, investigators identified specific brain activity patterns responsible for a single patient’s severe depression and customized a DBS protocol to modulate the patterns. Results showed rapid and sustained improvement in depression scores.
“This study points the way to a new paradigm that is desperately needed in psychiatry,” Andrew Krystal, PhD, Weill Institute for Neurosciences, University of California, San Francisco, said in a news release.
“ by identifying and modulating the circuit in her brain that’s uniquely associated with her symptoms,” Dr. Krystal added.
The findings were published online Oct. 4 in Nature Medicine.
Closed-loop, on-demand stimulation
The patient was a 36-year-old woman with longstanding, severe, and treatment-resistant major depressive disorder. She was unresponsive to multiple antidepressant combinations and electroconvulsive therapy.
The researchers used intracranial electrophysiology and focal electrical stimulation to identify the specific pattern of electrical brain activity that correlated with her depressed mood.
They identified the right ventral striatum – which is involved in emotion, motivation, and reward – as the stimulation site that led to consistent, sustained, and dose-dependent improvement of symptoms and served as the neural biomarker.
In addition, the investigators identified a neural activity pattern in the amygdala that predicted both the mood symptoms, symptom severity, and stimulation efficacy.
The patient was implanted with the Food and Drug Administration–approved NeuroPace RNS System. The device was placed in the right hemisphere. A single sensing lead was positioned in the amygdala and the second stimulation lead was placed in the ventral striatum.
When the sensing lead detected the activity pattern associated with depression, the other lead delivered a tiny dose (1 milliampere/1 mA) of electricity for 6 seconds, which altered the neural activity and relieved mood symptoms.
Remission achieved
Once this personalized, closed-loop therapy was fully operational, the patient’s depression score on the Montgomery-Åsberg Depression Rating Scale (MADRS) dropped from 33 before turning treatment ON to 14 at the first ON-treatment assessment carried out after 12 days of stimulation. The score dropped below 10, representing remission, several months later.
The treatment also rapidly improved symptom severity, as measured daily with Hamilton Depression Rating Scale (HAMD-6) and visual analog scales.
“Success was predicated on a clinical mapping stage before chronic device placement, a strategy that has been utilized in epilepsy to map seizure foci in a personalized manner but has not previously been performed in other neuropsychiatric conditions,” the investigators wrote.
This patient represents “one of the first examples of precision psychiatry – a treatment tailored to an individual,” the study’s lead author, Katherine Scangos, MD, also with UCSF Weill Institute, said in an interview.
She added that the treatment “was personally tailored both spatially,” meaning at the brain location, and temporally – the time it was delivered.
“This is the first time a neural biomarker has been used to automatically trigger therapeutic stimulation in depression as a successful long-term treatment,” said Dr. Scangos. However, “we have a lot of work left to do,” she added.
“This study provides proof-of-principle that we can utilize a multimodal brain mapping approach to identify a personalized depression circuit and target that circuit with successful treatment. We will need to test the approach in more patients before we can determine its efficacy,” Dr. Scangos said.
First reliable biomarker in psychiatry
In a statement from the UK nonprofit Science Media Centre, Vladimir Litvak, PhD, with the Wellcome Centre for Human Neuroimaging, University College London, said that the study is interesting, noting that it is from “one of the leading groups in the field.”
The fact that depression symptoms can be treated in some patients by electrical stimulation of the ventral striatum is not new, Dr. Litvak said. However, what is “exciting” is that the authors identified a particular neural activity pattern in the amygdala as a reliable predictor of both symptom severity and stimulation effectiveness, he noted.
“Patterns of brain activity correlated with disease symptoms when testing over a large group of patients are commonly discovered. But there are just a handful of examples of patterns that are reliable enough to be predictive on a short time scale in a single patient,” said Dr. Litvak, who was not associated with the research.
“Furthermore, to my knowledge, this is the first example of such a reliable biomarker for psychiatric symptoms. The other examples were all for neurological disorders such as Parkinson’s disease, dystonia, and epilepsy,” he added.
He cautioned that this is a single case, but “if reproduced in additional patients, it will bring at least some psychiatric conditions into the domain of brain diseases that can be characterized and diagnosed objectively rather than based on symptoms alone.”
Dr. Litvak pointed out two other critical aspects of the study: the use of exploratory recordings and stimulation to determine the most effective treatment strategy, and the use of a closed-loop device that stimulates only when detecting the amygdala biomarker.
“It is hard to say based on this single case how important these will be in the future. There is no comparison to constant stimulation that might have worked as well because the implanted device used in the study is not suitable for that,” Dr. Litvak said.
It should also be noted that implanting multiple depth electrodes at different brain sites is a “traumatic invasive procedure only reserved to date for severe cases of drug-resistant epilepsy,” he said. “Furthermore, it only allows [researchers] to test a small number of candidate sites, so it relies heavily on prior knowledge.
“Once clinicians know better what to look for, it might be possible to avoid this procedure altogether by using noninvasive methods,” such as functional MRI or EEG, to match the right treatment option to a patient, Dr. Litvak concluded.
The research was funded by the National Institutes of Health, the Brain & Behavior Research Foundation, and the Ray and Dagmar Dolby Family Fund through the department of psychiatry at UCSF. Dr. Scangos has reported no relevant financial relationships. A complete list of author disclosures is available in the original article. Dr. Litvak is participating in a research funding application to search for electrophysiological biomarkers of depression symptoms using invasive recordings.
A version of this article first appeared on Medscape.com.
Should clinicians recommend vitamin D for psychiatric patients during COVID-19?
Amid a flurry of conflicting reports concerning the efficacy of vitamin D for COVID-19 patients, a sense of consternation has emerged in the health care sector regarding its overall utility.
Vitamin D plays a critical role in the restorative function of mental health. Low vitamin D levels correlate with mood disorders as well as the development of schizophrenia. In light of the rise in mental health dysfunction and the body of evidence examined to develop this article, we recommend that patients continue to incorporate regular vitamin D supplementation during the course of the pandemic with the goal of preventing deterioration of well-being. Recent studies have generally overlooked the role of vitamin D in mental health by primarily focusing on the immediacy of therapeutic management for medical disorders within the context of COVID-19.
What is the role of vitamin D in human physiology?
Vitamins play an integral role in homeostatic metabolism. Vitamin D, in particular, is intimately responsible for regulating the body’s underlying phosphorus and calcium balance, thereby facilitating bone mineralization.1 As an immunomodulatory hormone, vitamin D coordinates activities across innate and adaptive immune systems, providing defense against autoimmune diseases and miscellaneous infections.2
It is uncommon for people to be affected with vitamin D deficiency in equatorial zones, yet an Indonesian study uncovered low vitamin D effects (hypovitaminosis D) in virtually all of the patients in its COVID-19 case series.3
Likewise, a study conducted in Spain indicated that a whopping 82.2% of the COVID-19 patients endorsed clinically deficient levels of vitamin D, often within the context of severe presentation. Those patients also expressed elevated inflammatory markers, namely, D-dimer and ferritin.4
Comparable studies across the globe continue to support a correlative, if not causative, role for hypovitaminosis D and susceptibility to COVID-19. Mental health awareness entails healthy emotional interactions, preservation of well-being, and the ability to govern one’s thoughts and actions in accordance with societal expectations against the backdrop of ongoing psychosocial stressors. Such awareness helps ensure that people can make resourceful choices and meaningful associations, and can handle stress. We know that mental health is pivotal in dictating one’s overall health. This article provides a detailed exploration of the dynamics of mental health, COVID-19, and vitamin D.
The rationale for vitamin D supplementation therapy in COVID-19
When it comes to respiratory tract infections (RTI) such as COVID-19, influenza, and pneumonia, considerable interest has been generated with respect to the therapeutic efficacy of vitamin D in the acute setting. Vitamin D, as an inflammatory modulator, exerts a protective effect in patients with RTI, especially in those with deviations from baseline vitamin D levels.5
What is the rationale for administering vitamin D supplementation therapy for COVID-19? It has been noted that emergent cases of COVID-19 arise during the autumn months for European countries6 and there is also a firmly established connection between the amount of solar radiation/UV exposure (or the lack thereof) and influenza outbreaks,7 further underscoring the relevance of vitamin D levels. Despite those observations, wholesale implementation of vitamin D therapy should not be used in the acute setting for conditions such as COVID-19 or pneumonia as it is not supported by evidence-based practices. Despite the compound’s inherent antimicrobial actions,8 four randomized clinical trials involving pediatric subjects failed to demonstrate a significantly beneficial response (for example, radiographic resolution) to adjunctive supplementation during the course of acute pneumonia symptomatology.9 Likewise, data collected from a randomized controlled trial confirmed the suspicion that high-dose vitamin D therapy has no tangible effect, tied to mortality or otherwise, on moderate or severe presentations of COVID-19.10
Revisiting vitamin D supplementation therapy for mental health patients with COVID-19
It is clear that recent studies have undermined the overall applicability of vitamin D therapy with respect to acute presentations of COVID-19. However, our team would like to underscore the importance of vitamin D supplementation with respect to maintenance of the integrity of underlying mental health processes.
Numerous studies (for example, cross-sectional, cohort, case-control) have uncovered a statistically significant relationship between vitamin D deficiency and depression, including variants such as postpartum and antepartum depression. It should be noted that the pathophysiology for those variables is not entirely known and that the overall clinical utility of supplementation therapy has not previously been recommended because of existing gaps in the literature.11
In another prospective study involving a relatively small sample size, subjects with seasonal affective disorder (SAD) were either exposed to 10,000 IUs of vitamin D or phototherapy, and depression endpoints were evaluated via the Hamilton Rating Scale for Depression, the SIGH-SAD, and the SAD-8 depression scale. Improvements in 25-hydroxyvitamin D (25-OH D) levels correlated with improvements in depression metrics. However, subjects exposed to phototherapy sessions did not exhibit any meaningful improvements in clinical outcome.12
It is also possible that vitamin D deficiency is reflective of an overall poor nutritional status. People with schizophrenia have frequently been observed to have vitamin D deficiency with more than half of all patients also manifesting symptoms of osteoporosis, a condition that often necessitates vitamin D supplementation. The literature shows that the jury is still out regarding the applicability of vitamin D supplementation for schizophrenia patients, with numerous conflicting studies, including one randomized trial indicating an improvement in positive and negative symptoms as well as in the metabolic profile.13
However, in light of the rather large and growing body of evidence suggesting an increased risk of deterioration, psychological distress, and worsened prognosis during the pandemic coupled with the presence of medical and/or mental health morbidities, it would be sensible for psychiatric patients, especially those with preexisting deviations from baseline vitamin D levels, to consider vitamin D supplementation.
Vitamin D supplementation therapy, as a preventive, but not curative measure – one that is also low cost/high benefit – allows for the patient to be in a much better position from the perspective of her/his general health and nutritional status to tackle the ongoing psychosocial challenges of the pandemic and/or COVID-19 exposure.
Dr. Aman is a faculty member in the biology department at City Colleges of Chicago. She is a postdoctoral researcher at the International Maternal and Child Health Foundation (IMCHF) in Montreal; fellow, medical staff development, American Academy of Medical Management; and master online teacher (MOT) at the University of Illinois at Chicago. Dr. Aman disclosed no relevant relationships. Dr. Islam is a medical writer for the IMCHF and is based in New York. He is a postdoctoral fellow, psychopharmacologist, and a board-certified medical specialist. He disclosed no relevant financial relationships. Dr. Dhillon is a staff neurologist at Brigham and Women’s Hospital in Boston and is affiliated with Sturdy Memorial Hospital in Attleboro, Mass. He is on the speakers bureaus/advisory boards of Biogen, Bristol Myers Squibb, Genzyme, and Teva Neuroscience. Mr. Zaid Ulhaq Choudhry is a research assistant at the IMCHF. He has no disclosures. Dr. Zia Choudhry (Mr. Choudhry’s father) is chief scientific officer and head of the department of mental health and clinical research at the IMCHF. Dr. Choudhry has no disclosures.
References
1. van Driel M and van Leeuwen JPTM. Mol Cellular Endocrinol. 2017;453:46-51.
2. Charoenngam N and Holick MF. Nutrients. 2020 Jul 15;12(7):2097. doi: 103390/nu12072097.
3. Pinzon RT et al. Trop Med Health. 2020 Dec 20;48:102. doi: 10.1186/S41182-020-00277-w.
4. Hernández JL et al. J Clin Endocrinol Metab. 2021 Mar;106(3)e1343-53.
5. Martineau AR et al. BMJ. 2017;356:i6583. doi: 1136/bmj.i6583.
6. Walrand S. Sci Rep. 2021 Jan 21;11(1981). doi: 10.1038/s41598-021-81419-w.
7. Moan J. et al. Dermatoendocrinol. 2009 Nov-Dec;1(6):307-9.
8. Fabri M et al. Sci Transl Med. 2011 Oct 12;3(104):104ra102. doi: 10.1126/scitranslmed.3003045.
9. Slow S et al. Sci Rep. 2018 Sep 14;8(1):13829. doi: 10.1038/s41598-018-32162-2.
10. Berman R. “Study confirms high doses of vitamin D have no effect on COVID-19.” Medical News Today. 2021 May 4.
11. Menon V et al. Indian J Psychol Med. 2020 Jan-Feb;42(1):11-21.
12. Gloth 3rd FM et al. Nutr Health Aging. 1999;3(1):5-7.
13. Cui X et al. Mol Psychiatry. 2021 Jan 26. doi:10.1038/s41380-021-01025-0.
Amid a flurry of conflicting reports concerning the efficacy of vitamin D for COVID-19 patients, a sense of consternation has emerged in the health care sector regarding its overall utility.
Vitamin D plays a critical role in the restorative function of mental health. Low vitamin D levels correlate with mood disorders as well as the development of schizophrenia. In light of the rise in mental health dysfunction and the body of evidence examined to develop this article, we recommend that patients continue to incorporate regular vitamin D supplementation during the course of the pandemic with the goal of preventing deterioration of well-being. Recent studies have generally overlooked the role of vitamin D in mental health by primarily focusing on the immediacy of therapeutic management for medical disorders within the context of COVID-19.
What is the role of vitamin D in human physiology?
Vitamins play an integral role in homeostatic metabolism. Vitamin D, in particular, is intimately responsible for regulating the body’s underlying phosphorus and calcium balance, thereby facilitating bone mineralization.1 As an immunomodulatory hormone, vitamin D coordinates activities across innate and adaptive immune systems, providing defense against autoimmune diseases and miscellaneous infections.2
It is uncommon for people to be affected with vitamin D deficiency in equatorial zones, yet an Indonesian study uncovered low vitamin D effects (hypovitaminosis D) in virtually all of the patients in its COVID-19 case series.3
Likewise, a study conducted in Spain indicated that a whopping 82.2% of the COVID-19 patients endorsed clinically deficient levels of vitamin D, often within the context of severe presentation. Those patients also expressed elevated inflammatory markers, namely, D-dimer and ferritin.4
Comparable studies across the globe continue to support a correlative, if not causative, role for hypovitaminosis D and susceptibility to COVID-19. Mental health awareness entails healthy emotional interactions, preservation of well-being, and the ability to govern one’s thoughts and actions in accordance with societal expectations against the backdrop of ongoing psychosocial stressors. Such awareness helps ensure that people can make resourceful choices and meaningful associations, and can handle stress. We know that mental health is pivotal in dictating one’s overall health. This article provides a detailed exploration of the dynamics of mental health, COVID-19, and vitamin D.
The rationale for vitamin D supplementation therapy in COVID-19
When it comes to respiratory tract infections (RTI) such as COVID-19, influenza, and pneumonia, considerable interest has been generated with respect to the therapeutic efficacy of vitamin D in the acute setting. Vitamin D, as an inflammatory modulator, exerts a protective effect in patients with RTI, especially in those with deviations from baseline vitamin D levels.5
What is the rationale for administering vitamin D supplementation therapy for COVID-19? It has been noted that emergent cases of COVID-19 arise during the autumn months for European countries6 and there is also a firmly established connection between the amount of solar radiation/UV exposure (or the lack thereof) and influenza outbreaks,7 further underscoring the relevance of vitamin D levels. Despite those observations, wholesale implementation of vitamin D therapy should not be used in the acute setting for conditions such as COVID-19 or pneumonia as it is not supported by evidence-based practices. Despite the compound’s inherent antimicrobial actions,8 four randomized clinical trials involving pediatric subjects failed to demonstrate a significantly beneficial response (for example, radiographic resolution) to adjunctive supplementation during the course of acute pneumonia symptomatology.9 Likewise, data collected from a randomized controlled trial confirmed the suspicion that high-dose vitamin D therapy has no tangible effect, tied to mortality or otherwise, on moderate or severe presentations of COVID-19.10
Revisiting vitamin D supplementation therapy for mental health patients with COVID-19
It is clear that recent studies have undermined the overall applicability of vitamin D therapy with respect to acute presentations of COVID-19. However, our team would like to underscore the importance of vitamin D supplementation with respect to maintenance of the integrity of underlying mental health processes.
Numerous studies (for example, cross-sectional, cohort, case-control) have uncovered a statistically significant relationship between vitamin D deficiency and depression, including variants such as postpartum and antepartum depression. It should be noted that the pathophysiology for those variables is not entirely known and that the overall clinical utility of supplementation therapy has not previously been recommended because of existing gaps in the literature.11
In another prospective study involving a relatively small sample size, subjects with seasonal affective disorder (SAD) were either exposed to 10,000 IUs of vitamin D or phototherapy, and depression endpoints were evaluated via the Hamilton Rating Scale for Depression, the SIGH-SAD, and the SAD-8 depression scale. Improvements in 25-hydroxyvitamin D (25-OH D) levels correlated with improvements in depression metrics. However, subjects exposed to phototherapy sessions did not exhibit any meaningful improvements in clinical outcome.12
It is also possible that vitamin D deficiency is reflective of an overall poor nutritional status. People with schizophrenia have frequently been observed to have vitamin D deficiency with more than half of all patients also manifesting symptoms of osteoporosis, a condition that often necessitates vitamin D supplementation. The literature shows that the jury is still out regarding the applicability of vitamin D supplementation for schizophrenia patients, with numerous conflicting studies, including one randomized trial indicating an improvement in positive and negative symptoms as well as in the metabolic profile.13
However, in light of the rather large and growing body of evidence suggesting an increased risk of deterioration, psychological distress, and worsened prognosis during the pandemic coupled with the presence of medical and/or mental health morbidities, it would be sensible for psychiatric patients, especially those with preexisting deviations from baseline vitamin D levels, to consider vitamin D supplementation.
Vitamin D supplementation therapy, as a preventive, but not curative measure – one that is also low cost/high benefit – allows for the patient to be in a much better position from the perspective of her/his general health and nutritional status to tackle the ongoing psychosocial challenges of the pandemic and/or COVID-19 exposure.
Dr. Aman is a faculty member in the biology department at City Colleges of Chicago. She is a postdoctoral researcher at the International Maternal and Child Health Foundation (IMCHF) in Montreal; fellow, medical staff development, American Academy of Medical Management; and master online teacher (MOT) at the University of Illinois at Chicago. Dr. Aman disclosed no relevant relationships. Dr. Islam is a medical writer for the IMCHF and is based in New York. He is a postdoctoral fellow, psychopharmacologist, and a board-certified medical specialist. He disclosed no relevant financial relationships. Dr. Dhillon is a staff neurologist at Brigham and Women’s Hospital in Boston and is affiliated with Sturdy Memorial Hospital in Attleboro, Mass. He is on the speakers bureaus/advisory boards of Biogen, Bristol Myers Squibb, Genzyme, and Teva Neuroscience. Mr. Zaid Ulhaq Choudhry is a research assistant at the IMCHF. He has no disclosures. Dr. Zia Choudhry (Mr. Choudhry’s father) is chief scientific officer and head of the department of mental health and clinical research at the IMCHF. Dr. Choudhry has no disclosures.
References
1. van Driel M and van Leeuwen JPTM. Mol Cellular Endocrinol. 2017;453:46-51.
2. Charoenngam N and Holick MF. Nutrients. 2020 Jul 15;12(7):2097. doi: 103390/nu12072097.
3. Pinzon RT et al. Trop Med Health. 2020 Dec 20;48:102. doi: 10.1186/S41182-020-00277-w.
4. Hernández JL et al. J Clin Endocrinol Metab. 2021 Mar;106(3)e1343-53.
5. Martineau AR et al. BMJ. 2017;356:i6583. doi: 1136/bmj.i6583.
6. Walrand S. Sci Rep. 2021 Jan 21;11(1981). doi: 10.1038/s41598-021-81419-w.
7. Moan J. et al. Dermatoendocrinol. 2009 Nov-Dec;1(6):307-9.
8. Fabri M et al. Sci Transl Med. 2011 Oct 12;3(104):104ra102. doi: 10.1126/scitranslmed.3003045.
9. Slow S et al. Sci Rep. 2018 Sep 14;8(1):13829. doi: 10.1038/s41598-018-32162-2.
10. Berman R. “Study confirms high doses of vitamin D have no effect on COVID-19.” Medical News Today. 2021 May 4.
11. Menon V et al. Indian J Psychol Med. 2020 Jan-Feb;42(1):11-21.
12. Gloth 3rd FM et al. Nutr Health Aging. 1999;3(1):5-7.
13. Cui X et al. Mol Psychiatry. 2021 Jan 26. doi:10.1038/s41380-021-01025-0.
Amid a flurry of conflicting reports concerning the efficacy of vitamin D for COVID-19 patients, a sense of consternation has emerged in the health care sector regarding its overall utility.
Vitamin D plays a critical role in the restorative function of mental health. Low vitamin D levels correlate with mood disorders as well as the development of schizophrenia. In light of the rise in mental health dysfunction and the body of evidence examined to develop this article, we recommend that patients continue to incorporate regular vitamin D supplementation during the course of the pandemic with the goal of preventing deterioration of well-being. Recent studies have generally overlooked the role of vitamin D in mental health by primarily focusing on the immediacy of therapeutic management for medical disorders within the context of COVID-19.
What is the role of vitamin D in human physiology?
Vitamins play an integral role in homeostatic metabolism. Vitamin D, in particular, is intimately responsible for regulating the body’s underlying phosphorus and calcium balance, thereby facilitating bone mineralization.1 As an immunomodulatory hormone, vitamin D coordinates activities across innate and adaptive immune systems, providing defense against autoimmune diseases and miscellaneous infections.2
It is uncommon for people to be affected with vitamin D deficiency in equatorial zones, yet an Indonesian study uncovered low vitamin D effects (hypovitaminosis D) in virtually all of the patients in its COVID-19 case series.3
Likewise, a study conducted in Spain indicated that a whopping 82.2% of the COVID-19 patients endorsed clinically deficient levels of vitamin D, often within the context of severe presentation. Those patients also expressed elevated inflammatory markers, namely, D-dimer and ferritin.4
Comparable studies across the globe continue to support a correlative, if not causative, role for hypovitaminosis D and susceptibility to COVID-19. Mental health awareness entails healthy emotional interactions, preservation of well-being, and the ability to govern one’s thoughts and actions in accordance with societal expectations against the backdrop of ongoing psychosocial stressors. Such awareness helps ensure that people can make resourceful choices and meaningful associations, and can handle stress. We know that mental health is pivotal in dictating one’s overall health. This article provides a detailed exploration of the dynamics of mental health, COVID-19, and vitamin D.
The rationale for vitamin D supplementation therapy in COVID-19
When it comes to respiratory tract infections (RTI) such as COVID-19, influenza, and pneumonia, considerable interest has been generated with respect to the therapeutic efficacy of vitamin D in the acute setting. Vitamin D, as an inflammatory modulator, exerts a protective effect in patients with RTI, especially in those with deviations from baseline vitamin D levels.5
What is the rationale for administering vitamin D supplementation therapy for COVID-19? It has been noted that emergent cases of COVID-19 arise during the autumn months for European countries6 and there is also a firmly established connection between the amount of solar radiation/UV exposure (or the lack thereof) and influenza outbreaks,7 further underscoring the relevance of vitamin D levels. Despite those observations, wholesale implementation of vitamin D therapy should not be used in the acute setting for conditions such as COVID-19 or pneumonia as it is not supported by evidence-based practices. Despite the compound’s inherent antimicrobial actions,8 four randomized clinical trials involving pediatric subjects failed to demonstrate a significantly beneficial response (for example, radiographic resolution) to adjunctive supplementation during the course of acute pneumonia symptomatology.9 Likewise, data collected from a randomized controlled trial confirmed the suspicion that high-dose vitamin D therapy has no tangible effect, tied to mortality or otherwise, on moderate or severe presentations of COVID-19.10
Revisiting vitamin D supplementation therapy for mental health patients with COVID-19
It is clear that recent studies have undermined the overall applicability of vitamin D therapy with respect to acute presentations of COVID-19. However, our team would like to underscore the importance of vitamin D supplementation with respect to maintenance of the integrity of underlying mental health processes.
Numerous studies (for example, cross-sectional, cohort, case-control) have uncovered a statistically significant relationship between vitamin D deficiency and depression, including variants such as postpartum and antepartum depression. It should be noted that the pathophysiology for those variables is not entirely known and that the overall clinical utility of supplementation therapy has not previously been recommended because of existing gaps in the literature.11
In another prospective study involving a relatively small sample size, subjects with seasonal affective disorder (SAD) were either exposed to 10,000 IUs of vitamin D or phototherapy, and depression endpoints were evaluated via the Hamilton Rating Scale for Depression, the SIGH-SAD, and the SAD-8 depression scale. Improvements in 25-hydroxyvitamin D (25-OH D) levels correlated with improvements in depression metrics. However, subjects exposed to phototherapy sessions did not exhibit any meaningful improvements in clinical outcome.12
It is also possible that vitamin D deficiency is reflective of an overall poor nutritional status. People with schizophrenia have frequently been observed to have vitamin D deficiency with more than half of all patients also manifesting symptoms of osteoporosis, a condition that often necessitates vitamin D supplementation. The literature shows that the jury is still out regarding the applicability of vitamin D supplementation for schizophrenia patients, with numerous conflicting studies, including one randomized trial indicating an improvement in positive and negative symptoms as well as in the metabolic profile.13
However, in light of the rather large and growing body of evidence suggesting an increased risk of deterioration, psychological distress, and worsened prognosis during the pandemic coupled with the presence of medical and/or mental health morbidities, it would be sensible for psychiatric patients, especially those with preexisting deviations from baseline vitamin D levels, to consider vitamin D supplementation.
Vitamin D supplementation therapy, as a preventive, but not curative measure – one that is also low cost/high benefit – allows for the patient to be in a much better position from the perspective of her/his general health and nutritional status to tackle the ongoing psychosocial challenges of the pandemic and/or COVID-19 exposure.
Dr. Aman is a faculty member in the biology department at City Colleges of Chicago. She is a postdoctoral researcher at the International Maternal and Child Health Foundation (IMCHF) in Montreal; fellow, medical staff development, American Academy of Medical Management; and master online teacher (MOT) at the University of Illinois at Chicago. Dr. Aman disclosed no relevant relationships. Dr. Islam is a medical writer for the IMCHF and is based in New York. He is a postdoctoral fellow, psychopharmacologist, and a board-certified medical specialist. He disclosed no relevant financial relationships. Dr. Dhillon is a staff neurologist at Brigham and Women’s Hospital in Boston and is affiliated with Sturdy Memorial Hospital in Attleboro, Mass. He is on the speakers bureaus/advisory boards of Biogen, Bristol Myers Squibb, Genzyme, and Teva Neuroscience. Mr. Zaid Ulhaq Choudhry is a research assistant at the IMCHF. He has no disclosures. Dr. Zia Choudhry (Mr. Choudhry’s father) is chief scientific officer and head of the department of mental health and clinical research at the IMCHF. Dr. Choudhry has no disclosures.
References
1. van Driel M and van Leeuwen JPTM. Mol Cellular Endocrinol. 2017;453:46-51.
2. Charoenngam N and Holick MF. Nutrients. 2020 Jul 15;12(7):2097. doi: 103390/nu12072097.
3. Pinzon RT et al. Trop Med Health. 2020 Dec 20;48:102. doi: 10.1186/S41182-020-00277-w.
4. Hernández JL et al. J Clin Endocrinol Metab. 2021 Mar;106(3)e1343-53.
5. Martineau AR et al. BMJ. 2017;356:i6583. doi: 1136/bmj.i6583.
6. Walrand S. Sci Rep. 2021 Jan 21;11(1981). doi: 10.1038/s41598-021-81419-w.
7. Moan J. et al. Dermatoendocrinol. 2009 Nov-Dec;1(6):307-9.
8. Fabri M et al. Sci Transl Med. 2011 Oct 12;3(104):104ra102. doi: 10.1126/scitranslmed.3003045.
9. Slow S et al. Sci Rep. 2018 Sep 14;8(1):13829. doi: 10.1038/s41598-018-32162-2.
10. Berman R. “Study confirms high doses of vitamin D have no effect on COVID-19.” Medical News Today. 2021 May 4.
11. Menon V et al. Indian J Psychol Med. 2020 Jan-Feb;42(1):11-21.
12. Gloth 3rd FM et al. Nutr Health Aging. 1999;3(1):5-7.
13. Cui X et al. Mol Psychiatry. 2021 Jan 26. doi:10.1038/s41380-021-01025-0.
Nontraditional therapies for treatment-resistant depression: Part 2
When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.
In Part 1 of this article (
Herbal/nutraceutical agents
This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:
- vitamin D
- essential fatty acids (omega-3, omega-6)
- S-adenosyl-L-methionine (SAMe)
- hypericum perforatum (St. John’s Wort)
- probiotics.
Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.1-3
A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.4 In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.5
Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.
Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.
Continue to: Although results from...
Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.5 A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.6 Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.7
Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.
S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.
- Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
- When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).
Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.
Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.
Continue to: A meta-analysis of 7 clinical trials...
A meta-analysis of 7 clinical trials (N = 3,808) comparing St. John’s Wort with various selective serotonin reuptake inhibitors (SSRIs) reported comparable rates of response (pooled relative risk .983, 95% CI .924 to 1.042; P < .001) and remission (pooled relative risk 1.013, 95% CI .892 to 1.134; P < .001).9 Further, there were significantly lower discontinuation/dropout rates (pooled odds ratio .587, 95% CI .478 to 0.697; P < .001) for St. John’s Wort compared with the SSRIs.
Existing evidence on the long-term efficacy and safety is limited (studies ranged from 4 to 12 weeks), as is evidence for patients with more severe depression or high suicidality.
Serious drug interactions include the potential for serotonin syndrome when St. John’s Wort is combined with certain antidepressants, compromised efficacy of benzodiazepines and standard antidepressants, and severe skin reactions to sun exposure. In addition, St. John’s Wort may not be safe to use during pregnancy or while breastfeeding. Because potential drug interactions can be serious and individuals often self-prescribe this agent, it is important to ask patients about their use of St. John’s Wort, and to be vigilant for such potential adverse interactions.
Probiotics. These agents produce neuroactive substances that act on the brain/gut axis. Preliminary evidence suggests that these “psychobiotics” confer mental health benefits.10-12 Relative to other approaches, their low-risk profile make them an attractive option for some patients.
Anti-inflammatory/immune system therapies
Inflammation is linked to various medical and brain disorders. For example, patients with depression often demonstrate increased levels of peripheral blood inflammatory biomarkers (such as C-reactive protein and interleukin-6 and -17) that are known to alter norepinephrine, neuroendocrine (eg, the hypothalamic-pituitary-adrenal axis), and microglia function in addition to neuroplasticity. Thus, targeting inflammation may facilitate the development of novel antidepressants. In addition, these agents may benefit depression associated with comorbid autoimmune disorders, such as psoriasis or rheumatoid arthritis. A systematic review and meta-analysis of 36 RCTs (N = 10,000) found 5 out of 6 anti-inflammatory agents improved depression.13,14 In general, reported disadvantages of anti-inflammatories/immunosuppressants include the potential to block the antidepressant effect of some agents, the risk of opportunistic infections, and an increased risk of suicide.
Continue to: Statins
Statins
In a meta-analysis of 3 randomized, double-blind trials, 3 statins (lovastatin, atorvastatin, and simvastatin) significantly improved depression scores when used as an adjunctive therapy to fluoxetine and citalopram, compared with adjunctive placebo (N = 165, P < .001).15
Specific adverse effects of statins include headaches, muscle pain (rarely rhabdomyolysis), dizziness, rash, and liver damage. Statins also have the potential for adverse interactions with other medications. Given the limited efficacy literature on statins for depression and the potential for serious adverse effects, these agents probably should be limited to patients with treatment-resistant depression for whom a statin is indicated for a comorbid medical disorder, such as hypercholesteremia.
Neurosteroids
Brexanolone is FDA-approved for the treatment of postpartum depression. It is an IV formulation of the neuroactive steroid hormone allopregnanolone (a metabolite of progesterone), which acts as a positive allosteric modulator of the GABA-A receptor. Unfortunately, the infusion needs to occur over a 60-hour period.
Ganaxolone is an oral analog formulation of allopregnanolone. In an uncontrolled, open-label pilot study, this medication was administered for 8 weeks as an adjunct to an adequately dosed antidepressant to 10 postmenopausal women with persistent MDD.16 Of the 9 women who completed the study, 4 (44%) improved significantly (P < .019) and the benefit was sustained for 2 additional weeks.16 Adverse effects of ganaxolone included dizziness in 60% of participants, and sleepiness and fatigue in all of them with twice-daily dosing. If the FDA approves ganaxolone, it would become an easier-to-administer option to brexanolone.
Zuranolone is an investigational agent being studied as a treatment for postpartum depression. In a double-blind RCT that evaluated 151 women with postpartum depression, those who took oral zuranolone, 30 mg daily at bedtime for 2 weeks, experienced significant reductions in Hamilton Depression Rating Scale-17 (HDRS-17) scores compared with placebo (P < .003).17 Improvement in core depression symptom ratings was seen as early as Day 3 and persisted through Day 45.
Continue to: The most common...
The most common (≥5%) treatment-emergent adverse effects were somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%). Two patients experienced a serious adverse event: one who received zuranolone (confusional state) and one who received placebo (pancreatitis). One patient discontinued zuranolone due to adverse effects vs no discontinuations among those who received placebo. The risk of taking zuranolone while breastfeeding is not known.
Device-based strategies
In addition to FDA-cleared approaches (eg, electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS]), other devices have also demonstrated promising results.
Transcranial direct current stimulation (tDCS) involves delivering weak electrical current to the cerebral cortex through small scalp electrodes to produce the following effects:
- anodal tDCS enhances cortical excitability
- cathodal tDCS reduces cortical excitability.
A typical protocol consists of delivering 1 to 2 mA over 20 minutes with scalp electrodes placed in different configurations based on the targeted symptom(s).
While tDCS has been evaluated as a treatment for various neuropsychiatric disorders, including bipolar depression, Parkinson’s disease, and schizophrenia, most trials have looked at its use for treating depression. Results have been promising but mixed. For example, 1 meta-analysis of 6 RCTs (comprising 96 active and 80 sham tDCS courses) reported that active tDCS was superior to a sham procedure (Hedges’ g = 0.743) for symptoms of depression.18 By contrast, another meta-analysis of 6 RCTs (N = 200) did not find a significant difference between active and sham tDCS for response and remission rates.19 More recently, a group of experts created an evidence-based guideline using a systematic review of the controlled trial literature. These authors concluded there is “probable efficacy for anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episodes without drug resistance but probable inefficacy for drug-resistant major depressive episodes.”20
Continue to: Adverse effects of tDCS...
Adverse effects of tDCS are typically mild but may include persistent skin lesions similar to burns; mania or hypomania; and one reported seizure in a pediatric patient.
Because various over-the-counter direct current stimulation devices are available for purchase at modest cost, clinicians should ask patients if they have been self-administering this treatment.
Chronotherapy strategies
Agomelatine combines serotonergic (5-HT2B and 5-HT2C antagonist) and melatonergic (MT1-MT2 agonist in the suprachiasmatic nucleus) actions that contribute to stabilization of circadian rhythms and subsequent improvement in sleep patterns. Agomelatine (n = 1,274) significantly lowered depression symptoms compared with placebo (n = 689) (standardized mean difference −0.26; P < 3.48×10-11), but the clinical relevance was questionable.21 A recent review of the literature and expert opinion suggest this agent may also have efficacy for anhedonia; however, in placebo-controlled, relapse prevention studies, its long-term efficacy was not consistent.22
Common adverse effects include anxiety; nausea, vomiting, and stomach pain; abnormal dreams and insomnia; dizziness; drowsiness and fatigue; and weight gain. Some reviewers have expressed concerns about agomelatine’s potential for hepatotoxicity and the need for repeated clinical laboratory tests. Although agomelatine is approved outside of the United States, limited efficacy data and the potential for serious adverse effects have precluded FDA approval of this agent.
Sleep deprivation as a treatment technique for depression has been developed over the past 50 years. With total sleep deprivation (TSD) over 1 cycle, patients stay awake for approximately 36 hours, from daytime until the next day’s evening. While 1 to 6 cycles can produce acute antidepressant effects, prompt relapse after sleep recovery is common.
Continue to: In a systematic review...
In a systematic review and meta-analysis of 7 studies that included a total of 311 patients with bipolar depression23:
- TSD plus medications resulted in a significant decrease in depressive symptoms at 1 week compared with medications alone
- higher response rates were maintained after 3 months with lithium.
Adverse effects commonly include general fatigue and headaches; possible switch into mania with bipolar depression; and rarely, seizures or other unexpected medical conditions (eg, acute coronary syndrome). Presently, this approach is limited to research laboratories with the appropriate sophistication to safely conduct such trials.
Other nontraditional strategies
Cardiovascular exercise, resistance training, mindfulness, and yoga have been shown to decrease severe depressive symptoms when used as adjuncts for patients with treatment-resistant depression, or as monotherapy to treat patients with milder depression.
Exercise. The significant benefits of exercise in various forms as treatment for mild to moderate depression are well described in the literature, but it is less clear if it is effective for treatment-resistant depression. A 2013 Cochrane report24 (39 studies with 2,326 participants total) and 2 meta-analyses undertaken in 2015 (Kvam et al25 included 23 studies with 977 participants, and Schuh et al26 included 25 trials with 1,487 participants) reported that various types of exercise ameliorate depression of differing subtypes and severity, with effect sizes ranging from small to large. Schuh et al26 found that publication bias underestimated effect size. Also, not surprisingly, separate analysis of only higher-quality trials decreased effect size.24-26 A meta-analysis that included tai chi and yoga in addition to aerobic exercise and strength training (25 trials with 2,083 participants) found low to moderate benefit for exercise and yoga.27 Finally, a meta-analysis by Cramer et al28 that included 12 RCTs (N = 619) supported the use of yoga plus controlled breathing techniques as an ancillary treatment for depression.
Two small exercise trials specifically evaluated patients with treatment-resistant depression.29,30 Mota-Pereira et al29 compared 22 participants who walked for 30 to 45 minutes, 5 days a week for 12 weeks in addition to pharmacotherapy with 11 patients who received pharmacotherapy only. Exercise improved all outcomes, including HDRS score (both compared to baseline and to the control group). Moreover, 26% of the exercise group went into remission. Pilu et al30 evaluated strength training as an adjunctive treatment. Participants received 1 hour of strength training twice weekly for 8 months (n = 10), or pharmacotherapy only (n = 20). The adjunct strength training group had a statistically significant (P < .0001) improvement in HDRS scores at the end of the 8 months, whereas the control group did not (P < .28).
Continue to: Adverse effects...
Adverse effects of exercise are typically limited to sprains or strains; rarely, participants experience serious injuries.
Mindfulness-based interventions involve purposely paying attention in the present moment to enhance self-understanding and decrease anxiety about the future and regrets about the past, both of which complicate depression. A meta-analysis of 12 RCTs (N = 578) found this approach significantly reduced depression severity when used as an adjunctive therapy.31 There may be risks if mindfulness-based interventions are practiced incorrectly. For example, some reports have linked mindfulness-based interventions to psychotic episodes, meditation addiction, and antisocial or asocial behavior.32
Bottom Line
Nonpharmacologic options for patients with treatment-resistant depression include herbal/nutraceuticals, anti-inflammatory/immune system therapies, and devices. While research suggests some of these approaches are promising, clinicians need to carefully consider potential adverse effects, some of which may be serious.
Related Resources
- Kaur M, Sanches M. Experimental therapeutics in treatmentresistant major depressive disorder. J Exp Pharmacol. 2021;13:181-196.
- Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
Drug Brand Names
Atorvastatin • Lipitor
Brexanolone • Zulresso
Citalopram • Celexa
Fluoxetine • Prozac
Lithium • Eskalith, Lithobid
Lovastatin • Altoprev, Mevacor
Minocycline • Dynacin, Minocin
Simvastatin • Flolipid, Zocor
1. Pittampalli S, Mekala HM, Upadhyayula, S, et al. Does vitamin D deficiency cause depression? Prim Care Companion CNS Disord. 2018;20(5):17l02263.
2. Parker GB, Brotchie H, Graham RK. Vitamin D and depression. J Affect Disord. 2017;208:56-61.
3. Berridge MJ. Vitamin D and depression: cellular and regulatory mechanisms. Pharmacol Rev. 2017;69(2):80-92.
4. Anglin RE, Samaan Z, Walter SD, et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100-107.
5. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry 2016;173(6);575-587.
6. Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019;9(1):190.
7. Mocking RJT, Steijn K, Roos C, et al. Omega-3 fatty acid supplementation for perinatal depression: a meta-analysis. J Clin Psychiatry. 2020;81(5):19r13106.
8. Sharma A, Gerbarg P, Bottiglieri T, et al; Work Group of the American Psychiatric Association Council on Research. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667.
9. Ng QX, Venkatanarayanan N, Ho CY. Clinical use of hypericum perforatum (St John’s wort) in depression: a meta-analysis. J Affect Disord 2017;210:211-221.
10. Huang R, Wang K, Hu J. Effect of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016;8(8):483.
11. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019;102:13-23.
12. Wallace CJK, Milev RV. The efficacy, safety, and tolerability of probiotics on depression: clinical results from an open-label pilot study. Front Psychiatry. 2021;12(132):618279.
13. Köhler-Forsberg O, N Lyndholm C, Hjorthøj C, et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139(5):404-419.
14. Jha MK. Anti-inflammatory treatments for major depressive disorder: what’s on the horizon? J Clin Psychiatry. 2019;80(6)18ac12630.
15. Salagre E, Fernandes BS, Dodd S, et al. Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Affect Disord. 2016;200:235-242.
16. Dichtel LE, Nyer M, Dording C, et al. Effects of open-label, adjunctive ganaxolone on persistent depression despite adequate antidepressant treatment in postmenopausal women: a pilot study. J Clin Psychiatry. 2020;81(4):19m12887.
17. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry. 2021;78(9):951-959.
18. Kalu UG, Sexton CE, Loo CK, et al. Transcranial direct current stimulation in the treatment of major depression: a meta-analysis. Psychol Med. 2012;42(9):1791-800.
19. Berlim MT, Van den Eynde F, Daskalakis ZJ. Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. J Psychiatr Res. 2013;47(1):1-7.
20. Lefaucheur JP, Antal A, Ayache SS, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017;128(1):56-92.
21. Singh SP, Singh V, Kar N. Efficacy of agomelatine in major depressive disorder: meta-analysis and appraisal. Int J Neuropsychopharmacol. 2012;15(3):417-428.
22. Norman TR, Olver JS. Agomelatine for depression: expanding the horizons? Expert Opin Pharmacother. 2019;20(6):647-656.
23. Ramirez-Mahaluf JP, Rozas-Serri E, Ivanovic-Zuvic F, et al. Effectiveness of sleep deprivation in treating acute bipolar depression as augmentation strategy: a systematic review and meta-analysis. Front Psychiatry. 2020;11:70.
24. Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;(9):CD004366.
25. Kvam S, Kleppe CL, Nordhus IH, et al. Exercise as a treatment for depression: a meta-analysis. J Affect Disord. 2016;202:67-86.
26. Schuch FB, Vancampfort D, Richards J, et al. Exercise as a treatment for depression: a meta-analysis adjusting for publication bias. J Psychiatr Res. 2016;77:42-51.
27. Seshadri A, Adaji A, Orth SS, et al. Exercise, yoga, and tai chi for treatment of major depressive disorder in outpatient settings: a systematic review and meta-analysis. Prim Care Companion CNS Disord. 2020;23(1):20r02722.
28. Cramer H, Lauche R, Langhorst J, et al. Yoga for depression: a systematic review and meta-analysis. Depress Anxiety. 2013;30(11):1068-1083.
29. Mota-Pereira J, Silverio J, Carvalho S, et al. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Psychiatr Res. 2011;45(8):1005-1011.
30. Pilu A, Sorba M, Hardoy MC, et al. Efficacy of physical activity in the adjunctive treatment of major depressive disorders: preliminary results. Clin Pract Epidemiol Ment Health. 2007;3:8.
31. Strauss C, Cavanagh K, Oliver A, et al. Mindfulness-based interventions for people diagnosed with a current episode of an anxiety or depressive disorder: a meta-analysis of randomised controlled trials. PLoS One. 2014;9(4):e96110.
32. Shonin E, Van Gordon W, Griffiths MD. Are there risks associated with using mindfulness for the treatment of psychopathology? Clinical Practice. 2014;11(4):389-392.
When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.
In Part 1 of this article (
Herbal/nutraceutical agents
This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:
- vitamin D
- essential fatty acids (omega-3, omega-6)
- S-adenosyl-L-methionine (SAMe)
- hypericum perforatum (St. John’s Wort)
- probiotics.
Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.1-3
A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.4 In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.5
Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.
Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.
Continue to: Although results from...
Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.5 A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.6 Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.7
Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.
S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.
- Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
- When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).
Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.
Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.
Continue to: A meta-analysis of 7 clinical trials...
A meta-analysis of 7 clinical trials (N = 3,808) comparing St. John’s Wort with various selective serotonin reuptake inhibitors (SSRIs) reported comparable rates of response (pooled relative risk .983, 95% CI .924 to 1.042; P < .001) and remission (pooled relative risk 1.013, 95% CI .892 to 1.134; P < .001).9 Further, there were significantly lower discontinuation/dropout rates (pooled odds ratio .587, 95% CI .478 to 0.697; P < .001) for St. John’s Wort compared with the SSRIs.
Existing evidence on the long-term efficacy and safety is limited (studies ranged from 4 to 12 weeks), as is evidence for patients with more severe depression or high suicidality.
Serious drug interactions include the potential for serotonin syndrome when St. John’s Wort is combined with certain antidepressants, compromised efficacy of benzodiazepines and standard antidepressants, and severe skin reactions to sun exposure. In addition, St. John’s Wort may not be safe to use during pregnancy or while breastfeeding. Because potential drug interactions can be serious and individuals often self-prescribe this agent, it is important to ask patients about their use of St. John’s Wort, and to be vigilant for such potential adverse interactions.
Probiotics. These agents produce neuroactive substances that act on the brain/gut axis. Preliminary evidence suggests that these “psychobiotics” confer mental health benefits.10-12 Relative to other approaches, their low-risk profile make them an attractive option for some patients.
Anti-inflammatory/immune system therapies
Inflammation is linked to various medical and brain disorders. For example, patients with depression often demonstrate increased levels of peripheral blood inflammatory biomarkers (such as C-reactive protein and interleukin-6 and -17) that are known to alter norepinephrine, neuroendocrine (eg, the hypothalamic-pituitary-adrenal axis), and microglia function in addition to neuroplasticity. Thus, targeting inflammation may facilitate the development of novel antidepressants. In addition, these agents may benefit depression associated with comorbid autoimmune disorders, such as psoriasis or rheumatoid arthritis. A systematic review and meta-analysis of 36 RCTs (N = 10,000) found 5 out of 6 anti-inflammatory agents improved depression.13,14 In general, reported disadvantages of anti-inflammatories/immunosuppressants include the potential to block the antidepressant effect of some agents, the risk of opportunistic infections, and an increased risk of suicide.
Continue to: Statins
Statins
In a meta-analysis of 3 randomized, double-blind trials, 3 statins (lovastatin, atorvastatin, and simvastatin) significantly improved depression scores when used as an adjunctive therapy to fluoxetine and citalopram, compared with adjunctive placebo (N = 165, P < .001).15
Specific adverse effects of statins include headaches, muscle pain (rarely rhabdomyolysis), dizziness, rash, and liver damage. Statins also have the potential for adverse interactions with other medications. Given the limited efficacy literature on statins for depression and the potential for serious adverse effects, these agents probably should be limited to patients with treatment-resistant depression for whom a statin is indicated for a comorbid medical disorder, such as hypercholesteremia.
Neurosteroids
Brexanolone is FDA-approved for the treatment of postpartum depression. It is an IV formulation of the neuroactive steroid hormone allopregnanolone (a metabolite of progesterone), which acts as a positive allosteric modulator of the GABA-A receptor. Unfortunately, the infusion needs to occur over a 60-hour period.
Ganaxolone is an oral analog formulation of allopregnanolone. In an uncontrolled, open-label pilot study, this medication was administered for 8 weeks as an adjunct to an adequately dosed antidepressant to 10 postmenopausal women with persistent MDD.16 Of the 9 women who completed the study, 4 (44%) improved significantly (P < .019) and the benefit was sustained for 2 additional weeks.16 Adverse effects of ganaxolone included dizziness in 60% of participants, and sleepiness and fatigue in all of them with twice-daily dosing. If the FDA approves ganaxolone, it would become an easier-to-administer option to brexanolone.
Zuranolone is an investigational agent being studied as a treatment for postpartum depression. In a double-blind RCT that evaluated 151 women with postpartum depression, those who took oral zuranolone, 30 mg daily at bedtime for 2 weeks, experienced significant reductions in Hamilton Depression Rating Scale-17 (HDRS-17) scores compared with placebo (P < .003).17 Improvement in core depression symptom ratings was seen as early as Day 3 and persisted through Day 45.
Continue to: The most common...
The most common (≥5%) treatment-emergent adverse effects were somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%). Two patients experienced a serious adverse event: one who received zuranolone (confusional state) and one who received placebo (pancreatitis). One patient discontinued zuranolone due to adverse effects vs no discontinuations among those who received placebo. The risk of taking zuranolone while breastfeeding is not known.
Device-based strategies
In addition to FDA-cleared approaches (eg, electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS]), other devices have also demonstrated promising results.
Transcranial direct current stimulation (tDCS) involves delivering weak electrical current to the cerebral cortex through small scalp electrodes to produce the following effects:
- anodal tDCS enhances cortical excitability
- cathodal tDCS reduces cortical excitability.
A typical protocol consists of delivering 1 to 2 mA over 20 minutes with scalp electrodes placed in different configurations based on the targeted symptom(s).
While tDCS has been evaluated as a treatment for various neuropsychiatric disorders, including bipolar depression, Parkinson’s disease, and schizophrenia, most trials have looked at its use for treating depression. Results have been promising but mixed. For example, 1 meta-analysis of 6 RCTs (comprising 96 active and 80 sham tDCS courses) reported that active tDCS was superior to a sham procedure (Hedges’ g = 0.743) for symptoms of depression.18 By contrast, another meta-analysis of 6 RCTs (N = 200) did not find a significant difference between active and sham tDCS for response and remission rates.19 More recently, a group of experts created an evidence-based guideline using a systematic review of the controlled trial literature. These authors concluded there is “probable efficacy for anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episodes without drug resistance but probable inefficacy for drug-resistant major depressive episodes.”20
Continue to: Adverse effects of tDCS...
Adverse effects of tDCS are typically mild but may include persistent skin lesions similar to burns; mania or hypomania; and one reported seizure in a pediatric patient.
Because various over-the-counter direct current stimulation devices are available for purchase at modest cost, clinicians should ask patients if they have been self-administering this treatment.
Chronotherapy strategies
Agomelatine combines serotonergic (5-HT2B and 5-HT2C antagonist) and melatonergic (MT1-MT2 agonist in the suprachiasmatic nucleus) actions that contribute to stabilization of circadian rhythms and subsequent improvement in sleep patterns. Agomelatine (n = 1,274) significantly lowered depression symptoms compared with placebo (n = 689) (standardized mean difference −0.26; P < 3.48×10-11), but the clinical relevance was questionable.21 A recent review of the literature and expert opinion suggest this agent may also have efficacy for anhedonia; however, in placebo-controlled, relapse prevention studies, its long-term efficacy was not consistent.22
Common adverse effects include anxiety; nausea, vomiting, and stomach pain; abnormal dreams and insomnia; dizziness; drowsiness and fatigue; and weight gain. Some reviewers have expressed concerns about agomelatine’s potential for hepatotoxicity and the need for repeated clinical laboratory tests. Although agomelatine is approved outside of the United States, limited efficacy data and the potential for serious adverse effects have precluded FDA approval of this agent.
Sleep deprivation as a treatment technique for depression has been developed over the past 50 years. With total sleep deprivation (TSD) over 1 cycle, patients stay awake for approximately 36 hours, from daytime until the next day’s evening. While 1 to 6 cycles can produce acute antidepressant effects, prompt relapse after sleep recovery is common.
Continue to: In a systematic review...
In a systematic review and meta-analysis of 7 studies that included a total of 311 patients with bipolar depression23:
- TSD plus medications resulted in a significant decrease in depressive symptoms at 1 week compared with medications alone
- higher response rates were maintained after 3 months with lithium.
Adverse effects commonly include general fatigue and headaches; possible switch into mania with bipolar depression; and rarely, seizures or other unexpected medical conditions (eg, acute coronary syndrome). Presently, this approach is limited to research laboratories with the appropriate sophistication to safely conduct such trials.
Other nontraditional strategies
Cardiovascular exercise, resistance training, mindfulness, and yoga have been shown to decrease severe depressive symptoms when used as adjuncts for patients with treatment-resistant depression, or as monotherapy to treat patients with milder depression.
Exercise. The significant benefits of exercise in various forms as treatment for mild to moderate depression are well described in the literature, but it is less clear if it is effective for treatment-resistant depression. A 2013 Cochrane report24 (39 studies with 2,326 participants total) and 2 meta-analyses undertaken in 2015 (Kvam et al25 included 23 studies with 977 participants, and Schuh et al26 included 25 trials with 1,487 participants) reported that various types of exercise ameliorate depression of differing subtypes and severity, with effect sizes ranging from small to large. Schuh et al26 found that publication bias underestimated effect size. Also, not surprisingly, separate analysis of only higher-quality trials decreased effect size.24-26 A meta-analysis that included tai chi and yoga in addition to aerobic exercise and strength training (25 trials with 2,083 participants) found low to moderate benefit for exercise and yoga.27 Finally, a meta-analysis by Cramer et al28 that included 12 RCTs (N = 619) supported the use of yoga plus controlled breathing techniques as an ancillary treatment for depression.
Two small exercise trials specifically evaluated patients with treatment-resistant depression.29,30 Mota-Pereira et al29 compared 22 participants who walked for 30 to 45 minutes, 5 days a week for 12 weeks in addition to pharmacotherapy with 11 patients who received pharmacotherapy only. Exercise improved all outcomes, including HDRS score (both compared to baseline and to the control group). Moreover, 26% of the exercise group went into remission. Pilu et al30 evaluated strength training as an adjunctive treatment. Participants received 1 hour of strength training twice weekly for 8 months (n = 10), or pharmacotherapy only (n = 20). The adjunct strength training group had a statistically significant (P < .0001) improvement in HDRS scores at the end of the 8 months, whereas the control group did not (P < .28).
Continue to: Adverse effects...
Adverse effects of exercise are typically limited to sprains or strains; rarely, participants experience serious injuries.
Mindfulness-based interventions involve purposely paying attention in the present moment to enhance self-understanding and decrease anxiety about the future and regrets about the past, both of which complicate depression. A meta-analysis of 12 RCTs (N = 578) found this approach significantly reduced depression severity when used as an adjunctive therapy.31 There may be risks if mindfulness-based interventions are practiced incorrectly. For example, some reports have linked mindfulness-based interventions to psychotic episodes, meditation addiction, and antisocial or asocial behavior.32
Bottom Line
Nonpharmacologic options for patients with treatment-resistant depression include herbal/nutraceuticals, anti-inflammatory/immune system therapies, and devices. While research suggests some of these approaches are promising, clinicians need to carefully consider potential adverse effects, some of which may be serious.
Related Resources
- Kaur M, Sanches M. Experimental therapeutics in treatmentresistant major depressive disorder. J Exp Pharmacol. 2021;13:181-196.
- Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
Drug Brand Names
Atorvastatin • Lipitor
Brexanolone • Zulresso
Citalopram • Celexa
Fluoxetine • Prozac
Lithium • Eskalith, Lithobid
Lovastatin • Altoprev, Mevacor
Minocycline • Dynacin, Minocin
Simvastatin • Flolipid, Zocor
When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.
In Part 1 of this article (
Herbal/nutraceutical agents
This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:
- vitamin D
- essential fatty acids (omega-3, omega-6)
- S-adenosyl-L-methionine (SAMe)
- hypericum perforatum (St. John’s Wort)
- probiotics.
Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.1-3
A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.4 In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.5
Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.
Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.
Continue to: Although results from...
Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.5 A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.6 Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.7
Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.
S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.
- Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
- When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).
Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.
Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.
Continue to: A meta-analysis of 7 clinical trials...
A meta-analysis of 7 clinical trials (N = 3,808) comparing St. John’s Wort with various selective serotonin reuptake inhibitors (SSRIs) reported comparable rates of response (pooled relative risk .983, 95% CI .924 to 1.042; P < .001) and remission (pooled relative risk 1.013, 95% CI .892 to 1.134; P < .001).9 Further, there were significantly lower discontinuation/dropout rates (pooled odds ratio .587, 95% CI .478 to 0.697; P < .001) for St. John’s Wort compared with the SSRIs.
Existing evidence on the long-term efficacy and safety is limited (studies ranged from 4 to 12 weeks), as is evidence for patients with more severe depression or high suicidality.
Serious drug interactions include the potential for serotonin syndrome when St. John’s Wort is combined with certain antidepressants, compromised efficacy of benzodiazepines and standard antidepressants, and severe skin reactions to sun exposure. In addition, St. John’s Wort may not be safe to use during pregnancy or while breastfeeding. Because potential drug interactions can be serious and individuals often self-prescribe this agent, it is important to ask patients about their use of St. John’s Wort, and to be vigilant for such potential adverse interactions.
Probiotics. These agents produce neuroactive substances that act on the brain/gut axis. Preliminary evidence suggests that these “psychobiotics” confer mental health benefits.10-12 Relative to other approaches, their low-risk profile make them an attractive option for some patients.
Anti-inflammatory/immune system therapies
Inflammation is linked to various medical and brain disorders. For example, patients with depression often demonstrate increased levels of peripheral blood inflammatory biomarkers (such as C-reactive protein and interleukin-6 and -17) that are known to alter norepinephrine, neuroendocrine (eg, the hypothalamic-pituitary-adrenal axis), and microglia function in addition to neuroplasticity. Thus, targeting inflammation may facilitate the development of novel antidepressants. In addition, these agents may benefit depression associated with comorbid autoimmune disorders, such as psoriasis or rheumatoid arthritis. A systematic review and meta-analysis of 36 RCTs (N = 10,000) found 5 out of 6 anti-inflammatory agents improved depression.13,14 In general, reported disadvantages of anti-inflammatories/immunosuppressants include the potential to block the antidepressant effect of some agents, the risk of opportunistic infections, and an increased risk of suicide.
Continue to: Statins
Statins
In a meta-analysis of 3 randomized, double-blind trials, 3 statins (lovastatin, atorvastatin, and simvastatin) significantly improved depression scores when used as an adjunctive therapy to fluoxetine and citalopram, compared with adjunctive placebo (N = 165, P < .001).15
Specific adverse effects of statins include headaches, muscle pain (rarely rhabdomyolysis), dizziness, rash, and liver damage. Statins also have the potential for adverse interactions with other medications. Given the limited efficacy literature on statins for depression and the potential for serious adverse effects, these agents probably should be limited to patients with treatment-resistant depression for whom a statin is indicated for a comorbid medical disorder, such as hypercholesteremia.
Neurosteroids
Brexanolone is FDA-approved for the treatment of postpartum depression. It is an IV formulation of the neuroactive steroid hormone allopregnanolone (a metabolite of progesterone), which acts as a positive allosteric modulator of the GABA-A receptor. Unfortunately, the infusion needs to occur over a 60-hour period.
Ganaxolone is an oral analog formulation of allopregnanolone. In an uncontrolled, open-label pilot study, this medication was administered for 8 weeks as an adjunct to an adequately dosed antidepressant to 10 postmenopausal women with persistent MDD.16 Of the 9 women who completed the study, 4 (44%) improved significantly (P < .019) and the benefit was sustained for 2 additional weeks.16 Adverse effects of ganaxolone included dizziness in 60% of participants, and sleepiness and fatigue in all of them with twice-daily dosing. If the FDA approves ganaxolone, it would become an easier-to-administer option to brexanolone.
Zuranolone is an investigational agent being studied as a treatment for postpartum depression. In a double-blind RCT that evaluated 151 women with postpartum depression, those who took oral zuranolone, 30 mg daily at bedtime for 2 weeks, experienced significant reductions in Hamilton Depression Rating Scale-17 (HDRS-17) scores compared with placebo (P < .003).17 Improvement in core depression symptom ratings was seen as early as Day 3 and persisted through Day 45.
Continue to: The most common...
The most common (≥5%) treatment-emergent adverse effects were somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%). Two patients experienced a serious adverse event: one who received zuranolone (confusional state) and one who received placebo (pancreatitis). One patient discontinued zuranolone due to adverse effects vs no discontinuations among those who received placebo. The risk of taking zuranolone while breastfeeding is not known.
Device-based strategies
In addition to FDA-cleared approaches (eg, electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS]), other devices have also demonstrated promising results.
Transcranial direct current stimulation (tDCS) involves delivering weak electrical current to the cerebral cortex through small scalp electrodes to produce the following effects:
- anodal tDCS enhances cortical excitability
- cathodal tDCS reduces cortical excitability.
A typical protocol consists of delivering 1 to 2 mA over 20 minutes with scalp electrodes placed in different configurations based on the targeted symptom(s).
While tDCS has been evaluated as a treatment for various neuropsychiatric disorders, including bipolar depression, Parkinson’s disease, and schizophrenia, most trials have looked at its use for treating depression. Results have been promising but mixed. For example, 1 meta-analysis of 6 RCTs (comprising 96 active and 80 sham tDCS courses) reported that active tDCS was superior to a sham procedure (Hedges’ g = 0.743) for symptoms of depression.18 By contrast, another meta-analysis of 6 RCTs (N = 200) did not find a significant difference between active and sham tDCS for response and remission rates.19 More recently, a group of experts created an evidence-based guideline using a systematic review of the controlled trial literature. These authors concluded there is “probable efficacy for anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episodes without drug resistance but probable inefficacy for drug-resistant major depressive episodes.”20
Continue to: Adverse effects of tDCS...
Adverse effects of tDCS are typically mild but may include persistent skin lesions similar to burns; mania or hypomania; and one reported seizure in a pediatric patient.
Because various over-the-counter direct current stimulation devices are available for purchase at modest cost, clinicians should ask patients if they have been self-administering this treatment.
Chronotherapy strategies
Agomelatine combines serotonergic (5-HT2B and 5-HT2C antagonist) and melatonergic (MT1-MT2 agonist in the suprachiasmatic nucleus) actions that contribute to stabilization of circadian rhythms and subsequent improvement in sleep patterns. Agomelatine (n = 1,274) significantly lowered depression symptoms compared with placebo (n = 689) (standardized mean difference −0.26; P < 3.48×10-11), but the clinical relevance was questionable.21 A recent review of the literature and expert opinion suggest this agent may also have efficacy for anhedonia; however, in placebo-controlled, relapse prevention studies, its long-term efficacy was not consistent.22
Common adverse effects include anxiety; nausea, vomiting, and stomach pain; abnormal dreams and insomnia; dizziness; drowsiness and fatigue; and weight gain. Some reviewers have expressed concerns about agomelatine’s potential for hepatotoxicity and the need for repeated clinical laboratory tests. Although agomelatine is approved outside of the United States, limited efficacy data and the potential for serious adverse effects have precluded FDA approval of this agent.
Sleep deprivation as a treatment technique for depression has been developed over the past 50 years. With total sleep deprivation (TSD) over 1 cycle, patients stay awake for approximately 36 hours, from daytime until the next day’s evening. While 1 to 6 cycles can produce acute antidepressant effects, prompt relapse after sleep recovery is common.
Continue to: In a systematic review...
In a systematic review and meta-analysis of 7 studies that included a total of 311 patients with bipolar depression23:
- TSD plus medications resulted in a significant decrease in depressive symptoms at 1 week compared with medications alone
- higher response rates were maintained after 3 months with lithium.
Adverse effects commonly include general fatigue and headaches; possible switch into mania with bipolar depression; and rarely, seizures or other unexpected medical conditions (eg, acute coronary syndrome). Presently, this approach is limited to research laboratories with the appropriate sophistication to safely conduct such trials.
Other nontraditional strategies
Cardiovascular exercise, resistance training, mindfulness, and yoga have been shown to decrease severe depressive symptoms when used as adjuncts for patients with treatment-resistant depression, or as monotherapy to treat patients with milder depression.
Exercise. The significant benefits of exercise in various forms as treatment for mild to moderate depression are well described in the literature, but it is less clear if it is effective for treatment-resistant depression. A 2013 Cochrane report24 (39 studies with 2,326 participants total) and 2 meta-analyses undertaken in 2015 (Kvam et al25 included 23 studies with 977 participants, and Schuh et al26 included 25 trials with 1,487 participants) reported that various types of exercise ameliorate depression of differing subtypes and severity, with effect sizes ranging from small to large. Schuh et al26 found that publication bias underestimated effect size. Also, not surprisingly, separate analysis of only higher-quality trials decreased effect size.24-26 A meta-analysis that included tai chi and yoga in addition to aerobic exercise and strength training (25 trials with 2,083 participants) found low to moderate benefit for exercise and yoga.27 Finally, a meta-analysis by Cramer et al28 that included 12 RCTs (N = 619) supported the use of yoga plus controlled breathing techniques as an ancillary treatment for depression.
Two small exercise trials specifically evaluated patients with treatment-resistant depression.29,30 Mota-Pereira et al29 compared 22 participants who walked for 30 to 45 minutes, 5 days a week for 12 weeks in addition to pharmacotherapy with 11 patients who received pharmacotherapy only. Exercise improved all outcomes, including HDRS score (both compared to baseline and to the control group). Moreover, 26% of the exercise group went into remission. Pilu et al30 evaluated strength training as an adjunctive treatment. Participants received 1 hour of strength training twice weekly for 8 months (n = 10), or pharmacotherapy only (n = 20). The adjunct strength training group had a statistically significant (P < .0001) improvement in HDRS scores at the end of the 8 months, whereas the control group did not (P < .28).
Continue to: Adverse effects...
Adverse effects of exercise are typically limited to sprains or strains; rarely, participants experience serious injuries.
Mindfulness-based interventions involve purposely paying attention in the present moment to enhance self-understanding and decrease anxiety about the future and regrets about the past, both of which complicate depression. A meta-analysis of 12 RCTs (N = 578) found this approach significantly reduced depression severity when used as an adjunctive therapy.31 There may be risks if mindfulness-based interventions are practiced incorrectly. For example, some reports have linked mindfulness-based interventions to psychotic episodes, meditation addiction, and antisocial or asocial behavior.32
Bottom Line
Nonpharmacologic options for patients with treatment-resistant depression include herbal/nutraceuticals, anti-inflammatory/immune system therapies, and devices. While research suggests some of these approaches are promising, clinicians need to carefully consider potential adverse effects, some of which may be serious.
Related Resources
- Kaur M, Sanches M. Experimental therapeutics in treatmentresistant major depressive disorder. J Exp Pharmacol. 2021;13:181-196.
- Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
Drug Brand Names
Atorvastatin • Lipitor
Brexanolone • Zulresso
Citalopram • Celexa
Fluoxetine • Prozac
Lithium • Eskalith, Lithobid
Lovastatin • Altoprev, Mevacor
Minocycline • Dynacin, Minocin
Simvastatin • Flolipid, Zocor
1. Pittampalli S, Mekala HM, Upadhyayula, S, et al. Does vitamin D deficiency cause depression? Prim Care Companion CNS Disord. 2018;20(5):17l02263.
2. Parker GB, Brotchie H, Graham RK. Vitamin D and depression. J Affect Disord. 2017;208:56-61.
3. Berridge MJ. Vitamin D and depression: cellular and regulatory mechanisms. Pharmacol Rev. 2017;69(2):80-92.
4. Anglin RE, Samaan Z, Walter SD, et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100-107.
5. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry 2016;173(6);575-587.
6. Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019;9(1):190.
7. Mocking RJT, Steijn K, Roos C, et al. Omega-3 fatty acid supplementation for perinatal depression: a meta-analysis. J Clin Psychiatry. 2020;81(5):19r13106.
8. Sharma A, Gerbarg P, Bottiglieri T, et al; Work Group of the American Psychiatric Association Council on Research. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667.
9. Ng QX, Venkatanarayanan N, Ho CY. Clinical use of hypericum perforatum (St John’s wort) in depression: a meta-analysis. J Affect Disord 2017;210:211-221.
10. Huang R, Wang K, Hu J. Effect of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016;8(8):483.
11. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019;102:13-23.
12. Wallace CJK, Milev RV. The efficacy, safety, and tolerability of probiotics on depression: clinical results from an open-label pilot study. Front Psychiatry. 2021;12(132):618279.
13. Köhler-Forsberg O, N Lyndholm C, Hjorthøj C, et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139(5):404-419.
14. Jha MK. Anti-inflammatory treatments for major depressive disorder: what’s on the horizon? J Clin Psychiatry. 2019;80(6)18ac12630.
15. Salagre E, Fernandes BS, Dodd S, et al. Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Affect Disord. 2016;200:235-242.
16. Dichtel LE, Nyer M, Dording C, et al. Effects of open-label, adjunctive ganaxolone on persistent depression despite adequate antidepressant treatment in postmenopausal women: a pilot study. J Clin Psychiatry. 2020;81(4):19m12887.
17. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry. 2021;78(9):951-959.
18. Kalu UG, Sexton CE, Loo CK, et al. Transcranial direct current stimulation in the treatment of major depression: a meta-analysis. Psychol Med. 2012;42(9):1791-800.
19. Berlim MT, Van den Eynde F, Daskalakis ZJ. Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. J Psychiatr Res. 2013;47(1):1-7.
20. Lefaucheur JP, Antal A, Ayache SS, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017;128(1):56-92.
21. Singh SP, Singh V, Kar N. Efficacy of agomelatine in major depressive disorder: meta-analysis and appraisal. Int J Neuropsychopharmacol. 2012;15(3):417-428.
22. Norman TR, Olver JS. Agomelatine for depression: expanding the horizons? Expert Opin Pharmacother. 2019;20(6):647-656.
23. Ramirez-Mahaluf JP, Rozas-Serri E, Ivanovic-Zuvic F, et al. Effectiveness of sleep deprivation in treating acute bipolar depression as augmentation strategy: a systematic review and meta-analysis. Front Psychiatry. 2020;11:70.
24. Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;(9):CD004366.
25. Kvam S, Kleppe CL, Nordhus IH, et al. Exercise as a treatment for depression: a meta-analysis. J Affect Disord. 2016;202:67-86.
26. Schuch FB, Vancampfort D, Richards J, et al. Exercise as a treatment for depression: a meta-analysis adjusting for publication bias. J Psychiatr Res. 2016;77:42-51.
27. Seshadri A, Adaji A, Orth SS, et al. Exercise, yoga, and tai chi for treatment of major depressive disorder in outpatient settings: a systematic review and meta-analysis. Prim Care Companion CNS Disord. 2020;23(1):20r02722.
28. Cramer H, Lauche R, Langhorst J, et al. Yoga for depression: a systematic review and meta-analysis. Depress Anxiety. 2013;30(11):1068-1083.
29. Mota-Pereira J, Silverio J, Carvalho S, et al. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Psychiatr Res. 2011;45(8):1005-1011.
30. Pilu A, Sorba M, Hardoy MC, et al. Efficacy of physical activity in the adjunctive treatment of major depressive disorders: preliminary results. Clin Pract Epidemiol Ment Health. 2007;3:8.
31. Strauss C, Cavanagh K, Oliver A, et al. Mindfulness-based interventions for people diagnosed with a current episode of an anxiety or depressive disorder: a meta-analysis of randomised controlled trials. PLoS One. 2014;9(4):e96110.
32. Shonin E, Van Gordon W, Griffiths MD. Are there risks associated with using mindfulness for the treatment of psychopathology? Clinical Practice. 2014;11(4):389-392.
1. Pittampalli S, Mekala HM, Upadhyayula, S, et al. Does vitamin D deficiency cause depression? Prim Care Companion CNS Disord. 2018;20(5):17l02263.
2. Parker GB, Brotchie H, Graham RK. Vitamin D and depression. J Affect Disord. 2017;208:56-61.
3. Berridge MJ. Vitamin D and depression: cellular and regulatory mechanisms. Pharmacol Rev. 2017;69(2):80-92.
4. Anglin RE, Samaan Z, Walter SD, et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100-107.
5. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry 2016;173(6);575-587.
6. Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019;9(1):190.
7. Mocking RJT, Steijn K, Roos C, et al. Omega-3 fatty acid supplementation for perinatal depression: a meta-analysis. J Clin Psychiatry. 2020;81(5):19r13106.
8. Sharma A, Gerbarg P, Bottiglieri T, et al; Work Group of the American Psychiatric Association Council on Research. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667.
9. Ng QX, Venkatanarayanan N, Ho CY. Clinical use of hypericum perforatum (St John’s wort) in depression: a meta-analysis. J Affect Disord 2017;210:211-221.
10. Huang R, Wang K, Hu J. Effect of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016;8(8):483.
11. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019;102:13-23.
12. Wallace CJK, Milev RV. The efficacy, safety, and tolerability of probiotics on depression: clinical results from an open-label pilot study. Front Psychiatry. 2021;12(132):618279.
13. Köhler-Forsberg O, N Lyndholm C, Hjorthøj C, et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139(5):404-419.
14. Jha MK. Anti-inflammatory treatments for major depressive disorder: what’s on the horizon? J Clin Psychiatry. 2019;80(6)18ac12630.
15. Salagre E, Fernandes BS, Dodd S, et al. Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials. J Affect Disord. 2016;200:235-242.
16. Dichtel LE, Nyer M, Dording C, et al. Effects of open-label, adjunctive ganaxolone on persistent depression despite adequate antidepressant treatment in postmenopausal women: a pilot study. J Clin Psychiatry. 2020;81(4):19m12887.
17. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry. 2021;78(9):951-959.
18. Kalu UG, Sexton CE, Loo CK, et al. Transcranial direct current stimulation in the treatment of major depression: a meta-analysis. Psychol Med. 2012;42(9):1791-800.
19. Berlim MT, Van den Eynde F, Daskalakis ZJ. Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. J Psychiatr Res. 2013;47(1):1-7.
20. Lefaucheur JP, Antal A, Ayache SS, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017;128(1):56-92.
21. Singh SP, Singh V, Kar N. Efficacy of agomelatine in major depressive disorder: meta-analysis and appraisal. Int J Neuropsychopharmacol. 2012;15(3):417-428.
22. Norman TR, Olver JS. Agomelatine for depression: expanding the horizons? Expert Opin Pharmacother. 2019;20(6):647-656.
23. Ramirez-Mahaluf JP, Rozas-Serri E, Ivanovic-Zuvic F, et al. Effectiveness of sleep deprivation in treating acute bipolar depression as augmentation strategy: a systematic review and meta-analysis. Front Psychiatry. 2020;11:70.
24. Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;(9):CD004366.
25. Kvam S, Kleppe CL, Nordhus IH, et al. Exercise as a treatment for depression: a meta-analysis. J Affect Disord. 2016;202:67-86.
26. Schuch FB, Vancampfort D, Richards J, et al. Exercise as a treatment for depression: a meta-analysis adjusting for publication bias. J Psychiatr Res. 2016;77:42-51.
27. Seshadri A, Adaji A, Orth SS, et al. Exercise, yoga, and tai chi for treatment of major depressive disorder in outpatient settings: a systematic review and meta-analysis. Prim Care Companion CNS Disord. 2020;23(1):20r02722.
28. Cramer H, Lauche R, Langhorst J, et al. Yoga for depression: a systematic review and meta-analysis. Depress Anxiety. 2013;30(11):1068-1083.
29. Mota-Pereira J, Silverio J, Carvalho S, et al. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Psychiatr Res. 2011;45(8):1005-1011.
30. Pilu A, Sorba M, Hardoy MC, et al. Efficacy of physical activity in the adjunctive treatment of major depressive disorders: preliminary results. Clin Pract Epidemiol Ment Health. 2007;3:8.
31. Strauss C, Cavanagh K, Oliver A, et al. Mindfulness-based interventions for people diagnosed with a current episode of an anxiety or depressive disorder: a meta-analysis of randomised controlled trials. PLoS One. 2014;9(4):e96110.
32. Shonin E, Van Gordon W, Griffiths MD. Are there risks associated with using mindfulness for the treatment of psychopathology? Clinical Practice. 2014;11(4):389-392.
Treating major depressive disorder after limited response to an initial agent
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used first-line agents for treating major depressive disorder. Less than one-half of patients with major depressive disorder experience remission after 1 acute trial of an antidepressant.1 After optimization of an initial agent’s dose and duration, potential next steps include switching agents or augmentation. Augmentation strategies may lead to clinical improvement but carry the risks of polypharmacy, including increased risk of adverse effects and drug interactions. Clinicians can consider the following evidence-based options for a patient with a limited response to an initial SSRI or SNRI.
Second-generation antipsychotics, when used as augmentation agents to treat a patient with major depressive disorder, can lead to an approximately 10% improvement in remission rate compared with placebo.2 Aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine only), and quetiapine are FDA-approved as adjunctive therapies with an antidepressant (Table 1). Second-generation antipsychotics should be started at lower doses than those used for schizophrenia, and these agents have an increased risk of metabolic adverse effects as well as extrapyramidal symptoms.
Atypical antidepressants are those that are not classified as an SSRI, SNRI, tricyclic antidepressant (TCA), or monoamine oxidase inhibitor (MAOI). These include bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine (Table 2). Bupropion is a dopamine and norepinephrine reuptake inhibitor. When used for augmentation in clinical studies, it led to a 30% remission rate.3 Mirtazapine is an alpha-2 antagonist that can be used as monotherapy or in combination with another antidepressant.4 Trazodone is an antidepressant with activity at histamine and alpha-1-adrenergic receptors that is often used off-label for insomnia. Trazodone can be used safely and effectively in combination with other agents for treatment-resistant depression.5 Vilazodone is a 5-HT1A partial agonist, and vortioxetine is a 5-HT1A agonist and 5-HT3 antagonist; both are FDA-approved as alternative agents for monotherapy for major depressive disorder. Choosing among these agents for switching or augmenting can be guided by patient preference, adverse effect profile, and targeting specific symptoms, such as using mirtazapine to address poor sleep and appetite.
Lithium augmentation has been frequently investigated in placebo-controlled, double-blind studies. A meta-analysis showed that patients receiving lithium augmentation with a serum level of ≥0.5 mEq/L were >3 times more likely to respond than those receiving placebo.6 When lithium is used to treat bipolar disorder, the therapeutic serum range for lithium is 0.8 to 1.2 mEq/L, with an increased risk of adverse effects (including toxicity) at higher levels.7
Triiodothyronine (T3) augmentation of antidepressants led to remission in approximately 1 in 4 patients who had not achieved remission or who were intolerant to an initial treatment with citalopram and a second switch or augmentation trial.8 In this study, the mean dose of T3 was 45.2 µg/d, with an average length of treatment of 9 weeks.
Tricyclic antidepressants are another option when considering switching agents (Table 3). TCAs are additionally effective for comorbid pain conditions.9 When TCAs are used in combination with SSRIs, drug interactions may occur that increase TCA plasma levels. There is also an increased risk of serotonin syndrome when used with serotonergic agents, though an SSRI/ TCA combination may be appropriate for a patient with treatment-resistant depression.10 Additionally, TCAs carry unique risks of cardiovascular effects, including cardiac arrhythmias. A meta-analysis comparing fluoxetine, paroxetine, and sertraline to TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) concluded that both classes had similar efficacy in treating depression, though the drop-out rate was significantly higher among patients receiving TCAs.11
Buspirone is approved for generalized anxiety disorder. In studies where buspirone was used as an augmentation agent for major depressive disorder at a mean daily dose of 40.9 mg divided into 2 doses, it led to a remission rate >30%.3
Continue to: Monoamine oxidase inhibitors
Monoamine oxidase inhibitors should typically be avoided in initial or early treatment of depression due to tolerability issues, drug interactions, and dietary restrictions to avoid hypertensive crisis. MAOIs are generally not recommended to be used with SSRIs, SNRIs, or TCAs, and typically require a “washout” period from other antidepressants (Table 4). One review found that MAOI treatment had advantage over TCA treatment for patients with early-stage treatment-resistant depression, though this advantage decreased as the number of failed antidepressant trials increased.12 One MAOI, selegiline, is available in a transdermal patch, and the 6-mg patch does not require dietary restriction.
Esketamine (intranasal) is FDA-approved for treatment-resistant depression (failure of response after at least 2 antidepressant trials with adequate dose and duration) in conjunction with an oral antidepressant. In clinical studies, a significant response was noted after 1 week of treatment.13 Esketamine requires an induction period of twice-weekly doses of 56 or 84 mg, with maintenance doses every 1 to 2 weeks. Each dosage administration requires monitoring for at least 2 hours by a health care professional at a certified treatment center. Esketamine’s indication was recently expanded to include treatment of patients with major depressive disorder with suicidal ideation or behavior.
Stimulants such as amphetamines, methylphenidate, or modafinil have been effective in open studies for augmentation in depression.14 However, no stimulant is FDA-approved for the treatment of depression. In addition to other adverse effects, these medications are controlled substances and carry risk of misuse, and their use may not be appropriate for all patients.
1. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
2. Kato M, Chang CM. Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs. 2013;27 Suppl 1:S11-S19.
3. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
4. Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60(1):45-49.
5. Maes M, Vandoolaeghe E, Desnyder R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord. 1996;41(3):201-210.
6. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-434.
7. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
8. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530; quiz 1665.
9. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;17(4):CD005454.
10. Taylor D. Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination. Interactions and therapeutic uses. Br J Psychiatry. 1995;167(5):575-580.
11. Steffens DC, Krishnan KR, Helms MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis. Depress Anxiety. 1997;6(1):10-18.
12. Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressant versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression. J Affect Disord. 2019;250:199-203.
13. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139-148.
14. DeBattista C. Augmentation and combination strategies for depression. J Psychopharmacol. 2006;20(3 Suppl):11-18.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used first-line agents for treating major depressive disorder. Less than one-half of patients with major depressive disorder experience remission after 1 acute trial of an antidepressant.1 After optimization of an initial agent’s dose and duration, potential next steps include switching agents or augmentation. Augmentation strategies may lead to clinical improvement but carry the risks of polypharmacy, including increased risk of adverse effects and drug interactions. Clinicians can consider the following evidence-based options for a patient with a limited response to an initial SSRI or SNRI.
Second-generation antipsychotics, when used as augmentation agents to treat a patient with major depressive disorder, can lead to an approximately 10% improvement in remission rate compared with placebo.2 Aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine only), and quetiapine are FDA-approved as adjunctive therapies with an antidepressant (Table 1). Second-generation antipsychotics should be started at lower doses than those used for schizophrenia, and these agents have an increased risk of metabolic adverse effects as well as extrapyramidal symptoms.
Atypical antidepressants are those that are not classified as an SSRI, SNRI, tricyclic antidepressant (TCA), or monoamine oxidase inhibitor (MAOI). These include bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine (Table 2). Bupropion is a dopamine and norepinephrine reuptake inhibitor. When used for augmentation in clinical studies, it led to a 30% remission rate.3 Mirtazapine is an alpha-2 antagonist that can be used as monotherapy or in combination with another antidepressant.4 Trazodone is an antidepressant with activity at histamine and alpha-1-adrenergic receptors that is often used off-label for insomnia. Trazodone can be used safely and effectively in combination with other agents for treatment-resistant depression.5 Vilazodone is a 5-HT1A partial agonist, and vortioxetine is a 5-HT1A agonist and 5-HT3 antagonist; both are FDA-approved as alternative agents for monotherapy for major depressive disorder. Choosing among these agents for switching or augmenting can be guided by patient preference, adverse effect profile, and targeting specific symptoms, such as using mirtazapine to address poor sleep and appetite.
Lithium augmentation has been frequently investigated in placebo-controlled, double-blind studies. A meta-analysis showed that patients receiving lithium augmentation with a serum level of ≥0.5 mEq/L were >3 times more likely to respond than those receiving placebo.6 When lithium is used to treat bipolar disorder, the therapeutic serum range for lithium is 0.8 to 1.2 mEq/L, with an increased risk of adverse effects (including toxicity) at higher levels.7
Triiodothyronine (T3) augmentation of antidepressants led to remission in approximately 1 in 4 patients who had not achieved remission or who were intolerant to an initial treatment with citalopram and a second switch or augmentation trial.8 In this study, the mean dose of T3 was 45.2 µg/d, with an average length of treatment of 9 weeks.
Tricyclic antidepressants are another option when considering switching agents (Table 3). TCAs are additionally effective for comorbid pain conditions.9 When TCAs are used in combination with SSRIs, drug interactions may occur that increase TCA plasma levels. There is also an increased risk of serotonin syndrome when used with serotonergic agents, though an SSRI/ TCA combination may be appropriate for a patient with treatment-resistant depression.10 Additionally, TCAs carry unique risks of cardiovascular effects, including cardiac arrhythmias. A meta-analysis comparing fluoxetine, paroxetine, and sertraline to TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) concluded that both classes had similar efficacy in treating depression, though the drop-out rate was significantly higher among patients receiving TCAs.11
Buspirone is approved for generalized anxiety disorder. In studies where buspirone was used as an augmentation agent for major depressive disorder at a mean daily dose of 40.9 mg divided into 2 doses, it led to a remission rate >30%.3
Continue to: Monoamine oxidase inhibitors
Monoamine oxidase inhibitors should typically be avoided in initial or early treatment of depression due to tolerability issues, drug interactions, and dietary restrictions to avoid hypertensive crisis. MAOIs are generally not recommended to be used with SSRIs, SNRIs, or TCAs, and typically require a “washout” period from other antidepressants (Table 4). One review found that MAOI treatment had advantage over TCA treatment for patients with early-stage treatment-resistant depression, though this advantage decreased as the number of failed antidepressant trials increased.12 One MAOI, selegiline, is available in a transdermal patch, and the 6-mg patch does not require dietary restriction.
Esketamine (intranasal) is FDA-approved for treatment-resistant depression (failure of response after at least 2 antidepressant trials with adequate dose and duration) in conjunction with an oral antidepressant. In clinical studies, a significant response was noted after 1 week of treatment.13 Esketamine requires an induction period of twice-weekly doses of 56 or 84 mg, with maintenance doses every 1 to 2 weeks. Each dosage administration requires monitoring for at least 2 hours by a health care professional at a certified treatment center. Esketamine’s indication was recently expanded to include treatment of patients with major depressive disorder with suicidal ideation or behavior.
Stimulants such as amphetamines, methylphenidate, or modafinil have been effective in open studies for augmentation in depression.14 However, no stimulant is FDA-approved for the treatment of depression. In addition to other adverse effects, these medications are controlled substances and carry risk of misuse, and their use may not be appropriate for all patients.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used first-line agents for treating major depressive disorder. Less than one-half of patients with major depressive disorder experience remission after 1 acute trial of an antidepressant.1 After optimization of an initial agent’s dose and duration, potential next steps include switching agents or augmentation. Augmentation strategies may lead to clinical improvement but carry the risks of polypharmacy, including increased risk of adverse effects and drug interactions. Clinicians can consider the following evidence-based options for a patient with a limited response to an initial SSRI or SNRI.
Second-generation antipsychotics, when used as augmentation agents to treat a patient with major depressive disorder, can lead to an approximately 10% improvement in remission rate compared with placebo.2 Aripiprazole, brexpiprazole, olanzapine (in combination with fluoxetine only), and quetiapine are FDA-approved as adjunctive therapies with an antidepressant (Table 1). Second-generation antipsychotics should be started at lower doses than those used for schizophrenia, and these agents have an increased risk of metabolic adverse effects as well as extrapyramidal symptoms.
Atypical antidepressants are those that are not classified as an SSRI, SNRI, tricyclic antidepressant (TCA), or monoamine oxidase inhibitor (MAOI). These include bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine (Table 2). Bupropion is a dopamine and norepinephrine reuptake inhibitor. When used for augmentation in clinical studies, it led to a 30% remission rate.3 Mirtazapine is an alpha-2 antagonist that can be used as monotherapy or in combination with another antidepressant.4 Trazodone is an antidepressant with activity at histamine and alpha-1-adrenergic receptors that is often used off-label for insomnia. Trazodone can be used safely and effectively in combination with other agents for treatment-resistant depression.5 Vilazodone is a 5-HT1A partial agonist, and vortioxetine is a 5-HT1A agonist and 5-HT3 antagonist; both are FDA-approved as alternative agents for monotherapy for major depressive disorder. Choosing among these agents for switching or augmenting can be guided by patient preference, adverse effect profile, and targeting specific symptoms, such as using mirtazapine to address poor sleep and appetite.
Lithium augmentation has been frequently investigated in placebo-controlled, double-blind studies. A meta-analysis showed that patients receiving lithium augmentation with a serum level of ≥0.5 mEq/L were >3 times more likely to respond than those receiving placebo.6 When lithium is used to treat bipolar disorder, the therapeutic serum range for lithium is 0.8 to 1.2 mEq/L, with an increased risk of adverse effects (including toxicity) at higher levels.7
Triiodothyronine (T3) augmentation of antidepressants led to remission in approximately 1 in 4 patients who had not achieved remission or who were intolerant to an initial treatment with citalopram and a second switch or augmentation trial.8 In this study, the mean dose of T3 was 45.2 µg/d, with an average length of treatment of 9 weeks.
Tricyclic antidepressants are another option when considering switching agents (Table 3). TCAs are additionally effective for comorbid pain conditions.9 When TCAs are used in combination with SSRIs, drug interactions may occur that increase TCA plasma levels. There is also an increased risk of serotonin syndrome when used with serotonergic agents, though an SSRI/ TCA combination may be appropriate for a patient with treatment-resistant depression.10 Additionally, TCAs carry unique risks of cardiovascular effects, including cardiac arrhythmias. A meta-analysis comparing fluoxetine, paroxetine, and sertraline to TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) concluded that both classes had similar efficacy in treating depression, though the drop-out rate was significantly higher among patients receiving TCAs.11
Buspirone is approved for generalized anxiety disorder. In studies where buspirone was used as an augmentation agent for major depressive disorder at a mean daily dose of 40.9 mg divided into 2 doses, it led to a remission rate >30%.3
Continue to: Monoamine oxidase inhibitors
Monoamine oxidase inhibitors should typically be avoided in initial or early treatment of depression due to tolerability issues, drug interactions, and dietary restrictions to avoid hypertensive crisis. MAOIs are generally not recommended to be used with SSRIs, SNRIs, or TCAs, and typically require a “washout” period from other antidepressants (Table 4). One review found that MAOI treatment had advantage over TCA treatment for patients with early-stage treatment-resistant depression, though this advantage decreased as the number of failed antidepressant trials increased.12 One MAOI, selegiline, is available in a transdermal patch, and the 6-mg patch does not require dietary restriction.
Esketamine (intranasal) is FDA-approved for treatment-resistant depression (failure of response after at least 2 antidepressant trials with adequate dose and duration) in conjunction with an oral antidepressant. In clinical studies, a significant response was noted after 1 week of treatment.13 Esketamine requires an induction period of twice-weekly doses of 56 or 84 mg, with maintenance doses every 1 to 2 weeks. Each dosage administration requires monitoring for at least 2 hours by a health care professional at a certified treatment center. Esketamine’s indication was recently expanded to include treatment of patients with major depressive disorder with suicidal ideation or behavior.
Stimulants such as amphetamines, methylphenidate, or modafinil have been effective in open studies for augmentation in depression.14 However, no stimulant is FDA-approved for the treatment of depression. In addition to other adverse effects, these medications are controlled substances and carry risk of misuse, and their use may not be appropriate for all patients.
1. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
2. Kato M, Chang CM. Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs. 2013;27 Suppl 1:S11-S19.
3. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
4. Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60(1):45-49.
5. Maes M, Vandoolaeghe E, Desnyder R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord. 1996;41(3):201-210.
6. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-434.
7. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
8. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530; quiz 1665.
9. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;17(4):CD005454.
10. Taylor D. Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination. Interactions and therapeutic uses. Br J Psychiatry. 1995;167(5):575-580.
11. Steffens DC, Krishnan KR, Helms MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis. Depress Anxiety. 1997;6(1):10-18.
12. Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressant versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression. J Affect Disord. 2019;250:199-203.
13. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139-148.
14. DeBattista C. Augmentation and combination strategies for depression. J Psychopharmacol. 2006;20(3 Suppl):11-18.
1. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
2. Kato M, Chang CM. Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs. 2013;27 Suppl 1:S11-S19.
3. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
4. Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60(1):45-49.
5. Maes M, Vandoolaeghe E, Desnyder R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord. 1996;41(3):201-210.
6. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-434.
7. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
8. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530; quiz 1665.
9. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;17(4):CD005454.
10. Taylor D. Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination. Interactions and therapeutic uses. Br J Psychiatry. 1995;167(5):575-580.
11. Steffens DC, Krishnan KR, Helms MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis. Depress Anxiety. 1997;6(1):10-18.
12. Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressant versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression. J Affect Disord. 2019;250:199-203.
13. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139-148.
14. DeBattista C. Augmentation and combination strategies for depression. J Psychopharmacol. 2006;20(3 Suppl):11-18.
Relapse risk increased with antidepressant discontinuation
a new study shows.
The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that “many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime,” said lead investigator Gemma Lewis, PhD, from University College London, in an interview.
The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.
The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients – 70% – had been using the drugs for more than 3 years, the researchers wrote.
Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.
Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).
The definition of relapse was answering yes to either of the following two questions:
- Have you had a spell of feeling sad, miserable, or depressed?
- Have you been unable to enjoy or take an interest in things as much as you usually do?
Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.
By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.
“We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year,” Dr. Lewis said.
Who can stop medications without relapsing is unknown
“Many people can stop their medication without relapsing, though at present we cannot identify who those people are,” noted Dr. Lewis.
“Our study did not investigate who is at higher risk of relapse … but this is something we will focus on in the future,” she said.
For primary care clinicians whose patients are considering discontinuation of antidepressant medication, “current best practice is to engage with patients’ priorities and collaborate in coming to a decision,” she noted.
“For the individual patient, it is only possible to know about the average likelihood of relapse – and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care.”
Findings are ‘important’ but ‘disappointing’
In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as “important but disappointing.”
“They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” he explained.
Dr. Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.
“It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression,” he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.
“I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission,” he wrote. “For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy.”
Protective effect of antidepressants was clear
“This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.
“The protective effect of antidepressant medication here was clear – those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year.”
Side effects can be significant
“It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse,” Dr. Skolnik said. “While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects.”
“So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient’s informed decision of what they would like to do,” he said.
The study was funded by the U.K. National Institute for Health Research
Dr. Lewis, Dr. Jackson, and Dr. Skolnik reported no conflicts of interest.
a new study shows.
The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that “many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime,” said lead investigator Gemma Lewis, PhD, from University College London, in an interview.
The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.
The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients – 70% – had been using the drugs for more than 3 years, the researchers wrote.
Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.
Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).
The definition of relapse was answering yes to either of the following two questions:
- Have you had a spell of feeling sad, miserable, or depressed?
- Have you been unable to enjoy or take an interest in things as much as you usually do?
Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.
By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.
“We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year,” Dr. Lewis said.
Who can stop medications without relapsing is unknown
“Many people can stop their medication without relapsing, though at present we cannot identify who those people are,” noted Dr. Lewis.
“Our study did not investigate who is at higher risk of relapse … but this is something we will focus on in the future,” she said.
For primary care clinicians whose patients are considering discontinuation of antidepressant medication, “current best practice is to engage with patients’ priorities and collaborate in coming to a decision,” she noted.
“For the individual patient, it is only possible to know about the average likelihood of relapse – and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care.”
Findings are ‘important’ but ‘disappointing’
In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as “important but disappointing.”
“They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” he explained.
Dr. Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.
“It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression,” he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.
“I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission,” he wrote. “For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy.”
Protective effect of antidepressants was clear
“This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.
“The protective effect of antidepressant medication here was clear – those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year.”
Side effects can be significant
“It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse,” Dr. Skolnik said. “While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects.”
“So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient’s informed decision of what they would like to do,” he said.
The study was funded by the U.K. National Institute for Health Research
Dr. Lewis, Dr. Jackson, and Dr. Skolnik reported no conflicts of interest.
a new study shows.
The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that “many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime,” said lead investigator Gemma Lewis, PhD, from University College London, in an interview.
The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.
The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients – 70% – had been using the drugs for more than 3 years, the researchers wrote.
Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.
Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).
The definition of relapse was answering yes to either of the following two questions:
- Have you had a spell of feeling sad, miserable, or depressed?
- Have you been unable to enjoy or take an interest in things as much as you usually do?
Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.
By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.
“We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year,” Dr. Lewis said.
Who can stop medications without relapsing is unknown
“Many people can stop their medication without relapsing, though at present we cannot identify who those people are,” noted Dr. Lewis.
“Our study did not investigate who is at higher risk of relapse … but this is something we will focus on in the future,” she said.
For primary care clinicians whose patients are considering discontinuation of antidepressant medication, “current best practice is to engage with patients’ priorities and collaborate in coming to a decision,” she noted.
“For the individual patient, it is only possible to know about the average likelihood of relapse – and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care.”
Findings are ‘important’ but ‘disappointing’
In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as “important but disappointing.”
“They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” he explained.
Dr. Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.
“It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression,” he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.
“I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission,” he wrote. “For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy.”
Protective effect of antidepressants was clear
“This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.
“The protective effect of antidepressant medication here was clear – those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year.”
Side effects can be significant
“It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse,” Dr. Skolnik said. “While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects.”
“So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient’s informed decision of what they would like to do,” he said.
The study was funded by the U.K. National Institute for Health Research
Dr. Lewis, Dr. Jackson, and Dr. Skolnik reported no conflicts of interest.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Dopamine and reward: The story of social media
How often do you find yourself on social media? The first thing I do when I wake up is check my email and text messages, as well as my Facebook, Snapchat, and Instagram notifications.
Some 150,000 messages are shared on Facebook each minute; 293 million daily active users worldwide were recorded on Snapchat during the second quarter of 2021; 127.2 million monthly active users in the United States are projected to be on Instagram by 2023.
Social media has gained the hearts and wonder of many around the world. It’s absolutely incredible how ingrained it has become in our lives as a medium for creativity, outlet for communication, and platform for information. In fact, these online network tools have now become essential during COVID-19 to ensure productive workflow, keep in touch with our loved ones, and, overall, maintain social capital. Social media has truly emerged as a powerful form of living beyond our physical selves.
Yet, increased (and addictive) social media use is associated with negative health outcomes, especially among adolescents. For example, in a study reporting parent and adolescent accounts of social media use, it was reported that social media use was associated with hyperactivity/impulsivity, depression, anxiety, loneliness, and a fear of missing out. Furthermore, a meta-analysis investigating the relationship between social media use and depressive symptoms among adolescents found a small but significant and positive relationship between the two. However, additional research is required to elucidate this association.
Notwithstanding, the addictive nature of social media has previously been called out as analogous to the addictive nature of gambling. Let’s think about it. Whether you’re on Instagram, TikTok, or a similar platform, you can’t help but scroll from one video to the next. It’s one 5- to 10-second video after the next, and before you know it, you’ve spent the past hour going through random videos – but you can’t stop. Why is that so?
Social media actually “rewires” our brain such that we expect instant gratification. In other words, when we get a notification, message, like, or share, we expect fast and short-term pleasure/reward because the brain will produce a “hit of dopamine.” However, it is important to note that the reward system is not delimited to the dopaminergic pathway and, in fact, should be understood as a complex network system (i.e., governed by changes in brain morphology through addiction and excessive behavior). Given the quick pace of the social media world, the reward pathways in our brain change and there’s an increasing demand for attention, perpetuating an addictive mindset.
When we refresh our page, we expect instant gratification. But what happens when we don’t get a like, or a message, or some sort of “reward”? Recounts of social media use by adolescents have likened online attention to popularity. Accordingly, a lack of constant attention on social media has created a vicious cycle of anxiety, loneliness, and depression because of a failure to receive “virtual” reward. Taken together, social media may be harmful because it distorts our self-image, and while social media platforms help connect us, they can also ironically make us feel isolated, lower our self-confidence, and diminish our overall sense of well-being.
As the platforms for communication and information have evolved so rapidly over the past decade, there is a need to establish boundaries between what is beneficial and what is potentially detrimental to our mental health. While social media companies should play a role in mitigating addictive social network behavior, it would also seem counterintuitive to the general business model. In that case, who takes charge? This multifaceted problem requires a multidisciplinary approach.
Leanna M.W. Lui is an MSc candidate at the University of Toronto.
A version of this article first appeared on Medscape.com.
How often do you find yourself on social media? The first thing I do when I wake up is check my email and text messages, as well as my Facebook, Snapchat, and Instagram notifications.
Some 150,000 messages are shared on Facebook each minute; 293 million daily active users worldwide were recorded on Snapchat during the second quarter of 2021; 127.2 million monthly active users in the United States are projected to be on Instagram by 2023.
Social media has gained the hearts and wonder of many around the world. It’s absolutely incredible how ingrained it has become in our lives as a medium for creativity, outlet for communication, and platform for information. In fact, these online network tools have now become essential during COVID-19 to ensure productive workflow, keep in touch with our loved ones, and, overall, maintain social capital. Social media has truly emerged as a powerful form of living beyond our physical selves.
Yet, increased (and addictive) social media use is associated with negative health outcomes, especially among adolescents. For example, in a study reporting parent and adolescent accounts of social media use, it was reported that social media use was associated with hyperactivity/impulsivity, depression, anxiety, loneliness, and a fear of missing out. Furthermore, a meta-analysis investigating the relationship between social media use and depressive symptoms among adolescents found a small but significant and positive relationship between the two. However, additional research is required to elucidate this association.
Notwithstanding, the addictive nature of social media has previously been called out as analogous to the addictive nature of gambling. Let’s think about it. Whether you’re on Instagram, TikTok, or a similar platform, you can’t help but scroll from one video to the next. It’s one 5- to 10-second video after the next, and before you know it, you’ve spent the past hour going through random videos – but you can’t stop. Why is that so?
Social media actually “rewires” our brain such that we expect instant gratification. In other words, when we get a notification, message, like, or share, we expect fast and short-term pleasure/reward because the brain will produce a “hit of dopamine.” However, it is important to note that the reward system is not delimited to the dopaminergic pathway and, in fact, should be understood as a complex network system (i.e., governed by changes in brain morphology through addiction and excessive behavior). Given the quick pace of the social media world, the reward pathways in our brain change and there’s an increasing demand for attention, perpetuating an addictive mindset.
When we refresh our page, we expect instant gratification. But what happens when we don’t get a like, or a message, or some sort of “reward”? Recounts of social media use by adolescents have likened online attention to popularity. Accordingly, a lack of constant attention on social media has created a vicious cycle of anxiety, loneliness, and depression because of a failure to receive “virtual” reward. Taken together, social media may be harmful because it distorts our self-image, and while social media platforms help connect us, they can also ironically make us feel isolated, lower our self-confidence, and diminish our overall sense of well-being.
As the platforms for communication and information have evolved so rapidly over the past decade, there is a need to establish boundaries between what is beneficial and what is potentially detrimental to our mental health. While social media companies should play a role in mitigating addictive social network behavior, it would also seem counterintuitive to the general business model. In that case, who takes charge? This multifaceted problem requires a multidisciplinary approach.
Leanna M.W. Lui is an MSc candidate at the University of Toronto.
A version of this article first appeared on Medscape.com.
How often do you find yourself on social media? The first thing I do when I wake up is check my email and text messages, as well as my Facebook, Snapchat, and Instagram notifications.
Some 150,000 messages are shared on Facebook each minute; 293 million daily active users worldwide were recorded on Snapchat during the second quarter of 2021; 127.2 million monthly active users in the United States are projected to be on Instagram by 2023.
Social media has gained the hearts and wonder of many around the world. It’s absolutely incredible how ingrained it has become in our lives as a medium for creativity, outlet for communication, and platform for information. In fact, these online network tools have now become essential during COVID-19 to ensure productive workflow, keep in touch with our loved ones, and, overall, maintain social capital. Social media has truly emerged as a powerful form of living beyond our physical selves.
Yet, increased (and addictive) social media use is associated with negative health outcomes, especially among adolescents. For example, in a study reporting parent and adolescent accounts of social media use, it was reported that social media use was associated with hyperactivity/impulsivity, depression, anxiety, loneliness, and a fear of missing out. Furthermore, a meta-analysis investigating the relationship between social media use and depressive symptoms among adolescents found a small but significant and positive relationship between the two. However, additional research is required to elucidate this association.
Notwithstanding, the addictive nature of social media has previously been called out as analogous to the addictive nature of gambling. Let’s think about it. Whether you’re on Instagram, TikTok, or a similar platform, you can’t help but scroll from one video to the next. It’s one 5- to 10-second video after the next, and before you know it, you’ve spent the past hour going through random videos – but you can’t stop. Why is that so?
Social media actually “rewires” our brain such that we expect instant gratification. In other words, when we get a notification, message, like, or share, we expect fast and short-term pleasure/reward because the brain will produce a “hit of dopamine.” However, it is important to note that the reward system is not delimited to the dopaminergic pathway and, in fact, should be understood as a complex network system (i.e., governed by changes in brain morphology through addiction and excessive behavior). Given the quick pace of the social media world, the reward pathways in our brain change and there’s an increasing demand for attention, perpetuating an addictive mindset.
When we refresh our page, we expect instant gratification. But what happens when we don’t get a like, or a message, or some sort of “reward”? Recounts of social media use by adolescents have likened online attention to popularity. Accordingly, a lack of constant attention on social media has created a vicious cycle of anxiety, loneliness, and depression because of a failure to receive “virtual” reward. Taken together, social media may be harmful because it distorts our self-image, and while social media platforms help connect us, they can also ironically make us feel isolated, lower our self-confidence, and diminish our overall sense of well-being.
As the platforms for communication and information have evolved so rapidly over the past decade, there is a need to establish boundaries between what is beneficial and what is potentially detrimental to our mental health. While social media companies should play a role in mitigating addictive social network behavior, it would also seem counterintuitive to the general business model. In that case, who takes charge? This multifaceted problem requires a multidisciplinary approach.
Leanna M.W. Lui is an MSc candidate at the University of Toronto.
A version of this article first appeared on Medscape.com.
New finasteride lawsuit brings renewed attention to psychiatric, ED adverse event reports
A new merit a closer look and, potentially, better counseling and monitoring from clinicians.
The nonprofit advocacy group Public Citizen filed the suit on behalf of the Post-Finasteride Syndrome Foundation (PFSF) in the U.S. District Court for the District of Columbia. The PFSF had filed a citizen’s petition in 2017 that requested that the FDA either take the 1-mg formulation off the market, or add warnings about the potential for erectile dysfunction, depression, and suicidal ideation, among other adverse reactions.
The PFSF has alleged that long-term use of Propecia (and its generic equivalents) can lead to postfinasteride syndrome (PFS), characterized by sexual dysfunction and psycho-neurocognitive symptoms. The symptoms may continue long after men stop taking the drug, according to PFSF.
Public Citizen said the FDA needs to take action in part because U.S. prescriptions of the hair loss formulation “more than doubled from 2015 to 2020,” and online and telemedicine companies such as Hims, Roman, and Keeps “aggressively market and sell generic finasteride for hair loss.” According to GoodRx, a 1-month supply of generic 1-mg tablets costs as little as $8-$10.
Both Canadian and British regulatory authorities have added warnings about depression and suicide to the Propecia label but the FDA has not changed its labeling. An agency spokesperson told this news organization that the “FDA does not comment on the status of pending citizen petitions or on pending litigation.”
Propecia’s developer, Merck, has not responded to several requests for comment from this news organization.
Why some patients develop PFS and others do not is still not understood, but some clinicians said they counsel all patients on the risks of severe and persistent side effects that have been associated with Propecia.
Robert M. Bernstein, MD, of the department of dermatology at Columbia University, New York, and a fellow of the International Society of Hair Restoration Surgery, said that 2%-4% of his patients have some side effects, similar to the original reported incidence, with sexual dysfunction being the most common.
If a man experiences an adverse effect, the drug should be stopped, Dr. Bernstein said in an interview. He noted that “there seems to be a significant increased risk of persistent side effects in people with certain psychiatric conditions, and those people should be counseled carefully before considering the medication.”
“Everybody should be warned that the risk of persistent side effects is real but in the average person it is quite uncommon,” added Dr. Bernstein, founder of Bernstein Medical, a division of Schweiger Dermatology Group focusing on the diagnosis and treatment of hair loss. “I don’t think it should be withdrawn from the market,” he said.
Alan Jacobs, MD, a Manhattan-based neuroendocrinologist and behavioral neurologist in private practice who said he has treated hundreds of men for PFS, and who is an expert witness for the plaintiff in a suit alleging that finasteride led to a man’s suicide, said that taking the drug off the market would be unfortunate because it helps so many men. “I don’t think you need to get rid of the drug per se,” he said in an interview. “But very rapidly, people need to do clinical research to find out how to predict who’s more at risk,” he added.
Michael S. Irwig, MD, associate professor of medicine at Harvard Medical School, Boston, who has studied the persistent sexual and nonsexual side effects of finasteride, said he believes there should be a boxed warning on the finasteride label to let the men who take it “know that they can have permanent persistent sexual dysfunction, and/or depression and suicide have been noted with this medicine.
“Those who prescribe it should be having a conversation with patients about the potential risks and benefits so that everybody knows about the potential before they get on the medicine,” said Dr. Irwig, who also is an endocrinologist at Beth Israel Deaconess Medical Center in Boston.
Other countries warn of psychiatric effects
The FDA approved the 1-mg form of finasteride for male pattern hair loss in 1997.
In 2012, the label and the patient insert were updated to state that side effects included less desire for sex, erectile dysfunction, and a decrease in the amount of semen produced, but that those adverse events occurred in less than 2% of men and generally went away in most men who stopped taking the drug.
That label change unleashed a flood of more than 1,000 lawsuits against Merck. The company reportedly settled at least half of them for $4.3 million in 2018. The Superior Court of New Jersey closed out the consolidated class action against Merck in May 2021, noting that all of the cases had been settled or dismissed.
The suits generally accused Merck of not giving adequate warning about sexual side effects, according to an investigation by Reuters. That 2019 special report found that Merck had understated the number of men who experienced sexual side effects and the duration of those symptoms. The news organization also reported that from 2009 to 2018, the FDA received 5,000 reports of sexual or mental health side effects – and sometimes both – in men who took finasteride. Some 350 of the men reported suicidal thoughts, and there were 50 reports of suicide.
Public Citizen’s lawsuit alleges that VigiBase, which is managed by the World Health Organization Collaborating Centre for International Drug Monitoring, lists 378 cases of suicidal ideation, 39 cases of suicide attempt, and 88 cases of completed suicide associated with finasteride use. VigiBase collects data from 153 countries on adverse reactions to medications.
In February 2021, more documents from the class action lawsuits were unsealed in response to a Reuters request. According to the news organization, the documents showed that Merck knew of reports of depression, including suicidal thoughts, as early as 2009.
However, according to Reuters, the FDA in 2011 granted Merck’s request to only note depression as a potential side effect, without including the risk of suicidal ideation.
The current FDA label notes a small incidence of sexual dysfunction, including decreased libido (1.8% in trials) and erectile dysfunction (1.3%) and mentions depression as a side effect observed during the postmarketing period.
The Canadian label has the same statistics on sexual side effects but is much stronger on mental adverse effects: “Psychiatric disorders: mood alterations and depression, decreased libido that continued after discontinuation of treatment. Mood alterations including depressed mood and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms, and if these occur, the patient should be advised to seek medical advice.”
In the United Kingdom, patients prescribed the drug are given a leaflet, which notes that “Mood alterations such as depressed mood, depression and, less frequently, suicidal thoughts have been reported in patients treated with Propecia,” and advises patients to stop taking the drug if they experience any of those symptoms and to discuss it with their physician.
Public Citizen noted in its lawsuit that French and German drug regulators have sent letters to clinicians advising them to inform patients of the risk of suicidal thoughts and anxiety.
Is there biological plausibility?
To bolster its argument that finasteride has dangerous psychiatric side effects, the advocacy organization cited a study first published in JAMA Dermatology in late 2020 that investigated suicidality and psychological adverse events in patients taking finasteride.
David-Dan Nguyen, MPH, and his colleagues at Brigham and Women’s Hospital in Boston, McGill University, Montreal, and the University of Montreal, examined the VigiBase database and found 356 cases of suicidality and 2,926 psychological adverse events; cases were highest from 2015 to 2019.
They documented what they called a “significant disproportionality signal for suicidality (reporting odds ratio, 1.63; 95% confidence interval, 2.90-4.15) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) with finasteride, especially in younger men and those with alopecia, but not in older men or those with benign prostatic hyperplasia.
The study authors noted that some studies have suggested that men with depression have low levels of the neurosteroid allopregnanolone, which is produced by the 5-alpha reductase enzyme. Finasteride is a 5-alpha reductase inhibitor.
According to Public Citizen’s lawsuit, “The product labeling does not disclose important information about finasteride’s mechanism of action,” and “the drug inhibits multiple steroid hormone pathways that are responsible for the formation of brain neurosteroids that regulate many critical functions in the central nervous system, like sexual function, mood, sleep, cognitive function, the stress response, and motivation.”
Dr. Jacobs said that “there’s a lot of good solid high-quality research, mostly in animals, but also some on humans, showing a plausible link between blocking 5-alpha reductase in the brain, deficiency of neuroactive steroids, and depression.”
The author of an accompanying editorial, Roger S. Ho, MD, MPH, an associate professor in the department of dermatology, New York University, was skeptical. “Without a plausible biological hypothesis pharmacodynamically linking the drug and the reported adverse event, this kind of analysis may lead to false findings,” Dr. Ho said in the editorial about the Nguyen study.
Dr. Ho also wrote that he believed that the lack of a suicidality signal for dutasteride, a drug with a similar mechanism of action, but without as much media attention, “hints at a potential reporting bias unique to finasteride.”
He recommended that clinicians “conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride.”
Important medicine, important caveats
Dr. Jacobs said that many of the men who come to him with side effects after taking finasteride have “been blown off by most of the doctors they go to see.”
Urologists dismiss them because their sexual dysfunction is not a gonad issue. They are told that it’s in their head, said Dr. Jacobs, adding that, “it is in their head, but it’s biological.”
The drug’s label advises that sexual side effects disappear when the drug is stopped. “That’s only true most of the time, not all of the time,” said Dr. Jacobs, adding that the persistence of any side effects impacts what he calls a “small subset” of men who take the drug.
“We have treated tens of thousands of patients who have benefited from the medicine and had no side effects,” said Dr. Bernstein. “But there is a lot that’s still not known about it.”
Even so, “baldness in young people is not a benign condition,” he said, adding that it can be socially debilitating. “An 18-year-old with a full head of thick hair who’s totally bald in 3 or 4 years – that can totally change his psyche,” Dr. Bernstein said. Finasteride may be the best option for those young men, and it is an important medication, he said. Does it need to be used more carefully? “Certainly you can’t argue with that,” he commented.
Dr. Bernstein and Dr. Irwig reported no conflicts. Dr. Jacobs disclosed that he is an expert witness for the plaintiffs in a suit against Propecia maker Merck.
A new merit a closer look and, potentially, better counseling and monitoring from clinicians.
The nonprofit advocacy group Public Citizen filed the suit on behalf of the Post-Finasteride Syndrome Foundation (PFSF) in the U.S. District Court for the District of Columbia. The PFSF had filed a citizen’s petition in 2017 that requested that the FDA either take the 1-mg formulation off the market, or add warnings about the potential for erectile dysfunction, depression, and suicidal ideation, among other adverse reactions.
The PFSF has alleged that long-term use of Propecia (and its generic equivalents) can lead to postfinasteride syndrome (PFS), characterized by sexual dysfunction and psycho-neurocognitive symptoms. The symptoms may continue long after men stop taking the drug, according to PFSF.
Public Citizen said the FDA needs to take action in part because U.S. prescriptions of the hair loss formulation “more than doubled from 2015 to 2020,” and online and telemedicine companies such as Hims, Roman, and Keeps “aggressively market and sell generic finasteride for hair loss.” According to GoodRx, a 1-month supply of generic 1-mg tablets costs as little as $8-$10.
Both Canadian and British regulatory authorities have added warnings about depression and suicide to the Propecia label but the FDA has not changed its labeling. An agency spokesperson told this news organization that the “FDA does not comment on the status of pending citizen petitions or on pending litigation.”
Propecia’s developer, Merck, has not responded to several requests for comment from this news organization.
Why some patients develop PFS and others do not is still not understood, but some clinicians said they counsel all patients on the risks of severe and persistent side effects that have been associated with Propecia.
Robert M. Bernstein, MD, of the department of dermatology at Columbia University, New York, and a fellow of the International Society of Hair Restoration Surgery, said that 2%-4% of his patients have some side effects, similar to the original reported incidence, with sexual dysfunction being the most common.
If a man experiences an adverse effect, the drug should be stopped, Dr. Bernstein said in an interview. He noted that “there seems to be a significant increased risk of persistent side effects in people with certain psychiatric conditions, and those people should be counseled carefully before considering the medication.”
“Everybody should be warned that the risk of persistent side effects is real but in the average person it is quite uncommon,” added Dr. Bernstein, founder of Bernstein Medical, a division of Schweiger Dermatology Group focusing on the diagnosis and treatment of hair loss. “I don’t think it should be withdrawn from the market,” he said.
Alan Jacobs, MD, a Manhattan-based neuroendocrinologist and behavioral neurologist in private practice who said he has treated hundreds of men for PFS, and who is an expert witness for the plaintiff in a suit alleging that finasteride led to a man’s suicide, said that taking the drug off the market would be unfortunate because it helps so many men. “I don’t think you need to get rid of the drug per se,” he said in an interview. “But very rapidly, people need to do clinical research to find out how to predict who’s more at risk,” he added.
Michael S. Irwig, MD, associate professor of medicine at Harvard Medical School, Boston, who has studied the persistent sexual and nonsexual side effects of finasteride, said he believes there should be a boxed warning on the finasteride label to let the men who take it “know that they can have permanent persistent sexual dysfunction, and/or depression and suicide have been noted with this medicine.
“Those who prescribe it should be having a conversation with patients about the potential risks and benefits so that everybody knows about the potential before they get on the medicine,” said Dr. Irwig, who also is an endocrinologist at Beth Israel Deaconess Medical Center in Boston.
Other countries warn of psychiatric effects
The FDA approved the 1-mg form of finasteride for male pattern hair loss in 1997.
In 2012, the label and the patient insert were updated to state that side effects included less desire for sex, erectile dysfunction, and a decrease in the amount of semen produced, but that those adverse events occurred in less than 2% of men and generally went away in most men who stopped taking the drug.
That label change unleashed a flood of more than 1,000 lawsuits against Merck. The company reportedly settled at least half of them for $4.3 million in 2018. The Superior Court of New Jersey closed out the consolidated class action against Merck in May 2021, noting that all of the cases had been settled or dismissed.
The suits generally accused Merck of not giving adequate warning about sexual side effects, according to an investigation by Reuters. That 2019 special report found that Merck had understated the number of men who experienced sexual side effects and the duration of those symptoms. The news organization also reported that from 2009 to 2018, the FDA received 5,000 reports of sexual or mental health side effects – and sometimes both – in men who took finasteride. Some 350 of the men reported suicidal thoughts, and there were 50 reports of suicide.
Public Citizen’s lawsuit alleges that VigiBase, which is managed by the World Health Organization Collaborating Centre for International Drug Monitoring, lists 378 cases of suicidal ideation, 39 cases of suicide attempt, and 88 cases of completed suicide associated with finasteride use. VigiBase collects data from 153 countries on adverse reactions to medications.
In February 2021, more documents from the class action lawsuits were unsealed in response to a Reuters request. According to the news organization, the documents showed that Merck knew of reports of depression, including suicidal thoughts, as early as 2009.
However, according to Reuters, the FDA in 2011 granted Merck’s request to only note depression as a potential side effect, without including the risk of suicidal ideation.
The current FDA label notes a small incidence of sexual dysfunction, including decreased libido (1.8% in trials) and erectile dysfunction (1.3%) and mentions depression as a side effect observed during the postmarketing period.
The Canadian label has the same statistics on sexual side effects but is much stronger on mental adverse effects: “Psychiatric disorders: mood alterations and depression, decreased libido that continued after discontinuation of treatment. Mood alterations including depressed mood and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms, and if these occur, the patient should be advised to seek medical advice.”
In the United Kingdom, patients prescribed the drug are given a leaflet, which notes that “Mood alterations such as depressed mood, depression and, less frequently, suicidal thoughts have been reported in patients treated with Propecia,” and advises patients to stop taking the drug if they experience any of those symptoms and to discuss it with their physician.
Public Citizen noted in its lawsuit that French and German drug regulators have sent letters to clinicians advising them to inform patients of the risk of suicidal thoughts and anxiety.
Is there biological plausibility?
To bolster its argument that finasteride has dangerous psychiatric side effects, the advocacy organization cited a study first published in JAMA Dermatology in late 2020 that investigated suicidality and psychological adverse events in patients taking finasteride.
David-Dan Nguyen, MPH, and his colleagues at Brigham and Women’s Hospital in Boston, McGill University, Montreal, and the University of Montreal, examined the VigiBase database and found 356 cases of suicidality and 2,926 psychological adverse events; cases were highest from 2015 to 2019.
They documented what they called a “significant disproportionality signal for suicidality (reporting odds ratio, 1.63; 95% confidence interval, 2.90-4.15) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) with finasteride, especially in younger men and those with alopecia, but not in older men or those with benign prostatic hyperplasia.
The study authors noted that some studies have suggested that men with depression have low levels of the neurosteroid allopregnanolone, which is produced by the 5-alpha reductase enzyme. Finasteride is a 5-alpha reductase inhibitor.
According to Public Citizen’s lawsuit, “The product labeling does not disclose important information about finasteride’s mechanism of action,” and “the drug inhibits multiple steroid hormone pathways that are responsible for the formation of brain neurosteroids that regulate many critical functions in the central nervous system, like sexual function, mood, sleep, cognitive function, the stress response, and motivation.”
Dr. Jacobs said that “there’s a lot of good solid high-quality research, mostly in animals, but also some on humans, showing a plausible link between blocking 5-alpha reductase in the brain, deficiency of neuroactive steroids, and depression.”
The author of an accompanying editorial, Roger S. Ho, MD, MPH, an associate professor in the department of dermatology, New York University, was skeptical. “Without a plausible biological hypothesis pharmacodynamically linking the drug and the reported adverse event, this kind of analysis may lead to false findings,” Dr. Ho said in the editorial about the Nguyen study.
Dr. Ho also wrote that he believed that the lack of a suicidality signal for dutasteride, a drug with a similar mechanism of action, but without as much media attention, “hints at a potential reporting bias unique to finasteride.”
He recommended that clinicians “conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride.”
Important medicine, important caveats
Dr. Jacobs said that many of the men who come to him with side effects after taking finasteride have “been blown off by most of the doctors they go to see.”
Urologists dismiss them because their sexual dysfunction is not a gonad issue. They are told that it’s in their head, said Dr. Jacobs, adding that, “it is in their head, but it’s biological.”
The drug’s label advises that sexual side effects disappear when the drug is stopped. “That’s only true most of the time, not all of the time,” said Dr. Jacobs, adding that the persistence of any side effects impacts what he calls a “small subset” of men who take the drug.
“We have treated tens of thousands of patients who have benefited from the medicine and had no side effects,” said Dr. Bernstein. “But there is a lot that’s still not known about it.”
Even so, “baldness in young people is not a benign condition,” he said, adding that it can be socially debilitating. “An 18-year-old with a full head of thick hair who’s totally bald in 3 or 4 years – that can totally change his psyche,” Dr. Bernstein said. Finasteride may be the best option for those young men, and it is an important medication, he said. Does it need to be used more carefully? “Certainly you can’t argue with that,” he commented.
Dr. Bernstein and Dr. Irwig reported no conflicts. Dr. Jacobs disclosed that he is an expert witness for the plaintiffs in a suit against Propecia maker Merck.
A new merit a closer look and, potentially, better counseling and monitoring from clinicians.
The nonprofit advocacy group Public Citizen filed the suit on behalf of the Post-Finasteride Syndrome Foundation (PFSF) in the U.S. District Court for the District of Columbia. The PFSF had filed a citizen’s petition in 2017 that requested that the FDA either take the 1-mg formulation off the market, or add warnings about the potential for erectile dysfunction, depression, and suicidal ideation, among other adverse reactions.
The PFSF has alleged that long-term use of Propecia (and its generic equivalents) can lead to postfinasteride syndrome (PFS), characterized by sexual dysfunction and psycho-neurocognitive symptoms. The symptoms may continue long after men stop taking the drug, according to PFSF.
Public Citizen said the FDA needs to take action in part because U.S. prescriptions of the hair loss formulation “more than doubled from 2015 to 2020,” and online and telemedicine companies such as Hims, Roman, and Keeps “aggressively market and sell generic finasteride for hair loss.” According to GoodRx, a 1-month supply of generic 1-mg tablets costs as little as $8-$10.
Both Canadian and British regulatory authorities have added warnings about depression and suicide to the Propecia label but the FDA has not changed its labeling. An agency spokesperson told this news organization that the “FDA does not comment on the status of pending citizen petitions or on pending litigation.”
Propecia’s developer, Merck, has not responded to several requests for comment from this news organization.
Why some patients develop PFS and others do not is still not understood, but some clinicians said they counsel all patients on the risks of severe and persistent side effects that have been associated with Propecia.
Robert M. Bernstein, MD, of the department of dermatology at Columbia University, New York, and a fellow of the International Society of Hair Restoration Surgery, said that 2%-4% of his patients have some side effects, similar to the original reported incidence, with sexual dysfunction being the most common.
If a man experiences an adverse effect, the drug should be stopped, Dr. Bernstein said in an interview. He noted that “there seems to be a significant increased risk of persistent side effects in people with certain psychiatric conditions, and those people should be counseled carefully before considering the medication.”
“Everybody should be warned that the risk of persistent side effects is real but in the average person it is quite uncommon,” added Dr. Bernstein, founder of Bernstein Medical, a division of Schweiger Dermatology Group focusing on the diagnosis and treatment of hair loss. “I don’t think it should be withdrawn from the market,” he said.
Alan Jacobs, MD, a Manhattan-based neuroendocrinologist and behavioral neurologist in private practice who said he has treated hundreds of men for PFS, and who is an expert witness for the plaintiff in a suit alleging that finasteride led to a man’s suicide, said that taking the drug off the market would be unfortunate because it helps so many men. “I don’t think you need to get rid of the drug per se,” he said in an interview. “But very rapidly, people need to do clinical research to find out how to predict who’s more at risk,” he added.
Michael S. Irwig, MD, associate professor of medicine at Harvard Medical School, Boston, who has studied the persistent sexual and nonsexual side effects of finasteride, said he believes there should be a boxed warning on the finasteride label to let the men who take it “know that they can have permanent persistent sexual dysfunction, and/or depression and suicide have been noted with this medicine.
“Those who prescribe it should be having a conversation with patients about the potential risks and benefits so that everybody knows about the potential before they get on the medicine,” said Dr. Irwig, who also is an endocrinologist at Beth Israel Deaconess Medical Center in Boston.
Other countries warn of psychiatric effects
The FDA approved the 1-mg form of finasteride for male pattern hair loss in 1997.
In 2012, the label and the patient insert were updated to state that side effects included less desire for sex, erectile dysfunction, and a decrease in the amount of semen produced, but that those adverse events occurred in less than 2% of men and generally went away in most men who stopped taking the drug.
That label change unleashed a flood of more than 1,000 lawsuits against Merck. The company reportedly settled at least half of them for $4.3 million in 2018. The Superior Court of New Jersey closed out the consolidated class action against Merck in May 2021, noting that all of the cases had been settled or dismissed.
The suits generally accused Merck of not giving adequate warning about sexual side effects, according to an investigation by Reuters. That 2019 special report found that Merck had understated the number of men who experienced sexual side effects and the duration of those symptoms. The news organization also reported that from 2009 to 2018, the FDA received 5,000 reports of sexual or mental health side effects – and sometimes both – in men who took finasteride. Some 350 of the men reported suicidal thoughts, and there were 50 reports of suicide.
Public Citizen’s lawsuit alleges that VigiBase, which is managed by the World Health Organization Collaborating Centre for International Drug Monitoring, lists 378 cases of suicidal ideation, 39 cases of suicide attempt, and 88 cases of completed suicide associated with finasteride use. VigiBase collects data from 153 countries on adverse reactions to medications.
In February 2021, more documents from the class action lawsuits were unsealed in response to a Reuters request. According to the news organization, the documents showed that Merck knew of reports of depression, including suicidal thoughts, as early as 2009.
However, according to Reuters, the FDA in 2011 granted Merck’s request to only note depression as a potential side effect, without including the risk of suicidal ideation.
The current FDA label notes a small incidence of sexual dysfunction, including decreased libido (1.8% in trials) and erectile dysfunction (1.3%) and mentions depression as a side effect observed during the postmarketing period.
The Canadian label has the same statistics on sexual side effects but is much stronger on mental adverse effects: “Psychiatric disorders: mood alterations and depression, decreased libido that continued after discontinuation of treatment. Mood alterations including depressed mood and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms, and if these occur, the patient should be advised to seek medical advice.”
In the United Kingdom, patients prescribed the drug are given a leaflet, which notes that “Mood alterations such as depressed mood, depression and, less frequently, suicidal thoughts have been reported in patients treated with Propecia,” and advises patients to stop taking the drug if they experience any of those symptoms and to discuss it with their physician.
Public Citizen noted in its lawsuit that French and German drug regulators have sent letters to clinicians advising them to inform patients of the risk of suicidal thoughts and anxiety.
Is there biological plausibility?
To bolster its argument that finasteride has dangerous psychiatric side effects, the advocacy organization cited a study first published in JAMA Dermatology in late 2020 that investigated suicidality and psychological adverse events in patients taking finasteride.
David-Dan Nguyen, MPH, and his colleagues at Brigham and Women’s Hospital in Boston, McGill University, Montreal, and the University of Montreal, examined the VigiBase database and found 356 cases of suicidality and 2,926 psychological adverse events; cases were highest from 2015 to 2019.
They documented what they called a “significant disproportionality signal for suicidality (reporting odds ratio, 1.63; 95% confidence interval, 2.90-4.15) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) with finasteride, especially in younger men and those with alopecia, but not in older men or those with benign prostatic hyperplasia.
The study authors noted that some studies have suggested that men with depression have low levels of the neurosteroid allopregnanolone, which is produced by the 5-alpha reductase enzyme. Finasteride is a 5-alpha reductase inhibitor.
According to Public Citizen’s lawsuit, “The product labeling does not disclose important information about finasteride’s mechanism of action,” and “the drug inhibits multiple steroid hormone pathways that are responsible for the formation of brain neurosteroids that regulate many critical functions in the central nervous system, like sexual function, mood, sleep, cognitive function, the stress response, and motivation.”
Dr. Jacobs said that “there’s a lot of good solid high-quality research, mostly in animals, but also some on humans, showing a plausible link between blocking 5-alpha reductase in the brain, deficiency of neuroactive steroids, and depression.”
The author of an accompanying editorial, Roger S. Ho, MD, MPH, an associate professor in the department of dermatology, New York University, was skeptical. “Without a plausible biological hypothesis pharmacodynamically linking the drug and the reported adverse event, this kind of analysis may lead to false findings,” Dr. Ho said in the editorial about the Nguyen study.
Dr. Ho also wrote that he believed that the lack of a suicidality signal for dutasteride, a drug with a similar mechanism of action, but without as much media attention, “hints at a potential reporting bias unique to finasteride.”
He recommended that clinicians “conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride.”
Important medicine, important caveats
Dr. Jacobs said that many of the men who come to him with side effects after taking finasteride have “been blown off by most of the doctors they go to see.”
Urologists dismiss them because their sexual dysfunction is not a gonad issue. They are told that it’s in their head, said Dr. Jacobs, adding that, “it is in their head, but it’s biological.”
The drug’s label advises that sexual side effects disappear when the drug is stopped. “That’s only true most of the time, not all of the time,” said Dr. Jacobs, adding that the persistence of any side effects impacts what he calls a “small subset” of men who take the drug.
“We have treated tens of thousands of patients who have benefited from the medicine and had no side effects,” said Dr. Bernstein. “But there is a lot that’s still not known about it.”
Even so, “baldness in young people is not a benign condition,” he said, adding that it can be socially debilitating. “An 18-year-old with a full head of thick hair who’s totally bald in 3 or 4 years – that can totally change his psyche,” Dr. Bernstein said. Finasteride may be the best option for those young men, and it is an important medication, he said. Does it need to be used more carefully? “Certainly you can’t argue with that,” he commented.
Dr. Bernstein and Dr. Irwig reported no conflicts. Dr. Jacobs disclosed that he is an expert witness for the plaintiffs in a suit against Propecia maker Merck.
Gut health ‘vitally important’ for mental health
Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.
“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.
“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.
The study was published online Sept. 15, 2021, in JAMA Psychiatry.
Reliable biomarkers
“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.
However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.
Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.
“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.
The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”
They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”
The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”
Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”
Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”
Control samples consisted of participants without the relevant condition.
Biological overlap?
The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.
However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.
When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”
“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.
“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered “preliminary,” the investigators noted.
Greater standardization needed
Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”
In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.
Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article first appeared on Medscape.com .
Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.
“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.
“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.
The study was published online Sept. 15, 2021, in JAMA Psychiatry.
Reliable biomarkers
“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.
However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.
Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.
“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.
The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”
They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”
The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”
Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”
Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”
Control samples consisted of participants without the relevant condition.
Biological overlap?
The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.
However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.
When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”
“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.
“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered “preliminary,” the investigators noted.
Greater standardization needed
Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”
In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.
Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article first appeared on Medscape.com .
Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.
“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.
“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.
The study was published online Sept. 15, 2021, in JAMA Psychiatry.
Reliable biomarkers
“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.
However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.
Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.
“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.
The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”
They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”
The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”
Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”
Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”
Control samples consisted of participants without the relevant condition.
Biological overlap?
The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.
However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.
When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”
“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.
“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered “preliminary,” the investigators noted.
Greater standardization needed
Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”
In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.
Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article first appeared on Medscape.com .